WO2013183035A2 - Amides of 2-amino-4-arylthiazole compounds and their salts - Google Patents

Amides of 2-amino-4-arylthiazole compounds and their salts Download PDF

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Publication number
WO2013183035A2
WO2013183035A2 PCT/IB2013/054703 IB2013054703W WO2013183035A2 WO 2013183035 A2 WO2013183035 A2 WO 2013183035A2 IB 2013054703 W IB2013054703 W IB 2013054703W WO 2013183035 A2 WO2013183035 A2 WO 2013183035A2
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Prior art keywords
formula
compound
trifluoromethyl
difluoro
dimethyl
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Ceased
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PCT/IB2013/054703
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English (en)
French (fr)
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WO2013183035A3 (en
Inventor
Suresh Mahadev Kadam
Abraham Thomas
Sukumar Sinha
Sukeerthi Kumar
Bipin Parsottam Kansagra
Sachin GAVHANE
Sandeep Bandu KHANDAGALE
Shailesh PAWASE
Jayant Prakashrao PATIL
Shailendra Bhadane
Bhavna MISHRA
Rajesh DWIVEDI
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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Priority to CA2873570A priority Critical patent/CA2873570C/en
Priority to MX2014014482A priority patent/MX354014B/es
Priority to KR1020147033855A priority patent/KR20150015488A/ko
Priority to HK15108333.2A priority patent/HK1207643A1/xx
Priority to US14/402,608 priority patent/US9458173B2/en
Priority to AP2014008076A priority patent/AP3546A/xx
Priority to IN2467MUN2014 priority patent/IN2014MN02467A/en
Priority to SG11201408093PA priority patent/SG11201408093PA/en
Application filed by Glenmark Pharmaceuticals SA filed Critical Glenmark Pharmaceuticals SA
Priority to BR112014029155A priority patent/BR112014029155A2/pt
Priority to CN201380030184.XA priority patent/CN104350058A/zh
Priority to EP13742279.6A priority patent/EP2858999B1/en
Priority to JP2015515642A priority patent/JP5989900B2/ja
Priority to AU2013273118A priority patent/AU2013273118B2/en
Priority to EA201492054A priority patent/EA031334B1/ru
Priority to NZ701721A priority patent/NZ701721A/en
Publication of WO2013183035A2 publication Critical patent/WO2013183035A2/en
Publication of WO2013183035A3 publication Critical patent/WO2013183035A3/en
Priority to PH12014502685A priority patent/PH12014502685B1/en
Priority to IL236084A priority patent/IL236084A0/en
Anticipated expiration legal-status Critical
Priority to ZA2015/00082A priority patent/ZA201500082B/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the present application relates to salts of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide and process for the preparation thereof.
  • TRPA1 transient receptor potential ankyrinl
  • Nociceptive neurons of the nervous system sense the peripheral damage and transmit pain signals.
  • TRPA1 is membrane bound and most likely acts as a heterodimeric voltage gated channel. It is believed to have a particular secondary structure, its N-terminus is lined with a large number of ankyrin repeats which are believed to form a spring-like edifice.
  • TRPA1 is activated by a variety of noxious stimuli, including cold temperatures (activated at 17°C), pungent natural compounds (e.g., mustard, cinnamon and garlic) and environmental irritants (MacPherson L J et al, Nature, 2007, 445; 541-545).
  • TRPA1 ion channels through covalent modification of cysteines to form covalently linked adducts.
  • Variety of endogenous molecules produced during tissue inflammation / injury have been identified as pathological activators of TRPAl receptor. These include hydrogen peroxide which is produced due to oxidative stress generated during inflammation, alkenyl aldehyde 4-HNE - an intracellular lipid peroxidation product and cyclopentenone prostaglandin 15dPGJ2 which is produced from PGD2 during inflammation / allergic response.
  • TRPAl is also activated in receptor dependant fashion by Bradykinin (BK) which is released during tissue injury at peripheral terminals.
  • BK Bradykinin
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (Ci-C4)alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(Ci-C 6 )alkyl and (C 3 -C 6 )cycloalkyl(Ci-C 6 )alkoxy.
  • the active pharmaceutical ingredient In the formulation of drug compositions, it is important for the active pharmaceutical ingredient to be in a form in which it can be conveniently handled and processed. Convenient handling is important not only from the perspective of obtaining a commercially viable manufacturing process, but also from the perspective of subsequent manufacture of pharmaceutical formulations comprising the active pharmaceutical ingredient.
  • the drug development therefore involves research regarding finding suitable pharmaceutically acceptable salt forms of a drug. It may be also desirable to explore various polymorphs of these salts, which display better handling properties as well as it may also show improved physicochemical as well as pharmacokinetic and pharmacodynamic properties. Further, development of a commercial drug candidate involves many steps, such as development of a cost effective synthetic method which is efficient in large scale manufacturing process.
  • the present application relates to salts of N- ⁇ 4-[2,4-difluoro-3-
  • the present invention relates to potassium salt of N- ⁇ 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide.
  • the present invention relates to Potassium salt of N- ⁇ 4- [2,4-difluoro-3-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide in crystalline form.
  • potassium salt of a compound of formula (II) is provided in an amorphous form.
  • the solid state forms of potassium salt of a compound of formula (II) exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate form.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering a solid state form of potassium salt of compound of formula (II), or a pharmaceutical composition that comprises the solid state form of potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering crystalline potassium salt of compound of formula (II), or a pharmaceutical composition that comprises crystalline potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • potassium salt of a compound of formula (II) has water content less than about 5 %.
  • crystalline potassium salt of a compound of formula (II) having water content less than about 5 %.
  • potassium salt of compound of formula (II) having water content about 0.2-2.0 % as determined by Karl Fischer method.
  • crystalline potassium salt of compound of formula (II) having water content about 0.2-2.0 % as determined by Karl Fischer method.
  • crystalline potassium salt of compound of formula (II) having water content in the range of 0.2 to 1.0 % as determined by Karl Fischer method.
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 16.0 % in 48 hours at 25°C/90% Relative Humidity (RH).
  • crystalline potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 16.0 % in 48 hours at 25°C/90% Relative Humidity (RH).
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 6.6 % in 48 hours at 25°C/80% RH.
  • crystalline potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 6.6 % in 48 hours at 25°C/80% RH.
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 3.5 % in 48 hours at 25°C/60% RH.
  • the crystalline potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 3.5 % in 48 hours at 25°C/60% RH.
  • the potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 100 ⁇ .
  • the potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 50 ⁇
  • potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 20 ⁇ .
  • crystalline potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 100 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 50 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 20 ⁇ .
  • the potassium salt of compound of formula (II) has about 10% of the particles (Di 0 ) having size in the range from about 0.3 ⁇ ⁇ about 10 ⁇ .
  • the potassium salt of compound of formula (II) has about 10% of the particles (Dio) having size in the range from about 0.5 ⁇ to about 8 ⁇ .
  • the potassium salt of compound of formula (II) has about 10% of the particles (Dio) having size in the range from about 0.5 ⁇ to about 5 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 10% of the particles (Di 0 ) having size in the range from about 0.3 ⁇ to about 10 ⁇ . In yet another embodiment, there is provided the crystalline potassium salt of compound of formula (II) has about 10% of the particles (D 10 ) having size in the range from about 0.5 ⁇ to about 8 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 10% of the particles (D 10 ) having size in the range from about 0.5 ⁇ to about 5 ⁇ .
  • the potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 4 ⁇ to about 300 ⁇ .
  • the potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 250 ⁇ .
  • the potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 200 ⁇ .
  • the potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 150 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 4 ⁇ to about 300 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 250 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 200 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 150 ⁇ .
  • the present invention also relates to substantially pure potassium salt of compound of formula (II).
  • substantially pure is greater than about 90% pure.
  • the present invention relates to substantially pure potassium salt of compound of formula (II) having purity greater than about 95%.
  • the present invention relates to substantially pure potassium salt of compound of formula (II) having purity greater than about 98%.
  • the present invention relates to substantially pure potassium salt of compound of formula (II) having purity greater than about 99%.
  • the present invention also relates to substantially pure crystalline potassium salt of compound of formula (II).
  • substantially pure is greater than about 90%> pure.
  • the present invention relates to substantially pure crystalline potassium salt of compound of formula (II) having purity greater than about 95%.
  • the present invention relates to substantially pure crystalline potassium salt of compound of formula (II) having purity greater than about 98%.
  • the present invention relates to substantially pure crystalline potassium salt of compound of formula (II) having purity greater than about 99%.
  • the present invention relates to crystalline potassium salt of compound of formula (II) and process for the preparation thereof.
  • the present invention relates to crystalline potassium salt of compound of formula (II).
  • the present invention relates to process to prepare crystalline form of potassium salt of compound of formula (II).
  • the present invention relates to crystalline form of potassium salt of compound of formula (II) which is designated as Form I.
  • the present invention relates to process to prepare crystalline form of potassium salt of compound of formula (II) which is designated as Form I.
  • the present invention relates to crystalline form of potassium salt of compound of formula (II) which is designated as Form II.
  • the present invention relates to process for the preparation of crystalline form of potassium salt of compound of formula (II) designated as Form II.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering Form I of potassium salt of compound of formula (II), or a pharmaceutical composition that comprises Form I of potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering Form II of potassium salt of compound of formula (II), or a pharmaceutical composition that comprises Form II of potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present invention relates to amorphous potassium salt of compound of formula (II) and process for the preparation thereof.
  • the present invention relates to amorphous potassium salt of compound of formula (II).
  • the present invention relates to process for the preparation of amorphous potassium salt of compound of formula (II).
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering amorphous form of potassium salt of compound of formula (II), or a pharmaceutical composition that comprises amorphous form of potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present invention relates to crystalline sodium salt of compound of formula (II) which is designated as Form A and process for the preparation thereof.
  • the present invention relates to crystalline sodium salt of compound of formula (II) which is designated as Form A.
  • the present invention relates to process for the preparation of crystalline sodium salt of compound of formula (II) which is designated as Form A.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering crystalline Form A of sodium salt of compound of formula (II), or a pharmaceutical composition that comprises crystalline Form A of sodium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present invention relates to amorphous sodium salt of compound of formula (II) and process for the preparation thereof.
  • the present invention relates to amorphous sodium salt of compound of formula (II).
  • the present invention relates to process for the preparation of amorphous sodium salt of compound of formula (II).
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering amorphous sodium salt of compound of formula (II), or a pharmaceutical composition that comprises amorphous sodium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present invention relates to lithium salt of compound of formula (II).
  • the present invention relates to process for the preparation of lithium salt of compound of formula (II).
  • the present invention relates to crystalline lithium salt of compound of formula (II) which may be designated as Form alpha and process for the preparation thereof.
  • the present invention relates to crystalline lithium salt of compound of formula (II) which may be designated as Form alpha.
  • the present invention relates to process for the preparation of crystalline lithium salt of compound of formula (II) which may be designated as Form alpha.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering lithium salt of compound of formula (II), or a pharmaceutical composition that comprises lithium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering crystalline lithium salt of compound of formula (II), or a pharmaceutical composition that comprises crystalline lithium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present application also relates to crystalline forms of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-(i]pyrimidin- -yl)acetamide designated as compound of formula (II)
  • the crystalline forms of compound of formula (II) exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate form.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering Form Y of compound of formula (II), or a pharmaceutical composition that comprises Form Y of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering Form Z of compound of formula (II), or a pharmaceutical composition that comprises Form Z of compound of formula (II) along with pharmaceutically acceptable excipients.
  • crystalline compound of formula (II) having water content less than about 5 %. In yet another embodiment, there is provided crystalline compound of formula (II) having water content about 0.2-2.0 % as determined by Karl Fischer method.
  • crystalline compound of formula (II) having water content in the range 0.2 to 1.0 % as determined by Karl Fischer method.
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 100 ⁇ , or preferably less than 50 ⁇ , or more preferably less than 20 ⁇ .
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 100 ⁇ .
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 50 ⁇ .
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 20 ⁇ .
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 10 ⁇ .
  • the crystalline compound of formula (II) has about 10% of the particles (D 10 ) having size less than 10 ⁇ , or preferably less than 5 ⁇ .
  • the crystalline compound of formula (II) has about 10%) of the particles (D 10 ) having size less than 10 ⁇ .
  • the crystalline compound of formula (II) has about
  • the crystalline compound of formula (II) has about 90% of the particles (D 90 ) having less than 200 ⁇ , or preferably less than 100 ⁇ , or more preferably less than 50 ⁇ .
  • the crystalline compound of formula (II) has about
  • the crystalline compound of formula (II) has about 90%) of the particles (D 90 ) having less than 100 ⁇ .
  • the crystalline compound of formula (II) has about 90%o of the particles (D 90 ) having less than 50 ⁇ .
  • the crystalline compound of formula (II) has about 90%) of the particles (D 90 ) having less than 20 ⁇ . In yet another embodiment, there is provided crystalline compound of formula (II) having surface area of less than about 50 m 2 /gm, preferably less than 25 m 2 /gm or more preferably less than 10 m 2 /gm.
  • crystalline compound of formula (II) having surface area of less than about 50 m 2 /gm.
  • crystalline compound of formula (II) having surface area of less than about 25 m 2 /gm.
  • crystalline compound of formula (II) having surface area of less than about 10 m 2 /gm.
  • the present invention also relates to the process for the preparation of thienopyrimidinedione compound of formula (II).
  • FIG. l is powder X-ray diffraction pattern of crystalline potassium salt of N- ⁇ 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form I.
  • FIG.2 is Infra-Red (IR) spectra of crystalline potassium salt of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form I.
  • IR Infra-Red
  • FIG.3 is powder X-ray diffraction pattern of crystalline potassium salt of N- ⁇ 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form II.
  • FIG.4 is Infra-Red (IR) spectra of crystalline potassium salt of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form II.
  • IR Infra-Red
  • FIG.5 is powder X-ray diffraction pattern of amorphous potassium salt of N- ⁇ 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide.
  • FIG.6 is powder X-ray diffraction pattern of crystalline sodium salt of N- ⁇ 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form A.
  • FIG.7 is Infra-Red (IR) spectra of crystalline sodium salt of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form A.
  • IR Infra-Red
  • FIG.8 is powder X-ray diffraction pattern of amorphous sodium salt of N- ⁇ 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide.
  • FIG.9 is Infra-Red (IR) spectra of amorphous sodium salt of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide.
  • IR Infra-Red
  • FIG.10 is powder X-ray diffraction pattern of crystalline lithium salt of N- ⁇ 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form Alpha.
  • FIG.11 is Infra-Red (IR) spectra of crystalline lithium salt of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form Alpha.
  • IR Infra-Red
  • FIG.12 is powder X-ray diffraction pattern of crystalline N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form X.
  • FIG.13 is Infra-Red (IR) spectra of crystalline N- ⁇ 4-[2,4-difiuoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form X.
  • IR Infra-Red
  • FIG.14 is powder X-ray diffraction pattern of crystalline of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form Y.
  • FIG.15 is Infra-Red (IR) spectra of crystalline N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form Y.
  • IR Infra-Red
  • FIG.16 is powder X-ray diffraction pattern of crystalline N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form Z.
  • FIG.17 is Infra-Red (IR) spectra of crystalline N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide designated as Form Z.
  • IR Infra-Red
  • the present application relates to salts of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3- ⁇ i]pyrimidin- -yl)acetamide designated as compound of formula (II)
  • the present invention relates to potassium salt of N- ⁇ 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide.
  • the present invention relates to Potassium salt of N- ⁇ 4- [2,4-difluoro-3-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide in crystalline form.
  • potassium salt of a compound of formula (II) is provided in an amorphous form.
  • the solid state forms of potassium salt of a compound of formula (II) exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate form.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering a solid state form of potassium salt of compound of formula (II), or a pharmaceutical composition that comprises the solid state form of potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering crystalline potassium salt of compound of formula (II), or a pharmaceutical composition that comprises crystalline potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • crystalline potassium salt of a compound of formula (II) having water content less than about 5 %.
  • potassium salt of compound of formula (II) having water content about 0.2-2.0 % as determined by Karl Fischer method, more preferably in the range 0.2 to 1.0 %.
  • potassium salt of compound of formula (II) having water content about 0.2-2.0 % as determined by Karl Fischer method.
  • potassium salt of compound of formula (II) having water content in the range of 0.2 to 1.0 % as determined by Karl Fischer method.
  • crystalline potassium salt of compound of formula (II) having water content about 0.2-2.0 % as determined by Karl Fischer method.
  • crystalline potassium salt of compound of formula (II) having water content in the range of 0.2 to 1.0 % as determined by Karl Fischer method.
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 16.0 % in 48 hours at 25°C/90% Relative Humidity (RH).
  • crystalline potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 16.0 % in 48 hours at 25°C/90% Relative Humidity (RH).
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 6.6 % in 48 hours at 25°C/80% RH.
  • crystalline potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 6.6 % in 48 hours at 25°C/80% RH.
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 3.5 % in 48 hours at 25°C/60% RH.
  • the crystalline potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 3.5 % in 48 hours at 25°C/60% RH.
  • the potassium salt of compound of formula (II) which exhibits a moisture content increase of about 15.2% or less when stored under a relative humidity of 90 % at a temperature of 25°C for 48 hrs.
  • the potassium salt of compound of formula (II) which exhibits a moisture content increase of about 5.8 % or less when stored under a relative humidity of 80 % at a temperature of 25°C for 48 hrs.
  • the potassium salt of compound of formula (II) which exhibits a moisture content increase of about 2.7 % or less when stored under a relative humidity of 60 % at a temperature of 25°C for 48 hrs.
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of 0.80 % to 16.0 % in 48 hrs at 25°C/90% Relative Humidity (RH).
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of 0.80 % to 6.6 % in 48 hrs at 25°C/80%RH.
  • the potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of 0.80 % to 3.5 % in 48 hrs at 25°C/60%RH.
  • the potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 100 ⁇ , or about 1 ⁇ to about 50 ⁇ or from about 1 ⁇ to about 20 ⁇ .
  • the potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 100 ⁇ .
  • the potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 50 ⁇
  • potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 20 ⁇ .
  • crystalline potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 100 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 50 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has an average particle size (D 50 ) in the range from about 1 ⁇ to about 20 ⁇ .
  • the potassium salt of compound of formula (II) has about 10% of the particles (Di 0 ) having size in the range from about 0.3 ⁇ to about 10 ⁇ , or from about 0.5 ⁇ to about 8 ⁇ , preferably from about 0.5 ⁇ to about 5 ⁇ .
  • the potassium salt of compound of formula (II) has about 10% of the particles (Di 0 ) having size in the range from about 0.3 ⁇ ⁇ about 10 ⁇ .
  • the potassium salt of compound of formula (II) has about 10% of the particles (Dio) having size in the range from about 0.5 ⁇ to about 8 ⁇ .
  • the potassium salt of compound of formula (II) has about 10% of the particles (Dio) having size in the range from about 0.5 ⁇ to about 5 ⁇ . In another embodiment, there is provided the crystalline potassium salt of compound of formula (II) has about 10% of the particles (D 10 ) having size in the range from about 0.3 ⁇ to about 10 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 10% of the particles (D 10 ) having size in the range from about 0.5 ⁇ to about 8 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 10% of the particles (Di 0 ) having size in the range from about 0.5 ⁇ to about 5 ⁇ .
  • the potassium salt of compound of formula (II) has about
  • the potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 4 ⁇ to about 300 ⁇ .
  • the potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 250 ⁇ .
  • the potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 200 ⁇ .
  • the potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 150 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 4 ⁇ to about 300 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 250 ⁇ .
  • the crystalline potassium salt of compound of formula (II) has about 90% of the particles (D 90 ) having size in the range from about 5 ⁇ to about 200 ⁇ . In yet another embodiment, there is provided the crystalline potassium salt of compound of formula (II) has about 90% of the particles (D90) having size in the range from about 5 ⁇ to about 150 ⁇ .
  • the present invention also relates to substantially pure potassium salt of compound of formula (II).
  • substantially pure is greater than about 90%> pure.
  • the present invention relates to substantially pure potassium salt of compound of formula (II) having purity greater than about 95%.
  • the present invention relates to substantially pure potassium salt of compound of formula (II) having purity greater than about 98%. In yet another embodiment, the present invention relates to substantially pure potassium salt of compound of formula (II) having purity greater than about 99%.
  • the present invention also relates to substantially pure crystalline potassium salt of compound of formula (II).
  • substantially pure is greater than about 90% pure.
  • the present invention relates to substantially pure crystalline potassium salt of compound of formula (II) having purity greater than about 95%.
  • the present invention relates to substantially pure crystalline potassium salt of compound of formula (II) having purity greater than about 98%.
  • the present invention relates to substantially pure crystalline potassium salt of compound of formula (II) having purity greater than about 99%.
  • the present invention relates to crystalline potassium salt of compound of formula (II) and process for the preparation thereof.
  • the present invention relates to crystalline potassium salt of compound of formula (II).
  • the present invention relates to crystalline form of potassium salt of compound of formula (II) which is designated as Form I.
  • Form I is characterized by the X-Ray Powder Diffraction (XRPD) pattern as shown in FIG. 1.
  • Form I is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 15.93, 20.61, 23.63, 24.47 and 25.08 ⁇ 0.2.
  • Form I is further characterized by the characteristic X-ray diffraction pattern comprising of the following peak expressed in terms of 2 ⁇ : 23.63 ⁇ 0.2.
  • Form I is further characterized by the characteristic X-ray diffraction pattern comprising of the following peak expressed in terms of 2 ⁇ : 24.47 ⁇ 0.2.
  • Form I is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 23.63 and 24.47 ⁇ 0.2. In yet another embodiment, Form I is further characterized by the characteristic X-ray diffraction pattern peaks expressed in terms of 2 ⁇ as presented in Table 2.
  • Form I is characterized by the Fourier Transform Infrared Spectroscopy (FT-IR) pattern as shown in FIG. 2.
  • FT-IR Fourier Transform Infrared Spectroscopy
  • the present invention relates to another crystalline form of potassium salt of compound of formula (II) which is designated as Form II.
  • Form II is characterized by the X-Ray Powder
  • Form II is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 12.07, 12.39, 20.98, 24.01 and 25.69 ⁇ 0.2.
  • Form II is further characterized by the characteristic
  • X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 24.01 and 25.69 ⁇ 0.2.
  • Form II is further characterized by the characteristic X-ray diffraction pattern comprising of the following peak expressed in terms of 2 ⁇ : 24.01 ⁇ 0.2.
  • Form II is further characterized by the characteristic X-ray diffraction pattern comprising of the following peak expressed in terms of 2 ⁇ : 25.69 ⁇ 0.2. In yet another embodiment, Form II is further characterized by the characteristic X-ray diffraction pattern peaks expressed in terms of 2 ⁇ as presented in Table 3.
  • Form II is characterized by the IR pattern as shown in
  • the present invention relates to amorphous potassium salt of compound of formula (II).
  • the amorphous form of potassium salt of compound of formula (II) is characterized by the X-ray powder diffraction pattern as shown in FIG 5.
  • the present invention relates to crystalline sodium salt of compound of formula (II). In another embodiment, the present invention relates to crystalline sodium salt of compound of formula (II) which is designated as Form A.
  • the Form A is characterized by the X-ray powder diffraction pattern as shown in FIG. 6.
  • Form A is further characterized by the characteristic
  • Form A is characterized by the IR pattern as shown in FIG. 7.
  • the present invention relates to amorphous sodium salt of compound of formula (II).
  • the amorphous form of sodium salt of compound of formula (II) characterized by the X-ray powder diffraction pattern as shown in FIG. 8.
  • the amorphous form of sodium salt of compound of formula (II) is characterized by the IR pattern shown in FIG. 9.
  • the present invention relates to lithium salt of compound of formula (II).
  • the present invention relates to crystalline lithium salt of compound of formula (II).
  • the present invention relates to crystalline lithium salt of compound of formula (II) which may be designated as Form alpha.
  • Form alpha is characterized by the X-ray powder diffraction pattern as shown in FIG. 10.
  • Form alpha is characterized by the IR pattern shown in FIG. 11
  • the Form alpha is further characterized by the characteristic X-ray diffraction pattern peaks expressed in terms of 2 ⁇ as presented in Table 5.
  • the present invention relates to process for the preparation of potassium salt of compound of formula (II), which comprises the following steps:
  • step (b) adding a source of potassium cation to the solution or suspension of step (a) or adding the solution or suspension of step (a) to the source of potassium cation;
  • Step (a) involves providing a solution or suspension of compound of formula (II) in a suitable solvent or mixture of solvents.
  • the solution or suspension of compound of formula (II) may be obtained by dissolving or suspending compound of formula (II) in a solvent or mixture of solvents, or may be obtained in situ, directly from the reaction in which compound of formula (II) is formed.
  • the suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the compound of formula (II), at least to some extent.
  • the solvent system is preferably selected so as to facilitate the salt formation.
  • Solvent(s) which may be used for dissolving or suspending compound of formula (II) include, but are not limited to, nitriles such as acetonitrile and propionitrile; alcohols, such as methanol, ethanol, isopropyl alcohol, n- propanol and tertiary butanol; ketones, such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; ethers, such as diethyl ether, dimethyl ether, diisopropyl ether, and 1,4-dioxane; halogenated hydrocarbons, such as dichloromethane, dichloroethane, and chloroform; hydrocarbons such as n-hexane, heptane, n-pentan
  • step (b) the solution or suspension compound of formula (II) is treated with a source of potassium cation.
  • the source of potassium cation can be potassium alkoxide such as potassium tertiary butoxide or potassium ethoxide.
  • compound of formula (II) can be treated with potassium tertiary butoxide taken in a suitable solvent such as alcohol.
  • the reaction can be carried out at a temperature ranging from about -5°C to about boiling point of the solvent(s). In one embodiment, the reaction can be carried out at about -5°C to 0°C.
  • the time required for the completion of the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above; a period of from about 1 hour to about 24 hours or longer is sufficient.
  • Step (c) involves isolation of desired salt.
  • the potassium salt of compound of formula (II) produced in the reaction can be isolated using techniques including precipitation and/or decantation, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent. In another embodiment, the washing is with the solvent used in the above reaction.
  • the obtained solid may be optionally washed with a suitable solvent such as acetonitrile or diethyl ether.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like.
  • the drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the product is not degraded in quality.
  • the drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the present invention relates to process for the preparation of crystalline potassium salt of compound of formula (II) which is designated as Form I.
  • the process comprises taking the compound of formula (II) in a mixture of ethanol and n-pentane, preferably under inert atmosphere.
  • the reaction mass may be cooled to about -5 to 0 '' € and stirred for about 10 minutes.
  • ethanolic solution of potassium tertiary butoxide or potassium ethoxide may be added.
  • the reaction mass may be stirred further at about -5 to 0 °C for about an hour.
  • n-pentane rnay be added and the reaction mixture may be further stirred at room temperature for suitable period of time such as for 1-2 h.
  • the solid may be collected by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other tech ique for the recovery of solids.
  • the obtained solid may be further taken in acetonitrile and the whole mass may be stirred at room temperature for suitable period of time such as for 1-2 h.
  • the solid rnay be collected by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids, in a preferred embodiment, the solid may he filtered and washed with acetonitrile.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the potassium salt of compound of formula (II) is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the present invention relates to another process for the preparation of crystalline potassium salt of compound of formula ( ⁇ ) designated as Form.
  • I which process involves taking amorphous form of potassium salt of compound of formula (II) in acetonitrile; stirring the reaction mass for suitable period of time and isolating crystalline Form I.
  • the mixture of amorphous form of potassium salt of compound of formula (II) and acetonitrile may be stirred for a period such as .1 -2 hours at a suitable temperature such as 25-35 °C.
  • the solid may be col lected by known techniques such as filtration.
  • the obtained solid may be further dried for a suitable period of time at a suitable temperature optionally under reduced pressure. For example the solid may be dried for 3-4 hours at 30-35 °C under vacuum.
  • the reaction mass may be cooled to about -5 to 0 °C and stirred for about 10 minutes.
  • potassium tertiary butoxide in tertiary butanol may be added.
  • the reaction mass may be stirred further at about -5 to 0 °C for about an hour.
  • the solid may be collected by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids.
  • the solid may be further washed with n- pentane.
  • the obtained solid may be further taken in acetonitrile and the whole mass may ⁇ be stirred at room temperature for suitable period of time such as for 1-2 h.
  • the solid may ⁇ be collected by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recover/ of solids.
  • the solid may be filtered and washed with acetonitrile.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the potassium salt of compound of formula (II) is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the present application also provides a process for the preparation of an amorphous form of potassium salt of compound of formula (II) which comprises heating the potassium salt of compound of formula (II) on heating mental at 300-320 °C. The heating may be carried out at a reduced pressure.
  • the present invention relates to process for the preparation of sodium salt of compound of formula (II), which comprises the following steps:
  • step (b) adding a source of sodium cation to the solution or suspension of step (a) or adding the solution or suspension of step (a) to the source of sodium cation; and (c) isolating the desired salt.
  • Step (a) involves providing a solution or suspension of compound of formula (II) in a suitable solvent or mixture of solvents.
  • the solution or suspension of compound of formula (II) may be obtained by dissolving or suspending compound of formula (II) in a solvent or mixture of solvents, or may be obtained in situ, directly from the reaction in which compound of formula (II) is formed.
  • the suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the compound of formula (II), at least to some extent.
  • the solvent system is preferably selected so as to facilitate the salt formation.
  • Solvent(s) which may be used for dissolving or suspending compound of formula (II) include, but are not limited to, nitriles such as acetonitrile and propionitrile; alcohols, such as methanol, ethanol, isopropyl alcohol, and n-propanol; ketones, such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; ethers, such as diethyl ether, dimethyl ether, diisopropyl ether, and 1,4-dioxane; halogenated hydrocarbons, such as dichloromethane, dichloroethane, and chloroform; hydrocarbons such as n-hexane, heptane, n-pentane, cyclopentane,
  • step (b) the solution or suspension compound of formula (II) is treated with a source of sodium cation.
  • the source of sodium cation can be selected from sodium methoxide, sodium ethoxide and sodium iert-butoxide.
  • the reaction can be carried out at a temperature ranging from about -5°C to about boiling point of the solvent(s). In one embodiment, the reaction can be carried out at about -5°C to 0°C.
  • the time required for the completion of the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above; a period of from about 1 hour to about 24 hours or longer is sufficient.
  • Step (c) involves isolation of desired salt.
  • the sodium salt of compound of formula (II) produced in the reaction can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent or mixture of solvents.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the product is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the present invention relates to process for the preparation of crystalline sodium salt of compound of formula (II) designated as Form A.
  • the compound of formula (II) may be taken in ethanol, preferably in absolute ethanol, preferably under inert atmosphere.
  • the reaction mass may be cooled to temperature of -5 to 0 °C.
  • ethanolic solution of sodium methoxide may be added.
  • the addition may be carried out at the temperature of -5 to 0 °C and the reaction mass may be maintained at that temperature for about an hour.
  • the solid may be collected by various techniques. The isolation of solid may be effected by methods including removal of solvent, concentrating the reaction mass, or any other suitable techniques. Suitable techniques that may be used for the removal of solvent include and are not limited to rotational distillation using a device, such as, for example, a Buchi® Rotavapor®.
  • the solvent may be removed under reduced pressure.
  • the recovered solid may be optionally further dried.
  • the dried solid may be further stirred with acetonitrile for a period of 1 to 2 hours.
  • the solid may be collected by known techniques such as filtration, centrifugation, or decantation.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the sodium salt of compound of formula (II) is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the present invention relates to another process for the preparation of crystalline sodium salt of compound of formula (II) designated as Form A which process involves taking amorphous form of sodium salt of compound of formula (II) in acetonitrile; stirring the reaction mass for suitable period of time and isolating crystalline Form A.
  • the mixture of amorphous form of sodium salt of compound of formula (II) and acetonitrile may be stirred for a period such as 1-2 hours at a suitable temperature such as 25-35 °C.
  • the solid may be collected by known techniques such as filtration.
  • the obtained solid may be further dried for a suitable period of time at a suitable temperature optionally under reduced pressure. For example the solid may be dried for 3-4 hours at 30-35 °C under vacuum.
  • the present application provides a process for the preparation of an amorphous form of sodium salt of compound of formula (II), comprising:
  • the compound of formula (II) may be taken in an alcohol for example in ethanol and ethanolic solution of sodium tertiary butoxide may be added at an appropriate temperature.
  • the addition may be carried out at a temperature range of -5 to 0 °C.
  • the reaction mixture may be stirred at -5 to 0 °C for about 1 hr.
  • Step b) involves isolation of an amorphous form of sodium salt of compound of formula (II).
  • the isolation step (b) may be carried out by removing solvent.
  • Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), or any other suitable technique.
  • the solvent may be removed, optionally under reduced pressure, at temperatures less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures.
  • the compound obtained from step (b) may be collected using techniques such as by scraping, or other techniques specific to the equipment used.
  • the product thus isolated may be optionally further dried to afford an amorphous form of sodium salt of compound of formula (II). Drying may be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
  • the present invention relates to process for the preparation of lithium salt of compound of formula (II) which comprises the following steps: (a) providing a solution or suspension of compound of formula (II) in a suitable solvent or mixture of solvents;
  • step (b) adding a source of lithium cation to the solution or suspension of step (a) or adding the solution or suspension of step (a) to the source of lithium cation;
  • Step (a) involves providing a solution or suspension of compound of formula (II) in a suitable solvent or mixture of solvents.
  • the solution or suspension of compound of formula (II) may be obtained by dissolving or suspending compound of formula (II) in a solvent or mixture of solvents, or may be obtained in situ, directly from the reaction in which compound of formula (II) is formed.
  • the suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the compound of formula (II), at least to some extent.
  • the solvent system is preferably selected so as to facilitate the salt formation.
  • Solvent(s) which may be used for dissolving or suspending compound of formula (II) include, but are not limited to, nitriles such as acetonitrile and propionitrile; alcohols, such as methanol, ethanol, isopropyl alcohol, and n-propanol; ketones, such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; ethers, such as diethyl ether, dimethyl ether, diisopropyl ether, and 1 ,4-dioxane; halogenated hydrocarbons, such as dichloromethane, dichloroethane, and chloroform; hydrocarbons such as n-hexane, heptane, n-pentane, cyclopentan
  • step (b) the solution or suspension compound of formula (II) is treated with a source of lithium cation.
  • the source of lithium cation can be lithium hydroxide or lithium hydroxide monohydrate.
  • compound of formula (II) is treated with lithium hydroxide monohydrate taken in a suitable solvent such as alcohol.
  • the reaction can be carried out at a temperature ranging from about -5°C to about boiling point of the solvent(s). In one embodiment, the reaction can be carried out at about -5°C to 0°C.
  • the time required for the completion of the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.
  • step (b) generally a solution of lithium hydroxide monohydrate in ethanol may be added to the solution or suspension or compound of formula (II).
  • step (c) involves isolation of desired salt.
  • the lithium salt of compound of formula (II) produced in the reaction can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent.
  • the reaction mixture of step (b) is subjected to evaporation under reduced pressure.
  • the obtained solid may be further optionally taken in a suitable solvent such as acetonitrile or diethyl ether and stirred for a suitable period of time.
  • the solid may be collected by filtration.
  • the recovered solid may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like.
  • the drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the product is not degraded in quality.
  • the drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the present invention relates to process for the preparation of crystalline lithium salt of compound of formula (II) which is designated as Form Alpha.
  • the compound of formula (II) may be taken in ethanol, for example in absolute ethanol preferably under inert atmosphere.
  • the reaction mass may be cooled to a temperature of -5 to 0 °C.
  • lithium hydroxide monohydrate may be added.
  • the addition may be carried out at the temperature of -5 to 0 °C and the reaction mass may be maintained at that temperature for about an hour.
  • the solid may be collected by various techniques.
  • the isolation of solid may be effected by methods including removal of solvent, concentrating the reaction mass, or any other suitable techniques.
  • Suitable techniques that may be used for the removal of solvent include and are not limited to rotational distillation using a device, such as, for example, a Buchi® Rotavapor®.
  • removal of solvent may be effected by methods including removal of solvent under reduced pressure.
  • the recovered solid may be optionally further dried.
  • the dried solid may be further stirred with a suitable solvent such as diethyl ether for a period of 1 to 2 hours.
  • the solid may be collected by known techniques such as filtration, centrifugation, or decantation.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like.
  • the drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the lithium salt of compound of formula (II) is not degraded in quality.
  • the drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the present invention relates to process for the preparation of crystalline lithium salt of compound of formula (II) designated as Form alpha which process involves taking amorphous form of lithium salt of compound of formula (II) in diethyl ether or any other suitable solvent such as acetonitrile; stirring the reaction mass for suitable period of time and isolating crystalline Form alpha.
  • the mixture of amorphous form of lithium salt of compound of formula (II) and diethyl ether may be stirred for a period such as 1-2 hours.
  • the solid may be collected by known techniques such as filtration.
  • the obtained solid may be further dried for a suitable period of time at a suitable temperature optionally under reduced pressure. For example the solid may be dried for 3-4 hours at 30-35 °C under vacuum.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an excipients, carriers, diluents or mixture thereof, and therapeutically acceptable amount of potassium salt of compound of formula (II).
  • the present application also relates to crystalline forms of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide designated as compound of formula (II):
  • the crystalline forms of compound of formula (II) of the present invention exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate form.
  • crystalline compound of formula (II) having water content less than about 5 %.
  • crystalline compound of formula (II) having water content about 0.2-2.0 % as determined by Karl Fischer method, more preferably in the range 0.2 to 1.0 %.
  • crystalline compound of formula (II) having surface area of less than about 50 m 2 /gm, preferably less than 25 m 2 /gm or more preferably less than 10 m 2 /gm.
  • crystalline compound of formula (II) having surface area of less than about 50 m 2 /gm.
  • crystalline compound of formula (II) having surface area of less than about 25 m 2 /gm.
  • crystalline compound of formula (II) having surface area of less than about 10 m 2 /gm.
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 100 ⁇ , or preferably less than 50 ⁇ , or more preferably less than 20 ⁇ .
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 100 ⁇ .
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 50 ⁇ .
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 20 ⁇ .
  • crystalline compound of formula (II) having an average particle size (D 50 ) less than 10 ⁇ .
  • the crystalline compound of formula (II) has about 10% of the particles (D 10 ) having size less than 10 ⁇ , or preferably less than 5 ⁇ .
  • the crystalline compound of formula (II) has about 10% of the particles (D 10 ) having size less than 10 ⁇ .
  • the crystalline compound of formula (II) has about
  • the crystalline compound of formula (II) has about 90% of the particles (D 90 ) having less than 200 ⁇ , or preferably less than 100 ⁇ , or more preferably less than 50 ⁇ . In yet another embodiment, the crystalline compound of formula (II) has about 90% of the particles (D 90 ) having less than 200 ⁇ .
  • the crystalline compound of formula (II) has about 90% of the particles (D 90 ) having less than 100 ⁇ .
  • the crystalline compound of formula (II) has about 90%) of the particles (D 90 ) having less than 50 ⁇ .
  • the crystalline compound of formula (II) has about 90%o of the particles (D 90 ) having less than 20 ⁇ .
  • the present invention relates to crystalline form of compound of formula (II) which is designated as Form X.
  • Form X is characterized by the X-Ray Powder Diffraction (XRPD) pattern as shown in FIG. 12.
  • Form X is characterized by the IR pattern as shown in FIG. 13.
  • Form X is further characterized by the characteristic X- ray diffraction pattern comprising one or more of the following peaks expressed in terms of 29: 11.06, 12.84 and 13.37 + 0.2.
  • Form X is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 19.93 and 24.94 + 0.2.
  • Form X is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 11.06, 12.84, 13.34, 19.93 and 24.94 + 0.2.
  • Form X is further characterized by the characteristic X- ray diffraction pattern peaks expressed in terms of 2 ⁇ as presented in Table 6.
  • the present invention relates to another crystalline form of compound of formula (II) which is designated as Form Y.
  • Form Y is characterized by the X-Ray Powder Diffraction (XRPD) pattern as shown in FIG.14.
  • Form Y is characterized by the Fourier Transform Infrared Spectroscopy (FT-IR) pattern as shown in FIG. 15.
  • FT-IR Fourier Transform Infrared Spectroscopy
  • crystalline N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide designated as Form Y characterised by the Fourier Transform Infrared Spectroscopy (FT-IR) pattern wherein the ratio between the intensity of the absorption bands at wavelengths 1500 cm "1 and 1480 cm "1 is from 1 : 1.7 to 1 :2.4.
  • FT-IR Fourier Transform Infrared Spectroscopy
  • Form Y is further characterized by the characteristic X- ray diffraction pattern comprising one or more of the following peaks expressed in terms of 29: 4.72 and 9.40 + 0.2.
  • Form Y is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 21.04, 25.87 and 31.73 + 0.2.
  • Form Y is further characterized by the characteristic
  • X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 4.72, 9.40, 21.04, 25.87 and 31.73 ⁇ 0.2.
  • Form Y is further characterized by the characteristic X- ray diffraction pattern peaks expressed in terms of 2 ⁇ as presented in Table 7.
  • Table 7 Prominent two theta positions and relative intensities of XRPD of Form Y
  • the present invention relates to yet another crystalline form of compound of formula (II) which is designated as Form Z.
  • Form Z is characterized by the X-Ray Powder Diffraction
  • Form Z is characterized by the Fourier Transform Infrared (FT-IR) pattern as shown in FIG. 17.
  • FT-IR Fourier Transform Infrared
  • crystalline N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide designated as Form Z characterised by the Fourier Transform Infrared (FT-IR) Spectroscopy pattern wherein the ratio between the intensity of the absorption bands at wavelengths 1500 cm "1 and 1480 cm _1 is from 1 :2.5 to 1 :2.9.
  • FT-IR Fourier Transform Infrared
  • Form Z is further characterized by the characteristic X- ray diffraction pattern comprising one or more of the following peaks expressed in terms of 29: 10.63 and 19.25 + 0.2.
  • Form Z is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2 ⁇ : 22.11, 22.76 and 27.27 + 0.2. In another embodiment, Form Z is further characterized by the characteristic X- ray diffraction pattern comprising one or more of the following peaks expressed in terms of 29: 10.63, 19.25, 22.11, 22.76 and 27.27 + 0.2.
  • Form Z is further characterized by the characteristic X- ray powder diffraction pattern peaks expressed in terms of 2 ⁇ as presented in Table 8.
  • Table 8 Prominent two theta positions and relative intensities of XRPD of Form Z
  • the crystalline forms of N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl ⁇ -2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3- ⁇ i]pyrimidin-5-yl)acetamide, forms X, Y and Z, can be independently or additionally distinguished by the ratio of the intensities of the absorption bands at wavelengths 1500 cm "1 and 1480 cm "1 , being the highest for form X and lowest for Form Z as presented in Table 9.
  • Table 9 The ratio between the intensity of absorption bands at wavelength 1500 cm “1 and 1480 cm “1 depending on crystalline form of compound of formula (II)
  • the present invention provides compound of formula (II) having purity greater than about 99.0%.
  • the present invention provides compound of formula (II) having purity greater than about 99.5%.
  • the present invention provides compound of formula (II) having less than about 0.1 % (by HPLC) of the compound of formula (III):
  • the present invention provides crystalline compound of formula (II) having purity greater than about 99.8%.
  • the present invention provides compound of formula (III)
  • the present invention relates to process for the preparation of crystalline form of compound of formula (II) which is designated as Form X, which process involves the following steps:
  • step I the compound of formula (II) is taken in an alcohol, preferably methanol or isopropanol.
  • the solvent is methanol.
  • the mixture may be stirred at suitable temperature. In a preferred embodiment, the mixture may be stirred at 25-30 °C for suitable period of time. The suitable period may be in the range from 1 hour to 24 hours.
  • step II the desired form is isolated.
  • the isolation of the solid may be effected by techniques known in the art, including but not limited to, decantation, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the compound of formula (II) is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the compound of formula (II) of step I may be obtained by the coupling of (1,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-(i]pyrimidin-5-yl) acetic acid with 4- [2,4-difluoro-3-(trifluoromethyl) phenyl] -1, 3 -thiazol-2-amine using a suitable coupling agent, in the presence of a suitable base in a suitable solvent.
  • the coupling agent used may be hydro xybenzotriazole (HOBt) or (l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide) or mixtures thereof.
  • the base used for the coupling may be 4- dimethylaminopyridine.
  • the solvent used may be 1,2-dichloroethane.
  • the present invention relates to process for the preparation of crystalline form of compound of formula (II) which is designated as Form Y, which process involves the following steps:
  • the halogenated solvent may be dichloromethane.
  • step II the desired form is isolated.
  • the isolation of the solid may be effected by techniques known in the art, including but not limited to, decantation, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the compound of formula (II) is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the compound of formula (II) of step I may be obtained by the coupling of (1,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-(i]pyrimidin-5-yl) acetic acid with 4- [2,4-difluoro-3-(trifluoromethyl) phenyl] -1, 3 -thiazol-2-amine using a suitable coupling agent, in the presence of a suitable base in a suitable solvent.
  • the coupling agent used may be hydro xybenzotriazole (HOBt) or (l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide) or mixtures thereof.
  • the base used for the coupling may be N-methyl morpholine.
  • the solvent used may be dichloromethane.
  • the present invention relates to process for the preparation of crystalline form of compound of formula (II) which is designated as Form Z, which process involves the following steps:
  • step I the compound of formula (II) is taken in polar solvent.
  • the solvent is DMSO.
  • the mixture may be stirred at suitable temperature.
  • the mixture may be stirred at 50-60 °C for suitable period of time. The suitable period may be till a clear solution of the mixture was observed.
  • Charcoal may be further added to the mixture and the mixture may be filtered prior to addition of water.
  • step III the desired form is isolated.
  • the isolation of the solid may be effected by techniques known in the art, including but not limited to, decantation, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent.
  • the recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at suitable temperatures as long as the compound of formula (II) is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.
  • the crystalline form Z of compound of formula (II) may also be obtained from Form Y of the compound of formula (II).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an excipients, carriers, diluents or mixture thereof, and therapeutically acceptable amount of crystalline compound of formula (II) designated as Form Y.
  • the present invention pertains to a method of treating diseases or conditions or disorders associated with TRPA1 function in a subject in need thereof by administering to the subject an effective amount of potassium salt of compound of formula (II).
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 16.0 % in 48 hrs at 25°C/90%RH, or a pharmaceutical composition that comprises the said potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 6.6 % in 48 hrs at 25°C/80%RH, or a pharmaceutical composition that comprises the said potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering potassium salt of compound of formula (II) which exhibits the gradual increase of moisture content from initial value of about 0.80 % to about 3.5 % in 48 hrs at 25°C/60%RH, or a pharmaceutical composition that comprises the said potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering a solid state form of potassium salt of compound of formula (II), or a pharmaceutical composition that comprises the solid state form of potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering Form I or Form II or amorphous form of potassium salt of compound of formula (II), or a pharmaceutical composition that comprises the Form I or Form II or amorphous form of potassium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present invention pertains to a pharmaceutical composition comprising an excipients, carriers, diluents or mixture thereof, and therapeutically acceptable amount of sodium salt of compound of formula (II).
  • the present invention pertains to a method of treating diseases or conditions or disorders associated with TRPA1 function in a subject in need thereof by administering to the subject an effective amount of sodium salt of compound of formula (II).
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering a solid state form of sodium salt of compound of formula (II), or a pharmaceutical composition that comprises the solid state form of sodium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering a amorphous form of sodium salt of compound of formula (II), or a pharmaceutical composition that comprises the amorphous form of sodium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering a crystalline form A of sodium salt of compound of formula (II), or a pharmaceutical composition that comprises the crystalline form A of sodium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising an excipients, carriers, diluents or mixture thereof, and therapeutically acceptable amount of lithium salt of compound of formula (II).
  • the present invention pertains to a method of treating diseases or conditions or disorders associated with TRPA1 function in a subject in need thereof by administering to the subject an effective amount of lithium salt of compound of formula (II).
  • a method for treating diseases, conditions and/or disorders modulated by TRPA1 comprising administering a solid state form of lithium salt of compound of formula (II), or a pharmaceutical composition that comprises the solid state form of lithium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering a crystalline form of lithium salt of compound of formula (II), or a pharmaceutical composition that comprises the crystalline form of lithium salt of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present invention pertains to a method of treating diseases or conditions or disorders associated with TRPAl which are selected from pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus by administering potassium, lithium
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering a salt of compound of formula (II), or a pharmaceutical composition that comprises the salt of compound of formula (II) along with pharmaceutically acceptable excipients, wherein the salt of compound of formula (II) is a potassium salt, a sodium salt, or a lithium salt.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering a solid state forms of salt of compound of formula (II), or a pharmaceutical composition that comprises the solid state forms of salt of compound of formula (II) along with pharmaceutically acceptable excipients, wherein the salt of compound of formula (II) is a potassium salt, a sodium salt, or a lithium salt.
  • the present invention pertains to a method of treating diseases or conditions or disorders associated with TRPAl function in a subject in need thereof by administering to the subject an effective amount of crystalline compound of formula (II) designated as Form Y.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering Form X of compound of formula (II), or a pharmaceutical composition that comprises Form X of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering Form Y of compound of formula (II), or a pharmaceutical composition that comprises Form Y of compound of formula (II) along with pharmaceutically acceptable excipients.
  • a method for treating diseases, conditions and/or disorders modulated by TRPAl comprising administering Form Z of compound of formula (II), or a pharmaceutical composition that comprises Form Z of compound of formula (II) along with pharmaceutically acceptable excipients.
  • the present invention pertains to a method of treating diseases or conditions or disorders associated with TRPAl which are selected from pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus by administering Form X
  • process for the preparation of compound of formula (II) and its pharmaceutically acceptable salt which process comprises following steps as shown in the below scheme 1.
  • the process comprises following steps:
  • Step (a) involves reacting dimethylbarbituric acid with chlorinating agent.
  • the chlorinating agent comprises phosphorous trichloride, phosphorous pentachloride or phosphorous oxychloride.
  • the reaction may be carried out in a suitable solvent such as water at a suitable temperature which involves heating the reaction mixture at reflux temperature.
  • Step (b) involves treating compound of formula (1) with sodium hydrosulphide hydrate to give compound of the formula (2).
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent comprises Ci-C 6 alcohols, chlorinating solvent, water and/or mixtures thereof.
  • the suitable solvent(s) may be used in step (b) are ethanol, chloroform and/or combination thereof.
  • the reaction is preferably carried out a temperature range of 0-5 °C.
  • the reaction may be carried out using ethanol as solvent followed by stirring the reaction mixture at room temperature overnight.
  • the reaction mixture was evaporated to dryness under vacuum and the residue obtained was dissolved in water and extracted with dichloromethane.
  • the aqueous layer was separated and acidified with 1 N HC1.
  • the precipitated solid was filtered, washed with water and dried to obtain the compound of formula (2).
  • Step (c) involves reacting compound of formula (2) with the compound of formula (3, wherein R is (Ci-C 4 )alkyl, e.g. methyl or ethyl) to give ester compound of formula (4, wherein R is (Ci-C 4 )alkyl).
  • the reaction may be optionally carried out in the presence of suitable base and suitable solvent(s).
  • Bases that are useful in the reaction include, but are not limited to, organic bases, such as, tertiary amines, e.g., triethylamine, N,N-diisopropylethylamine, N,N-diethylethanamine, N-(l -methylethyl)-2-propanamine, 4-ethylmorpholine, l ,4-diazabicyclo[2.2.2]-octane, N-methylmorpholine, pyridine, and the like; or any mixtures thereof.
  • organic bases such as, tertiary amines, e.g., triethylamine, N,N-diisopropylethylamine, N,N-diethylethanamine, N-(l -methylethyl)-2-propanamine, 4-ethylmorpholine, l ,4-diazabicyclo[2.2.2]-octane, N-methylmorpholine
  • the reaction may be carried out in a suitable solvent or mixture of solvents.
  • the reaction is carried out in a chlorinating solvent.
  • the chlorinating solvent includes dichloromethane, 1 ,2-dichloroethane, chloroform, and carbon tetrachloride. Other suitable solvent may also be used.
  • the reaction may be carried out at a suitable temperature, preferably at room temperature ( ⁇ 25 to 30 °C).
  • Step (d) involves cyclising ester compound of formula (4) to obtain thieno[2,3- d]pyrimidinyl ester of the formula (5).
  • the cyclization step may be carried out using a suitable dehydrating agent such as polyphosphoric acid, phosphorous pentoxide, zinc chloride, sulphuric acid, boron triflouride or Pd 2 (dba) 3 and xantphos.
  • the reaction may be carried out in a suitable solvent or it may be carried out in the absence of a solvent.
  • the reaction may be carried out at an elevated temperature such as 60-70 °C or it may be carried out at a reflux temperature of the solvent employed in the reaction.
  • Step (e) involves reacting the compound of formula (5) with amine of the formula (7) in the presence of a suitable base and suitable solvent to give compound of formula (II).
  • the reaction may be carried out in the presence of suitable base.
  • the suitable base includes inorganic and organic bases such as, for example sodium hydride.
  • the suitable solvent may include, but not limited to, hydrocarbon solvents such as toluene, xylene, n- heptane, cyclohexane and n-hexane.
  • the reaction may be carried out at an elevated temperature such as reflux temperature of the solvent or mixture of solvents employed.
  • the base used in step (e) is sodium hydride and solvent such as toluene.
  • Step (el) involves ester hydrolysis of the compound of formula (5) to obtain compound of formula (6).
  • the ester hydrolysis can be carried out using acid (e.g. H 2 S0 4 or HCl) or base (e.g., sodium hydroxide, potassium hydroxide or lithium hydroxide) under suitable condition (e.g. at reflux temperature) in the presence of suitable solvent such as alcohol, water or 1,4-dioxane and/or combination thereof.
  • suitable solvent such as alcohol, water or 1,4-dioxane and/or combination thereof.
  • the ester hydrolysis can be carried out using 3N or 6N H 2 S0 4 in 1,4- dioxane at reflux temperature.
  • the compound of formula (6) may be coupled with compound of formula (7) in the presence of coupling reagent.
  • the suitable coupling reagents include but are not limited to N-hydroxybenzotriazole (HOBT), 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiirnide hydrochloride (EDCI.HC1), ⁇ , ⁇ - carbonyldiimidazole, cyclohexylisopropylcarbodiimide (CIC), bis[[4-(2,2-dimethyl-l,3- dioxolyl)]-methyl]carbodiimide, N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-CI).
  • HOBT N-
  • the coupling may be carried out in the presence of suitable base and a suitable solvent.
  • the acid group of compound of formula (6) can be converted to its acid chloride by treating it with chlorinating agent such as oxalyl chloride or thionyl chloride in suitable solvent, followed by treating the acid chloride derivative with compound of formula (7) in the presence of base such as triethylamine, pyridine or diisopropyl amine in suitable solvent to give compound of formula (II).
  • Step (a) involves reacting dimethylbarbituric acid with chlorinating agent.
  • the chlorinating agent comprises phosphorous trichloride, phosphorous pentachloride or phosphorous oxychloride.
  • the reaction may be carried out in a suitable solvent such as water at a suitable temperature which involves heating the reaction mixture at reflux temperature.
  • Step (b) involves treating compound of formula (1) with sodium hydrosulphide hydrate to give compound of the formula (2).
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent comprises Ci-C 6 alcohols, chlorinating solvent, water and/or mixtures thereof.
  • the suitable solvent(s) may be used in step (b) are ethanol, chloroform and/or combination thereof.
  • the reaction is preferably carried out a temperature range of 0-5 °C.
  • the reaction may be carried out using ethanol as solvent followed by stirring the reaction mixture at room temperature overnight.
  • the reaction mixture was evaporated to dryness under vacuum and the residue obtained was dissolved in water and extracted with dichloromethane.
  • the aqueous layer was separated and acidified with 1 N HC1.
  • the precipitated solid was filtered, washed with water and dried to obtain the compound of formula (2).
  • Step (c) involves reacting compound of formula (2) with the compound of formula (3, wherein R is (Ci-C 4 )alkyl, e.g. methyl or ethyl) to give ester compound of formula (4, wherein R is (Ci-C 4 )alkyl).
  • the reaction may be optionally carried out in the presence of suitable base and suitable solvent(s).
  • Bases that are useful in the reaction include, but are not limited to, organic bases, such as, tertiary amines, e.g., triethylamine, N,N-diisopropylethylamine, N,N-diethylethanamine, N-(l -methylethyl)-2-propanamine, 4-ethylmorpholine, l ,4-diazabicyclo[2.2.2]-octane, N-methylmorpholine, pyridine, and the like; or any mixtures thereof.
  • organic bases such as, tertiary amines, e.g., triethylamine, N,N-diisopropylethylamine, N,N-diethylethanamine, N-(l -methylethyl)-2-propanamine, 4-ethylmorpholine, l ,4-diazabicyclo[2.2.2]-octane, N-methylmorpholine
  • the reaction may be carried out in a suitable solvent or mixture of solvents.
  • the reaction is carried out in a chlorinating solvent.
  • the chlorinating solvent includes dichloromethane, 1 ,2-dichloroethane, chloroform, and carbon tetrachloride. Other suitable solvent may also be used.
  • the reaction may be carried out at a suitable temperature, preferably at room temperature ( ⁇ 25 to 30 °C).
  • step (f) thioglycolic ester of the formula (4) (wherein R is (Ci-C4)alkyl e.g. methyl or ethyl) is reacted with amine of the formula (7) in the presence of a suitable base and suitable solvent to give thioglycolic amide of the formula (8).
  • the suitable base may include organic or inorganic base. In one of the embodiments, the base used is sodium hydride.
  • the suitable solvent may include, but does not limit to, hydrocarbon solvents such as toluene, xylene, w-heptane, cyclohexane and w-hexane.
  • the compound of formula (8) is cyclized to obtain the compound of formula (II).
  • the cyclization may be carried out using dehydrating agent.
  • the suitable dehydrating agents are such as polyphosphoric acid, phosphorous pentoxide, zinc chloride, sulphuric acid and boron triflouride.
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent may include, but are not limited to, hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and w-hexane or it may be carried out in the absence of a solvent.
  • the reaction may be carried out at an elevated temperature such as 60-70 °C or it may be carried out at a reflux temperature of the solvent employed in the reaction.
  • the present invention pertains to process for the preparation of compound of formula (II) and its pharmaceutically acceptable salt, which comprises the following steps:
  • step (h) thieno[2,3-d]pyrimidinyl acetic acid of the formula (6) is converted to N-acylbenzotriazole derivative of the formula (10) by the reaction of compound of formula (6) with 1H- 1,2,3-benzotriazole (9) in the presence of SOCl 2 and in a suitable solvent.
  • the suitable solvent is chlorinated solvent for example dichloromethane.
  • reaction of N-acylbenzotrazole derivative of the formula (10) with amine compound of the formula (7) may be carried out in the presence of suitable base to afford the compound of the formula (II).
  • ethyl 4-bromoacetoacetate and ethylcyanoacetate can be coupled in the presence of sodium sulfide hydrate to give amino compound of formula (13).
  • the obtained product may be treated with t-butyl nitrite followed by copper bromide to afford bromo compound of formula (14).
  • the cyclization of (14) using N,N-dimethylurea in presence of palladium reagent such as tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) provides the desired ester compound of formula (5').
  • process for the preparation of compound of formula (7) which comprises treating a solution of l-[2,4 -difluoro-3- (trifluoromethyl)phenyl]ethanone (16) in glacial acetic acid with liquid bromine to obtain the crude bromo derivative.
  • the crude bromo derivative, without further purification can be treated with thiourea to afford the 2-amino-4-aryl-thiazole compound (7).
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxy ethylene .
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
  • compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
  • crystalline as used herein, means having a regularly repeating arrangement of molecules or external face planes.
  • amorphous as used herein, means essentially without regularly repeating arrangement of molecules or external face planes.
  • mixture means a combination of at least two substances, in which one substance may be completely soluble, partially soluble or essentially insoluble in the other substance.
  • treating or “treatment” of a state, disorder or condition includes; (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non- domestic animals such as wildlife.
  • peak heights in a powder x-ray diffraction pattern may vary and will be dependent on variables such as the temperature, crystal size, crystal habit, sample preparation or sample height in the analysis well of the Scintagx2 Diffraction Pattern System.
  • average particle size refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined average particle size value. This can be identified by the term "D50” or "d (0.5)".
  • D 10 refers to the distribution of particles, wherein about 10 volume percent of all the particles measured have a size less than the defined particle size value. This can be identified by the term “d(0.1)” as well.
  • D90 refers to the distribution of particles, wherein about 90 volume percent of all the particles measured have a size less than the defined particle size value. This can be identified by the term or "d (0.9)" as well.
  • the average particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy and Coulter's principle.
  • instruments like ZETASIZER ® 3000 HS (Malvern ® Instruments Ltd., Malvern, United Kingdom), NICOMP 388TM ZLS system (PSS-Nicomp Particle Sizing Systems, Santa Barbara, CA, USA), or Coulter Counter are generally used to determine the mean particle size.
  • Mastersizer 2000 (Malvern ® Instruments Ltd., Malvern, United Kingdom) is used to determine the particle size of the particles.
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses. The following abbreviations are used in the text: DMSC ) - ⁇ : Hexadeuterodimethyl sulfoxide; AcOEt: ethyl acetate; equiv.
  • Hygroscopicity study was performed under the following conditions: The material was exposed to relative humidity (for example 60%, 80%, 90%>) at 25°C condition. The material was thinly spread in dried and pre-weighed Petri plate. The plate was exposed to the relative humidity conditions at 25°C. The Petri plate was withdrawn at regular intervals and weighed. Withdrawn samples were tested for description and moisture content by Karl Fischer method.
  • relative humidity for example 60%, 80%, 90%>
  • the particle size distribution was measured using Mastersizer 2000 (Malvern® instruments Ltd., Malvern, United Kingdom) with following measuring equipment and settings:
  • Dispersant 0.1 %> w/v Dioctyl sulfosuccinate sodium salt in n-Hexane
  • All powder X-ray diffraction patterns were obtained using: Panalytical X'PERT-PRO diffractometer model and measured with Cu— Kal radiation at wavelength of 1.54060 A°. The obtained powder X-ray diffraction profiles were integrated using X'Pert High Score Plus Software.
  • Apparatus A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and Integrator software or equivalent.
  • Step 2 - Synthesis of l-(2,4-difluoro-3-(trifluoromethyl)phenyl)ethanone
  • Step 3 Synthesis of 4-[2,4-difluoro- -(trifluoromethyl)phenyl]-l,3-thiazol-2-amine
  • Step 1 Synthesis of 2,4-difluoro-3-(trifluoromethyl)benzoic acid
  • Step 4 Synthesis of 4-[2,4-difluoro- -(trifluoromethyl)phenyl]-l,3-thiazol-2-amine
  • the pH of the mixture was adjusted to 9 - 10 using 30 % sodium hydroxide solution and was stirred for 3 h.
  • the mixture was filtered and product was washed with water.
  • the wet material was dissolved in ethyl acetate (4.0 L) and 60 g charcoal was added and it was stirred for 30 min.
  • the mixture was filtered through celite and the filtrate was dried over Na 2 S0 4 .
  • Eethyl acetate was evaporated and residue obtained was stirred in hexane (1.3 L) for lh.
  • the solid product separated out was collected by filtration to obtain 640 g (76%) of title product.
  • Step-1 Preparation of malonate salt of 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-l,3- thiazol-2-amine:
  • Step 2 Preparation of 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine To a stirred solution of malonate salt of 4-[2,4-difluoro-3-
  • Step 1 Preparation of PTSA salt of 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-l ,3- thiazol-2-amine
  • Step 2 Preparation of 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-l ,3-thiazol-2-amine
  • PTSA salt in ethyl acetate or dichloromethane was basified to pH 12 using aqueous solution of sodium hydroxide.
  • the workup and isolation of the product provided free thiazole amine as a white solid.
  • 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-amine can be prepared by following method as described in WO 2010/10933.
  • Method B To ice-cold solution of 1 ,3-dimethylbarbituric acid (1 Kg) in water (300 ml), phosphorous oxychloride (3.3 L) was drop wise added and the reaction mixture was refluxed for 3 h. After completion of reaction, the excess of phosphorous oxychloride was evaporated under reduced pressure. The reaction mixture was quenched using ice cold water under cooling. The mixture was extracted with dichloromethane (2 x 2.5 L). The combined organic extract was washed with saturated sodium bicarbonate solution (2.5 L), dried (anhydrous Na 2 S0 4 ) and concentrated to obtain the product. The product was washed with ethanol (0.5 L) and dried to obtain 0.9 Kg of the title compound.
  • Method A A solution of sodium hydrosulphide hydrate (74.77 g, 1335.243 mmol) in water (125 ml) was added drop wise to a stirred solution of 6-chloro-l ,3- dimethylpyrimidine-2,4(lH,3H)-dione (50.0 g, 286.532 mmol) in a mixture of chloroform (250 ml) and ethanol (636 ml) at 0°C and the resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under vacuum. The residue obtained was dissolved in water (100 ml) and extracted with dichloromethane (2 x 100 ml). The aqueous layer was acidified with 1 N hydrochloric acid.
  • Method B To a stirred solution of 6-chloro-l ,3-dimethylpyrimidine-2,4(lH,3H)-dione (550.0 g, 3.16 mol) in absolute ethanol (5.5 L) was added portions wise sodium hydrosulphide hydrate (550.0 g 9.8 mol) at 0-5°C over a period of 45 min. After complete addition, the reaction mixture was stirred at 25-30°C for 1 to 2 h. The reaction mixture was filtered and washed with absolute ethanol (1.1 L). The filtrate was concentrated under vacuum to obtain residue which was then dissolved in water (2.75 L). The aqueous solution was washed with dichloromethane (2 x 2.2 L) followed by petroleum ether (1.1 L).
  • the aqueous solution was acidified using hydrochloric acid (2.2 L) [equal portion of cone, hydrochloric acid and water (1 : 1)].
  • the precipitated solid was filtered and washed with water and dried to obtain the desired product (yield: 440 g, 86.2%).
  • Method C The stirred solution of solution of 6-chloro-l ,3-dimethylpyrimidine- 2,4(lH,3H)-dione (1 Kg) in ethanol (12 L) was added portion wise sodium hydrosulphide hydrate (1 kg) over a period of 1 h at 0 to 5°C. After addition, the reaction mixture was stirred at 25 to 30°C for 2 h. The reaction mixture was filtered and washed with ethanol (2 L). The filtrate was collected and concentrated under vacuum to obtain residue which was then dissolved in water (8 L). The aqueous solution was washed with dichloromethane (3 L) followed by petroleum ether (2 L).
  • the aqueous layer was separated and was acidified using hydrochloric acid solution [4 L, cone, hydrochloric acid and water (1 : 1)].
  • the precipitated solid was filtered and washed with water followed by ethanol and dried to obtain the 0.8 Kg of the title compound.
  • Method B The mixture of l ,3-dimethyl-6-sulfanylpyrimidine-2,4(lH,3H)-dione (837 g, 0.01 1 mol) and 4-chloro ethyl acetoacetate (1315 ml, 0.022 mol) in ethanol (6.6 L) was stirred at 25 to 30 °C for 36 h. The solid obtained was filtered and washed with ethanol (418 ml) to yield product as an off white solid (yield: 962g, 66 %>).
  • Method C The mixture of l ,3-dimethyl-6-sulfanylpyrimidine-2,4(lH,3H)-dione (1 Kg) and 4-chloro ethyl acetoacetate (1.58 L) in ethanol (6.6 L) were stirred at 25 to 30°C for 36-40 h. The product obtained was filtered and washed with ethanol (0.5 L) followed by petroleum ether (1 L) to get 1 Kg off white solid title compound.
  • Method A A mixture of ethyl 4-[(l ,3-dimethyl-2,6-dioxo-l ,2,3,6-tetrahydropyrimidin-4- yl) sulfanyl]-3-oxobutanoate (450 g) and polyphosphoric acid (4 Kg) was stirred at 60- 70°C for 2 h. The reaction mixture was cooled to room temperature and carefully quenched with water (24 L). The mixture was extracted with ethyl acetate (2 x 2.25 L) and combined organic layer was washed with water (2 x 2.25 L).
  • Method B To a stirred solution of ethyl 4-[(l ,3-dimethyl-2,6-dioxo-l ,2,3,6- tetrahydropyrimidin-4-yl) sulfanyl]-3-oxobutanoate (42.10 g, 140.802 mmol) in dry toluene (420 ml) was added phosphorous pentoxide (29.97 g, 21 1.204 mmol) and the reaction mixture was heated at reflux temperature for 2 h. The reaction mixture was cooled to room temperature and quenched with water (400 ml).
  • Method D To a stirred solution of ethyl 4-[(l ,3-dimethyl-2,6-dioxo-l ,2,3,6- tetrahydropyrimidin-4-yl) sulfanyl]-3-oxobutanoate (200 mg, 0.666 mmol) in dry toluene (5 ml) was added a drop of concentrated sulphuric acid at room temperature and the resulting mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue obtained was diluted with water (25 ml). The precipitated solid was filtered, washed with water and dried to obtain the desired product as off white solid (yield: 33%).
  • Method E A mixture of ethyl 2-bromo-4-(2-ethoxy-2-oxoethyl)thiophene-3-carboxylate (1.5 g, 0.0046 mol, Intermediate- 10), N,N'-dimethylurea (0.48 g, ,0.0055 mol), Pd 2 (dba) 3 (0.2 g,4.2 mol%>), xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) (0.2 g, 6.5 mol%>) and Cs 2 C0 3 (4.0 g, 0.012 mol in dioxane (15 ml) was refluxed for 4 to 5 h.
  • Method F A mixture of ethyl 4-[(l ,3-dimethyl-2,6-dioxo-l ,2,3,6-tetrahydropyrimidin-4- yl) sulfanyl]-3-oxobutanoate (1 Kg) and polyphosphoric acid (8 Kg) were stirred at 60- 70°C for 2 h. The reaction mixture was cooled to room temperature and carefully quenched with water (40 L). The precipitated solid was filtered and washed with water (2L). The precipitate was dissolved in dichloromethane (10 L), and the mixture was washed with water (2 x 3 L). The layers were separated, organic layer was dried over anhydrous sodium sulphate and treated with charcoal (10 g) and filtered. The filtrate was concentrated to give residue which was triturated with ethanol (0.5 L) to afford 0.7 Kg of title compound.
  • Method A A mixture of ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3- JJpyrimidin-5-yl)acetate (1.3 g, 4.850 mmol) and H 2 SO 4 (6 N , 12 ml) in 1,4-dioxane (12 ml) was heated to reflux for 1 h. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water (50 ml), separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Method B A solution of ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3- JJpyrimidin-5-yl)acetate (340.0 g, 1.20 mol) in 1,4-dioxane (1700 ml) was stirred for 30 min at room temperature, followed by addition of sulfuric acid (3 N, 133 ml in 1700 ml water). The reaction mixture was refluxed for 3 to 4 h and concentrated under vacuum to get an oily mass. It was diluted with water (1700 ml) and stirred for 30 min at 25 to 30°C to obtain the product as a light brown solid which was further washed with water. The product was dried well and further stirred in dichloromethane (1220 ml). The solid was filtered, washed with dichloromethane (680 ml) and dried to yield the title compound (yield: 244g, 80 %).
  • Method A A solution of 4-[2,4-difluoro-3-(trifluoromethyl) phenyl] -1 , 3 -thiazol-2-amine (38.66 g, 0.138 mol) in dichloromethane (154 ml) was added to a solution of (1 ,3- dimethyl-2,4-dioxo-l ,2,3,4-tetrahydrothieno[2,3-(i]pyrimidin-5-yl) acetic acid (29.0 g, 0.1 14 mol) in dichloromethane (174 ml) at 0°C and the resulting mixture was stirred for 5 min.
  • Method B To a stirred solution of 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-l ,3-thiazol- 2-amine (1 1.9 g, 42.553 mmol) in dry toluene (350 ml) was added sodium hydride (60% dispersion in mineral oil, 1.02 g, 42.553 mmol) and the reaction mixture was stirred for 30 min at room temperature.
  • Method D To a stirred solution of 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-l,3- thiazol-2-amine (118 mg, 0.422 mmol) in dry THF (15 ml), sodium hydride (60% dispersion in mineral oil, (12.17 mg, 0.507 mmol) was added and the reaction mixture was stirred for 30 min at room temperature.
  • Method F To a stirred solution of (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3- JJpyrimidin-5-yl) acetic acid (1 Kg) in dichloromethane (6 L), solution of 4-[2,4- difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (1.33 Kg) in dichloromethane (4 L) was added at 0-5 °C and the mixture was stirred for 5 min. To the reaction mixture HOBt (0.2 kg) and N-methyl morpholine (0.46 kg) were added and the reaction mixture was stirred for 30 min.
  • w-Pentane (5. 0 ml) was added and the reaction mixture was maintained for 1-2 h at room temperature.
  • the solid obtained was filtered and dried for 3 to 4 h at 30 to 35°C under vacuum.
  • the dried solid was stirred in acetonitrile (10 ml) for 1 to 2 h.
  • the solid was collected on Buchner funnel and washed with acetonitrile (2 ml).
  • the solid was dried for 8 to 10 h at 30 to 35°C under vacuum.
  • Example-6 Preparation of crystalline potassium salt of [N- ⁇ 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(l,3-dimethyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3-(i]pyrimidin-5-yl)acetamide] designated as Form II.
  • sodium iert-butoxide solution in ethanol (0.195 g of sodium iert-butoxide in 5 ml of ethanol) was prepared.
  • the sodium iert-butoxide solution was slowly added into the reaction mass at -5 to 0 °C and maintained for 1 h.
  • the solvent was distilled off completely at 30 to 35 °C under vacuum till to get solid.
  • the solid was dried for 1 to 2 h at 30 to 35 °C under vacuum.
  • Shake flask method was used to determine the solubility of compound in various bio- relevant media of different pH and quantification is done using HPLC method.
  • FaSSIF Fested state simulated intestinal fluid
  • FeSSIF Fed state simulated intestinal fluid
  • Test substance (1 mg) was taken in a test tube and medium [FaSSIF (pH 6.5) or FeSSIF (pH 5.0) or water] was added in the increment of 1 ml with shaking. After completion of addition of 10 ml of media, test tubes containing sample solution were put on a mechanical shaker set at 37°C and 200 rpm for shaking up to about 15 minutes. After shaking, the content of each flask, it was filtered through 0.45 ⁇ filter. The filtered solution was analysed using HPLC for quantification. A sample solution of 1 mg in 10 ml of DMSO was used as reference standard for quantifying dissolved test substance in each media. The solubility in each media is expressed as ⁇ g/ml (Table- 10).
  • the salts of the compound of formula II were stored under conditions as shown in below table and a total amount of degradation products (related substances) as well as single maximum impurity formed during storage was estimated by HPLC.
  • the material was packed in inner clear polythene bag under nitrogen lined with black polythene bag, covered with triple laminated aluminium bag placed in HDPE drum and subjected to the conditions mentioned in the table 11.

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NZ701721A NZ701721A (en) 2012-06-08 2013-06-08 Amides of 2-amino-4-arylthiazole compounds and their salts
CN201380030184.XA CN104350058A (zh) 2012-06-08 2013-06-08 2-氨基-4-芳基噻唑化合物的酰胺及其盐
KR1020147033855A KR20150015488A (ko) 2012-06-08 2013-06-08 2-아미노-4-아릴티아졸 화합물의 아미드 및 그의 염
HK15108333.2A HK1207643A1 (en) 2012-06-08 2013-06-08 Amides of 2-amino-4-arylthiazole compounds and their salts
US14/402,608 US9458173B2 (en) 2012-06-08 2013-06-08 Amides of 2-amino-4-arylthiazole compounds and their salts
AP2014008076A AP3546A (en) 2012-06-08 2013-06-08 Amides of 2-amino-4-arylthiazole compounds and their salts
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JP2015515642A JP5989900B2 (ja) 2012-06-08 2013-06-08 ２−アミノ−４−アリールチアゾール化合物のアミド及びその塩類
MX2014014482A MX354014B (es) 2012-06-08 2013-06-08 Amidas de compuestos de 2-amino-4-ariltiazol y sus sales.
BR112014029155A BR112014029155A2 (pt) 2012-06-08 2013-06-08 amidas de compostos de 2-amino-4-ariltiazol e respectivos sais e processos de preparação
EP13742279.6A EP2858999B1 (en) 2012-06-08 2013-06-08 Amides of 2-amino-4-arylthiazole compounds and their salts
CA2873570A CA2873570C (en) 2012-06-08 2013-06-08 Amides of 2-amino-4-arylthiazole compounds and their salts as trpa1 modulators
SG11201408093PA SG11201408093PA (en) 2012-06-08 2013-06-08 Amides of 2-amino-4-arylthiazole compounds and their salts
AU2013273118A AU2013273118B2 (en) 2012-06-08 2013-06-08 Amides of 2-amino-4-arylthiazole compounds and their salts
EA201492054A EA031334B1 (ru) 2012-06-08 2013-06-08 Амиды 2-амино-4-арилтиазольных соединений и их соли
PH12014502685A PH12014502685B1 (en) 2012-06-08 2014-12-02 Amides of 2-amino-4-arylthiazole compounds and their salts
IL236084A IL236084A0 (en) 2012-06-08 2014-12-04 Compounds of amides of 2-amino-4-arylthiazole and their salts
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USRE47334E1 (en) 2012-06-08 2019-04-02 Gilead Sciences, Inc. Macrocyclic inhibitors of flaviviridae viruses
US10472392B2 (en) 2012-06-08 2019-11-12 Gilead Sciences, Inc. Macrocyclic inhibitors of flaviviridae viruses
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WO2016042501A1 (en) * 2014-09-16 2016-03-24 Glenmark Pharmaceuticals S.A. Trpa1 antagonist for the treatment of pain associated to diabetic neuropathic pain
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WO2023023242A1 (en) 2021-08-18 2023-02-23 Fmc Corporation Fungicidal substituted heterocycles
CN114891003A (zh) * 2022-04-27 2022-08-12 成都施贝康生物医药科技有限公司 新型二氢嘧啶类化合物、中间体或盐及其制备方法和用途
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