WO2012158117A1 - Traitements combinés pour le traitement de la douleur - Google Patents

Traitements combinés pour le traitement de la douleur Download PDF

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Publication number
WO2012158117A1
WO2012158117A1 PCT/SE2012/050532 SE2012050532W WO2012158117A1 WO 2012158117 A1 WO2012158117 A1 WO 2012158117A1 SE 2012050532 W SE2012050532 W SE 2012050532W WO 2012158117 A1 WO2012158117 A1 WO 2012158117A1
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WIPO (PCT)
Prior art keywords
formula
compound
acceptable salt
pharmaceutically acceptable
acetaminophen
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PCT/SE2012/050532
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English (en)
Inventor
Louis-David Cantin
John Martino
Miroslaw Tomaszewski
Xiao Hong YU
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Astrazeneca Ab
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Publication of WO2012158117A1 publication Critical patent/WO2012158117A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • This invention generally relates to a combination therapy comprising the use of a substituted benzoimidazole compound and a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, and, in particular, to the use of methyl 2-((2-(2,6-difluoro-4- (methylcarbamoyl)phenyl)-5-methyl-lH-benzo[d]imidazol-l-yl)methyl)mo holine-4- carboxylate or a salt thereof and an NSAID or acetaminophen to treat pain.
  • This invention also relates to the combinations themselves, uses of such a combination, and
  • compositions and kits comprising such a combination.
  • P2X purinoreceptors are a family of ion channels that are activated by extracellular adenosine triphosphate (ATP). Purinoreceptors have been implicated in a variety of biological functions, especially those related to pain sensitivity.
  • the P2X3 receptor subunit is a member of this family. It was originally cloned from rat dorsal root ganglia. Chen et al., Nature, vol. 377, pp. 428-431 (1995). The nucleotide and amino acid sequences of both rat and human P2X3 are now known. Lewis, et al., Nature, vol. 377, pp. 432-435 (1995); and Garcia-Guzman, et al., Brain Res. Mol. Brain Res., vol. 47, pp. 59-66 (1997).
  • P2X3 also is selectively expressed on nociceptive, small diameter sensory neurons ⁇ i.e., neurons that are stimulated by pain or injury), which is consistent with a role in pain sensitivity. And blocking P2X3 receptors has been reported to be analgesic in animal models of chronic inflammatory and neuropathic pain. Jarvis, et al., PNAS, 99, 17179-17184 (2002). It is, therefore, believed that a method for reducing the P2X3 level or activity would be useful for modulating pain sensation in a subject suffering from pain.
  • WO2008/136756 generally discusses a list of various pain therapies, including NSAIDs and paracetamol (also known as acetaminophen), that could be used with pyrrolopyrimidin-7-one compounds characterized as P2X3 and/or P2X2/3 antagonists to treat various conditions including pain.
  • Figure 1 shows an isobologram generated in accordance with the methodology discussed in Tallarida, R.J., et al., "Statistical analysis of drug-drug and site- site interactions with isobolograms" Life Sci., vol. 45, pp. 947-961 (1989)
  • FIG. 1 shows synergy effects of naproxen and (S)-methyl 2-((2-(2,6- difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-lH-benzo[d]imidazol-l- yl)methyl)morpholine-4-carboxylate ("Compound 1 ”) on both heat-hyperalgesia and mechanical hyperalgesia in rat FCA model.
  • the left panel shows: DRCs of naproxen alone, Compound 1 alone, and combination of naproxen plus Compound 1.
  • the right panel shows: isobolographic analysis of p.o. naproxen/Compound 1 interactions.
  • Figure 3 shows synergy effects of acetaminophen/Compound 1 on both heat-hyperalgesia and mechanical hyperalgesia in rat FCA model.
  • Left panel DRCs of acetaminophen alone, Compound 1 alone and combination of acetaminophen plus Compound 1; right panel: isobolographic analysis of p.o. acetaminophen/Compound 1 interactions.
  • This invention comprises, inter alia, a combination therapy comprising the use of a substituted benzoimidazole compound and a nonsteroidal anti-inflammatory drug (NSAJD).
  • NSAJD nonsteroidal anti-inflammatory drug
  • this invention is directed, in part, to a method for treating pain in a mammalian patient in need of such treatment.
  • the method comprises administering to the patient:
  • composition comprises a compound of Formula I or a pharmaceutically acceptable salt thereof and an NSAID or acetaminophen.
  • a pharmaceutically acceptable inert ingredient inert ingredients are sometimes collectively identified in this patent as "carriers, diluents, or excipients").
  • carriers, diluents, or excipients inert ingredients are sometimes collectively identified in this patent as "carriers, diluents, or excipients").
  • carriers, diluents, or excipients are sometimes collectively identified in this patent as "carriers, diluents, or excipients").
  • carriers, diluents, or excipients inert ingredient
  • the composition may further comprise one or more other ingredients.
  • the composition may further comprise one or more additional carriers, diluents, and/or excipients.
  • the composition also may comprise one or more additional active ingredients.
  • This invention also is directed, in part, to a kit for treating pain in a mammalian patient.
  • the kit comprises a compound of Formula I or a pharmaceutically acceptable salt thereof; an NSAID or acetaminophen; and instructions for administering the compound of Formula I or pharmaceutically acceptable salt thereof and the NSAID or acetaminophen to the patient.
  • This invention also is directed, in part, to a combination of a compound of Formula I or a pharmaceutically acceptable salt thereof and a nonsteroidal antiinflammatory drug or acetaminophen.
  • This invention also is directed, in part, to a combination of a compound of Formula I or a pharmaceutically acceptable salt thereof and a nonsteroidal antiinflammatory drug or acetaminophen for use in therapy.
  • This invention also is directed, in part, to a combination of a compound of Formula I or a pharmaceutically acceptable salt thereof and a nonsteroidal antiinflammatory drug or acetaminophen for use in treating pain.
  • This invention also is directed, in part, to use of a compound of Formula I or a pharmaceutically acceptable salt thereof and a nonsteroidal anti-inflammatory drug or acetaminophen in the manufacture of a medicament for the treatment of pain.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof and a nonsteroidal anti-inflammatory drug or acetaminophen in the manufacture of a medicament for the treatment of pain.
  • Mammals include, for example, humans. Mammals also include, for example, companion animals (e.g., dogs, cats, and horses), livestock animals (e.g., cattle and swine); lab animals (e.g., mice and rats); and wild, zoo, and circus animals (e.g., bears, lions, tigers, apes, and monkeys).
  • companion animals e.g., dogs, cats, and horses
  • livestock animals e.g., cattle and swine
  • lab animals e.g., mice and rats
  • wild, zoo, and circus animals e.g., bears, lions, tigers, apes, and monkeys.
  • such pain comprises chronic pain, osteoarthritic pain, rheumatoid arthritis pain, urinary tract pain, or chronic nociceptive pain.
  • the pain comprises visceral pain, cancer pain, or chemotherapy-induced pain.
  • the treated pain comprises chronic pain.
  • the treated pain comprises osteoarthritic pain.
  • the treated pain comprises rheumatoid arthritis pain.
  • the treated pain comprises urinary tract pain.
  • the treated pain comprises chronic nociceptive pain.
  • the treated pain comprises visceral pain.
  • the treated pain comprises cancer pain.
  • the treated pain comprises chemotherapy-induced pain.
  • This combination therapy tends to allow a lower amount of the NSAID or acetaminophen to be used relative to a therapy in which the NSAID or acetaminophen is administered alone. This, in turn, may reduce adverse effects related to the NSAID or acetaminophen.
  • the amount of the compound of Formula I or salt thereof and the NSAID or acetaminophen are, when combined, therapeutically effective to treat a targeted disorder in the animal patient.
  • the combined amounts are "therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the pain disorder; cure the pain disorder; or reverse, completely stop, or slow the progress of the pain disorder.
  • such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this patent for the compound of Formula I or salt thereof and an approved or otherwise published dosage range(s) of the NSAID or acetaminophen.
  • a skilled physician will start with at least about 10 pg/kg of body weight per day of the compound of Formula I or salt thereof. In some embodiments, the skilled artisan starts with no greater than about 100 mg/kg of body weight per day. In some embodiments, the skilled artisan starts with from about 10 pg/kg to about 100 mg/kg of body weight per day. In some embodiments, the skilled artisan starts with from about 0.01 to about 10 mg/kg of body weight per day. In some embodiments, the skilled artisan starts with from about 2 to about 20 mg/kg of body weight per day. In some embodiments, the skilled artisan starts with from about 2.5 to about 8 mg/kg of body weight per day. In still other embodiments, the skilled artisan starts with from about 0.8 to about 2.5 mg/kg of body weight per day.
  • naproxen is administered
  • acetaminophen it is contemplated that one skilled in the art will start with a dosage range of, for example, 650-1000 mg every 4 to 6 hours (not to exceed 3900 mg in 24 hr).
  • each ingredient will depend on the particular pain condition being treated and its severity; whether an NSAID or acetaminophen is being used, and, if an NSAID is being used, the specific NSAID being used; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
  • the compound of Formula I or salt thereof and the NSAID or acetaminophen may be administered in a single composition, as completely separate compositions, or a combination thereof. It also is contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately.
  • the particular composition(s) and how the active ingredients are administered relative to each other will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to the animal patient, and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
  • each ingredient is administered as separate dosage forms wherein each dosage form is administered once daily or in divided doses, such as, for example, from 2 to 4 times per day.
  • the separate dosage forms are administered at the same frequency. In other embodiments, the separate dosage forms are administered at different frequencies.
  • a mixture of such isomers may, for example, be a racemic mixture, i.e., a mixture wherein about 50% of the compound is in the form of the S isomer, and about 50% of the mixture is in the form of the R isomer.
  • the S enantiomer i.e., (S)-methyl 2-((2-(2,6-difluoro-4- (methylcarbamoyl)phenyl)-5-methyl-lH-benzo[d]imidazol-l-yl)methyl)mo holine-4- carboxylate
  • R enantiomer i.e., (R)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5- methyl-lH-benzo[d]imidazol-l-yl)methyl)mo holine-4-carboxylate
  • a single chiral isomer of Formula I is obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation.
  • a single chiral isomer is obtained through direct synthesis from, for example, a chiral starting material. The latter is illustrated in the Examples below.
  • Example 6 the chiral isomers of the compound of Formula I have been observed to modulate, and, in particular, act as antagonists against, P2X3. Accordingly, it is believed that the compound of Formula I and salts thereof can be used to modulate P2X3 and/or P2X2/3 to treat various pain conditions mediated by (or otherwise associated with) P2X3 and/or P2X2/3. It is believed that the compound of Formula I and salts thereof exhibit one or more of the following characteristics: desirable potency, desirable efficacy, desirable stability on the shelf, desirable tolerability for a range of patients, and desirable safety.
  • the compound of Formula I or salt thereof is administered as a pharmaceutical composition comprising from about 0.05% to about 99% (by weight) of the compound of Formula I or salt thereof.
  • the pharmaceutical composition comprises from about 0.10% to about 50% (by weight) of the compound of Formula I or a salt thereof.
  • the compound of Formula I or salt thereof is administered as a pharmaceutical composition comprising from about 0.05% to about 99% (by weight) of the S isomer (i.e., the compound of Formula II) or a salt thereof.
  • the pharmaceutical composition comprises from about 0.10%) to about 50% (by weight) of the S isomer or a salt(s) thereof.
  • the compound of Formula I or salt thereof is administered as a pharmaceutical composition comprising from about 0.05% to about 99% (by weight) of the R isomer (i.e., the compound of Formula III) or a salt thereof.
  • the pharmaceutical composition comprises from about 0.10%) to about 50% (by weight) of the R isomer or a salt(s) thereof.
  • the compound of Formula I or salt thereof is administered as a pharmaceutical composition wherein at least about 50% (by weight) of the composition is the S isomer or a salt(s) thereof.
  • the concentration is greater than about 70% (by weight), greater than about 85% (by weight), greater than about 90% (by weight), greater than about 95% (by weight), greater than about 98%) (by weight), greater than about 99% (by weight), or greater than about 99.5% (by weight).
  • a composition may be, for example, a pharmaceutical composition or a composition used in the preparation of a pharmaceutical composition (e.g., a composition that is, for example, dispersed into a carrier, diluent, or excipient before being
  • the compound of Formula I or salt thereof is administered as a pharmaceutical composition wherein at least about 50% (by weight) of the composition is the R isomer or a salt(s) thereof.
  • the concentration is greater than about 70% (by weight), greater than about 85% (by weight), greater than about 90% (by weight), greater than about 95% (by weight), greater than about 98%) (by weight), greater than about 99% (by weight), or greater than about 99.5% (by weight).
  • a composition may be, for example, a pharmaceutical composition or a composition used in the preparation of a pharmaceutical composition (e.g., a composition that is, for example, dispersed into a carrier, diluent, or excipient before being
  • the compound of Formula I or salt thereof is administered as a pharmaceutical composition wherein the molar ratio of the S isomer (or salt(s) thereof) to the R isomer (or salt(s) thereof) is about 1 : 1, i.e. , the composition comprises a racemic mixture.
  • the compound of Formula I or salt thereof is administered as a pharmaceutical composition wherein the molar ratio of the S isomer (or salt(s) thereof) to the R isomer of Formula I (or salt(s) thereof) is greater than about 70:30. In some such embodiments, the ratio is greater than about 85 : 15, greater than about 90: 10, greater than about 95 :5, greater than about 98:2, greater than about 99: 1, or greater than about 99.5 :0.5.
  • the compound of Formula I or salt thereof is administered as a pharmaceutical composition wherein the molar ratio of the R isomer (or salt(s) thereof) to the S isomer of Formula I (or salt(s) thereof) is greater than about 70:30. In some such embodiments, the ratio is greater than about 85 : 15, greater than about 90: 10, greater than about 95 :5, greater than about 98:2, greater than about 99: 1, or greater than about 99.5 :0.5.
  • Contemplated salts of the compound of Formula I include both acid addition salts and base addition salts. A salt may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in water, oil, or other solvent.
  • a salt may be used to aid in the isolation or purification of the compound.
  • the salt is pharmaceutically acceptable.
  • an acid addition salt can be prepared using various inorganic or organic acids.
  • Such salts can typically be formed by, for example, mixing the compound with an acid (e.g., a stoichiometric amount of acid) using various methods known in the art. This mixing may occur in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile), or an aqueous/organic mixture.
  • organic solvent e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
  • examples of inorganic acids that typically may be used to form acid addition salts include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • organic acids include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • organic salts include cholate, sorbate, laurate, acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid (and derivatives thereof, e.g., dibenzoyltartrate), citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p- hydroxybenzoate, phenylacetate, mandelate (and derivatives thereof), embonate
  • the salt comprises a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate, or /?-toluenesulphonate salt.
  • the compound of Formula I or a salt may form a tautomer.
  • a "tautomer” is any other structural isomer that exists in equilibrium resulting from the migration of a hydrogen atom, e.g., amide-imidic acid tautomerism.
  • the compound of Formula I or salt thereof is administered in combination with an NSAID.
  • the NSAID comprises naproxen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, loxoprofen, or oxaprozin.
  • the NSAID comprises aspirin, diflunisal, or salsalate.
  • the NSAID comprises declofenac, etodolac, indomethacin, ketorolac, nabumetone, or sulindac.
  • the NSAID comprises celecoxib, etroricoxib, firocoxib, or paracoxib. In other embodiments, it is contemplated that the NSAID comprises licofelone. In other embodiments, it is contemplated that the NSAID comprises droxican, isoxicam, lornoxicam, meloxicam, piroxicam, or tenoxicam. And in other embodiments, it is contemplated that the NSAID comprises flufenamic acid, meclofenamic acid, mefenamic acid, or telfenamic acid.
  • the NSAID comprises naproxen.
  • the compound of Formula I or a salt thereof is administered in combination with acetaminophen (also known as paracetamol).
  • the route of administration for the compound of Formula I or salt thereof is the same as the route of administration for the NSAID or acetaminophen. In other embodiments, the route of administration for the compound of Formula I or salt thereof is different from the route of administration for the NSAID or acetaminophen.
  • the compound of Formula I or salt thereof and the NSAID or acetaminophen may be administered orally, buccally, vaginally, rectally, via inhalation, via insufflation, intranasally, sublingually, topically, or parenterally (e.g., intramuscularly, subcutaneously, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly, or by injection into the joints).
  • parenterally e.g., intramuscularly, subcutaneously, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly, or by injection into the joints.
  • the compound of Formula I or a salt thereof is administered orally.
  • the NSAID or acetaminophen is administered orally.
  • the compound of Formula I or a salt thereof and the NSAID or acetaminophen is administered orally.
  • the compound of Formula I or salt thereof and NSAID or acetaminophen is used to make a medicament (i.e., a pharmaceutical composition).
  • a medicament i.e., a pharmaceutical composition
  • the pharmaceutical composition comprises a therapeutically effective amount of the combination.
  • the pharmaceutical compositions used with this invention may vary widely and will typically comprise one or more additional active ingredients and/or inert ingredients.
  • the inert ingredients in the pharmaceutical compositions of this invention are sometimes collectively referred to as "carriers, diluents, and excipients.” Methods for making pharmaceutical compositions and the use of carriers, diluents, and excipients are well known in the art. See, e.g., for example, Remington 's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 15th Edition, 1975.
  • compositions used for this invention may be formulated for a variety of suitable routes and means of administration, including oral, rectal, nasal, topical, buccal, sublingual, vaginal, inhalation, insufflation, or parenteral administration. It is contemplated that such compositions may, for example, be in the form of solids, aqueous or oily solutions, suspensions, emulsions, creams, ointments, mists, gels, nasal sprays, suppositories, finely divided powders, and aerosols or nebulisers for inhalation.
  • each of the compound of Formula I or salt thereof and the NSAID or acetaminophen are administered either together in a solid dosage form or separately in two solid dosage forms. In some embodiments, each of the compound of Formula I or salt thereof and the NSAID or acetaminophen are administered either together in a liquid dosage form or separately in two liquid dosage forms. In some embodiments, the compound of Formula I or salt thereof and the NSAID or
  • acetaminophen are administered separately wherein one is contained in a solid dosage form and the other is contained in a liquid dosage form.
  • Solid form compositions may include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier may comprise one or more substances. Such substances are generally inert.
  • a carrier also may act as, for example, a diluent, flavoring agent, solubilizer, lubricant, preservative, stabilizer, suspending agent, binder, or disintegrating agent. It also may act as, for example, an encapsulating material.
  • Examples of often suitable carriers include pharmaceutical grade mannitol, lactose, magnesium carbonate, magnesium stearate, talc, lactose, sugar ⁇ e.g., glucose and sucrose), pectin, dextrin, starch, tragacanth, cellulose, cellulose derivatives (e.g., methyl cellulose and sodium carboxymethyl cellulose), sodium saccharin, low-melting wax, and cocoa butter.
  • the carrier is typically a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is typically mixed with the carrier having the desirable binding properties in suitable proportions and compacted into the desired shape and size.
  • a low-melting wax e.g., a mixture of fatty acid glycerides and cocoa butter
  • a low-melting wax e.g., a mixture of fatty acid glycerides and cocoa butter
  • the molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
  • non-irritating excipients include, for example, cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • Liquid compositions can be prepared by, for example, dissolving or dispersing the active ingredient in a carrier, such as, for example, water, water/propylene glycol solutions, saline aqueous dextrose, glycerol, or ethanol.
  • aqueous solutions for oral administration can be prepared by dissolving the compound of Formula I or a salt thereof in water with a solubilizer (e.g., a polyethylene glycol).
  • aqueous suspensions for oral use can be made by dispersing the active ingredient in a finely divided form in water, together with a viscous material, such as, for example, one or more natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, or other suspending agents.
  • a viscous material such as, for example, one or more natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, or other suspending agents.
  • the liquid composition also may contain other non-toxic auxiliary inert ingredients, such as, for example, wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan
  • compositions also may contain other ingredients, such as, for example, one or more pharmaceutical adjuvants.
  • kits for treating pain comprises the compound of Formula I or a salt thereof and the NSAID or acetaminophen.
  • the kit also comprises instructions for administering the compound of Formula I or a salt thereof and the NSAID or acetaminophen.
  • the kit further comprises one or more additional components, such as, for example: (a) an apparatus for administering the compound of Formula I or salt thereof and/or the NSAID or
  • acetaminophen (b) a carrier, diluent, or excipient (e.g., a re-suspending agent); or (c) an additional active ingredient.
  • a carrier e.g., a re-suspending agent
  • excipient e.g., a re-suspending agent
  • compound structures are associated with compound names.
  • names were generated from the structures using AutoNom 2000 within ISIS/Draw, ChemDraw 9.0.7, Isis/Draw 2.5SP4, or Chemdraw 11.0.2.
  • AutoNom Automatic Nomenclature
  • ChemDraw contain programs that assign systematic IUPAC (International Union of Pure and Applied
  • Examples 1-5 below illustrate the preparation of the compound of Formula I or a salt thereof and intermediates for making such compounds. It is expected that one skilled in the art of organic synthesis, after reading these examples alone or in combination with the general knowledge in the art, can adapt and apply the methods as desired.
  • the general knowledge in the art includes, for example:
  • references discussing heterocyclic chemistry include, for example, example, Heterocyclic Chemistry, J.A. Joule, K. Mills, G.F. Smith, 3rd ed., Cheapman and Hall, p. 189-225 (1995); and Heterocyclic Chemistry, T.L. Gilchrist, 2 nd ed.
  • H 4 HCO3 (pH 10) or water with 0.1% TFA; and mobile phase B: MeCN).
  • Mass spectra were recorder using either Single-Quad mass spectrometers equipped with an electrospray ion source (ES) operated in a positive or negative ion mode or a Triple-Quad mass spectrometer configured with an atmospheric pressure chemical ionisation (APCI) ion source operated in positive and negative ion mode.
  • the mass spectrometers were scanned between m/z 100-1000 with a scan time of 0.3 sec.
  • the aqueous phase was removed and extracted with 2-methyltetrahydrofuran (250 mL). The organics were combined and washed with a mixture of water (100 mL) and brine (100 mL). The resulting mixture was concentrated under reduced pressure, and then dimethylsulfoxide (110 mL), calcium carbonate (12.51 g, 125.03 mmol), and 4-fluoro-3-nitrotoluene (15.37 mL, 125.03 mmol) were added.
  • the aqueous phase was extracted with EtOAc (200 mL), and the combined organic phases were washed with a mixture of water (75 mL) and brine (75 mL).
  • the organic phase was transferred to a round-bottom flask and concentrated under reduced pressure to form a foam, which, in turn, was dried under mechanical vacuum at 45°C to produce the title compound (58.4 g, 1 17 mmol, 81%).
  • Methanesulfonyl chloride (12 mL, 0.15 mol) was added to a solution of ⁇ S)-tert-bu ⁇ y ⁇ 2- (hydroxymethyl)moipholine-4-carboxylate (28 g, 0.13 mmol) in CH 2 CI 2 (172 mL) and triethylamine (23.4 mL, 0.17 mol) at 0°C. The resulting mixture was stirred at a temperature of from 0°C to room temperature over 1.5 hr. The mixture was then diluted with water (35 mL), and the phases were separated. The aqueous layer was extracted with CH 2 CI 2 (3 x 20 mL).
  • Example 6 Biological evaluation of the compound of Formula I as an antagonist at human P2X3 receptor in vitro.
  • the RLE/hP2X3 cells were grown in William's medium IX (Gibco, 12551-032), supplemented with 10% Fetal bovine serum (Wisent, 090850), 2 mM L- Glutamine (Wisent, 609-065-EL), and 600 ⁇ g/mL Geneticin G-418 (Wisent, 61234) in a humidified incubator (5% C0 2 and 37°C).
  • Method 1 Fluo-4 assay on FDSS7000 (Hamamatsu) was performed using cryopreserved RLE cells stably expressing hP2X3 plated in 384 well plates, 24 hr before the experiment at a density appropriate for obtaining the desired final confluence. After processing the cell plates with Fluo-4 and performing a subsequent incubation followed by washing steps, a double addition was carried out. The first addition included the test compounds diluted in HBSS buffer containing 2mM CaCl 2 preincubated for 20 min before a second addition. The second addition included 2uM of ATP. Calcium mobilization was measured with the FDSS7000 over a time lapse of 3min, and fluorescent counts were exported for analysis. This resulted in a pIC 5 o, which was calculated in
  • Method 2 In another assay, a procedure similar to Method 1 was used on RLE cells stably expressing hP2X3. In this method, however, ⁇ , ⁇ methylene- ATP (Sigma M6517) was used instead of ATP as the hP2X3 agonist.
  • Method 3 In a third assay, hP2X3 -expressing cells were maintained in culture and the day before the experiment, the cells were plated in 384-black polylysine coated plates (Becton/Dickinson, 356663) at 8000 cells/well in 50 ⁇ in William's medium without Geneticin, and then placed in an incubator for 24 hr. On the day of the experiment, the cells and test compounds were prepared as follows.
  • ⁇ , ⁇ -methylene-ATP 500 nM, final concentration
  • reference compounds spanning a range of 10 dilutions, three-fold apart
  • hP2X3 assay buffer 125 mM Choline chloride, 5 mM Glucose, 0.2 g/L BSA, 25 mM Hepes, 5 mM KC1, 1 mM MgCl 2 , 1.5 mM CaCl 2 , pH 7.4
  • HBSS 125 mM NaCl
  • 5 mM Glucose 0.2 g/L BSA
  • 25 mM Hepes 5 mM KC1, 1 mM MgCl 2 , 1.5 mM CaCl 2 , pH 7.4
  • HBSS 125 mM NaCl
  • 5 mM Glucose 0.2 g/L BSA
  • 25 mM Hepes 5 mM KC1, 1 mM MgCl 2 , 1.5 mM CaCl
  • the medium was removed from the cell plates by inversion.
  • a loading solution of 30 ⁇ assay buffer containing 4 ⁇ of the calcium indicator dye FLUO-4 AM (Molecular Probes F 14202) was added to each well using a Multidrop (Labsystems).
  • the cell plates were then incubated at room temperature for 30- 40 min to allow loading of the dye into the cells.
  • the incubation was terminated by washing the cells four times in assay buffer using a Skatron Embla (Molecular Devices), and leaving 25 ⁇ . of assay buffer in each well.
  • Cell plates were then transferred to the FLIPR. Experiments were initiated by measuring a baseline fluorescence reading for 10 sec, followed by addingl2 ⁇ L of compounds and data sampling for a total 280 seconds.
  • Rat subjects were male Sprague Dawley rats, weighing 175-200g (Charles River, St Constant, QC, Canada). Rats were housed in groups of six in a temperature- and humidity-controlled animal colony. Food and water were available ad libitum, and the room was illuminated with fluorescent lighting on a daily 12 h light/dark cycle.
  • FCA Freund's complete adjuvant
  • Heat hyperalgesia thermal sensitivity of the plantar surface of the hind paw was assessed using a paw thermal stimulator system (IITC Life Science, Woodland Hills, USA, Model 390 Series 8) to measure paw withdrawal latency. Two trials were conducted with 5 min intervals between each trial. A cutoff time of 20 sec was used to prevent tissue injury.
  • Mechanical hyperalgesia mechanical sensitivity was measured using an analgesy meter (Ugo Basile, Varese, Italy). Briefly, a rat was gently restrained by hand, and an increasing force was gradually applied to the left hind paw until the threshold force causing the rat to withdraw its paw was determined. A maximal cut-off force of 270 g was implemented for this study.
  • Dose-response curves were determined at the 30 min after oral dosing of the chemical compounds. The testing time was decided on the peak effects of these chemical agents. For combination therapy, doses were administered at the ratios calculated based on the ED 50 of individual compound. Ratio of Naproxen/Compound 1 on both heat and mechanical hyperalgesia were 1.0.9 and those for
  • acetaminophen/Compound 1 were 15: 1 and 36: 1 for heat hyperalgesia and mechanical hyperalgesia measurements.
  • Acetaminophen produced a peak effect at 60 min after injection while the peak effect of Compound 1 was generated at 30 min after p.o. administration.
  • the combination effect of acetaminophen and Compound 1 was tested at 30 min post p.o. to ensure the peak effects of both agents.
  • the ED 50 values for acetaminophen and Compound 1 combination are shown in Table 2.
  • the dose-response curves ( Figure 3, left panel) were parallel to the dose-response curve for Acetaminophen and for Compound 1 within each test. Isobolographic analysis of p.o. Acetaminophen -v interactions are represented as isobolograms in Figure 3 (right panel). The combination of acetaminophen with Compound 1 demonstrated significant synergy.
  • a pharmaceutically acceptable moiety e.g., a salt, dosage form, carrier, diluent, or excipient
  • a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
  • DCM dichloromethane
  • DMEA means dimethylethylamine
  • DMF N,N-dimethyl formamide
  • DMSO-c/g means dimethyl sulfoxide- ⁇ .
  • DMT-MM means 4-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium chloride.
  • EI electrospray ionization
  • HPLC means high-performance liquid chromatography
  • HRMS means high-resolution mass spectrometry.
  • MeCN means acetonitrile
  • MS means mass spectrometry
  • MTBE means methyl tert-butyl ether
  • R t means retention time (HPLC).
  • TFA means trifluoroacetic acid.
  • TLC means thin layer chromatography
  • TEDA means N,N,N',N'-tetramethyl-l,2-ethylenediamine.
  • UV means ultraviolet

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Abstract

Cette invention concerne de façon générale un traitement combiné qui comporte l'utilisation d'un composé de benzimidazole substitué et d'un médicament anti-inflammatoire non stéroïdien (AINS) ou de paracétamol et, en particulier, l'utilisation de 2-((2-(2,6-difluoro-4-(méthylcarbamoyl)phényl)-5-méthyl-1H-benzo[d]imidazol-1-yl)méthyl)morpholine-4-carboxylate de méthyle ou d'un sel de celui-ci et d'un AINS ou de paracétamol pour traiter la douleur. Cette invention concerne également les combinaisons elles-mêmes, l'utilisation d'une telle combinaison, ainsi que les compositions pharmaceutiques et les nécessaires comportant une telle combinaison.
PCT/SE2012/050532 2011-05-17 2012-05-16 Traitements combinés pour le traitement de la douleur WO2012158117A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111094259A (zh) * 2017-05-15 2020-05-01 里科瑞尔姆Ip控股有限责任公司 止痛化合物
CN113164490A (zh) * 2018-10-10 2021-07-23 贝卢斯医疗咳嗽病公司 采用p2x3拮抗剂治疗瘙痒症
WO2022033567A1 (fr) * 2020-08-13 2022-02-17 上海拓界生物医药科技有限公司 Dérivés de benzimidazole, leur procédé de préparation et leur utilisation médicale
CN114478508A (zh) * 2021-12-31 2022-05-13 淮北师范大学 一种苯并咪唑化合物的结晶形式
WO2022117062A1 (fr) * 2020-12-04 2022-06-09 上海拓界生物医药科技有限公司 Composés contenant un noyau tricyclique condensé et leur utilisation pharmaceutique
WO2023151658A1 (fr) * 2022-02-11 2023-08-17 江苏恒瑞医药股份有限公司 Sel pharmaceutiquement acceptable d'un antagoniste du récepteur p2x3 et son procédé de préparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108958A2 (fr) * 2007-03-02 2008-09-12 Schering Corporation Dérivés de benzimidazole et leurs procédés d'utilisation
WO2011062550A1 (fr) * 2009-11-18 2011-05-26 Astrazeneca Ab Composés de benzoimidazole et utilisations de ceux-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108958A2 (fr) * 2007-03-02 2008-09-12 Schering Corporation Dérivés de benzimidazole et leurs procédés d'utilisation
WO2011062550A1 (fr) * 2009-11-18 2011-05-26 Astrazeneca Ab Composés de benzoimidazole et utilisations de ceux-ci

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111094259A (zh) * 2017-05-15 2020-05-01 里科瑞尔姆Ip控股有限责任公司 止痛化合物
CN111094259B (zh) * 2017-05-15 2023-08-11 里科瑞尔姆Ip控股有限责任公司 止痛化合物
CN113164490A (zh) * 2018-10-10 2021-07-23 贝卢斯医疗咳嗽病公司 采用p2x3拮抗剂治疗瘙痒症
EP3863640A4 (fr) * 2018-10-10 2022-07-06 Bellus Health Cough Inc. Traitement du prurit avec des antagonistes des récepteurs p2x3
WO2022033567A1 (fr) * 2020-08-13 2022-02-17 上海拓界生物医药科技有限公司 Dérivés de benzimidazole, leur procédé de préparation et leur utilisation médicale
CN115835867A (zh) * 2020-08-13 2023-03-21 上海拓界生物医药科技有限公司 苯并咪唑类衍生物、其制备方法及医药用途
EP4198034A4 (fr) * 2020-08-13 2024-01-17 Tuojie Biotech Shanghai Co Ltd Dérivés de benzimidazole, leur procédé de préparation et leur utilisation médicale
WO2022117062A1 (fr) * 2020-12-04 2022-06-09 上海拓界生物医药科技有限公司 Composés contenant un noyau tricyclique condensé et leur utilisation pharmaceutique
CN114478508A (zh) * 2021-12-31 2022-05-13 淮北师范大学 一种苯并咪唑化合物的结晶形式
WO2023151658A1 (fr) * 2022-02-11 2023-08-17 江苏恒瑞医药股份有限公司 Sel pharmaceutiquement acceptable d'un antagoniste du récepteur p2x3 et son procédé de préparation

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