WO2014104414A1 - Salts and crystal forms - Google Patents

Salts and crystal forms Download PDF

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Publication number
WO2014104414A1
WO2014104414A1 PCT/JP2014/000010 JP2014000010W WO2014104414A1 WO 2014104414 A1 WO2014104414 A1 WO 2014104414A1 JP 2014000010 W JP2014000010 W JP 2014000010W WO 2014104414 A1 WO2014104414 A1 WO 2014104414A1
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Prior art keywords
salt
pharmaceutical composition
compound
present
preparing
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PCT/JP2014/000010
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English (en)
French (fr)
Inventor
Yoshiyuki Okumura
Yasuhiro Iwata
Toyoharu Numata
Masaki Sudo
Takako Okumura
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Askat Inc
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Askat Inc
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Priority to ES14733062.5T priority Critical patent/ES2694422T3/es
Priority to RU2015130602A priority patent/RU2654855C2/ru
Priority to US14/655,175 priority patent/US9447066B2/en
Priority to EP14733062.5A priority patent/EP2938607B1/en
Priority to CN201480003563.4A priority patent/CN104870431B/zh
Priority to KR1020157019802A priority patent/KR102220999B1/ko
Priority to JP2015527377A priority patent/JP6210604B2/ja
Publication of WO2014104414A1 publication Critical patent/WO2014104414A1/en
Anticipated expiration legal-status Critical
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A—HUMAN NECESSITIES
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    • 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]
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • 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

Definitions

  • This invention relates to salts and crystal forms of (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, which is cyclooxygenase-2 inhibiter, wherein the compound may be called Compound A through the present specification.
  • NSAIDs common non-steroidal antiinflammatory drugs
  • An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
  • NSAIDs prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).
  • COX cyclooxygenase
  • the expression of cyclooxygenase-2 (COX-2) is specifically induced in the pathological conditions such as inflammation, pain, and cancer, and is involved in the generation and maintenance of these conditions.
  • coxibs such as celecoxib, rofecoxib, valdecoxib, parecoxib, and etoricoxib have been developed.
  • Compound A is disclosed in the patent literature 1, and selectively inhibits cyclooxygenase-2 over cyclooxygenase-1. Compound A affords more potent analgesia, than ibuprofen which is the first choice among the conventional drugs. Furthermore it has been confirmed in the preclinical studies that Compound A has lower renal problem which are a matter of concern in conventional COX-2 inhibitors and NSAIDs.
  • Coxib-drugs are useful for the treatment of diseases mediated by cyclooxygenase-2, such as inflammation, pain, cancer, fever, osteoarthritis, rheumatoid arthritis, migraine, neurodegenerative diseases, cardiovascular disease, osteoporosis, asthma, lupus and psoriasis, dysmenorrhea, premature labor, glaucoma, gout, ankylosing spondylitis, bursitis, heat burn, sprain, and contusion.
  • diseases mediated by cyclooxygenase-2 such as inflammation, pain, cancer, fever, osteoarthritis, rheumatoid arthritis, migraine, neurodegenerative diseases, cardiovascular disease, osteoporosis, asthma, lupus and psoriasis, dysmenorrhea, premature labor, glaucoma, gout, ankylosing spondylitis, bursitis, heat burn, sprain, and contusion.
  • active ingredients involved in coxib-drugs have a sulfonamide group
  • Compound A is a unique chemical structure, which has neither sulfonamide group nor alkylsulfonyl group but has a carboxylic acid group.
  • such coxib-drugs or coxib-compounds, which have neither a sulfonamide group nor an alkylsulfonyl group but have a carboxylic acid group are called third generation coxib-drugs or third generation coxib-compounds.
  • Compound A has a carboxylic acid group in its chemical structure, the solubility in the low pH field is inferior to that in the neutral or basic condition.
  • the patent literature 2 discloses "a novel injectable pharmaceutical composition comprising at least one COX-2 inhibitor or NSAID or COX/LOX inhibitor or its tautomeric forms, or its analogues, isomers, polymorphs, solvates, prodrugs, or salts or thereof as active ingredient from 0.1% to 80% w/v and a solvent system comprising a mixture of glycols from 1% to 80% v/v; optionally with other pharmaceutically acceptable excipients" and also discloses "a composition according to claim 1, wherein the said composition additionally comprises at least one alkalizing agent from 0.2% to 60% v/v".
  • this is a pharmaceutical formulation as an injectable drug, and therefore an effectual means as an oral formulation which solves these issues has been desired.
  • other technologies for solving such issues have also been desired.
  • the present invention also provides a crystal form thereof, process for preparing the said salt and a pharmaceutical composition thereof and its use.
  • counter bases against Compound A as an excipient were tried, no preferable results were obtained.
  • Examples of counter bases include sodium hydroxide, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium silicate, magnesium aluminate as mentioned in the background art.
  • ammonia, L-ariginine, benzathine, betaine, calcium hydroxide, choline hydroxide, diethyl amine, nicotinamide, L-tartaric acid, and the like were neither suitable for the salt formation nor suitable for formulation.
  • two Compound A salts, the meglumine salt and the potassium salt have much more suitable for formulation than any other salt in terms of crystallization of the selected salts, manufacturability related studies (stability under variable temperature and humidity, slurry experiments) or bioavailability related studies (solubility and dissolution rate).
  • Meglumine salt The meglumine salt was readily obtained from the crystallization experiments in ethanol and isopropanol. The solids precipitated right after addition of the solvents. All performed stability tests, under variable temperature and humidity XRPD experiments as well as the slurry experiments, showed that the meglumine salt is stable, both physically and chemically while its chiral purity remained practically unchanged. Therefore, from the manufacturing point of view, the meglumine salt is a very suitable candidate salt and performed the best amongst the tested salts.
  • the meglumine salt of Compound A has higher solubility and faster dissolution rates compared to the free acid of Compound A. Therefore, from the aspect of the solubility/dissolution rate, the meglumine salt is suitable for an active pharmaceutical ingredient of a pharmaceutical composition of Compound A. By using the meglumine salt, bioavailability of Compound A is improved.
  • the present invention is based on the above unexpected and surprising findings. In addition, compared to the case where free carboxylic acid of Compound A was administered, in the case where meglumine salt was administered, more rapid onset of effect and long duration of action are observed in the dog-Pharmacokinetic studies as shown in Figure 10.
  • Potassium salt The potassium salt of Compound A was obtained from aqueous solvent mixtures. Although it is not difficult to obtain a potassium salt of Compound A, it is difficult to obtain a stable and single crystal form of the potassium salt because, in crystallization process, the water content in solvent mixtures sensitively influences to the formation of the crystal. Therefore, the control of water content is essential for obtaining the stable and single crystal form, and excess water must be removed under azeotropic condition with suitable solvent, such as toluene, ethyl acetate, and ethanol.
  • suitable solvent such as toluene, ethyl acetate, and ethanol.
  • the water content is 1 to 1.5 molar equivalent against the free acid, preferably, the water content is 1 to 1.2 molar equivalent, more preferably the water content is 1 to 1.1 molar equivalent, the most preferably the water content is 1 to 1.05 molar equivalent. If the water content is more than 1.5 molar equivalent against the free acid, target single crystal form is never obtained.
  • the potassium salt showed good stability both chemically and enantiomerically after the solid-state stability experiments.
  • the solubility of the potassium salt is more than 120 mg/mL in a neutral to basic environment.
  • the potassium salt was completely dissolved in the neutral media within 15 min, especially dissolved in water within 5 min, while Compound A free acid showed very limited dissolution.
  • the present invention is based on the above unexpected and surprising findings.
  • meglumine salt with free carboxylic acid more rapid onset of effect, long duration of action and improved bioavailability have been observed in the dog-Pharmacokinetic studies as shown in Figure 10.
  • this invention discloses: [1] A salt of (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; wherein the salt is selected from the group consisting of the meglumine salt and the potassium salt;
  • a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an amount of the salt as defined in any one of [1] to [5];
  • a process for preparing a pharmaceutical composition comprising a step for combining the salt as defined in any one of [1] to [5] and a pharmaceutically acceptable carrier;
  • the disease is one or more diseases selected from the group consisting of inflammation, pain, cancer, fever, osteoarthritis, rheumatoid arthritis, migraine, neurodegenerative diseases, cardiovascular diseases, osteoporosis, asthma, lupus and psoriasis, dysmenorrhea, premature labor, glaucoma, gout, ankylosing spondylitis, bursitis, heat burn, sprain, and contusion.
  • diseases selected from the group consisting of inflammation, pain, cancer, fever, osteoarthritis, rheumatoid arthritis, migraine, neurodegenerative diseases, cardiovascular diseases, osteoporosis, asthma, lupus and psoriasis, dysmenorrhea, premature labor, glaucoma, gout, ankylosing spondylitis, bursitis, heat burn, sprain, and contusion.
  • the present invention provides a salt of compound A, a polymorph form thereof, a process for preparing the said salt and a pharmaceutical composition thereof and its use.
  • the salts and/or co-crystals of Compound A of the present invention show good formulation properties such as high aqueous solubility, good crystallinity, good thermal stability or low hygroscopicity.
  • Figure 1 shows the NMR spectrum of (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid meglumine salt.
  • Figure 2 shows the XRPD pattern of (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid meglumine salt.
  • Figure 3 shows the FTIR spectrum of (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid meglumine salt.
  • Figure 4 shows the NMR spectrum of (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid potassium salt.
  • Figure 5 shows the XRPD pattern of (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid potassium salt.
  • Figure 6 shows FITR spectrum of (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid potassium salt.
  • Figure 7 shows the solubility of the salts.
  • Figure 8 shows the concentrations vs.
  • Figure 9 shows the concentrations vs. time of all solids measured in water.
  • Figure 10 shows the time-course of mean plasma concentrations after oral administration of capsule formulations of API (free acid), Potassium-salt and Meglumine-salt to male Beagle dogs.
  • Compound A can be prepared by a method known per se.
  • the amount of the salt of the present invention contained in a pharmaceutical composition for treating circulatory system diseases according to the present invention is not specifically restricted, however, the dose preferably should be sufficient to treat, ameliorate, or reduce the symptoms associated with the circulatory system disease.
  • the dosage of a pharmaceutical composition for treating circulatory system diseases according to the present invention will depend on the method of use, the age, sex, and condition of the patient. For example, about 1 mg to 1000 mg of the salt of the present invention may be contained in a dosage form. Preferably, about 5 mg to 500 mg of the salt of the present invention may be contained there.
  • the pharmaceutical composition of the present invention may be prepared by any conventional means such as, but not limited to, wet or dry granulation and direct compression.
  • the process for preparing the pharmaceutical composition of the present invention is characterized by containing a process for combining the meglumine, or the potassium hydroxide with an active pharmaceutical ingredient, Compound A.
  • the process for preparing a pharmaceutical composition comprises combining a salt of the present invention and at least one carrier , wherein the carrier is intimately admixed with a salt of the present invention.
  • the carrier is intimately admixed with a salt of the present invention.
  • one or more other excipients are added to the pharmaceutical composition and the resulting combination is compressed into a solid pharmaceutical composition such as tablets, pills, granules, etc.
  • the solid pharmaceutical composition is compressed into a tablet.
  • a wet granulation process comprises adding and kneading an appropriate amount of water to the pharmaceutical composition to be formulated and through a further suitable process.
  • the granulated pharmaceutical composition is dried under a suitable condition, and is subject to compression molding to tablet etc after particle size regulation.
  • a dry granulation process comprises compression molding which comprises compressing a pharmaceutical composition to be formulated to the form of plates with a suitable compressor, crushing the resulting plate with a grinder mill, successively regulating a particle size, and then compression molding to tablet etc.
  • agents such as sodium hydroxide, potassium hydroxide, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium silicate, magnesium aluminate, ammonia, L-ariginine, benzathine, betaine, calcium hydroxide, choline hydroxide, diethyl amine, potassium hydroxide, meglumine, nicotinamide, and L-tartaric acid, which are used in the present specification are commercially available.
  • the salt of this invention may be used alone or in a combination of one or two or more kinds of salts of Compound A thereof.
  • the agent of meglumine or potassium hydroxide is added in the form of liquid, solid, or suspensions.
  • the salt of this invention is generally ranged from about 1 to 60 % (w/w) in the said composition.
  • the pharmaceutical composition of the invention may take any form but it is preferably a solid composition. More preferably, the pharmaceutical composition of the invention is compressed to solid composition by molding (e.g. granulation and pressurization). Suitable solid dosage forms include, but are not limited to, tablets, pill, granules, capsules, powders, and sachets, and the like. Particularly tablets are preferable.
  • the dosage form can be produced by incorporating the salt of the present invention, followed by subjecting the mixture to molding.
  • the incorporation is conducted by a method conventionally employed in the field of pharmaceutical preparations, such as mixing, kneading, massing, sieving, stirring and the like.
  • a pharmaceutically acceptable carrier may be directly mixed with the salt of the present invention (addition in a powder state), or a solvent may be added to the mixture, followed by conventional kneading, granulating and drying.
  • a carrier is dissolved in a suitable solvent, then the solution is uniformly mixed with the active ingredient, followed by conventional kneading, granulating and drying (addition in a liquid state).
  • any solvent which does not exert undesirable influence on the active ingredient for example, water, dimethylformamide, acetone, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, methylene chloride, trichloroethane etc.
  • the material is subjected to a conventional molding process under pressurization to prepare tablets containing the active ingredient.
  • the molding under pressurization means that a material is compressed under pressurization into a desired form, which most generally refers to tableting.
  • solid pharmaceutical composition e.g. solid preparations
  • carriers include, but not limited to, fillers, diluents, disintegrants, glidants, excipients, binders, lubricants, colorant, flavoring agents, odor-improving agents, wetting agents, and the like.
  • Suitable fillers and diluents include, but are not limited to, cellulose-derived materials like powdered cellulose, microcrystalline cellulose (e.g. Avicel (registered trademark)), microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; lactose; talc; waxes; sugars; sugar alcohols like mannitol and sorbitol; acrylate polymers and copolymers; dextrates; dextrin; dextrose; maltodextrin; pectin; gelatin; inorganic diluents like calcium carbonate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, sodium chloride and other diluents known to the pharmaceutical industry.
  • Suitable disintegrants include, but are not limited to, croscarmellose sodium (e.g. Ac Di Sol (registered trademark), Primellose (registered trademark)), crospovidone (e.g. Kollidon (registered trademark), Polyplasdone (registered trademark)), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab (registered trademark), Primoljel (registered trademark)) and starch, and the like.
  • croscarmellose sodium e.g. Ac Di Sol (registered trademark), Primellose (registered trademark)
  • crospovidone e.g. Kollidon (registered trademark), Polyplasdone (registered trademark)
  • microcrystalline cellulose e.g. Explotab (registered trademark), Primoljel (registered trademark)
  • starch glycolate e.g. Explotab (registered trademark), Primo
  • Glidants can be added to improve the flowability of a solid composition before compaction and to improve the accuracy of dosing especially during compaction and capsule filling.
  • Excipients that may function as glidants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, and the like.
  • Suitable excipients that may be incorporated into the formulation include, but are not limited to, microcrystalline cellulose (for example, Avicel PH101, PH101 (manufactured by Asahi Kasei Corporation)), carboxymethylcellulose calcium, corn starch, wheat starch, lactose, sucrose, glucose, calcium sulfate, calcium phosphate, sodium chloride, and so on.
  • excipients include preservatives, surfactants, antioxidants, or any other excipient commonly used in the pharmaceutical industry.
  • Suitable binders that may be incorporated into the formulation include, but are not limited to, water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, gum arabic, gelatin, sodium alginate, methyl cellulose, carboxymethylcellulose, shelac, polyvinylpyrrolidone, crospovidone, hydroxypropylcellulose (which may be hereinafter referred to as HPC), hydroxypropylmethylcellulose, and the like.
  • such binders include other binders used in wet or dry granulation and in direct compression tableting processes.
  • Suitable lubricants that may be incorporated into the formulation include, but are not limited to, magnesium stearate, talc, synthetic aluminum silicate, sodium lauryl sulfate, boric acid, magnesium oxide, paraffin, and the like.
  • colorant, flavoring agents, odor-improving agents, wetting agents, and the like may be added.
  • the solid pharmaceutical composition of the present invention can be prepared into coated tablets as well.
  • the coating may be conducted by a method known per se.
  • conventional coating agents e.g. hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone etc.
  • auxiliary agents for coating use is made of, for example, polyethylene glycol 6000, polysorbate (e.g. Tween 80 etc.), titanium oxide, and pigments such as red iron oxide or the like.
  • the pharmaceutical composition of this invention for the treatment of diseases mediated by cyclooxygenase-2 in animals (e.g. man, dog, rabbit or rat), it can be administered orally as tablets, etc.
  • the dosage ranges from 0.0075 to 15 mgA/kg per day, preferably from 0.07 to 7.2 mgA/kg per day in terms of the active pharmaceutical ingredient (wherein mgA means mg weight of the active pharmaceutical ingredient based on the free acid).
  • mgA means mg weight of the active pharmaceutical ingredient based on the free acid.
  • the dosage can be increased or decreased depending on the disease or condition.
  • Compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is envisioned.
  • the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is envisioned.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, including about 200: 1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • salt or crystal forms thereof may be administered simultaneously, sequentially or separately in combination with one or more agents selected from
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
  • opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nal
  • NSAID nonsteroidal antiinflammatory drug
  • diclofenac diflusinal, etodolac
  • fenbufen fenoprofen
  • flufenisal flurbiprofen
  • ibuprofen indomethacin
  • ketoprofen ketorolac
  • meclofenamic acid mefenamic acid, meloxicam
  • nabumetone naproxen
  • nimesulide nitroflurbiprofen
  • olsalazine oxaprozin
  • phenylbutazone piroxicam
  • sulfasalazine sulindac
  • tolmetin or zomepirac a nonsteroidal antiinflammatory drug
  • a barbiturate sedative e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • an H1 antagonist having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; - a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex(registered trademark), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g.
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphon
  • an alpha-adrenergic e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g. carbamazepine, lamotrigine, topiratmate or valproate;
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g. alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino
  • a muscarinic antagonist e.g. oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium;
  • COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
  • coal-tar analgesic in particular paracetamol
  • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion(registered trademark) or sarizotan;
  • vanilloid receptor agonist e.g. resiniferatoxin
  • antagonist e.g. capsazepine
  • V1, V2, V3, V4, M8, M2, A1 a transient receptor potential cation channel subtype (V1, V2, V3, V4, M8, M2, A1) agonist or antagonist;
  • beta-adrenergic such as propranolol
  • corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
  • a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy
  • an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (3-(aminomethyl)-bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-((1H-tetrazol
  • mGluR1 metabotropic glutamate subtype 1 receptor
  • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
  • noradrenaline (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan (registered trademark)), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)
  • an acetylcholinesterase inhibitor such as donepezil
  • a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[( ⁇ 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl ⁇ amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-( ⁇ [5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl ⁇ amino)ethyl]benzoic acid;
  • leukotriene B4 antagonist such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870,
  • a 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);
  • a sodium channel blocker such as lidocaine
  • a calcium channel blocker such as ziconotide, zonisamide, mibefradil
  • a 5-HT3 antagonist such as ondansetron
  • a chemotherapy drug such as oxaliplatin, 5-fluorouracil, leukovolin, paclitaxel
  • CGRP calcitonin gene related peptide
  • BK1 and BK2 bradykinin
  • a voltage gated sodium dependent channel blocker Na v1.3 , Na v1.7 , Na v1.8
  • - a voltage dependent calcium channel blocker N-type, T-type
  • P2X ion channel type ATP receptor
  • ASIC1a, ASIC3 acid-sensing ion channel
  • Angiotensin AT2 antagonist - a Chemokine CCR2B receptor antagonist
  • - a sigma1 receptor agonist or antagonist a 5-HT3 antagonist, such as ondansetron
  • a chemotherapy drug such as oxaliplatin, 5-fluorouracil, leukovolin, pac
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g.
  • lactose microcrystalline cellulose or calcium hydrogen phosphate
  • tabletting lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • acceptable wetting agents e.g. sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound or pharmaceutically acceptable salt thereof.
  • fluid unit dosage forms are prepared utilising a salt of Compound A of the present invention or a crystal form thereof and a sterile vehicle.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a salt of Compound A of the present invention or a crystal form thereof and a sterile vehicle, optionally with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
  • a salt of Compound A of the present invention or a crystal form thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • a salt of Compound A of the present invention or a crystal form thereof may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • a salt of Compound A of the present invention or a crystal form thereof may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a salt of Compound A of the present invention or a crystal form thereof may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • a salt of Compound A of the present invention or a crystal form thereof may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • a salt of Compound A of the present invention or a crystal form thereof may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.
  • the capsule may contain the pharmaceutical composition of the invention in a form of uncompressed or compressed granulates or powder mixes, etc.
  • the capsules may be covered with either a hard shell or a soft shell.
  • the shells may be made from, but not limited to gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • Methods of administration of a pharmaceutical composition for treating diseases mediated by cyclooxygenase-2 in the present invention are not specifically restricted, and can be administered in various preparations depending on the age, sex, and symptoms of the patient.
  • Suitable routes for administrating a pharmaceutical composition may include, but not limited to, oral, buccal, and rectal administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of administration of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods commonly known in the pharmaceutical art.
  • Compound A can be prepared using any method known in the art (for example, patent literature 1, JP Patent No. 4577534). DEFINITIONS AND ABBREVIATIONS
  • API Active Pharmaceutical Ingredient, i.e. (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
  • DSC Differential Scanning Calorimetry
  • FTIR Fourier Transform Infrared spectroscopy
  • HPLC High-Performance Liquid Chromatography
  • LCMS Liquid Chromatography coupled with Mass Spectroscopy
  • MS Mass Spectroscopy
  • RH Relative Humidity
  • XRPD X-Ray Powder Diffraction ANALYSIS
  • X-ray powder diffraction XRPD patterns were obtained using the Crystallics T2 high-throughput XRPD set-up. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings.
  • the meglumine salt was also obtained using ethanol instead of isopropanol.
  • VH-XRPD Variable humidity XRPD
  • Quantitative Solubility Assessment were performed on the free acid, the meglumine salt, and the potassium salt. The measurements were carried out in pH 6.8 phosphate buffer (0.05M) and water.
  • a standard 1.8 ml screw cap vial was charged with the material, each solvent (medium) and a magnetic stirring bar. The vials were subsequently closed and equilibrated at the ambient temperature for 24 h while stirring.
  • the liquid part was retrieved with a syringe and filtrated (0.5 micron filter); the isolated mother liquors were diluted to two dilutions selected according to the calibration curve. Quantities of the API in the diluted solutions were determined via HPLC analysis (DAD). The calibration curve was obtained from two independently prepared stock solutions of the API in 50% water / 50% acetonitrile.
  • the press used for tablet preparation for intrinsic dissolution rate measurements was a mini-IDR compression system (pION/Heath Scientific). Approximately 11 mg of material was pressed in the cylindrical hole of a passivated stainless steel die, to a uniform, flat surface, with an exposed area of 0.072 cm 2 . The pressure applied was approximately 50 bar for 3-5 min.
  • the sample die was inserted in a cylindrical Teflon rotating disk carrier containing an embedded magnetic stirring bar at its base.
  • the die/stirrer assembly was placed in a flat bottomed glass vial, ready for dissolution analysis.
  • the meglumine salt and the potassium salt are much better than the free acid in the intrinsic dissolution rate. Especially, the potassium salt dissolved the fastest in all cases.
  • API (2.0 g) was charged to a round-bottom flask equipped with a stir bar.
  • 2-MeTHF (20.0 ml) was added so that the solid was dissolved.
  • the solution was evaporated to dryness on a rotavap.
  • MTBE 40 ml was added so that the dry matter was dissolved, and the solution was evaporated to dryness. Addition of MTBE and evaporating to dryness was repeated three times to ensure complete removal of MeOH.
  • the foamy residue was dissolved in 2-MeTHF (8 ml) in a round- 1.
  • n-heptane 10 ml of n-heptane was added as the first portion. At this point, approximately 5 mg of seed crystal of potassium salt was added to the solution. The seeds remained undissolved. It was observed that precipitation started to occur prior to seeding at the sides of the round bottom flask possibly due to solvent evaporation. 2. An additional 10 ml of n-heptane was added. Precipitation progressed rapidly and resulted in thick slurry. 3. A third portion of n-heptane (20 ml) was added so that the slurry can be stirred. 4. A fourth portion of n-heptane (80 ml) was added and cooling was initiated at the rate of 20 5.
  • n-heptane 40 ml
  • n-heptane 40 ml
  • a sample was aliquoted from the slurry, filtered and analyzed by XRPD.
  • XRPD of the sample indicated poor crystallinity and likely presence of some anhydrate form.
  • Seed crystal of potassium salt (100.7 mg, 5 wt%; XRPD pattern identical with example 5) was added and the mixture was stirred overnight.
  • a sample was aliquoted the next day and analyzed by XRPD. XRPD did not show improvement in crystallinity. It was hypothesized that formation of hydrate following day was consistent with an authentic sample.
  • the reaction was filtered and dried
  • FIG. 10 shows the time-course of mean plasma concentrations after oral administration of capsule formulations of API (free acid), Potassium-salt and Meglumine-salt to male Beagle dogs. Plasma concentration rapidly increased after oral dose of Potassium-salt and Meglumine-salt in comparison with API. As shown in Table 1, the C max and AUC 0-24h values were increased after administration of Potassium-salt and Meglumine-salt in comparison with API. The unique characteristics of Potassium-salt and Meglumine-salt were identified in dog- pharmacokinetic studies.

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PCT/JP2014/000010 2012-12-28 2014-01-06 Salts and crystal forms Ceased WO2014104414A1 (en)

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ES14733062.5T ES2694422T3 (es) 2012-12-28 2014-01-06 Sales y formas cristalinas de un inhibidor de COX-2
RU2015130602A RU2654855C2 (ru) 2012-12-28 2014-01-06 Соли и кристаллические формы
US14/655,175 US9447066B2 (en) 2012-12-28 2014-01-06 Salts and crystal forms
EP14733062.5A EP2938607B1 (en) 2012-12-28 2014-01-06 Salts and crystal forms of a cox-2 inhibitor
CN201480003563.4A CN104870431B (zh) 2012-12-28 2014-01-06 盐形式及晶体形式
KR1020157019802A KR102220999B1 (ko) 2012-12-28 2014-01-06 (s)-6-클로로-7-(1,1-디메틸에틸)-2-트리플루오로메틸-2h-1-벤조피란-3-카르복시산의 칼륨염 일수화물 또는 메글루민염의 결정형, 이를 포함하는 약제학적 조성물 및 이의 제조 방법
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DE102022134398B3 (de) 2022-12-21 2024-05-23 FAE Elektrotechnik GmbH & Co. KG Portables Speichersystem für Kraftstoffe sowie Ringdruckspeicher und Gehäuse für das Speichersystem

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KR20160046757A (ko) 2016-04-29
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EP2938607A4 (en) 2016-07-27

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