WO2015114479A1 - Crystalline forms of darapladib oxalate, adipate, succinate, phosphate, sulphate, fumaratetartrate, nitrate and borate - Google Patents

Crystalline forms of darapladib oxalate, adipate, succinate, phosphate, sulphate, fumaratetartrate, nitrate and borate Download PDF

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WO2015114479A1
WO2015114479A1 PCT/IB2015/050284 IB2015050284W WO2015114479A1 WO 2015114479 A1 WO2015114479 A1 WO 2015114479A1 IB 2015050284 W IB2015050284 W IB 2015050284W WO 2015114479 A1 WO2015114479 A1 WO 2015114479A1
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darapladib
crystalline form
depicted
xrpd pattern
values
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PCT/IB2015/050284
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French (fr)
Inventor
Amit K. Jain
Gyanendra Pandey
Md Abul Kalam AZAD
Kaptan Singh
Mohan Prasad
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Ranbaxy Laboratories Limited
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    • 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
    • C07D239/56—One oxygen atom and one sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention provides darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, and darapladib borate, their polymorphic forms, processes for their preparation, and pharmaceutical compositions thereof.
  • Darapladib of Formula A chemically known as N-[2-(diethylamino)ethyl]-2- ⁇ 2- [(4-fluorobenzyl)sulfanyl] -4-oxo-4,5 ,6,7-tetrahydro- lH-cyclopenta[ ⁇ f]pyrimidin- 1 -yl ⁇ -N- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ acetamide is an Lp-PLA 2 inhibitor.
  • Darapladib is known for the treatment of atherosclerosis.
  • PCT Publication No. WO 01/60805 provides darapladib bitartrate and darapladib hydrochloride, and processes for their preparation.
  • the present invention provides darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, and darapladib borate.
  • the present invention provides crystalline forms of darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, and darapladib borate.
  • the present invention further provides processes for the preparation of the above salts of darapladib and their use for the preparation of darapladib free base, or salts, solvates, or polymorphs thereof.
  • a first aspect of the present invention provides a crystalline form of darapladib oxalate.
  • the present invention provides a crystalline form of darapladib oxalate, characterized by: an X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1; an XRPD pattern exhibiting interplanar spacing (d) values at 6.52, 5.28, 4.39, 4.26, 4.15, 3.98, 3.49, and 3.42 (A); an XRPD pattern with characteristic peak values (2 ⁇ ) at 13.59, 16.79, 20.22, 20.83, 21.41, 22.35, 25.48, and 26.04 ⁇ 0.2°; a thermogravimetric analysis (TGA) thermogram as depicted in Figure 2; a differential scanning calorimetry (DSC) thermogram as depicted in Figure 3; a DSC thermogram with a characteristic endothermic peak value at about 175.80°C and an additional endothermic peak at about 221.59°C;
  • TGA
  • the crystalline form of darapladib oxalate can be also characterized by an XRPD pattern with additional characteristic peak values (2 ⁇ ) at 9.45, 12.65, 14.79, 14.99, 17.43, 17.95, 18.22, 18.57, 18.87, 20.04, 22.84, 23.18, 23.60, 24.30, 24.55, 24.99, 26.34, 26.67, and 26.89 ⁇ 0.2°.
  • a second aspect of the present invention provides a crystalline form of darapladib adipate.
  • the present invention provides a crystalline form of darapladib adipate, characterized by: an XRPD pattern as depicted in Figure 4; an XRPD pattern exhibiting interplanar spacing (d) values at 4.51, 4.45, 4.02, and 4.01 (A); an XRPD pattern with characteristic peak values (2 ⁇ ) at 19.68, 19.98, 22.08, and 22.18 ⁇ 0.2°; a TGA thermogram as depicted in Figure 5; a DSC thermogram as depicted in Figure 6; a DSC thermogram with a characteristic endothermic peak value at about 148.85°C, an additional endothermic peak at about 111.99°C, and an exothermic peak at about 196.04°C; or combinations thereof.
  • the crystalline form of darapladib adipate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 20.79, 11.04, 10.65, 7.03, 5.77, 5.37, 5.29, 4.74, 4.30, 4.24, and 3.59 (A).
  • the crystalline form of darapladib adipate can be also characterized by an XRPD pattern with additional characteristic peak values (2 ⁇ ) at 4.25, 8.01, 8.30, 12.59, 15.35, 16.49, 16.77, 18.72, 20.65, 20.93, and 24.83 ⁇ 0.2°.
  • a third aspect of the present invention provides a crystalline form of darapladib succinate.
  • the present invention provides a crystalline form of darapladib succinate, characterized by: an XRPD pattern as depicted in Figure 7; an XRPD pattern exhibiting interplanar spacing (d) values at 20.39, 6.82, 4.55, 4.48, and 4.12 (A); an XRPD pattern with characteristic peak values (2 ⁇ ) at 4.33, 12.99, 19.52, 19.81, and 21.56 ⁇ 0.2°; a TGA thermogram as depicted in Figure 8; a DSC thermogram as depicted in Figure 9; a DSC thermogram with a characteristic endothermic peak value at about 145.10°C, an additional endothermic peak at about 91.82°C, and an exothermic peak at about 194.05°C; or combinations thereof.
  • the crystalline form of darapladib succinate can be also characterized by an XRPD pattern with additional characteristic peak values (2 ⁇ ) at 7.99, 8.63, 16.41, 18.56, 20.24, 20.59, 20.91, 21.22, 21.71, 23.36, 24.09, 26.10, and 31.43 ⁇ 0.2°.
  • a fourth aspect of the present invention provides a crystalline form of darapladib phosphate.
  • the present invention provides a crystalline form of darapladib phosphate, characterized by: an XRPD pattern as depicted in Figure 10; an XRPD pattern exhibiting interplanar spacing (d) values at 14.31, 9.05, 7.99, 4.44, 4.31, 4.23, and 4.07 (A); an XRPD pattern with characteristic peak values (2 ⁇ ) at 6.18, 9.77, 11.08, 19.99, 20.59, 21.01, and 21.83 ⁇ 0.2°; a TGA thermogram as depicted in Figure 11; a DSC thermogram as depicted in Figure 12; a DSC thermogram with a characteristic endothermic peak value at about 208.75°C; or combinations thereof.
  • the crystalline form of darapladib phosphate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 23.90, 16.15, 9.95, 9.47, 6.01, 5.56, 5.33, 5.11, 4.89, 4.75, 4.65, 4.54, 4.17, 3.92, 3.89, 3.77, 3.62, 3.56, 3.49, and 3.37 (A).
  • the crystalline form of darapladib phosphate can be also characterized by an XRPD pattern with additional characteristic peak values (2 ⁇ ) at 3.69, 5.47, 8.88, 9.34, 14.74, 15.94, 16.63, 17.35, 18.14, 18.68, 19.09, 19.55, 21.29, 22.67, 22.87, 23.62, 24.56, 24.99, 25.46, and 26.43 ⁇ 0.2°.
  • a fifth aspect of the present invention provides a crystalline form of darapladib sulphate.
  • the present invention provides a crystalline form of darapladib sulphate, characterized by: an XRPD pattern as depicted in Figure 13; an XRPD pattern exhibiting interplanar spacing (d) values at 11.37, 5.92, 5.72, 4.44, and 4.21 (A); an XRPD pattern with characteristic peak values (2 ⁇ ) at 7.77, 14.98, 15.49, 19.99, and 21.12 ⁇ 0.2°; a TGA thermogram as depicted in Figure 14; a DSC thermogram as depicted in Figure 15; a DSC thermogram with a characteristic endothermic peak value at about 193.78°C; or combinations thereof.
  • the crystalline form of darapladib sulphate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 14.43, 5.54, 4.53, 4.29, 3.98, 3.88, 3.78, 3.43, and 3.01 (A).
  • the crystalline form of darapladib sulphate can be also characterized by a XRPD pattern with additional characteristic peak values (2 ⁇ ) at 6.12, 15.99, 19.59, 20.69, 22.36, 22.94, 23.53, 25.97, and 29.64 ⁇ 0.2°.
  • a sixth aspect of the present invention provides a crystalline form of darapladib fumarate.
  • the present invention provides a crystalline form of darapladib fumarate, characterized by: an XRPD pattern as depicted in Figure 16; an XRPD pattern exhibiting interplanar spacing (d) values at 15.43, 11.71, 7.73, 5.88, and 3.99 (A); an XRPD pattern with characteristic peak values (2 ⁇ ) at 5.73, 7.55, 1 1.44, 15.06, and 22.23 ⁇ 0.2°; a TGA thermogram as depicted in Figure 17; a DSC thermogram as depicted in Figure 18; a DSC
  • thermogram with a characteristic endothermic peak value at about 150.70°C, an additional endothermic peak at about 119.35°C, and an exothermic peak at about 201.91°C; or combinations thereof.
  • the crystalline form of darapladib fumarate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 8.96, 6.77, 5.17, 5.01, 4.63, 4.49, 4.33, 4.18, 3.88, 3.78, 3.63, 3.49, 3.41, and 3.32 (A).
  • the crystalline form of darapladib fumarate can be also characterized by a XRPD pattern with additional characteristic peak values (2 ⁇ ) at 9.87, 13.07, 17.14, 17.69, 19.16, 19.76, 20.52, 21.27, 22.89, 23.53, 24.51, 25.49, 26.10, and 26.83 ⁇ 0.2°.
  • a seventh aspect of the present invention provides a crystalline form of darapladib tartrate.
  • the present invention provides a crystalline form of darapladib tartrate, characterized by: an XRPD pattern as depicted in Figure 19; an XRPD pattern exhibiting interplanar spacing (d) values at 16.98,
  • the crystalline form of darapladib tartrate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 10.58, 7.62, 6.05, 5.26, 5.18, 4.75, 4.69, 4.64, 3.88, 3.34, and 3.16 (A).
  • the crystalline form of darapladib tartrate can be also characterized by an XRPD pattern with additional characteristic peak values (2 ⁇ ) at 8.35, 11.62, 14.65, 16.87, 17.13, 18.67, 18.94, 19.13, 22.91, 26.73, and 28.21 ⁇ 0.2°.
  • An eighth aspect of the present invention provides a crystalline form of darapladib nitrate.
  • the present invention provides a crystalline form of darapladib nitrate, characterized by: an XRPD pattern as depicted in Figure 22; an XRPD pattern exhibiting interplanar spacing (d) values at 6.59, 5.63, 5.00, 4.31, 4.22, 4.15, and 3.82 (A); an XRPD pattern with characteristic peak values (2 ⁇ ) at 13.44, 15.73, 17.73, 20.63, 21.05, 21.39, and 23.29 ⁇ 0.2°; a TGA thermogram as depicted in Figure 23; a DSC thermogram as depicted in Figure 24; a DSC thermogram with a characteristic endothermic peak value at about 161.74°C and an additional exothermic peak at about 206.75°C; or combinations thereof.
  • the crystalline form of darapladib nitrate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 14.93, 11.22, 8.64, 7.55, 6.53, 4.68, 4.59, 3.98, 3.89, 3.75, and 3.49 (A).
  • the crystalline form of darapladib nitrate can be also characterized by an XRPD pattern with additional characteristic peak values (2 ⁇ ) at 5.92, 7.88, 10.23, 11.72, 13.56, 18.98, 19.35, 22.36, 22.84, 23.72, and 25.53 ⁇ 0.2°.
  • a ninth aspect of the present invention provides darapladib borate.
  • the present invention provides a crystalline form of darapladib borate.
  • the crystalline form of darapladib borate can be characterized by: an XRPD pattern as depicted in Figure 25; an XRPD pattern exhibiting interplanar spacing (d) values at 13.84, 5.06, and 4.67 (A); an XRPD pattern with characteristic peak values (2 ⁇ ) at 6.39, 17.54, and 19.02 ⁇ 0.2°; a TGA thermogram as depicted in Figure 26; a DSC thermogram as depicted in Figure 27; a DSC thermogram with a characteristic endothermic peak value at about 125.63°C and an additional exothermic peak at about 216.83°C; or combinations thereof.
  • the crystalline form of darapladib borate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 19.71, 6.98, 5.89, 4.1, 4.09, and 4.03 (A).
  • the crystalline form of darapladib borate can be also characterized by an XRPD pattern with additional characteristic peak values (2 ⁇ ) at 4.48, 12.69, 15.04, 21.68, and 21.78 ⁇ 0.2°.
  • a tenth aspect of the present invention provides a process for the preparation of a compound of Formula 1
  • darapladib or salts thereof which comprises treating darapladib or salts thereof with HX, wherein HX is selected from the group consisting of oxalic acid, adipic acid, succinic acid, orthophosphoric acid, sulphuric acid, fumaric acid, tartaric acid, nitric acid, and boric acid.
  • HX is selected from the group consisting of oxalic acid, adipic acid, succinic acid, orthophosphoric acid, sulphuric acid, fumaric acid, tartaric acid, nitric acid, and boric acid.
  • the darapladib or salts thereof used as the starting material may be prepared by any of the methods known in the art, including those described in PCT Publication No. WO 01/60805.
  • the darapladib or its salts prepared by any of the methods known in the art may be isolated or directly treated with HX.
  • the darapladib or salts thereof prepared by any of the methods known in the art may be optionally purified prior to treatment with HX to remove foreign particulate matter. Alternatively, they may be treated with activated charcoal in a suitable solvent to remove coloring and other related impurities.
  • the darapladib salt may optionally be converted to darapladib free base before treatment with HX.
  • Treating darapladib or salts thereof with HX may include adding, dissolving, slurrying, stirring, or a combination thereof.
  • Darapladib or salts thereof may be treated with HX in the presence of a suitable solvent at a suitable temperature.
  • solvent includes a single solvent or solvent mixtures, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof.
  • esters include ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and «-butyl acetate.
  • alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms.
  • alkanols include methanol, ethanol, «-propanol, isopropanol, and butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone and methyl ethyl ketone.
  • ethers include diethyl ether and tetrahydrofuran.
  • polar aprotic solvents include NN-dimethylformamide, NN-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
  • Darapladib or salts thereof are treated with HX at a temperature of about 25 °C to reflux for a time period sufficient to complete the reaction, preferably for about 10 minutes to about 6 hours.
  • the compound of Formula 1 can be isolated by a common isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or combinations thereof.
  • An eleventh aspect of the present invention provides the use of a compound of Formula 1 for the preparation of darapladib free base or salts, solvates, or polymorphs thereof.
  • the compound of Formula 1 may be used for the preparation of darapladib by contacting with a base.
  • the base is selected from the group comprising hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals; ammonia; alkyl amines; hydrazine; and the like.
  • hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • alkyl amines include diethyl amine, triethyl amine, and methyl diethyl amine.
  • Darapladib thus obtained may be converted to salts, solvates, or polymorphs thereof.
  • a twelfth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, or darapladib borate, and a pharmaceutically acceptable carrier.
  • a thirteenth aspect of the present invention provides a method of treating atherosclerosis which comprises administering to a patient in need thereof a therapeutically effective amount of darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, or darapladib borate, and a pharmaceutically acceptable carrier.
  • Figure 1 and Figure la depict the XRPD of darapladib oxalate and the associated values, respectively, prepared as per Example 1.
  • Figure 2 depicts the TGA thermogram of darapladib oxalate prepared as per Example 1.
  • Figure 3 depicts the DSC thermogram of darapladib oxalate prepared as per
  • Example 1 Figure 4 and Figure 4a depict the XRPD of darapladib adipate and the associated values, respectively, prepared as per Example 2.
  • Figure 5 depicts the TGA thermogram of darapladib adipate prepared as per Example 2.
  • Figure 6 depicts the DSC thermogram of darapladib adipate prepared as per
  • Figure 7 and Figure 7a depict the XRPD of darapladib succinate and the associated values, respectively, prepared as per Example 3.
  • Figure 8 depicts the TGA thermogram of darapladib succinate prepared as per Example 3.
  • Figure 9 depicts the DSC thermogram of darapladib succinate prepared as per Example 3.
  • Figure 10 and Figure 10a depict the XRPD of darapladib phosphate and the associated values, respectively, prepared as per Example 4.
  • Figure 11 depicts the TGA thermogram of darapladib phosphate prepared as per
  • Figure 12 depicts the DSC thermogram of darapladib phosphate prepared as per Example 4.
  • Figure 13 and Figure 13a depict the XRPD of darapladib sulphate and the associated values, respectively, prepared as per Example 5.
  • Figure 14 depicts the TGA thermogram of darapladib sulphate prepared as per Example 5.
  • Figure 15 depicts the DSC thermogram of darapladib sulphate prepared as per Example 5.
  • Figure 16 and Figure 16a depict the XRPD of darapladib fumarate and the associated values, respectively, prepared as per Example 6.
  • Figure 17 depicts the TGA thermogram of darapladib fumarate prepared as per Example 6.
  • Figure 18 depicts the DSC thermogram of darapladib fumarate prepared as per Example 6.
  • Figure 19 and Figure 19a depict the XRPD of darapladib tartrate and the associated values, respectively, prepared as per Example 7.
  • Figure 20 depicts the TGA thermogram of darapladib tartrate prepared as per
  • Figure 21 depicts the DSC thermogram of darapladib tartrate prepared as per Example 7.
  • Figure 22 and Figure 22a depict the XRPD of darapladib nitrate and the associated values, respectively, prepared as per Example 8.
  • Figure 23 depicts the TGA thermogram of darapladib nitrate prepared as per Example 8.
  • Figure 24 depicts the DSC thermogram of darapladib nitrate prepared as per Example 8.
  • Figure 25 and Figure 25a depict the XRPD of darapladib borate and the associated values, respectively, prepared as per Example 9.
  • Figure 26 depicts the TGA thermogram of darapladib borate prepared as per Example 9.
  • Figure 27 depicts the DSC thermogram of darapladib borate prepared as per Example 9.
  • the XRPD of the samples were determined by using a PANalytical ® ; Mode: X'Pert PRO; Detector: X'celerator ® ; Scan Range: 3-40°2 theta; Step size: 0.02°; CuKa radiation at 45kV; Time per step: 40 seconds.
  • the DSC thermogram of the samples was determined by using a Mettler Toledo ® DSC 821; Rate of heating: 10°C/minute, from 30°C to 300°C; Nitrogen flow rate: 20 mL per minute.
  • thermogram of the samples was determined by using a TA Instruments ® Q500; Rate of heating: 10°C/minute from 30°C to 300°C.
  • Tartrate content 17.1% w/w

Abstract

The present invention provides darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, and darapladib borate, their polymorphic forms, processes for their preparation, and pharmaceutical compositions thereof.

Description

CRYSTALLINE FORMS OF DARAPLADIB OXALATE, ADIPATE, SUCCINATE, PHOSPHATE, SULPHATE, FUMARATE.TARTRATE, NITRATE AND BORATE
Field of the Invention
The present invention provides darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, and darapladib borate, their polymorphic forms, processes for their preparation, and pharmaceutical compositions thereof.
Background of the Invention
Darapladib of Formula A, chemically known as N-[2-(diethylamino)ethyl]-2-{2- [(4-fluorobenzyl)sulfanyl] -4-oxo-4,5 ,6,7-tetrahydro- lH-cyclopenta[<f]pyrimidin- 1 -yl } -N- {[4'-(trifluoromethyl)biphenyl-4-yl]methyl}acetamide is an Lp-PLA2 inhibitor.
Darapladib is known for the treatment of atherosclerosis.
Figure imgf000002_0001
Formula A
PCT Publication No. WO 01/60805 provides darapladib bitartrate and darapladib hydrochloride, and processes for their preparation.
In the pharmaceutical industry there is a constant need to identify critical physicochemical parameters, such as salts and polymorphic forms, which affect the drug's performance and stability.
Since darapladib constitutes an important therapeutic agent, additional salts of darapladib are of value to pharmaceutical science. Thus, there is a need for the development of novel salts of darapladib having improved solubility, stability, bioavailability, and less susceptibility to degradation at lower temperatures.
Summary of the Invention
The present invention provides darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, and darapladib borate. The present invention provides crystalline forms of darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, and darapladib borate. The present invention further provides processes for the preparation of the above salts of darapladib and their use for the preparation of darapladib free base, or salts, solvates, or polymorphs thereof.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
A first aspect of the present invention provides a crystalline form of darapladib oxalate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib oxalate, characterized by: an X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1; an XRPD pattern exhibiting interplanar spacing (d) values at 6.52, 5.28, 4.39, 4.26, 4.15, 3.98, 3.49, and 3.42 (A); an XRPD pattern with characteristic peak values (2Θ) at 13.59, 16.79, 20.22, 20.83, 21.41, 22.35, 25.48, and 26.04 ±0.2°; a thermogravimetric analysis (TGA) thermogram as depicted in Figure 2; a differential scanning calorimetry (DSC) thermogram as depicted in Figure 3; a DSC thermogram with a characteristic endothermic peak value at about 175.80°C and an additional endothermic peak at about 221.59°C; or combinations thereof.
The crystalline form of darapladib oxalate may be further characterized by an
XRPD pattern with additional interplanar spacing (d) values at 9.35, 6.99, 5.99, 5.91, 5.09, 4.94, 4.87, 4.78, 4.70, 4.43, 3.89, 3.84, 3.77, 3.66, 3.63, 3.56, 3.38, 3.34, and 3.31 (A). The crystalline form of darapladib oxalate can be also characterized by an XRPD pattern with additional characteristic peak values (2Θ) at 9.45, 12.65, 14.79, 14.99, 17.43, 17.95, 18.22, 18.57, 18.87, 20.04, 22.84, 23.18, 23.60, 24.30, 24.55, 24.99, 26.34, 26.67, and 26.89 ±0.2°.
A second aspect of the present invention provides a crystalline form of darapladib adipate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib adipate, characterized by: an XRPD pattern as depicted in Figure 4; an XRPD pattern exhibiting interplanar spacing (d) values at 4.51, 4.45, 4.02, and 4.01 (A); an XRPD pattern with characteristic peak values (2Θ) at 19.68, 19.98, 22.08, and 22.18 ±0.2°; a TGA thermogram as depicted in Figure 5; a DSC thermogram as depicted in Figure 6; a DSC thermogram with a characteristic endothermic peak value at about 148.85°C, an additional endothermic peak at about 111.99°C, and an exothermic peak at about 196.04°C; or combinations thereof.
The crystalline form of darapladib adipate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 20.79, 11.04, 10.65, 7.03, 5.77, 5.37, 5.29, 4.74, 4.30, 4.24, and 3.59 (A). The crystalline form of darapladib adipate can be also characterized by an XRPD pattern with additional characteristic peak values (2Θ) at 4.25, 8.01, 8.30, 12.59, 15.35, 16.49, 16.77, 18.72, 20.65, 20.93, and 24.83 ±0.2°.
A third aspect of the present invention provides a crystalline form of darapladib succinate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib succinate, characterized by: an XRPD pattern as depicted in Figure 7; an XRPD pattern exhibiting interplanar spacing (d) values at 20.39, 6.82, 4.55, 4.48, and 4.12 (A); an XRPD pattern with characteristic peak values (2Θ) at 4.33, 12.99, 19.52, 19.81, and 21.56 ±0.2°; a TGA thermogram as depicted in Figure 8; a DSC thermogram as depicted in Figure 9; a DSC thermogram with a characteristic endothermic peak value at about 145.10°C, an additional endothermic peak at about 91.82°C, and an exothermic peak at about 194.05°C; or combinations thereof.
The crystalline form of darapladib succinate may be further characterized by an
XRPD pattern with additional interplanar spacing (d) values at 11.06, 10.25, 5.40, 4.78, 4.39, 4.31, 4.25, 4.19, 4.09, 3.81, 3.69, 3.41, and 2.85 (A). The crystalline form of darapladib succinate can be also characterized by an XRPD pattern with additional characteristic peak values (2Θ) at 7.99, 8.63, 16.41, 18.56, 20.24, 20.59, 20.91, 21.22, 21.71, 23.36, 24.09, 26.10, and 31.43 ±0.2°.
A fourth aspect of the present invention provides a crystalline form of darapladib phosphate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib phosphate, characterized by: an XRPD pattern as depicted in Figure 10; an XRPD pattern exhibiting interplanar spacing (d) values at 14.31, 9.05, 7.99, 4.44, 4.31, 4.23, and 4.07 (A); an XRPD pattern with characteristic peak values (2Θ) at 6.18, 9.77, 11.08, 19.99, 20.59, 21.01, and 21.83 ±0.2°; a TGA thermogram as depicted in Figure 11; a DSC thermogram as depicted in Figure 12; a DSC thermogram with a characteristic endothermic peak value at about 208.75°C; or combinations thereof.
The crystalline form of darapladib phosphate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 23.90, 16.15, 9.95, 9.47, 6.01, 5.56, 5.33, 5.11, 4.89, 4.75, 4.65, 4.54, 4.17, 3.92, 3.89, 3.77, 3.62, 3.56, 3.49, and 3.37 (A). The crystalline form of darapladib phosphate can be also characterized by an XRPD pattern with additional characteristic peak values (2Θ) at 3.69, 5.47, 8.88, 9.34, 14.74, 15.94, 16.63, 17.35, 18.14, 18.68, 19.09, 19.55, 21.29, 22.67, 22.87, 23.62, 24.56, 24.99, 25.46, and 26.43 ±0.2°.
A fifth aspect of the present invention provides a crystalline form of darapladib sulphate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib sulphate, characterized by: an XRPD pattern as depicted in Figure 13; an XRPD pattern exhibiting interplanar spacing (d) values at 11.37, 5.92, 5.72, 4.44, and 4.21 (A); an XRPD pattern with characteristic peak values (2Θ) at 7.77, 14.98, 15.49, 19.99, and 21.12 ±0.2°; a TGA thermogram as depicted in Figure 14; a DSC thermogram as depicted in Figure 15; a DSC thermogram with a characteristic endothermic peak value at about 193.78°C; or combinations thereof.
The crystalline form of darapladib sulphate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 14.43, 5.54, 4.53, 4.29, 3.98, 3.88, 3.78, 3.43, and 3.01 (A). The crystalline form of darapladib sulphate can be also characterized by a XRPD pattern with additional characteristic peak values (2Θ) at 6.12, 15.99, 19.59, 20.69, 22.36, 22.94, 23.53, 25.97, and 29.64 ±0.2°.
A sixth aspect of the present invention provides a crystalline form of darapladib fumarate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib fumarate, characterized by: an XRPD pattern as depicted in Figure 16; an XRPD pattern exhibiting interplanar spacing (d) values at 15.43, 11.71, 7.73, 5.88, and 3.99 (A); an XRPD pattern with characteristic peak values (2Θ) at 5.73, 7.55, 1 1.44, 15.06, and 22.23 ±0.2°; a TGA thermogram as depicted in Figure 17; a DSC thermogram as depicted in Figure 18; a DSC
thermogram with a characteristic endothermic peak value at about 150.70°C, an additional endothermic peak at about 119.35°C, and an exothermic peak at about 201.91°C; or combinations thereof. The crystalline form of darapladib fumarate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 8.96, 6.77, 5.17, 5.01, 4.63, 4.49, 4.33, 4.18, 3.88, 3.78, 3.63, 3.49, 3.41, and 3.32 (A). The crystalline form of darapladib fumarate can be also characterized by a XRPD pattern with additional characteristic peak values (2Θ) at 9.87, 13.07, 17.14, 17.69, 19.16, 19.76, 20.52, 21.27, 22.89, 23.53, 24.51, 25.49, 26.10, and 26.83 ±0.2°.
A seventh aspect of the present invention provides a crystalline form of darapladib tartrate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib tartrate, characterized by: an XRPD pattern as depicted in Figure 19; an XRPD pattern exhibiting interplanar spacing (d) values at 16.98,
13.47, 6.38, 6.25, 4.27, 4.11, and 3.55 (A); an XRPD pattern with characteristic peak values (2Θ) at 5.21, 6.56, 13.89, 14.17, 20.78, 21.64, and 25.08 ±0.2°; a TGA thermogram as depicted in Figure 20; a DSC thermogram as depicted in Figure 21; a DSC thermogram with a characteristic endothermic peak value at about 135.10°C and an exothermic peak at about 206.35°C; or combinations thereof.
The crystalline form of darapladib tartrate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 10.58, 7.62, 6.05, 5.26, 5.18, 4.75, 4.69, 4.64, 3.88, 3.34, and 3.16 (A). The crystalline form of darapladib tartrate can be also characterized by an XRPD pattern with additional characteristic peak values (2Θ) at 8.35, 11.62, 14.65, 16.87, 17.13, 18.67, 18.94, 19.13, 22.91, 26.73, and 28.21 ±0.2°.
An eighth aspect of the present invention provides a crystalline form of darapladib nitrate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib nitrate, characterized by: an XRPD pattern as depicted in Figure 22; an XRPD pattern exhibiting interplanar spacing (d) values at 6.59, 5.63, 5.00, 4.31, 4.22, 4.15, and 3.82 (A); an XRPD pattern with characteristic peak values (2Θ) at 13.44, 15.73, 17.73, 20.63, 21.05, 21.39, and 23.29 ±0.2°; a TGA thermogram as depicted in Figure 23; a DSC thermogram as depicted in Figure 24; a DSC thermogram with a characteristic endothermic peak value at about 161.74°C and an additional exothermic peak at about 206.75°C; or combinations thereof.
The crystalline form of darapladib nitrate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 14.93, 11.22, 8.64, 7.55, 6.53, 4.68, 4.59, 3.98, 3.89, 3.75, and 3.49 (A). The crystalline form of darapladib nitrate can be also characterized by an XRPD pattern with additional characteristic peak values (2Θ) at 5.92, 7.88, 10.23, 11.72, 13.56, 18.98, 19.35, 22.36, 22.84, 23.72, and 25.53 ±0.2°.
A ninth aspect of the present invention provides darapladib borate. In one embodiment of this aspect, the present invention provides a crystalline form of darapladib borate. The crystalline form of darapladib borate can be characterized by: an XRPD pattern as depicted in Figure 25; an XRPD pattern exhibiting interplanar spacing (d) values at 13.84, 5.06, and 4.67 (A); an XRPD pattern with characteristic peak values (2Θ) at 6.39, 17.54, and 19.02 ±0.2°; a TGA thermogram as depicted in Figure 26; a DSC thermogram as depicted in Figure 27; a DSC thermogram with a characteristic endothermic peak value at about 125.63°C and an additional exothermic peak at about 216.83°C; or combinations thereof.
The crystalline form of darapladib borate may be further characterized by an XRPD pattern with additional interplanar spacing (d) values at 19.71, 6.98, 5.89, 4.1, 4.09, and 4.03 (A). The crystalline form of darapladib borate can be also characterized by an XRPD pattern with additional characteristic peak values (2Θ) at 4.48, 12.69, 15.04, 21.68, and 21.78 ±0.2°.
A tenth aspect of the present invention provides a process for the preparation of a compound of Formula 1
Figure imgf000007_0001
Formula 1
which comprises treating darapladib or salts thereof with HX, wherein HX is selected from the group consisting of oxalic acid, adipic acid, succinic acid, orthophosphoric acid, sulphuric acid, fumaric acid, tartaric acid, nitric acid, and boric acid. The darapladib or salts thereof used as the starting material may be prepared by any of the methods known in the art, including those described in PCT Publication No. WO 01/60805.
The darapladib or its salts prepared by any of the methods known in the art may be isolated or directly treated with HX.
The darapladib or salts thereof prepared by any of the methods known in the art may be optionally purified prior to treatment with HX to remove foreign particulate matter. Alternatively, they may be treated with activated charcoal in a suitable solvent to remove coloring and other related impurities. The darapladib salt may optionally be converted to darapladib free base before treatment with HX.
Treating darapladib or salts thereof with HX may include adding, dissolving, slurrying, stirring, or a combination thereof. Darapladib or salts thereof may be treated with HX in the presence of a suitable solvent at a suitable temperature.
The term "solvent," as used herein, includes a single solvent or solvent mixtures, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof.
Examples of esters include ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms. Examples of alkanols include methanol, ethanol, «-propanol, isopropanol, and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
Examples of ketones include acetone and methyl ethyl ketone. Examples of ethers include diethyl ether and tetrahydrofuran. Examples of polar aprotic solvents include NN-dimethylformamide, NN-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
Darapladib or salts thereof are treated with HX at a temperature of about 25 °C to reflux for a time period sufficient to complete the reaction, preferably for about 10 minutes to about 6 hours.
After completion of the reaction, the compound of Formula 1 can be isolated by a common isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or combinations thereof.
An eleventh aspect of the present invention provides the use of a compound of Formula 1 for the preparation of darapladib free base or salts, solvates, or polymorphs thereof.
The compound of Formula 1 may be used for the preparation of darapladib by contacting with a base. The base is selected from the group comprising hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals; ammonia; alkyl amines; hydrazine; and the like. Examples of hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Examples of alkyl amines include diethyl amine, triethyl amine, and methyl diethyl amine. Darapladib thus obtained may be converted to salts, solvates, or polymorphs thereof.
A twelfth aspect of the present invention provides a pharmaceutical composition comprising darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, or darapladib borate, and a pharmaceutically acceptable carrier.
A thirteenth aspect of the present invention provides a method of treating atherosclerosis which comprises administering to a patient in need thereof a therapeutically effective amount of darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, or darapladib borate, and a pharmaceutically acceptable carrier.
Brief Description of the Figures
Figure 1 and Figure la depict the XRPD of darapladib oxalate and the associated values, respectively, prepared as per Example 1.
Figure 2 depicts the TGA thermogram of darapladib oxalate prepared as per Example 1.
Figure 3 depicts the DSC thermogram of darapladib oxalate prepared as per
Example 1. Figure 4 and Figure 4a depict the XRPD of darapladib adipate and the associated values, respectively, prepared as per Example 2.
Figure 5 depicts the TGA thermogram of darapladib adipate prepared as per Example 2.
Figure 6 depicts the DSC thermogram of darapladib adipate prepared as per
Example 2.
Figure 7 and Figure 7a depict the XRPD of darapladib succinate and the associated values, respectively, prepared as per Example 3.
Figure 8 depicts the TGA thermogram of darapladib succinate prepared as per Example 3.
Figure 9 depicts the DSC thermogram of darapladib succinate prepared as per Example 3.
Figure 10 and Figure 10a depict the XRPD of darapladib phosphate and the associated values, respectively, prepared as per Example 4.
Figure 11 depicts the TGA thermogram of darapladib phosphate prepared as per
Example 4.
Figure 12 depicts the DSC thermogram of darapladib phosphate prepared as per Example 4.
Figure 13 and Figure 13a depict the XRPD of darapladib sulphate and the associated values, respectively, prepared as per Example 5.
Figure 14 depicts the TGA thermogram of darapladib sulphate prepared as per Example 5.
Figure 15 depicts the DSC thermogram of darapladib sulphate prepared as per Example 5.
Figure 16 and Figure 16a depict the XRPD of darapladib fumarate and the associated values, respectively, prepared as per Example 6.
Figure 17 depicts the TGA thermogram of darapladib fumarate prepared as per Example 6. Figure 18 depicts the DSC thermogram of darapladib fumarate prepared as per Example 6.
Figure 19 and Figure 19a depict the XRPD of darapladib tartrate and the associated values, respectively, prepared as per Example 7.
Figure 20 depicts the TGA thermogram of darapladib tartrate prepared as per
Example 7.
Figure 21 depicts the DSC thermogram of darapladib tartrate prepared as per Example 7.
Figure 22 and Figure 22a depict the XRPD of darapladib nitrate and the associated values, respectively, prepared as per Example 8.
Figure 23 depicts the TGA thermogram of darapladib nitrate prepared as per Example 8.
Figure 24 depicts the DSC thermogram of darapladib nitrate prepared as per Example 8.
Figure 25 and Figure 25a depict the XRPD of darapladib borate and the associated values, respectively, prepared as per Example 9.
Figure 26 depicts the TGA thermogram of darapladib borate prepared as per Example 9.
Figure 27 depicts the DSC thermogram of darapladib borate prepared as per Example 9.
The XRPD of the samples were determined by using a PANalytical®; Mode: X'Pert PRO; Detector: X'celerator®; Scan Range: 3-40°2 theta; Step size: 0.02°; CuKa radiation at 45kV; Time per step: 40 seconds.
The DSC thermogram of the samples was determined by using a Mettler Toledo® DSC 821; Rate of heating: 10°C/minute, from 30°C to 300°C; Nitrogen flow rate: 20 mL per minute.
The TGA thermogram of the samples was determined by using a TA Instruments® Q500; Rate of heating: 10°C/minute from 30°C to 300°C. While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be within the scope of the present invention.
EXAMPLES
Example 1 : Preparation of darapladib oxalate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25°C. A methanolic solution of oxalic acid (2.25 g oxalic acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25°C.
Methanol (120 mL) was charged to the reaction mixture at 20°C to 25°C, then the reaction mixture was stirred at 20°C to 25°C for 3 hours. The reaction mixture was filtered at 20°C to 25 °C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45°C to 50°C for overnight to obtain the title compound.
Yield: 14 g
Example 2: Preparation of darapladib adipate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25 °C. A methanolic solution of adipic acid (3.62 g adipic acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25°C.
Methanol (75 mL) was charged to the reaction mixture at 20°C to 25°C, then the reaction mixture was stirred at 20°C to 25°C for 3 hours. The reaction mixture was filtered at 20°C to 25 °C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45°C to 50°C for overnight to obtain the title compound.
Yield: 11.2 g
Example 3 : Preparation of darapladib succinate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25 °C. A methanolic solution of succinic acid (2.95 g succinic acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was heated to 60°C. The reaction mixture was gradually cooled to 20°C to 25 °C over 45 minutes. The reaction mixture was further cooled to 5°C to 10°C, then the reaction mixture was stirred at 5°C to 10°C for 3 hours. The reaction mixture was filtered at 5°C to 10°C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45°C to 50°C for overnight to obtain the title compound.
Yield: 5 g
Example 4: Preparation of darapladib phosphate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25°C. A methanolic solution of orthophosphoric acid (2.43 g orthophosphoric acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25°C. Methanol (75 mL) was charged to the reaction mixture at 20°C to 25°C, then the reaction mixture was stirred at 20°C to 25°C for 3 hours. The reaction mixture was filtered at 20°C to 25°C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45 °C to 50°C for overnight to obtain the title compound.
Yield: 15.8 g
Example 5 : Preparation of darapladib sulphate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25°C. A methanolic solution of sulphuric acid (2.43 g sulphuric acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was stirred for 60 minutes at 20°C to 25°C, then was cooled to 10°C. Methanol (45 mL) was charged to the reaction mixture, then the temperature was raised to 20°C. The reaction mixture was stirred at 20°C to 25°C for 3 hours. The reaction mixture was filtered at 20°C to 25°C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45 °C to 50°C for overnight to obtain the title compound.
Yield: 10 g
Example 6: Preparation of darapladib fumarate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25°C. A methanolic solution of fumaric acid (2.87 g fumaric acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25°C. The reaction mixture was heated to 60°C. The reaction mixture was gradually cooled to 20°C to 25°C over 45 minutes. Methanol (30 mL) was charged to the reaction mixture at 20°C to 25°C, then the reaction mixture was stirred at 20°C to 25°C for 3 hours. The reaction mixture was filtered at 20°C to 25°C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45°C to 50°C for overnight to obtain the title compound.
Yield: 11 g
Example 7: Preparation of darapladib tartrate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25°C. A methanolic solution of tartaric acid (3.72 g tartaric acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25°C.
Methanol (45 mL) was charged to the reaction mixture at 20°C to 25°C, then the reaction mixture was stirred at 20°C to 25°C for 3 hours. The reaction mixture was filtered at 20°C to 25 °C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45°C to 50°C for overnight to obtain the title compound.
Yield: 10.5 g
Tartrate content: 17.1% w/w
Example 8: Preparation of darapladib nitrate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25 °C. A methanolic solution of nitric acid (1.56 g nitric acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was heated to 60°C. The reaction mixture was gradually cooled to 20°C to 25°C over 45 minutes. The reaction mixture was stirred at 20°C to 25°C for 3 hours. The reaction mixture was filtered at 20°C to 25 °C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45 °C to 50°C for overnight to obtain the title compound.
Yield: 10 g
Example 9: Preparation of darapladib borate
Darapladib (15 g) and methanol (30 mL) were combined at 20°C to 25 °C. A methanolic solution of boric acid (1.55 g boric acid in 75 mL methanol) was charged at 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25°C.
Methanol (30 mL) was charged to the reaction mixture at 20°C to 25 °C, then the reaction mixture was stirred at 20°C to 25°C for 3 hours. The reaction mixture was filtered at 20°C to 25 °C. The wet solid obtained was washed with methanol (30 mL). The wet solid was suck dried for 15 minutes and then dried under vacuum at 45°C to 50°C for overnight to obtain the title compound.
Yield: 7.5 g

Claims

CLAIMS:
1. A crystalline form of darapladib oxalate characterized by an XRPD pattern substantially as depicted in Figure 1.
2. A crystalline form of darapladib oxalate characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 6.52, 5.28, 4.39, 4.26, 4.15, 3.98, 3.49, and 3.42 (A).
3. A crystalline form of darapladib oxalate characterized by an XRPD pattern with characteristic peak values (2Θ) at about 13.59, 16.79, 20.22, 20.83, 21.41, 22.35, 25.48, and 26.04 ±0.2°.
4. A crystalline form of darapladib oxalate characterized by a TGA thermogram substantially as depicted in Figure 2.
5. A crystalline form of darapladib oxalate characterized by a DSC thermogram substantially as depicted in Figure 3.
6. A crystalline form of darapladib oxalate characterized by a DSC thermogram with a characteristic endothermic peak value at about 175.80°C and an additional endothermic peak at about 221.59°C
7. A crystalline form of darapladib adipate characterized by an XRPD pattern substantially as depicted in Figure 4.
8. A crystalline form of darapladib adipate characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 4.51, 4.45, 4.02, and 4.01 (A).
9. A crystalline form of darapladib adipate characterized by an XRPD pattern with characteristic peak values (2Θ) at about 19.68, 19.98, 22.08, and 22.18 ±0.2°.
10. A crystalline form of darapladib adipate characterized by a TGA thermogram as depicted in Figure 5.
11. A crystalline form of darapladib adipate characterized by a DSC thermogram substantially as depicted in Figure 6.
12. A crystalline form of darapladib adipate characterized by a DSC thermogram with a characteristic endothermic peak value at about 148.85°C, an additional endothermic peak at about 111.99°C, and an exothermic peak at about 196.04°C.
13. A crystalline form of darapladib succinate characterized by an XRPD pattern substantially as depicted in Figure 7.
14. A crystalline form of darapladib succinate characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 20.39, 6.82, 4.55, 4.48, and 4.12 (A).
15. A crystalline form of darapladib succinate characterized by an XRPD pattern with characteristic peak values (2Θ) at about 4.33, 12.99, 19.52, 19.81, and 21.56 ±0.2°.
16. A crystalline form of darapladib succinate characterized by a TGA thermogram substantially as depicted in Figure 8.
17. A crystalline form of darapladib succinate characterized by a DSC thermogram substantially as depicted in Figure 9.
18. A crystalline form of darapladib succinate characterized by a DSC thermogram with a characteristic endothermic peak value at about 145.10°C, an additional endothermic peak at about 91.82°C, and an exothermic peak at about 194.05°C.
19. A crystalline form of darapladib phosphate characterized by an XRPD pattern substantially as depicted in Figure 10.
20. A crystalline form of darapladib phosphate characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 14.31, 9.05, 7.99, 4.44, 4.31, 4.23, and 4.07 (A).
21. A crystalline form of darapladib phosphate characterized by an XRPD pattern with characteristic peak values (2Θ) at about 6.18, 9.77, 11.08, 19.99, 20.59, 21.01, and 21.83 ±0.2°.
22. A crystalline form of darapladib phosphate characterized by a TGA thermogram substantially as depicted in Figure 11.
23. A crystalline form of darapladib phosphate characterized by a DSC thermogram substantially as depicted in Figure 12.
24. A crystalline form of darapladib phosphate characterized by a DSC thermogram with a characteristic endothermic peak value at about 208.75°C.
25. A crystalline form of darapladib sulphate characterized by an XRPD pattern substantially as depicted in Figure 13.
26. A crystalline form of darapladib sulphate characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 11.37, 5.92, 5.72, 4.44, and 4.21 (A).
27. A crystalline form of darapladib sulphate characterized by an XRPD pattern with characteristic peak values (2Θ) at about 7.77, 14.98, 15.49, 19.99, and 21.12 ±0.2°.
28. A crystalline form of darapladib sulphate characterized by a TGA thermogram substantially as depicted in Figure 14.
29. A crystalline form of darapladib sulphate characterized by a DSC thermogram substantially as depicted in Figure 15.
30. A crystalline form of darapladib sulphate characterized by a DSC thermogram with a characteristic endothermic peak value at about 193.78°C.
31. A crystalline form of darapladib fumarate characterized by an XRPD pattern substantially as depicted in Figure 16.
32. A crystalline form of darapladib fumarate characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 15.43, 11.71, 7.73, 5.88, and 3.99 (A).
33. A crystalline form of darapladib fumarate characterized by an XRPD pattern with characteristic peak values (2Θ) at about 5.73, 7.55, 11.44, 15.06, and 22.23 ±0.2°.
34. A crystalline form of darapladib fumarate characterized by a TGA thermogram substantially as depicted in Figure 17.
35. A crystalline form of darapladib fumarate characterized by a DSC thermogram substantially as depicted in Figure 18.
36. A crystalline form of darapladib fumarate characterized by a DSC thermogram with a characteristic endothermic peak value at about 150.70°C, an additional endothermic peak at about 119.35°C, and an exothermic peak at about 201.91°C.
37. A crystalline form of darapladib tartrate characterized by an XRPD pattern substantially as depicted in Figure 19.
38. A crystalline form of darapladib tartrate characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 16.98, 13.47, 6.38, 6.25, 4.27, 4.11, and 3.55 (A).
39. A crystalline form of darapladib tartrate characterized by an XRPD pattern with characteristic peak values (2Θ) at about 5.21, 6.56, 13.89, 14.17, 20.78, 21.64, and 25.08 ±0.2°.
40. A crystalline form of darapladib tartrate characterized by a TGA thermogram substantially as depicted in Figure 20.
41. A crystalline form of darapladib tartrate characterized by a DSC thermogram substantially as depicted in Figure 21.
42. A crystalline form of darapladib tartrate characterized by a DSC thermogram with a characteristic endothermic peak value at about 135.10°C and an exothermic peak at about 206.35°C.
43. A crystalline form of darapladib nitrate characterized by an XRPD pattern substantially as depicted in Figure 22.
44. A crystalline form of darapladib nitrate characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 6.59, 5.63, 5.00, 4.31, 4.22, 4.15, and 3.82 (A).
45. A crystalline form of darapladib nitrate characterized by an XRPD pattern with characteristic peak values (2Θ) at about 13.44, 15.73, 17.73, 20.63, 21.05, 21.39, and 23.29 ±0.2°.
46. A crystalline form of darapladib nitrate characterized by a TGA thermogram substantially as depicted in Figure 23.
47. A crystalline form of darapladib nitrate characterized by a DSC thermogram substantially as depicted in Figure 24.
48. A crystalline form of darapladib nitrate characterized by a DSC thermogram with a characteristic endothermic peak value at about 161.74°C and an additional exothermic peak at about 206.75°C.
49. Darapladib borate.
50. The darapladib borate of claim 49, in a crystalline form.
51. The darapladib borate of claim 49, characterized by an XRPD pattern substantially as depicted in Figure 25.
52. The darapladib borate of claim 49, characterized by an XRPD pattern exhibiting interplanar spacing (d) values at about 13.84, 5.06, and 4.67 (A).
53. The darapladib borate of claim 49, characterized by an XRPD pattern with characteristic peak values (2Θ) at about 6.39, 17.54, and 19.02 ±0.2°.
54. The darapladib borate of claim 49, characterized by a TGA thermogram substantially as depicted in Figure 26.
55. The darapladib borate of claim 49, characterized by a DSC thermogram substantially as depicted in Figure 27.
56. The darapladib borate of claim 49, characterized by a DSC thermogram with a characteristic endothermic peak value at about 125.63°C and an additional exothermic peak at about 216.83°C.
57. A process for the preparation of a compound of Formula 1
Figure imgf000020_0001
Formula 1
which comprises treating darapladib with HX, wherein HX is selected from the group consisting of oxalic acid, adipic acid, succinic acid, orthophosphoric acid, sulphuric acid, fumaric acid, tartaric acid, nitric acid, and boric acid.
58. The process according to claim 57, wherein the darapladib is treated with HX in the presence of a solvent.
59. The process according to claim 58, wherein the solvent is selected from the group comprising water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof.
60. The process according to claim 57, wherein the reaction is carried out at a temperature of about 25 °C to reflux.
61. A process for the preparation of darapladib free base, or salts, solvates, or polymorphs thereof, comprising contacting the compound of Formula 1 with a base
Figure imgf000021_0001
Formula 1
wherein HX is selected from the group consisting of oxalic acid, adipic acid, succinic acid, orthophosphoric acid, sulphuric acid, fumaric acid, tartaric acid, nitric acid, and boric acid.
62. A pharmaceutical composition comprising darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, or darapladib borate, and a pharmaceutically acceptable carrier
63. A method of treating atherosclerosis which comprises administering to a patient in need thereof a therapeutically effective amount of darapladib oxalate, darapladib adipate, darapladib succinate, darapladib phosphate, darapladib sulphate, darapladib fumarate, darapladib tartrate, darapladib nitrate, or darapladib borate, and a pharmaceutically acceptable carrier.
PCT/IB2015/050284 2014-01-28 2015-01-14 Crystalline forms of darapladib oxalate, adipate, succinate, phosphate, sulphate, fumaratetartrate, nitrate and borate WO2015114479A1 (en)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2001060805A1 (en) 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Pyrimidine-4-one derivatives as ldl-pla2 inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060805A1 (en) 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Pyrimidine-4-one derivatives as ldl-pla2 inhibitors

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