WO2018109786A1 - Nouveaux polymorphes et sels de dérivés de carbamoyle pyridone polycycliques - Google Patents

Nouveaux polymorphes et sels de dérivés de carbamoyle pyridone polycycliques Download PDF

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Publication number
WO2018109786A1
WO2018109786A1 PCT/IN2017/050595 IN2017050595W WO2018109786A1 WO 2018109786 A1 WO2018109786 A1 WO 2018109786A1 IN 2017050595 W IN2017050595 W IN 2017050595W WO 2018109786 A1 WO2018109786 A1 WO 2018109786A1
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methyl
pyrido
dioxo
pyrazine
oxazolo
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PCT/IN2017/050595
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English (en)
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Manjinder Singh Phull
Sanoj Jose THOPPIL
Sagar Narayan TARATE
Shankar Vishwanath VIDHATE
Dharmaraj Ramachandra Rao
Geena Malhotra
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Cipla Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to novel polymorphs and salts of polycyclic carbamoyl pyridone derivatives and processes for their preparation.
  • Polycyclic carbamoyl pyridone derivatives are known to act as human immunodeficiency virus type-1 (HIV-1) integrase strand transfer inhibitors (INSTI) in combination with other antiretroviral medicinal products for the treatment of HIV-1 infection in adults and children aged 12 years and older and weighing at least 40 kg.
  • HIV-1 human immunodeficiency virus type-1
  • INSTI integrase strand transfer inhibitors
  • Compound of formula (A) is chemically termed as (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[ 1 , 2-d]pyrazine-8-carboxamide.
  • tricyclic series of carbamoyl pyridines have superior potency against resistant viral strains.
  • tricyclic series of carbamoyl pyridines are effective against viral strains is of utmost importance. At the same time it is necessary that these effective compounds are available at an economic rate and are easily manufactured. It is also necessary that these compounds are easily manufactured with no or minimal production hazards and that there exist simple and efficient methods to manufacture the same on the production floor.
  • a crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. Crystalline forms may also exhibit improved solubility, hygroscopicity, bulk properties, and/or flowability.
  • the solid state form of a compound can also affect its behavior on compaction and its storage stability.
  • a new crystalline form of a pharmaceutically useful compound provides an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Another criterion which may be of exceptional importance under certain circumstances depending on the choice of formulation or the choice of manufacturing process is the solubility of the active substance. If for example pharmaceutical solutions are prepared (eg for infusions) it is essential that the active substance should be sufficiently soluble in physiologically acceptable solvents. It is also very important for drugs which are to be taken orally that the active substance should be sufficiently soluble. It is clearly advantageous when this repertoire is enlarged by the discovery of new crystalline forms of a useful compound.
  • the object of the present invention is to provide novel crystalline forms of (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide.
  • Another object of the present invention is to provide process for the preparation of crystalline forms of (3S, 1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3- methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2- d]pyrazine-8-carboxamide.
  • Another object of the present invention is to provide a novel salts of (3S, 1 laR)-N- [(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide, namely potassium salt.
  • Yet another object of the present invention is to provide novel crystalline forms of (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide potassium salt.
  • Yet another object of the present invention is to provide process for the preparation of (3S, l laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3 -methyl -5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide potassium salt.
  • Yet another object of the present invention is to provide novel crystalline forms of (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide sodium salt.
  • Another object of the present invention is to provide process for the preparation of crystalline forms of (3S, 1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3- methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2- d]pyrazine-8-carboxamide sodium salt.
  • Yet another object of the present invention is to provide pharmaceutical composition
  • pharmaceutical composition comprising novel crystal forms of (3S,1 laR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide.
  • Yet another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising novel forms of (3S,1 laR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide potassium salt.
  • Yet another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising novel crystal forms of (3S, 1 laR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide sodium salt.
  • the present invention provides novel polymorphic forms of (3S,1 laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide.
  • the present invention provides crystalline forms of (3 S, 11 aR)- N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide, hereinafter referred to as Form C-I and Form C-II.
  • the present invention provides novel pharmaceutical salt namely (3S, 1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide potassium salt .
  • the potassium salt according to the invention is characterized by good crystallinity and further observed to exhibit different crystal modifications. These crystalline potassium salts herein after referred to as Form K-I, Form K-II and Form K-III.
  • the present invention provides crystalline forms of (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide sodium salt, hereinafter referred to as Form N-I and Form N-II.
  • the crystalline nature of the forms according to the present invention is characterized by X-ray powder diffraction. Accordingly, the invention also provides methods for preparing these novel salts and forms.
  • the invention also provides pharmaceutical compositions comprising any of these forms optionally in association with pharmaceutical carriers/excipients.
  • the invention also provides methods of treatment of diseases or symptoms wherein (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide or salt thereof is useful.
  • these new methods are for similar therapeutic indications to those described in the above identified patents and applications and are incorporated herein by reference.
  • FIG. 1 represents a powder X-ray diffraction pattern of Form C-I of (3S,1 laR)-N- [(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide.
  • FIG. 2 represents a powder X-ray diffraction pattern of Form C-II of (3S, l laR)- N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide.
  • FIG. 3 represents a powder X-ray diffraction pattern of Form K-I of (3S,1 laR)-N- [(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide potassium salt.
  • FIG. 4 represents a powder X-ray diffraction pattern of Form K-II of (3S, l laR)- N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide potassium salt.
  • FIG. 4 represents a powder X-ray diffraction pattern of Form K-II of (3S, l laR)- N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide potassium salt.
  • FIG. 4 represents a powder X-ray
  • FIG. 6 represents a powder X-ray diffraction pattern of Form N-II of (3S,1 laR)-N- [(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide sodium salt.
  • FIG. 7 represents a powder X-ray diffraction pattern of Form K-III of (3S, 1 laR)- N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide potassium salt.
  • the present invention is based on a surprising discovery that (3S,1 laR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide can exist in different crystalline forms and salts, and these forms and salts can be prepared readily from environmentally friendly solvent systems using appropriate methods.
  • the polymorphs of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the particular crystalline form. Measurements of 2 ⁇ values are accurate to within ⁇ 0.2 degrees. All the powder diffraction patterns were measured on a MiniFlex 2 advanced X-ray powder diffractometer with a copper- ⁇ - ⁇ radiation source.
  • the present invention provides the crystalline (3S, l laR)-N- [(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide which is herein and in the claims designated as Form C-I, which is substantially non- hygroscopic and has good flow characteristics.
  • the crystalline Form C-I is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa, radiation.
  • the crystalline Form C-I has an XRD pattern with characteristics peaks at 5.497, 12.905, 15.419, 16.663, 17.944, 18.610, 22.474, 23.894, and 26.111 ⁇ 0.2 °2 ⁇ .
  • the crystalline Form C-I has an XRPD pattern with those peaks at °2 ⁇ values ⁇ 0.2 °2 ⁇ as depicted in Table 1.
  • Table 1 Table of values for the XRPD pattern depicted in Figure 1
  • Form C-I may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.
  • a process for the preparation of the crystalline Form C-I comprise: dissolving (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in a polar solvent , non-polar solvent or an admixture thereof , and isolating any resulting precipitated solid therefrom.
  • Suitable polar solvents include, but are not limited to the CI- C4 alcohols e.g. methanol, ethanol, isopropanol, n-buatnol and the like and mixtures thereof; ketone such as acetone; organic solvents, such as nitriles, e.g., acetonitrile and the like DMF; DMSO; NMP; THF and the like and mixtures thereof.
  • Suitable non polar solvents include, but are not limited to, aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents and the like and mixtures thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the solvent used is selected from an admixture of polar and non polar solvent in a ratio of 1 : 10 to 10: 1.
  • the temperature during the dissolution step is about 40°C to about boiling point of the solvent used. More preferably, the temperature during the dissolution step is about 40°C to about 90°C.
  • the isolating includes precipitating the Form C-I by cooling, solvent removal, adding a non-solvent, or a combination of these methods.
  • the (3S, l laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide used for the above process, as well as for the following processes, may be in any polymorphic form such as crystalline or amorphous or in a mixture of any polymorphic forms such as hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof.
  • the present invention provides the crystalline (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide, which is herein and in the claims designated as Form C-II which is substantially non-hygroscopic and has good flow characteristics.
  • the crystalline Form C-II is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa, radiation:
  • the crystalline Form C-II has an XRD pattern with characteristics peaks at 24.075 and 24.561 ⁇ 0.2 °2 ⁇ .
  • the crystalline Form C-II may have an XRD pattern with characteristics peaks at 24.075 and 24.561 ⁇ 0.2°2 ⁇ .
  • the XRD pattern may have further peaks at 17.058 and 27.598 ⁇ 0.2°2 ⁇ .
  • the XRD pattern may have still further peaks at 5.295, 12.150, 14.283, 16.286, 17.670, 20.184, and 24.917 ⁇ 0.2°2 ⁇ .
  • the crystalline Form C-II has an XRPD pattern with those peaks at °2 ⁇ values ⁇ 0.2 °2 ⁇ as depicted in Table 2.
  • Table 2 Table of values for the XRPD pattern depicted in Figure 2
  • Form C-II may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.
  • a process for the preparation of the crystalline Form C-II comprise: stirring (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in a polar solvent/s , non polar solvent/s or an admixture thereof , and isolating any resulting precipitated solid.
  • Suitable polar solvents include, but are not limited to the CI- C4 alcohols e.g., methanol, ethanol, isopropanol, n-buatnol and the like and mixtures thereof; ketone such as acetone; organic solvents, such as nitriles, e.g., acetonitrile and the like DMF; DMSO; NMP; THF and the like and mixtures thereof.
  • Suitable non polar solvents include, but are not limited to, aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents and the like and mixtures thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the solvent used is selected from an admixture of polar and non-polar solvent in a ratio of 1 : 10 to 10: 1.
  • the temperature during the dissolution step is about 40°C to about boiling point of the solvent used. More preferably, the temperature during the dissolution step is about 40°C to about 90°C.
  • the isolating includes precipitating the Form C-II by cooling, solvent removal, adding a non-solvent, or a combination of these methods.
  • novel pharmaceutical salt namely potassium salt of (3S, l laR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide.
  • the present invention provides processes for preparation of (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide potassium salt , which comprises the step of mixing (3S, l laR)-N- [(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide in a suitable solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 1 hour to about 5 hours, isolating the precipitated potassium salt.
  • mixing includes dissolving, slurrying or suspending the (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in the solvent.
  • Suitable sources of potassium include potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like and mixtures thereof.
  • the source of potassium can be added either as a solution in water or it may be added as a solid to the solution of (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy - 3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2- d]pyrazine-8-carboxamide in a suitable organic solvent.
  • the sequence of addition of water and/or potassium source is not particularly critical.
  • the potassium salt formation can be carried out in any known manner, for example, the potassium source can be added into a (3S, l laR)-N-[(2,4-difluorophenyl)methyl]- 6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide solution or a (3S,1 laR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide solution may be added to the potassium source.
  • the potassium source can be added into a (3S, l laR)-N-[(2,4-difluoroph
  • Suitable solvents include, but are not limited to, aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; ketones; nitriles; alcohols and the like and mixture thereof.
  • aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • Useful ketones include acetone, iso butyl ketone, methyl isobutyl ketone, and the like and mixtures thereof.
  • Useful organic solvents are selected such as nitriles, e.g., acetonitrile and the like; CI -C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like and mixtures thereof.
  • the isolating includes obtaining the potassium salt from a mixture formed after addition of source of potassium. In one embodiment, the isolating includes precipitating the potassium salt by cooling, solvent removal, adding a non-solvent, or a combination of these methods.
  • the (3S, 1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3- methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2- d]pyrazine-8-carboxamide potassium salt may be prepared by a process comprising; converting any salt of (3S, 1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide into the free base and subsequently converting free base into the (3S,l laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5,
  • potassium salt obtained may be in any polymorphic form or in a mixture of any polymorphic forms such as amorphous, crystalline, hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof.
  • the potassium salt obtained according to the invention is characterized by good crystallinity and low amorphisation during grinding and compression. In addition it is not hygroscopic and is readily soluble in physiologically acceptable solvents.
  • the crystalline Form K-I is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa, radiation:
  • the crystalline Form K-I has an XRD pattern with characteristics peaks at 6.877 and 17.846, ⁇ 0.2 °2 ⁇ .
  • the crystalline Form K-I may have an XRD pattern with characteristics peaks at 6.877 and 17.846 ⁇ 0.2 °2 ⁇ .
  • the XRD pattern may have further peaks at 11.341, 18.599, 20.436, 23.02, 23.792, 24.194, 26.55 and 30.23 ⁇ 0.2 °2 ⁇ .
  • the XRD pattern may have still further peaks at 5.496, 12.268, 13.847, 16.433, 17.294, 24.671, and 27.78 ⁇ 0.2 °2 ⁇ .
  • the crystalline Form K-I has an XRPD pattern with those peaks at °2 ⁇ values ⁇ 0.2 °2 ⁇ as depicted in Table 3.
  • Table 3 Table of values for the XRPD pattern depicted in Figure 3
  • Form K-I may be further characterized by other methods including, but not limited to DSC, IR, solid state MR and Raman spectroscopy.
  • a process for preparing crystalline Form K-I of 3S, 1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide potassium salt the process comprising; mixing 3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide , in a suitable first solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 1 hour to about 5 hours,
  • mixing includes dissolving, slurrying or suspending the (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in the solvent.
  • Suitable first solvent/s include, but are not limited to, polar solvents and non- polar solvents.
  • Polar solvents include nitriles, e.g., acetonitrile and the like; CI 4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketiones , e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof.
  • Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the solvent is preferably a CI -C4 alcohols, with methanol being preferred.
  • Suitable sources of potassium include potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate, potassium chloride and the like and mixtures thereof, with potassium hydroxide being preferred.
  • the source of potassium can be added either as a solution in a suitable second solvent or it may be added as a solid to the mixture of (3S,l laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide in a suitable first solvent.
  • the sequence of addition of potassium source is not particularly critical.
  • the potassium salt formation can be carried out in any known manner, for example, the potassium source can be added into a (3S,1 laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide mixture or a (3S,l laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide mixture may be added to the potassium source.
  • the potassium source can be added into a (3S,1 laR)-N-[(2,4- difluorophen
  • Suitable second solvent/s includes, but are not limited to, polar solvents and non- polar solvents.
  • Polar solvents include nitriles, e.g., acetonitrile and the like; CI 4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketiones , e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof.
  • Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the second solvent is preferably a CI -C4 alcohols, with methanol being preferred.
  • the process of preparation of Form K-I comprises stirring (3S, 1 laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in methanol at about 30°C to about 65°C, adding a solution of potassium hydroxide in methanol to the suspension at about 30°C to about 65°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form K-I from the suspension.
  • the present invention provides the crystalline (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide potassium salt which is herein and in the claims designated as Form K-II which is substantially non-hygroscopic and has good flow characteristics.
  • the crystalline Form K-II is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa, radiation: In an embodiment, the crystalline Form K-II has an XRD pattern with characteristics peaks at 6.573 and 18.876 ⁇ 0.2 °2 ⁇ .
  • the crystalline Form K-II may have an XRD pattern with characteristics peaks at, 6.573 and 18.876 ⁇ 0.2 °2 ⁇ .
  • the XRD pattern may have further peaks at 22.804 ⁇ 0.2 °2 ⁇ .
  • the XRD pattern may have still further peaks at 7.083, 11.401, 15.411, 24.923 and 26.612 ⁇ 0.2 °2 ⁇ .
  • the crystalline Form K-II has an XRPD pattern with those peaks at °2 ⁇ values ⁇ 0.2 °2 ⁇ as depicted in Table 4.
  • Table 4 Table of values for the XRPD pattern depicted in Figure 4
  • Form K-II may be further characterized by other methods including, but not limited to DSC, IR, solid state MR and Raman spectroscopy.
  • a process for preparing crystalline Form K-II of 3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide potassium salt the process comprising; mixing 3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide , in a suitable first solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 1 hour to about 5 hours
  • mixing includes dissolving, slurrying or suspending the (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in the solvent.
  • Suitable first solvent/s include, but are not limited to, polar solvents and non-polar solvents.
  • Polar solvents include nitriles, e.g., acetonitrile and the like; C1-C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof.
  • Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the solvent is preferably a CI - C4 alcohols, with t-butanol being preferred.
  • Suitable sources of potassium include potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like and mixtures thereof, with potassium t-butoxide being preferred.
  • the source of potassium can be added either as a solution in a suitable second solvent or it may be added as a solid to the mixture of (3S,l laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide in a suitable first solvent.
  • the sequence of addition of potassium source is not particularly critical.
  • the potassium salt formation can be carried out in any known manner, for example, the potassium source can be added into a (3S,1 laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide mixture or a (3S,l laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide mixture may be added to the potassium source.
  • the potassium source can be added into a (3S,1 laR)-N-[(2,4- difluorophen
  • Suitable second solvent/s includes, but are not limited to, polar solvents and non- polar solvents.
  • Polar solvents include nitriles, e.g., acetonitrile and the like; C1-C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof.
  • Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the second solvent is preferably a C1C4 alcohols, with t-butanol being preferred.
  • the process of preparation of Form K-II comprises stirring (3S, 1 laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in t-butanol at about 30°C; adding a solution of potassium hydroxide to the suspension at about 30°C; heating the suspension at about 80°C to about 85°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form K-II from the suspension.
  • the present invention provides the crystalline (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide, sodium salt which is herein and in the claims designated as Form N- I, which is substantially non-hygroscopic and has good flow characteristics.
  • the crystalline Form N-I is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa, radiation:
  • the crystalline Form N-I has an XRD pattern with characteristics peaks at 20.157, and 23.596 ⁇ 0.2 °2 ⁇ .
  • the crystalline Form N-I may have an XRD pattern with characteristics peaks at, 20.157, and 23.596 ⁇ 0.2°2 ⁇ .
  • the XRD pattern may have further peaks at 6.637, 18.280, 18.669, and 22.582 ⁇ 0.2°2 ⁇ .
  • the XRD pattern may have still further peaks at 14.341, 14.991, 15.855, 17.458, 21.381, 26.051, 27.098, 28.426, and 29.166 ⁇ 0.2°2 ⁇ .
  • the crystalline Form N-I has an XRPD pattern with those peaks at °2 ⁇ values ⁇ 0.2 °2 ⁇ as depicted in Table 5.
  • Table 5 Table of values for the XRPD pattern depicted in Figure 5
  • Form N-I may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy. According to another aspect of the present invention there is provided a process for the preparation of the crystalline Form N-I.
  • the process comprise: stirring (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide, in a first polar solvent or mixture of polar solvents for a period of time ranging from about 30 minutes to about 5 hours at a temperature ranging from about 25°C to boiling point of the solvent used, adding a source of sodium, stirring for at least 1 hour to about 5 hours and isolating the precipitated Form N-I of sodium salt.
  • Suitable first polar solvent/s include, but are not limited organic solvents, such as water; CI- C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; nitriles, e.g., acetonitrile and the like; ketones, e.g., acetone, methyl isobutyl ketone, iso butyl ketone, and the like and mixtures thereof.
  • Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the first solvent is preferably a C1-C4 alcohols, with ethanol being preferred.
  • Suitable sources of sodium include sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium carbonate and the like and mixtures thereof, with sodium hydroxide being preferred.
  • the source of sodium can be added either as a solution in a suitable second solvent/s or it may be added as a solid to the mixture of (3S, 1 laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide in a suitable first solvent.
  • the sequence of addition of sodium source is not particularly critical.
  • the sodium salt formation can be carried out in any known manner, for example, the sodium source can be added into a (3S,1 laR)-N-[(2,4-difluorophenyl) methyl]- 6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide mixture or a (3S,1 laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide mixture may be added to the sodium source.
  • the sodium source can be added into a (3S,1 laR)-N-[(2,4-difluoroph
  • Suitable second solvent/s include, but are not limited to, polar solvents and non- polar solvents.
  • Polar solvents include water; nitriles, e.g., acetonitrile and the like; C1-C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof.
  • Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the second solvent is preferably a mixture of water and CI- C4 alcohols, with ethanol being preferred.
  • the process of preparation of Form N-I comprises stirring (3S, 1 laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in ethanol at about 30°C; heating the suspension at about 60°C to about 65°C; adding an aqueous sodium hydroxide solution in ethanol to the suspension at about 60°C to about 65°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form N-I from the suspension.
  • the process of preparation of Form N-I comprises stirring (3S, 1 laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in t-butanol at about 30°C; adding sodium t-butoxide to the suspension at about 30°C; heating the suspension at about 30°C to about 85°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form N-I from the suspension.
  • the present invention provides the crystalline (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide sodium salt which is herein and in the claims designated as Form N- II which is substantially non-hygroscopic and has good flow characteristics.
  • the crystalline Form N-II is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa, radiation:
  • the crystalline Form N-II may have an XRD pattern with characteristics peaks at 5.191, 9.264, 13.686, 15.185, 15.513 and 21 .317 ⁇ 0.2 °2 ⁇ .
  • the XRD pattern may have further peaks at 10.777, 12.585, 12.876, 15.936, 18.693, 23.635, 24.282, 25.84, 26.57, 27.931 and 29.24 ⁇ 0.2 °2 ⁇ .
  • the crystalline Form N-II has an XRPD pattern with those peaks at °2 ⁇ values ⁇ 0.2 °2 ⁇ as depicted in Table 6.
  • Table 6 Table of values for the XRPD pattern depicted in Figure 6
  • Form N-II may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.
  • a process for the preparation of the crystalline Form N-II comprise: stirring (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide, in a first polar solvent or mixture of polar solvents for a period of time ranging from about 30 minutes to about 5 hours at a temperature ranging from about 25°C to boiling point of the solvent used, adding a source of sodium, stirring for at least 1 hour to about 5 hours and isolating the precipitated Form N-II of sodium salt.
  • Suitable first polar solvent/s include, but are not limited organic solvents, such as water; CI- C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; nitriles, e.g., acetonitrile and the like; ketones, e.g., acetone, methyl isobutyl ketone, iso butyl ketone, and the like and mixtures thereof.
  • the first solvent is preferably a mixture of water and a CI -C4 alcohols, with ethanol being preferred.
  • Suitable sources of sodium include sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium carbonate and the like and mixtures thereof, with sodium hydroxide being preferred.
  • the source of sodium can be added either as a solution in a suitable second solvent/s or it may be added as a solid to the mixture of (3S, 1 laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide in a suitable first solvent.
  • the sequence of addition of sodium source is not particularly critical.
  • the sodium salt formation can be carried out in any known manner, for example, the sodium source can be added into a (3S,1 laR)-N-[(2,4-difluorophenyl) methyl]- 6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide mixture or a (3S,1 laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide mixture may be added to the sodium source.
  • the sodium source can be added into a (3S,1 laR)-N-[(2,4-difluoroph
  • Suitable second solvent/s include, but are not limited to, polar solvents.
  • Polar solvents include water; nitriles, e.g., acetonitrile and the like; CI -C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketiones , e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof.
  • the second solvent is preferably water.
  • the process of preparation of Form N-II comprises stirring (3S, 1 laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in a mixture of water and ethanol in the ratio of 1 : 10 to 10: 1, more preferably in the ratio of 1 :4, at about 30°C; heating the suspension at about 70°C to about 85°C; adding an aqueous sodium hydroxide solution to the suspension at about 70°C to about 85°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and iso
  • the present invention provides the crystalline (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide potassium salt which is herein and in the claims designated as Form K-III which is substantially non-hygroscopic and has good flow characteristics.
  • the crystalline Form K-III is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa, radiation:
  • the crystalline Form K-III has an XRD pattern with characteristics peaks at 6.698, 17.627, 18.383, 22.808 and 25.897 ⁇ 0.2°2 ⁇ .
  • the crystalline Form K-III may have an XRD pattern with characteristics peaks at, 6.698, 17.627, 18.383, 22.208 and 25.897 ⁇ 0.2°2 ⁇ .
  • the XRD pattern may have further peaks at 11.13, 20.402, 23.707,24.112, 31.102 ⁇ 0.2°2 ⁇ .
  • the XRD pattern may have still further peaks at 12.107, 13.608, 17.070, 22.344, 24.588, 26.914 and 27.663 ⁇ 0.2°2 ⁇ .
  • the crystalline Form K-III has an XRPD pattern with those peaks at °2 ⁇ values ⁇ 0.2 °2 ⁇ as depicted in Table 7.
  • Table 7 Table of values for the XRPD pattern depicted in Figure 7
  • Form K-III may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.
  • a process for preparing crystalline Form K-III of 3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide potassium salt the process comprising; mixing 3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide , in a suitable first solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 10 minutes to about 2 hours,
  • 'mixing' includes dissolving, slurrying or suspending the (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in the solvent.
  • Suitable first solvent/s includes, but are not limited to, polar solvents and non- polar solvents.
  • Polar solvents include nitriles, e.g., acetonitrile and the like; CI to C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, TUF and mixtures thereof.
  • Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the solvent is preferably a C 1 to C4 alcohols solvent, with methanol being preferred.
  • Suitable sources of potassium include potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like and mixtures thereof, with potassium hydroxide being preferred.
  • the source of potassium can be added either as a solution in a suitable second solvent or it may be added as a solid to the mixture of (3S,l laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide in a suitable first solvent.
  • the sequence of addition of potassium source is not particularly critical.
  • the potassium salt formation can be carried out in any known manner, for example, the potassium source can be added into a (3S,1 laR)-N-[(2,4- difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide mixture or a (3S,l laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide mixture may be added to the potassium source.
  • the potassium source can be added into a (3S,1 laR)-N-[(2,4- difluorophen
  • Suitable second solvent/s include, but are not limited to, polar solvents and non- polar solvents.
  • Polar solvents include nitriles, e.g., acetonitrile and the like; CI to C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof.
  • Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof.
  • Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof.
  • Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof.
  • the second solvent is preferably a CI to C4 alcohols, with methanol being preferred.
  • the process of preparation of Form K-III comprises stirring (3S, 1 laR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide in methanol at about 30°C; heating the suspension at about 60°C to about 65°C; adding a solution of potassium hydroxide to the suspension at about 65°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form K-III from the suspension.
  • the process of invention may be used as a method for purifying any form or salts of (3S, l laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3 -methyl -5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide, as well as for the preparation of the new polymorphic forms and salts.
  • the present invention provides solid pharmaceutical compositions, comprising, as an active ingredient, any one or combination of the crystalline forms of (3S, 1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3- methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2- d]pyrazine-8-carboxamide and/or crystalline forms of potassium salt or sodium salt of (3S, l laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3 -methyl -5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide described herein, optionally together with one or more pharmaceutically acceptable excipients.
  • suitable pharmaceutically any one
  • the compounds in accordance with the present invention may be administered to a patient in need thereof in any type of galenical form such as tablets, capsules or in a liquid formulation.
  • the pharmaceutical composition is in the form of a tablet suitable for oral delivery.
  • the present invention provides a method of treating or preventing viral infection, for example, an HIV infection, in a human comprising administering to the human a therapeutically effective amount of (3S, l laR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide selected from the group consisting of any one or combination of the crystalline forms of (3S,1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, l la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide and/or crystalline forms of potassium salt or
  • Example 2 Preparation of Form C-I of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide
  • Example 3 Preparation of Form C-II of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide
  • the XRD of the final product is set forth in FIG. 2 which was recorded and identified as polymorph Form C-II of(3S, l laR)-N-[(2,4-difluorophenyl)methyl]- 6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[ 1 , 2-d]pyrazine-8-carboxamide
  • Example 5 Preparation of Form K-I of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide , potassium salt
  • the XRD of the final product is set forth in FIG. 3 which was recorded and identified as polymorph Form K-I of(3S,l laR)-N-[(2,4-difluorophenyl)methyl]- 6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide, potassium salt.
  • Example 6 Preparation of Form K-II of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide , potassium salt
  • the XRD of the final product is set forth in FIG. 4 which was recorded and identified as polymorph Form K-II of(3S, l laR)-N-[(2,4-difluorophenyl)methyl]- 6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide, potassium salt.
  • Example 7 Preparation of Form N-I of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide, sodium salt
  • the XRD of the final product is set forth in FIG. 5 which was recorded and identified as polymorph Form N-I of(3S,l laR)-N-[(2,4-difluorophenyl)methyl]- 6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide, sodium salt.
  • Example 8 Preparation of Form N-I of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide, sodium salt
  • the suspension was heated under stirring to 60-65°C and treated with 8% sodium hydroxide solution (2 ml).
  • the resulting suspension was heated under stirring to 60- 65°C, for 30 minutes, cooled to room temperature and further stirred for about 1 hour.
  • the solid was isolated by filtration and dried under vacuum at 50°C -55°C for 12-15 hours to yield 1 g of titled compound.
  • the XRD of the final product is set forth in FIG. 5 which was recorded and identified as polymorph Form N-I of(3S,l laR)-N-[(2,4-difluorophenyl)methyl]- 6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide, sodium salt.
  • Example 9 Preparation of Form N-II of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide , sodium salt
  • the XRD of the final product is set forth in FIG. 6 and was recorded and identified as polymorph Form N-II of(3S, l laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide, sodium salt.
  • Example 10 Preparation of Form K-III of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide , potassium salt
  • the XRD of the final product is set forth in FIG. 7 and was recorded and identified as polymorph Form K-III of(3S,l laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide, potassium salt.

Abstract

La présente invention concerne de nouveaux polymorphes de (3S,11aR)-N-[(2,4-difluorophényl) méthyl]-6- hydroxy-3-méthyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide comprenant des sels de sodium et de potassium et des compositions pharmaceutiques contenant ces polymorphes. L'invention concerne également des procédés de préparation de nouveaux polymorphes.
PCT/IN2017/050595 2016-12-16 2017-12-15 Nouveaux polymorphes et sels de dérivés de carbamoyle pyridone polycycliques WO2018109786A1 (fr)

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US11613546B2 (en) 2021-01-19 2023-03-28 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
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US11548902B1 (en) 2019-03-22 2023-01-10 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
US11697652B2 (en) 2020-02-24 2023-07-11 Gilead Sciences, Inc. Tetracyclic compounds and uses thereof
US11613546B2 (en) 2021-01-19 2023-03-28 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
US11897892B2 (en) 2021-01-19 2024-02-13 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof

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