WO2006024930A1 - Nouveaux co-cristaux entre polyethylene glycols et 5-phenylpyrazolyl-1-benzenesulfonamides - Google Patents

Nouveaux co-cristaux entre polyethylene glycols et 5-phenylpyrazolyl-1-benzenesulfonamides Download PDF

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Publication number
WO2006024930A1
WO2006024930A1 PCT/IB2005/002590 IB2005002590W WO2006024930A1 WO 2006024930 A1 WO2006024930 A1 WO 2006024930A1 IB 2005002590 W IB2005002590 W IB 2005002590W WO 2006024930 A1 WO2006024930 A1 WO 2006024930A1
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Prior art keywords
peg
crystal
trifluoromethyl
pyrazol
benzenesulfonamide
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PCT/IB2005/002590
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English (en)
Inventor
Changquan Calvin Sun
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Pharmacia & Upjohn Company Llc
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Publication of WO2006024930A1 publication Critical patent/WO2006024930A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to novel and unexpected co-crystals between polyethylene glycols (PEGs) and 5-phenylpyrazolyl-l-benzenesulfonamides of Formula I.
  • 5-Phenylpyrazolyl-l-benzenesulfonamides of Formula I constitute a novel synthetic class of compounds with potent COX-2 inhibitory activity useful for the treatment of arthritis and other conditions due to inflammation as disclosed in U.S. Pat. No. 5,521,207, which is incorporated herein by reference. The inventors have found that compounds of Formula I form novel co-crystals with PEGs.
  • the co-crystals between PEGs and 5-Phenylpyrazolyl-l-benzenesulfonamides of Formula I have lower melting points than pure drug crystals. Further, these co- crystals exhibit physical stability at ambient conditions because of their crystalline nature. This contrasts with the physical instability of solid dispersions of amorphous solids that have been used to improve drug dissolution.
  • amorphous solids that have been used to improve drug dissolution.
  • the present invention provides a co-crystal of a compound of Formula I with a PEG.
  • R 1 is H
  • R 2 is haloalkyl
  • R 3 is hydrogen.
  • the PEG is selected from the group of PEG 400, PEG 600, PEG 800, and PEG 1000.
  • the co-crystal comprises 4-[5-(4-fluorophenyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide and a PEG.
  • the co-crystal comprises 4-[5-(3,4-difluorophenyl)-3-
  • the co-crystal comprises 4-[5-(2,4-difluorophenyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide and a PEG.
  • a process for preparing the co- crystals of the present invention.
  • the co-crystals are made by a method comprising a) dissolving a compound of Formula I and a polyethylene glycol in a solvent; b) allowing the solvent to evaporate; and c) collecting the resulting crystals.
  • the co-crystals are made by a method comprising a) mixing a compound of Formula I and a polyethylene glycol in water; b) stirring the mixture of Step a for about one to 21 days; c) collecting the resulting crystals; and d) washing the crystals with a solution comprising the compound and a suitable, solvent.
  • the invention provides a pharmaceutical composition which comprises a co-crystal of a compound of Formula I with a polyethylene glycol.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
  • Still another object of the present invention is to provide a method for preventing or treating inflammatory conditions in mammals by administering to said mammals a co-crystal of a compound of Formula I with a polyethylene glycol.
  • a further object of the present invention is to provide a method for producing a medicament using a co-crystal of a compound of Formula I with a polyethylene glycol.
  • PXRD Powder X-ray diffraction
  • co-crystal means a composition comprising two compounds which form a crystal in which both compounds are integral parts of the crystal.
  • alkyl unless otherwise specified, where used either alone or within other terms such as "haloalkyl”, “alkoxyalkyl”, and “hydroxyalkyl”, embraces linear, branched, or cyclic radicals having one to 20 carbon atoms, or preferably one to about twelve carbon atoms, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals.
  • a saturated alkyl group is one having the maximum amount of hydrogens possible, .that is, no double bonds. Examples of.
  • saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tbutyj, isobutyl,_secrbutyl,.cyclohexyl,_(cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4- pentadienyl), ethynyl, I- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • a "lower alkyl” is a shorter chain alkyl or group, having eight or fewer carbon atoms.
  • hydrodo denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (--CH 2 -) radical.
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to six carbon atoms.
  • alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl.
  • alkenyl "lower alkenyl”, embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • halo means halogens such as fluorine, chlorine, bromine, or iodine.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals.
  • a monohaloalkyl radical for example, may have either an iodo, bromo, chloro, or fluoro atom within the radical.
  • Dihalo radicals may have two of the same halo atoms or a combination of different halo radicals.
  • Trihaloalkyl radicals would have three of the same halo atoms or a combination of different halo radicals.
  • Polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, difluorochloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.
  • the term "halomethyl" would be an example of a haloalkyl.
  • perhaloalkyl embraces haloalkyl compounds in which all available valence positions are occupied by halogens.
  • examples of such radicals include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to six carbon atoms attached through sulfur. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio, and hexylthio.
  • carboxyalkyl embraces alkyl radicals substituted with a carboxy radical and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl, and carboxypropyl.
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical.
  • alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and hexyloxycarbonyl.
  • aminoalkyl embraces alkyl radicals substituted with one or more amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • alkylamino denotes amino groups that have been substituted with one or two alkyl radicals having alkyl portions of 1 to 6 carbon atoms.
  • Suitable lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.
  • arylamino denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino.
  • the "arylamino" radicals may be further substituted on the aryl ring portion of the radical.
  • alkylaminocarbonyl denotes an aminocarbonyl group that has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “lower N-alkylaminocarbonyl” and “lower N,N-dialkylaminocarbonyr' radicals with lower alkyl portions as defined above.
  • polyethylene glycol (PEG) means a condensation polymer of ethylene glycol with the general formula H(-OCH 2 CH 2 -) n OH or HOCH 2 (CH 2 ⁇ CH 2 ) n CH 2 OH.
  • R 1 is selected from H or C 1-4 alkyl
  • R 2 and R 3 are independently selected from the group consisting of H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, cyano, nitro, formyl, carboxyl, and alkoxycarbonyl
  • R 4 represents one to three substitutents independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 haloalkyl, cyano, nitro, and halogen; form novel co-crystals with PEGs.
  • Preparation of the compounds of Formula I is achieved by procedures described in U.S. Pat. No. 5,521,207.
  • the co-crystals of the present invention exhibit physical stability at ambient conditions and therefore provide stable formulations, tablets, powders, and the like.
  • Inflammatory conditions in mammals may be prevented or treated by administering to a mammal in need of such treatment a compound of Formula I with a polyethylene glycol.
  • the amount of the compound to be administered ranges from about 0.001 to 100 mg per kg of animal body weight, such total dose being given at one time or in divided doses.
  • Eor_use_as an..anti inflammatory-agentin-animals
  • the jnv.entive- composition may be administered either orally or by injection.
  • capsules, boluses, or tablets containing the desired amount of active compounds usually are employed.
  • These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents, and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums, and the like.
  • Such unit dosage formulations may be varied widely with respect to their total weight and content of the anti-inflammatory agent depending upon factors such as the type of host animal to be treated, the severity and type of inflammation, and the weight of the host.
  • the anti-inflammatory compositions of the present invention may be administered to animals parenterally, for example, by intraruminal, intramuscular, or subcutaneous injection in which event the active ingredients are dissolved or dispersed in a liquid carrier vehicle.
  • the active materials are suitably admixed with an acceptable vehicle, preferably of the vegetable oil variety such as peanut oil, cottonseed oil, and the like.
  • parenteral vehicles such as organic preparations using solketal, propylene glycol, glycerol formal, and aqueous parenteral formulations are also used, often in combination in various proportions.
  • the active compound or compounds are dissolved or suspended in the parenteral formulation for administration; such formulations generally contain from about 0.005 to about 5% by weight of the active compound.
  • the co-crystals of this invention are prepared by evaporation of a solution of a suitable PEG and a compound of Formula I in a suitable solvent.
  • suitable solvents include water, alcohols such as methanol, ethanol, isopropanol, and the like.
  • Suitable PEGs include PEG 200, PEG 300, PEG 400, PEG 600, PEG 800, PEG 1000, and the like.
  • the molar ratio of PEG to a compound of Formula I in the crystallization solution is from about 0.5 to 1 to about 10 to 1 at a temperature of about 5 0 C to about 3O 0 C.
  • the co-crystals of this invention may also be prepared by stirring a compound of Formula I in a mixture of an appropriate PEG and water.
  • the ratio of water to PEG can be from about 1:2, v:v to about 1:3. v:v.
  • the solid obtained is filtered and the crystals are washed with a near-saturated solution of the compound in a suitable solvent to remove excess PEG.
  • suitable solvents include, but are not limited to, water, methanol, isopropanol, and the like, or mixtures thereof.
  • Preparation 1 Preparation of the amorphous form of 4-[5-(4-fluorophenyl)-3- (trifluoromethyl)- 1 H-pyrazol- 1 -yl]benzenesulfonamide. 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yl]benzenesulfonamide was heated in a drying oven at 180 °C until completely melted. The hot melt was then removed from the oven and stored at 5 0 C for 30 minutes to give a glassy solid. X-ray diffraction showed no intensive diffraction peak and therefore the solid was amorphous.
  • Powder X-ray diffraction analysis was performed using a Scintag X2 Advanced Diffraction System (controlled by Scintag DMS/NT 1.30a and Microsoft Windows NT 4.0 software).
  • the system uses a Copper X-ray source (45 kV and 40 mA) to provide CuKa 1 emission of 1.5406A and a solid-state Peltier cooled detector.
  • the beam aperture was controlled using tube divergence and anti-scatter slits of 2 and 4 mm and detector anti-scatter and receiving slits of 0.5 and 0.2 mm width.
  • Data were collected from 2 to 35° two-theta using a step scan of 0.037step with a counting time of one second per step.
  • Scintag round, top loading aluminum sample holders with a 12 mm diameter cavity were utilized for the experiments. Powders were packed into the holder and were gently pressed by a glass slide to ensure coplanarity between the sample surface and the surface of the sample holder.
  • IR data were collected from 4000 ⁇ 400 cm “1 at 4-cm "1 resolution on a Nicolet 760 spectrometer equipped with a TGS detector. Sensitivity, expressed as instrument gain, was 2. Data were processed as a Fourier transform utilizing a Happ-Genzel apodization function and plotted as % transmittance vs. frequency. The final spectra were the-sum of-200individual scans.
  • PEG 400 130.8 mg
  • 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH- pyrazol-l-yl]benzenesulfonamide 133.3 mg
  • the molar ratio between PEG 400 and 4- [5-(4-fluorophenyl)-3-(trifluoromethyl)- 1 H-pyrazol- 1 -yl]benzenesulfonamide was 1.1:1 in the solution.
  • the vial was placed in a fume-hood at ambient temperature to allow evaporation of ethanol. Diamond shaped crystals were obtained after two days.
  • the infrared spectrum shows significant absorbtions at 3277,2892, 1610, 1594,1556, 1497, 1470, 1448, 1409, 1373, 1355, 1306, 1271,1295, 1236, 1201, 1172,1130,1110, 977, 839, 821,776,750, 733, 626, 610, 564, 544, and 481 cm "1 .
  • Example 8 Stability of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yl]benzenesulfonamide and PEG 400 co-crystals versus amorphous form of 4-[5-(4- fluorophenyl)-3 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl]benzenesulf onamide
  • Example 9 Compaction studies Samples of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yl]benzenesulfonamide (150 - 190 mg) were compressed using flat-faced punches with 10/32" diameter. Compaction forces were 1000, 1500, 2000, and 3000 lbf. After being ejected from the die, tablets were subjected to diametrical pressure using a hardness tester. AU tablets of non-PEG containing powder laminated, i.e., fracture planes were roughly parallel to the tablet faces. However, for tablets of the PEG co- crystals, all tablets fractured diametrically, i.e., fracture planes ran through the center of the tablet and were roughly perpendicular to the tablet faces. No obvious lamination was observed.
  • Ben 8/3 Ti ⁇ (U 1 !(aa*) 2 + U 2 2(bb*) 2 + U 3 3(cc*) 2 + 2U 1 2(aa*bb*)cos ⁇ + 2U 1 3(aa*cc*)cos ⁇ + 2U2 3 (bb*cc*)cos ⁇ )

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

La présente invention concerne des co-cristaux nouveaux et inattendus entre des polyéthylène glycols (PEG) et des 5-phénylpyrazolyl-1-benzènesulfonamides représentés par la formule (I).
PCT/IB2005/002590 2004-09-01 2005-08-22 Nouveaux co-cristaux entre polyethylene glycols et 5-phenylpyrazolyl-1-benzenesulfonamides WO2006024930A1 (fr)

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US60/606,404 2004-09-01

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
US8362062B2 (en) 2002-02-15 2013-01-29 Mcneil-Ppc, Inc. Pharmaceutical compositions with improved dissolution
US10633344B2 (en) 2002-03-01 2020-04-28 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1167355A1 (fr) * 2000-06-26 2002-01-02 Fako Ilaclari A.S. Une Forme cristalline de celecoxib
US6492411B1 (en) * 1993-11-30 2002-12-10 G. D. Searle & Co. Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
WO2005055983A2 (fr) * 2003-12-09 2005-06-23 Medcrystalforms, Llc Procede de preparation de cocristaux a phase mixte avec des agents actifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6492411B1 (en) * 1993-11-30 2002-12-10 G. D. Searle & Co. Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
EP1167355A1 (fr) * 2000-06-26 2002-01-02 Fako Ilaclari A.S. Une Forme cristalline de celecoxib
WO2005055983A2 (fr) * 2003-12-09 2005-06-23 Medcrystalforms, Llc Procede de preparation de cocristaux a phase mixte avec des agents actifs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
B. M. EL-HOUSIENY YOUSEF: "Thermal investigation on co-crystallization of Ketoprofen with some excipients and the effect of some ionic and non-ionic surfactants on properties of the resultant solid dispersion", J. DRUG RES. EGYPT, vol. 24, no. 1-2, 2002, pages 79 - 86, XP009056813 *
V. KUSUM DEVI, P. VIJAYALAKSHMI AND M. AVINASH: "Preformulation Studies on Celecoxib with a view to improve bioavailability", INDIAN JOURNAL OF PHARMACEUTICAL SCIENCE, 2003, pages 542 - 545, XP009056819 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
US8362062B2 (en) 2002-02-15 2013-01-29 Mcneil-Ppc, Inc. Pharmaceutical compositions with improved dissolution
US10633344B2 (en) 2002-03-01 2020-04-28 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen

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TW200621718A (en) 2006-07-01

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