WO2012012890A1 - Composés, compositions et méthodes de traitement de l'arthrite - Google Patents

Composés, compositions et méthodes de traitement de l'arthrite Download PDF

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Publication number
WO2012012890A1
WO2012012890A1 PCT/CA2011/000879 CA2011000879W WO2012012890A1 WO 2012012890 A1 WO2012012890 A1 WO 2012012890A1 CA 2011000879 W CA2011000879 W CA 2011000879W WO 2012012890 A1 WO2012012890 A1 WO 2012012890A1
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WIPO (PCT)
Prior art keywords
compound
arthritis
formula
piperazin
pyridin
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PCT/CA2011/000879
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English (en)
Inventor
Antonio Cruz
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Waratah Pharmaceuticals Inc.
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Publication of WO2012012890A1 publication Critical patent/WO2012012890A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • TITLE Compounds, Compositions and Methods for Treatment of Arthritis
  • the invention generally relates to compounds, compositions, formulations and methods for treating arthritis.
  • Arthritis includes many rheumatic diseases and other conditions that can cause pain, stiffness and swelling in the joints.
  • the incidence of arthritis increases with age, but the majority of sufferers are under age 65. It is estimated that by the year 2020, 59.4 million Americans will be affected with some form of arthritis (Lawrence et al, Arthritis Rheum., 1998, 41 :778-799). If left untreated, many types of arthritis can cause irreversible damage to the joints, bones, organs, and skin. The two most common types of arthritis are osteoarthritis and rheumatoid arthritis.
  • Osteoarthritis mainly affects weight bearing joints and it is a major cause of morbidity and disability especially for the elderly, due to joint pain, morning stiffness, and limited movement typically of the neck, lower back, knees, hips and finger joints.
  • the disease is characterized by cartilage erosion, subchondral bone thickening, hypertrophy of the bone, inflammation and joint damage. As the disease progresses underlying bone can be exposed which is prone to microfractures, and localized osteonecrosis beneath the bone surface can lead to cysts that further weaken the bone's support of the cartilage.
  • Osteoarthritis is also characterized by the release of inflammatory mediators during cartilage degradation resulting in local inflammation such as synovitis, thickening of the joint capsule resulting in restricted movement of nutrients into and waste products out of the joint, and muscle wasting as the joint is used less often or improperly. Osteoarthritis is typically treated with aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac and naproxen.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • RA Rheumatoid arthritis
  • Activated macrophages and synoviocytes produce many key cytokines and mediators that contribute to the inflammation and joint destruction.
  • Blocking proinflammatory cytokines such as TNFa, IL- ⁇ ⁇ , and IL-6 has led to clinical and radiographic benefits in patients with RA.
  • Therapeutic agents have been identified which possess profiles of activity that indicate that they are particularly useful in the treatment of arthritis.
  • the present invention rovides a compound of the formula I
  • the invention provides a compound of the formula I for prophylactic treatment of arthritis, for treatment of arthritis in an early stage, during early phases of exacerbation, or as maintenance therapy to prevent disease flares or disease progression in a subject.
  • the arthritis is osteoarthritis.
  • the arthritis is rheumatoid arthritis.
  • a compound of the formula I is used for prophylactic treatment in a subject having a predisposition for developing arthritis to prevent the disease from erupting.
  • the invention also provides a compound of the formula I for treating, delaying the onset of, or preventing arthritis in an individual.
  • a compound of the formula I is used for treatment of arthritis in an early stage.
  • a compound of the formula 1 is used for treatment of rheumatoid arthritis in an early stage.
  • An early stage of rheumatoid arthritis can be diagnosed in a patient using a disease activity score or by determining factors that are typical for rheumatoid arthritis.
  • a DAS28 score below 5.1 is generally an indication that a low to moderate activity of RA is present.
  • Biomarkers may also be assayed to determine the stage of rheumatoid arthritis in a patient.
  • anti-CCP antibodies, interleukin-6, interleukin-3, and/or timp-1 can be measured in the patient's serum.
  • the invention provides a compound of the formula I for treatment of arthritis in subjects where an increased level of IL-6 in one or more joints is detectable.
  • the invention provides a compound of the formula 1 for maintenance therapy for the treatment of arthritis in a subject that has developed arthritis but has no, or a low to moderate, disease activity.
  • the invention provides a compound of the formula 1 for inhibition or reduction of the progression of arthritis.
  • the invention provides a compound of the formula I for reducing cell infiltration of synovial tissue.
  • the invention relates to a method of treating arthritis in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula I.
  • the methods comprise treating arthritis by administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I.
  • a method of the invention comprises treating a subject exhibiting clinical symptoms of arthritis comprising administering a compound of the formula I to ameliorate the disease.
  • the present invention relates to methods of treating osteoarthritis comprising: administering, to a subject suffering from osteoarthritis, a therapeutically effective amount of a compound of the formula I.
  • the present invention relates to methods of treating rheumatoid arthritis comprising: administering, to a subject suffering from rheumatoid arthritis, a therapeutically effective amount of a compound of the formula I.
  • methods are provided for treating arthritis comprising reducing pathology associated with arthritis in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula I.
  • methods are provided for reducing or improving pathology associated with arthritis in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula I.
  • the pathology may include pathology associated with inflammatory events such as excessive activation of glia, macrophages, and/or synoviocytes and their increased production of endogenous proinflammatory mediators including cytokines, chemokines, complement proteins and reactive free radicals.
  • the pathology may also include leukocyte infiltration, destruction of collagen, erosive bone damage, abnormal growth and division of synovium cells, joint effusion, synovial hyperplasia, synovial pannus, invasion of abnormal synovial cells into cartilage and bone, weakening of muscles, ligaments and tendons in joints, bone loss, cartilage depletion, pain, swelling, stiffness, fatigue, loss of joint range of motion, rheumatoid nodules or lumps under the skin, accumulation of fluid in joints, reduction in red blood cells, and/or inflammation of the blood vessels, the lining of the lungs or the sac enclosing the heart.
  • the pathology includes marked growth of synovial cells, formation of a multilayer structure due to abnormal growth of the synovial cells (pannus formation), invasion of the synovial cells into cartilage tissue and bone tissue, vascularization toward the synovial tissue, and infiltration of inflammatory cells such as lymphocytes, macrophages and/or synoviocytes.
  • the present invention relates to a method of reducing inflammation associated with arthritis in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula I.
  • the invention relates to a method of treating arthritis in a subject comprising administering to the subject a compound of the formula I in a therapeutically effective amount to modulate inflammatory responses.
  • the invention relates to a method of treating arthritis in a subject comprising administering to the subject a compound of the formula I in a therapeutically effective amount to modulate inflammatory responses to improve outcomes.
  • methods of the invention can be used to treat at least one symptom or feature of arthritis selected from the group consisting of joint effusion, leukocytic infiltration of synovial fluid, tissue leukocytic infiltration, synovial hyperplasia, synovial pannus, bone erosion, cartilage depletion, pain, swelling, morning stiffness, fatigue, loss of joint range of motion, and combinations thereof.
  • the invention provides a method of treating rheumatoid arthritis in a mammal who experiences an inadequate response to a second therapeutic agent (e.g., a disease modifying arthritis drug (DMARD) such as a TNFa-inhibitor), comprising administering to the mammal a therapeutically effective amount of a compound of the formula I.
  • a second therapeutic agent e.g., a disease modifying arthritis drug (DMARD) such as a TNFa-inhibitor
  • DMARD disease modifying arthritis drug
  • TNFa-inhibitor e.g., a TNFa-inhibitor
  • the invention also concerns a method of reducing the risk of a negative side effect of a second therapeutic agent (e.g. a DMARD) selected from the group consisting of an infection, heart failure and demyelination, comprising administering to a mammal with arthritis a therapeutically effective amount of a compound of the formula I.
  • a second therapeutic agent e.g. a DMARD
  • a mammal with arthritis e.g. a DMARD
  • the arthritis is osteoarthritis.
  • the arthritis is classical rheumatoid arthritis, spondylitic rheumatoid arthritis, psoriatic rheumatoid arthritis, osteorheumatoid arthritis, Felty's syndrome, seronegative rheumatoid arthritis, progressive and/or relapsing rheumatoid arthritis, and rheumatoid arthritis with vasculitis.
  • a method of treating arthritis in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula I, wherein the amount of a compound of the formula I administered ranges from about 0.1 to 1000 mg/day. In embodiments, the amount of a compound of the formula I administered is from about 5 to 500 mg/day. In embodiments, the amount of a compound of the formula I administered is from about 5 to 100 mg/day. In embodiments, the amount of a compound of the formula I administered is from about 50 to 500 mg/day.
  • the invention provides a method of treating or preventing arthritis wherein the amount of compound of formula I administered to the subject ranges from about 0.01 to 50 mg/kg. In embodiments, the amount of a compound of the formula I administered is from about 0.1 to 50 mg/kg. In embodiments, the amount of a compound of the formula I administered is from about 0.1 to 25 mg/kg. In embodiments, the amount of a compound of the formula I administered is from about 0.1 to 10 mg/kg. In embodiments, the amount of a compound of the formula I administered is from about 1 to 10 mg/kg. In embodiments of the invention, a compound of the formula I is administered once or twice daily.
  • a compound of the formula 1 is administered to the patient in the treatment or prevention of arthritis in a unit dosage form.
  • the unit dosage form is an immediate release dosage form.
  • the unit dosage form is an extended release dosage form.
  • the prevention or treatment of arthritis is performed with a unit dosage form comprising 1 to 1000 mg, 1 to 500 mg, 5 to 500 mg or 1 to 100 mg.
  • the amount of a compound of the formula I administered in the unit dosage form is from about 10 to 100 mg.
  • the amount of a compound of the formula I administered in the unit dosage form is from about 50 to 500 mg.
  • the amount of a compound of the formula I administered in the unit dosage form is about 5 mg, 10 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 500 mg.
  • a method of the invention may also comprise administering a compound of the formula I in combination with a second treatment (e.g., a second therapeutic agent) effective for treating or preventing arthritis. Therefore, the invention relates to a combination treatment for arthritis comprising administering therapeutically effective amounts of a compound of the formula I, and a second therapeutic agent, in particular a conventional therapeutic agent for arthritis.
  • a method of the invention can further comprise administering at least one second therapeutic agent at a therapeutically effective dosage in an effective dosage form at a selected interval.
  • methods include administering a disease modifying arthritis drug (DMARD).
  • DMARD disease modifying arthritis drug
  • a method of treating rheumatoid arthritis in a human comprising: (a) administering to the human a compound of the formula I, and (b) administering to the human one or more of rituximab and methotrexate.
  • the compound of the formula I, and optionally second therapeutic agent are administered for periods up to about 4, 5, 6, 7, 8, 9, 10, 14 or 15 days or 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 24 or 48 weeks.
  • the invention relates to a pharmaceutical composition for treating arthritis comprising therapeutically effective amounts of a compound of the formula I, and a pharmaceutically acceptable carrier, excipient, or vehicle.
  • the present invention relates to a pharmaceutical composition for treatment of arthritis comprising a compound of the formula I as the effective component.
  • a pharmaceutical composition is provided comprising therapeutically effective amounts of a compound of the formula I, and a pharmaceutically acceptable carrier, excipient, or vehicle that is useful for treating or preventing arthritis.
  • the pharmaceutical composition is adapted to be administered to a human subject to treat arthritis.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound of the formula I for treating arthritis, and at least one pharmaceutically acceptable component chosen from a carrier, an excipient and a vehicle.
  • the invention relates to a pharmaceutical composition effective in the treatment of an arthritic condition selected from rheumatoid arthritis and osteoarthritis, comprising a compound of the formula I.
  • a pharmaceutical composition for treatment of arthritis according to the invention can be a drug which when administered to arthritis patients suppresses growth of synovial cells in joints and has an alleviating and therapeutic effect on the symptoms.
  • a pharmaceutical composition for treatment of arthritis according to the invention can be a drug which when administered to arthritis patients suppresses cytokine production in joints and has an alleviating and therapeutic effect on the symptoms.
  • a pharmaceutical composition for treatment of a chronic arthritis according to the invention can be a drug which when administered to chronic arthritis patients suppresses production of TNFa, IL-6, IL- ⁇ ⁇ , RANTES and/or monocyte chemotactic protein (MCP-l /CCL-2) in joints and has an alleviating and therapeutic effect on the symptoms.
  • a pharmaceutical composition for treatment of chronic arthritis whose effective component suppresses IL-6 according to the invention is effective for treatment of chronic arthritis if it suppresses IL-6 and abnormal growth of synovial cells induced by IL-6, which are implicated in the disease.
  • the pharmaceutical compositions of the invention contain adjuvants, excipients, vehicles, preservatives, agents for delaying absorption, fillers, binders, adsorbents, buffers, disintegrating agents, solubilizing agents, other carriers, other inert ingredients, or combinations thereof.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injections as a sterile solution, suspension or emulsion, or for topical administration as an ointment or cream or for rectal administration as a suppository.
  • a pharmaceutical composition of the invention can be in a unit dosage form suitable for single administration of precise dosages.
  • the amount of a compound of the formula I present in the unit dosage form ranges from about 1 to 1000 mg, 1 to 500 mg, 5 to 500 mg or 1 to 100 mg.
  • the amount of a compound of the formula I in the unit dosage form is about 10 to 100 mg.
  • the amount of a compound of the formula I in the unit dosage form is about 50 to 500 mg.
  • the amount of a compound of the formula I in the unit dosage form is about 5 mg, 10 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 500 mg.
  • a unit dosage form comprises a suboptimal dose of a compound of the formula I.
  • the invention provides a unit dosage form comprising a compound of the formula I in an amount effective to maintain the compound within an effective drug concentration in joints that results in therapeutic effects in a subject with arthritis.
  • the invention in another aspect, relates to a sustained-release dosage form of a compound of the formula I which provides beneficial release profiles in the treatment of arthritis.
  • the release profiles may exhibit different rates and durations of release and may be continuous or pulsatile.
  • Continuous release profiles include release profiles in which a quantity of one or more pharmaceutical compounds is released continuously throughout the dosing interval at either a constant or variable rate.
  • Pulsatile release profiles include release profiles in which at least two discrete quantities of one or more pharmaceutical compounds are released at different rates and/or over different time frames.
  • a compound of the formula I is administered in a single dose, once daily. In additional embodiments, a compound of the formula I, or a pharmaceutically acceptable salt thereof, is administered twice daily. In further or additional embodiments, a compound of the formula I is administered three times per day. In additional embodiments, a compound of the formula I is administered four times per day.
  • a composition or dosage form of the invention may be administered to a subject for about or at least about or up to 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks to 4 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, or 2 weeks to 24 months, periodically or continuously.
  • a pharmaceutical composition of the invention may also comprise a second therapeutic agent.
  • Combinations of a compound of the formula I and a second therapeutic agent in compositions of the invention may be selected to provide additive effects or greater than additive effects, for example, synergistic effects.
  • the invention relates to a pharmaceutical composition comprising a compound of the formula I and a second therapeutic agent, optionally in combination with at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle, wherein the amount of a compound of the formula I and second therapeutic agent are selected to provide an additive or synergistic effect in treating or preventing a condition disclosed herein.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula I and a second therapeutic agent in combination with at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle, wherein the compound of the formula I, or a pharmaceutically acceptable salt thereof, and second therapeutic agent are selected to provide a synergistic effect, as a combined preparation for simultaneous, separate, or sequential use in treatment of arthritis.
  • the invention relates to a pharmaceutical composition comprising a compound of the formula I and a second therapeutic agent, wherein said composition achieves a synergistic effect for treating rheumatoid arthritis in a subject in need thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula I and a second therapeutic agent, wherein said composition achieves a synergistic effect for treating osteoarthritis in a subject in need thereof.
  • the invention also relates to a pharmaceutical composition in separate containers and intended for simultaneous or sequential administration to a subject, comprising a compound of the formula I and a second therapeutic agent both optionally together with pharmaceutically acceptable carriers, excipients, or vehicles.
  • a unit dosage form comprises a suboptimal dose of a compound of the formula I and a suboptimal dose of a second therapeutic agent.
  • the second therapeutic agent is a DMARD which acts synergistically with a compound of the formula I to diminish the symptoms of arthritis.
  • a pharmaceutical composition of the invention comprises: (i) a compound of the formula I; (ii) one or more DMARD; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicles.
  • a pharmaceutical composition of the invention comprises: (i) a compound of the formula I; (ii) an anti-inflammatory drug; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicles.
  • the second therapeutic agent is an antiinflammatory drug which acts synergistically with a compound of the formula I to diminish the symptoms of rheumatoid arthritis.
  • the invention still further relates to the use of a compound of the formula I, and optionally at least one second therapeutic agent, composition, or combination treatment of the present disclosure for ameliorating disease severity, disease symptoms, and/or periodicity of recurrence of arthritis. Further, the invention relates to the use of a compound of the formula I, and optionally a second therapeutic agent, as a medicament or in the preparation of a medicament for treating arthritis.
  • the medicament may be suitable for use in treating arthritis or is suitable for use in patients who are at risk of developing a condition disclosed herein.
  • the invention contemplates pharmaceutical packs or kits comprising a compound of the formula I or a pharmaceutical composition disclosed herein, and optionally a second therapeutic agent.
  • the invention is directed to a kit comprising a first container comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula I and at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle.
  • the kit may further comprise a second container comprising a second therapeutic agent.
  • a pharmaceutically acceptable salt in particular an acid addition salt, of a compound of the formula I is provided for use in the compositions, formulations, dosage forms, methods, uses and kits of the invention. Due to its solubility in water and its dissolution rate, a pharmaceutical composition, formulation or unit dosage form comprising a salt may be obtained with an acceptable bioavailability.
  • a compound of the formula I that is particularly useful is 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine.
  • a compound of the formula I that is particularly useful is an acid addition salt of 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l- yl)-pyridazine.
  • a compound of the formula I that is particularly useful is a halide salt of 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)- pyridazine.
  • a compound of the formula I that is particularly useful is 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine hydrochloride.
  • Figure 1 is a graph showing the arthritis severity score for high and low doses of 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine hydrochloride in an EAE model.
  • Figure 2 is a graph showing the radiographic scores for high and low doses of 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine hydrochloride.
  • Figure 3 is a graph showing arthritis onset for high and low doses of 6- phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin- 1 -yl)-pyridazine hydrochloride.
  • Figure 4 is a graph showing dose-dependent inhibition of induction of TNFa, IL- ⁇ ⁇ , and MCP-l/CCL-2 by increasing concentrations of 6-phenyl-4-pyridin-4-yl- 3-(4-pyrimidin-2-yl-piperazin-l -yl)-pyridazine hydrochloride in stimulated mouse RAW264.7 macrophages.
  • Figure 5 is a graph showing dose-dependent inhibition of induction of TNFa and IL- ⁇ ⁇ by increasing concentrations of 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2- yl-piperazin-l -yl)-pyridazine hydrochloride in stimulated human synovial fibroblasts.
  • a compound of formula I includes pharmaceutically acceptable salts, solvates and complexes thereof and solvates and complexes of salts thereof, polymorphs, prodrugs, dehydrates, crystals, co-crystals, anhydrous and amorphous forms, and isomers thereof (including optical, geometric and tautomeric isomers).
  • pharmaceutically acceptable salt(s) refers to a salt that is pharmaceutically acceptable and has the desired pharmacokinetic properties.
  • salts are meant those salts which are suitable for use in contact with the tissues of a subject or patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are described for example, in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66: 1 and the Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta-Zurich, 2002, 329-345.
  • Suitable salts include salts that may be formed where acidic protons in the compounds are capable of reacting with inorganic or organic bases.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, magnesium, calcium, aluminum, lithium, ammonium, iron, zinc, copper, manganese salts and the like.
  • the inorganic salts are sodium, potassium or ammonium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, polyamine resins and the like.
  • the organic salts are ethylenediamine, diethylamine, ethanolamine and trimethylamine salts.
  • Particularly suitable salts include acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like) and organic acids (e.g. acetic acid, trifluoroacetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and benezenesulfonic acid, hydroxyacetic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, oxalic acid, tartaric acid, succinic acid, ascorbic acid, benzoic acid, tannic acid, cinnamic acid, mandelic acid, salicylic acid, glycolic acid, pamoic acid, formic acid, and the like).
  • the salts are sulfate salts.
  • the salts are halide salts.
  • a pharmaceutically acceptable addition salt may be a mono-acid-mono-salt, or when there are two or three acidic groups present, a di-salt or a tri-salt, or mixtures of these salts; and similarly where there are more than three or more acidic groups present, some or all of such groups can be salified.
  • a compound of the formula I that is particularly useful is an acid addition salt of 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l- yl)-pyridazine.
  • a compound of the formula I that is particularly useful is a halide salt of 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l -yl)- pyridazine.
  • a compound of the formula I that is particularly useful is 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine hydrobromide.
  • a compound of the formula I that is particularly useful is 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine hydrochloride.
  • compositions, formulations, dosage forms, methods, uses and kits of the invention comprise at least one of 6-phenyl-4-pyridin- 4-yl-3-(4-pyrimidin-2-yl-piperazin-l -yl)-pyridazine.
  • HC! (1 : 1), 6-phenyl-4-pyridin- 4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine.
  • HCl (2: 1) 6-phenyl-4-pyridin- 4-yl-3-(4-pyrimidin-2-yl-piperazin-l -yl)-pyridazine.HBr or 6-phenyl-4-pyridin-4-yl-
  • compositions, formulations, dosage forms, methods, uses and kits of the invention comprise at least one of 6-phenyl-4-pyridin-
  • a “solvate” refers to a physical association of a compound with one or more solvent molecules or a complex of variable stoichiometry formed by a solute (for example, ethanol or cyclohexanehexol) and a solvent, for example, water, ethanol, or acetic acid.
  • a solute for example, ethanol or cyclohexanehexol
  • a solvent for example, water, ethanol, or acetic acid.
  • Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • the term “hydrate” means a solvate wherein the solvent molecule(s) is/are H 2 0, including, mono-, di-, and various poly-hydrates thereof. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • the solvents selected do not interfere with the biological activity of the solute.
  • Solvates encompass both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like. Solvates can be formed using various methods known in the art. The amount of solvent used to make solvates can be determined by routine testing. For example, a monohydrate of a compound of the formula I may have about 1 equivalent of solvent (H 2 0) for each equivalent of a compound of the formula I. However, more or less solvent may be used depending on the choice of solvate desired.
  • solvates which can form crystal structures via hydrogen bonding, van der Waals forces, or dispersion forces, or a combination of any two or all three forces.
  • a compound of the formula I may be amorphous or may have different crystalline polymorphs, possibly existing in different solvation or hydration states.
  • crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
  • Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility.
  • prodrug means a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
  • prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood, and generally include esters and amide analogs of the parent compounds.
  • the prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
  • prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
  • Prodrugs may be produced by replacing appropriate functionalities in a compound of the formula I with certain moieties known to those skilled in the art as 'pro-moieties' (for example, see the methods as described, in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991 , particularly Chapter 5: "Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol.
  • a compound of the formula I includes all stereoisomers, geometric isomers and tautomeric forms, including compounds of the formula I exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • a pharmaceutically acceptable salt of a tautomeric, geometric or stereoisomeric form is also contemplated herein.
  • a compound of the formula I includes without limitation, cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S- enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof.
  • Individual enantiomers may be isolated using conventional methods such as chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • a racemate (or a racemic precursor) may also be reacted with a suitable optically active compound, for example, an alcohol, or, an acidic or basic moiety of a compound of the formula I.
  • Stereoisomeric mixtures may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel and Samuel H. Wilen (Wiley India Pvt. Ltd, 2009).
  • a mixture of diastereoisomers may be separated by chromatography and/or fractional crystallization, and one or both of the diastereoisomers may be converted to corresponding pure enantiomer(s).
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1 , or 100:0 isomer ratios are all contemplated by the present invention.
  • a compound of the formula I also includes a compound of the formula I which is substituted.
  • substituted refers to the replacement of one or more moiety of a compound of the formula I with a selected group provided that the designated atom's normal valency is not exceeded, and the substitution results in a stable compound having a profile of activity that suggests it is useful in the treatment of arthritis. Combinations of substituents and/or radicals are permissible only if such combinations result in stable compounds with the desired activity.
  • “Stable compound” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Selected substituents include acyl, nitro, cyano, hydroxyl, carboxyl, O, S, C]-C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, C1 -C4 alkoxy and haloalkyl.
  • C] -C6 alkyl includes a branched or straight chained monovalent saturated aliphatic hydrocarbon radical containing from 1 to 6 carbon atoms.
  • Examples of Ci-C 6 alkyl groups include but are not limited to methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, sec-butyl, tert- butyl, tert-pentyl, n-hexyl, and the like.
  • C2-C4 alkenyl includes a branched or straight hydrocarbon chain of 2 to 4 carbon atoms with at least one double bond.
  • C2-C4 alkenyl groups include but are not limited to, ethenyl, propen-l-yl, propen-2-yl (isoprenyl), propen-3-yl (allyl), 2-methyl-propen-3-yl, 2-buten-4-yl, 2-methyl- propen- 1 -yl, 2-buten- 1 -yl, 1 -buten- 1 -yl, and the like.
  • C2-C4 alkynyl includes a branched or straight hydrocarbon chain of 2 to 4 carbon atoms with at least one carbon-carbon triple bond.
  • suitable C2-C4 alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, propyn-3-yl, 2-methyl-propyn-3-yl, 2-butyn-4-yl, 2-methyl-propyn-l- yl, butyn-l-yl, butyn-3-yl, and the like.
  • halo or halogen includes halogen groups such as fluoro, chloro, bromo or iodo atoms.
  • C1 -C4 alkoxy includes a straight or branched oxy-containing radical having an alkyl portion of one to four carbon atoms.
  • suitable C1-C4 alkoxy groups include, but are not limited to methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls.
  • haloalkyl includes a Ci -C 6 alkyl group, which is substituted with one or more halo atoms selected from fluoro, chloro, bromo, and iodo.
  • haloalkyl groups include but are not limited to trifluoromethyl, CH 2 CF 3 and the like.
  • acyl includes a "-COR” group where R is hydrogen, Ci-C 6 alkyl, halo, haloalkyl, and/or C1-C4 alkoxy.
  • R is hydrogen, Ci-C 6 alkyl, halo, haloalkyl, and/or C1-C4 alkoxy.
  • acyl groups include but are not limited to those in which the alkyl group is Ci-C 6 alkyl, in particular formyl, acetyl and propionyl.
  • a compound of the formula I including a pharmaceutically acceptable salt thereof may be prepared by the processes described herein and any process known to be applicable to the preparation of chemically-related compounds.
  • subject refers to an animal including a warm-blooded animal, such as a mammal.
  • Mammal includes without limitation any member of the kingdom Mammalia.
  • Mammal includes humans, but the term also includes domestic animals bred for food or as pets, such as horses, cows, sheep, poultry, fish, pigs, cats, dogs, and zoo animals, goats, apes (e.g. gorilla or chimpanzee), and rodents such as rats and mice.
  • Subjects for treatment include mammals, such as humans, susceptible to, suffering from, suspected of having being pre-disposed, at risk for, or that have suffered a condition disclosed herein.
  • a subject or individual who is "suffering from” a disease, disorder, and/or condition has been diagnosed with or displays one or more symptoms of the disease, disorder, and/or condition.
  • a subject or individual who is "susceptible to" a disease, disorder, and/or condition has not been diagnosed with the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.
  • a subject or individual "at risk” for a disease, disorder, and/or condition disclosed herein includes a subject with one or more risk factors for developing the condition.
  • Risk factors include, but are not limited to, gender, age, genetic predisposition, smoking and tobacco use, joint injury, occupation, body weight and bacterial infection.
  • a compound of the formula I has been found to modify, in particular suppress, inflammatory cytokine (e.g. TNF-a, IL-1 or IL-6) production from cells involved in arthritis, diseases associated with arthritis may be treated in accordance with the invention.
  • inflammatory cytokine e.g. TNF-a, IL-1 or IL-6
  • arthritis includes rheumatic disease and other conditions that can cause pain, stiffness and swelling in the joints.
  • the pathology associated with arthritis in a subject may include pathology associated with inflammatory events such as excessive activation of glia, macrophages and/or synoviocytes and their increased production of endogenous proinflammatory mediators including cytokines, chemokines, complement proteins and/or reactive free radicals.
  • the pathology may also include leukocyte infiltration, destruction of collagen, erosive bone damage, abnormal growth and division of synovium cells, joint effusion, synovial hyperplasia, synovial pannus, invasion of abnormal synovial cells into cartilage and bone, weakening of muscles, ligaments and tendons in joints, bone loss, cartilage depletion, pain, swelling, stiffness, fatigue, loss of joint range of motion, rheumatoid nodules or lumps under the skin, accumulation of fluid in joints, reduction in red blood cells, and/or inflammation of the blood vessels, the lining of the lungs or the sac enclosing the heart.
  • the pathology includes marked growth of synovial cells, formation of a multilayer structure due to abnormal growth of the synovial cells (pannus formation), invasion of the synovial cells into cartilage tissue and bone tissue, vascularization toward the synovial tissue, and infiltration of inflammatory cells such as lymphocytes, synoviocytes and/or macrophages.
  • Arthritis includes without limitation rheumatoid arthritis, osteoarthritis
  • hypotrophic or degenerative arthritis hypertrophic or degenerative arthritis
  • psoriatic arthritis infectious arthritis (e.g. Lyme disease, tuberculosis, rheumatic fever, etc), suppurative arthritis, juvenile arthritis, and gouty arthritis.
  • infectious arthritis e.g. Lyme disease, tuberculosis, rheumatic fever, etc
  • suppurative arthritis juvenile arthritis, and gouty arthritis.
  • rheumatoid arthritis refers to an autoimmune inflammatory disease that causes pain, swelling, stiffness, and loss of function in the joints. It can be distinguished from other kinds of arthritis since it generally occurs in a symmetrical pattern, it often affects the wrist joints and the finger joints closest to the hand, and it can also affect other parts of the body besides the joints.
  • rheumatoid Arthritis National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, NIH Publication No. 09-4179, April, 2009
  • CPMP - Committee for Proprietary Medicinal Products "Note for Guidance on Clinical Investigation of Medicinal Products for the Treatment of Rheumatoid arthritis." London, 16 November 2006, Doc. Ref. CPMP/EWP/561/98 Rev. 1.]
  • the term includes all types of rheumatoid arthritis and its variants including without limitation, classical rheumatoid arthritis, chronic rheumatoid arthritis, spondylitic rheumatoid arthritis, psoriatic rheumatoid arthritis, osteorheumatoid arthritis, Felty's syndrome, Caplan's syndrome, malignant rheumatoid arthritis, seronegative rheumatoid arthritis, progressive and/or relapsing rheumatoid arthritis, juvenile idiopathic arthritis or juvenile rheumatoid arthritis, and rheumatoid arthritis with vasculitis.
  • the rheumatoid arthritis is chronic rheumatoid arthritis.
  • osteoarthritis also referred to as degenerative joint disease
  • degenerative joint disease is associated with degradation and breakdown of cartilage in joints resulting in pain, swelling, and loss of motion of the joint. It commonly occurs in the hips, knees and spine, often affects the finger joints, the joint at the base of the thumb, and the joint at the base of the big toe. The disease is especially common with older people.
  • osteoarthritis is generally assessed based on the patient's description of symptoms, the location and pattern of pain, and certain findings upon physical examination. Radiological methods such as x-rays of affected joints, and determination of The Western Ontario and McMaster Universities Osteoarthritis Index (“WOMAC”) can also be used to diagnose the disease (see e. g., Creamer et al.
  • WOMAC Western Ontario and McMaster Universities Osteoarthritis Index
  • Osteoarthritis also includes, without limitation, steroidal osteoporosis, disuse osteoporosis due to pain, local juxta- articular osteoporosisautoimmune, early stage osteoarthritis, and late stage osteoarthritis.
  • “Late stage osteoarthritis” is characterized by tender joints, joint deformity, a loss of mobility and new bone formation (osteophytes). Passive joint movement during examination may elicit crepitus or the grinding of bone-on-bone as the joint moves. X-rays may reveal obliteration of the joint space and misalignment of the joint.
  • Psoriatic arthritis refers to a chronic condition commonly associated with psoriasis that affects the skin, the joints, the insertion sites of tendons, ligaments, and fascia.
  • diseases accompanying arthritis may be treated in accordance with the invention.
  • diseases include without limitation, systemic lupus erythematosus, polymyositis, Bechet's disease, Sjogren's syndrome, mixed connective tissue disease, and overlap syndrome.
  • a patient is typically diagnosed with arthritis based on clinical symptoms but other diagnostic tests may be utilized including without limitation, erythrocyte sedimentation rate, biomarkers, X-rays, arthroscopy and joint aspiration.
  • diagnostic tests for rheumatoid arthritis may include, without limitation, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, biomarkers (e.g. anti-CCP antibodies, interleukin-6, interleukin-3, and/or timp-l), antinuclear antibody, X-rays and joint aspiration.
  • a patient may be in the early phases of exacerbation of arthritis.
  • the term "early phases of exacerbation of arthritis” refers to a progressive stage of the disease where the disease activity is still moderate or low and/or where the inflammatory cytokine levels in joints is increased compared to a standard where the standard is the average inflammatory cytokine levels in the joints of healthy individuals.
  • a person skilled in the art can determine disease activity and inflammatory cytokine levels in samples including joints and tissue or any other sample using methods known in the art.
  • disease activity or the level of disease activity refers to the stage and severity of arthritis. Disease activity can be evaluated using different disease scores. For example, disease activity for rheumatoid arthritis can be evaluated using the "disease activity score 28" (DAS28) (van Riel, Piet LCM and Fransen, J, Arthritis Res Ther. 2005, 7(5): 189-190).
  • DAS28 score is determined based on the number of swollen joints, the number of painful joints, erythrocyte sedimentation rate and other factors. In embodiments, a subject has no disease or low disease activity and a DAS28 score of between 0 and 3.2.
  • a subject has moderate disease activity and a DAS28 score between 3.2 and 5.1. In embodiments, a subject has high disease activity and a DAS28 score above 5.1.
  • the compounds, compositions and methods of the invention may have particular utility for subjects with a DAS28 score of up to 5.1, in particular a DAS28 score up to 3.2.
  • the subject has a value for the DAS28 of up to or less than 5.1. In other aspects, the subject has a DAS28 score of up to or less than 3.2.
  • treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or exhibits only early signs of the disease, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • the term in some aspects of the invention may refer to preventing a disease, disorder, and/or condition, and includes preventing the onset, or preventing the symptoms associated with a disease, disorder, and/or condition.
  • the term also includes maintaining the disease, disorder, and/or condition and/or symptom such that the disease, disorder, and/or condition and/or symptom do not progress in severity.
  • a treatment may be either performed in an acute or chronic way.
  • the term also refers to reducing the severity of a disease, disorder, and/or condition or symptoms associated with such disease, disorder, and/or condition prior to affliction with the condition.
  • Such prevention or reduction of the severity of a disease, disorder, and/or condition prior to affliction refers to administration of a compound of the formula I, or composition, or combination of the present invention to a subject that is not at the time of administration afflicted with the disease, disorder, and/or condition.
  • Preventing also includes preventing the recurrence of a disease, disorder, and/or condition, or of one or more symptoms associated with such disease, disorder, and/or condition.
  • treatment and “therapeutically” refer to the act of treating, as “treating” is defined above.
  • the purpose of intervention is to combat the condition and includes the administration of an active compound or combination to prevent or delay the onset of the symptoms or complications, or alleviate the symptoms or complications, or eliminate the disease, disorder, and/or condition.
  • an active compound or combination to prevent or delay the onset of the symptoms or complications, or alleviate the symptoms or complications, or eliminate the disease, disorder, and/or condition.
  • a compound, composition, or combination disclosed herein may be used to ameliorate symptoms associated with rheumatoid arthritis.
  • maintenance therapy refers to treatment of a disease, disorder and/or condition during phases when the disease, disorder and/or condition is not active or disease activity is low. Maintenance therapy is directed at preventing disease exacerbation or disease progression.
  • administering refers to the process by which a compound of the formula I, compositions, dosage forms and/or combinations disclosed herein are delivered to a subject for treatment or prophylactic purposes.
  • Compounds of the formula 1, compositions, dosage forms and/or combinations are administered in accordance with good medical practices taking into account the subject's clinical condition, the site and method of administration, dosage, subject age, sex, body weight, and other factors known to the physician.
  • administering refers to (1) providing, giving, dosing and/or prescribing by either a health practitioner or his/her authorized agent or under his/her direction a compound of the formula I, compositions, dosage forms and/or combinations disclosed herein, and (2) putting into, taking or consuming by the patient or individual himself or herself, a compound of the formula I, compositions, dosage forms and/or combinations disclosed herein.
  • a “combination treatment,” “in combination with” or “administered in combination” means use of multiple pharmaceutical agents in combination as active ingredients administered concurrently to a subject being treated.
  • the terms include use as a combination drug, use as a kit, and use in a combination characterized by independent administration of each by the same or different administration routes and the like.
  • each component When administered in combination, each component may be administered at the same time, or sequentially in any order at different points in time. Therefore, each component may be administered separately, but sufficiently close in time to provide a desired effect, such as an additive or synergistic effect.
  • the first compound may be administered in a regimen that additionally comprises treatment with a second therapeutic agent.
  • the terms refer to the administration of a compound of the formula I or a composition of the invention, and a second therapeutic agent including separate administration of medicaments each containing one of the compounds, as well as simultaneous administration whether or not the compounds are combined in one formulation or whether they are in separate formulations.
  • additive effect of a compound of the formula I and a second therapeutic agent refers to an effect that is equal to the sum of the effects of the two individual agents.
  • a “synergistic effect" of a compound of the formula I and a second therapeutic agent refers to an effect that is greater than the additive effect that results from the sum of the effects of the two individual agents.
  • phrases "pharmaceutically acceptable carrier, excipient, and (or) vehicle” refers to a medium which is useful for the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable. It is generally selected so that it does not interfere with the effectiveness or activity of an active ingredient and is not toxic to the hosts to which it is administered.
  • the phrase as used in the specification and claims includes one, and more than one such carrier, excipient, or vehicle. Acceptable carriers, excipients, or vehicles may be chosen or selected from any of those commercially used in the art.
  • a carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, adjuvants, preservatives, agents for delaying absorption, fillers, adsorbents, buffers, solubilizing agents, other inert ingredients, or combinations thereof, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition.
  • Examples of carriers, excipients, and vehicles include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
  • “Therapeutically effective amount” refers to the amount or dose of active compound(s) or a composition of the invention that will lead to one or more desired effects, in particular therapeutic effects.
  • a therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance to elicit a desired response in the individual.
  • a dosage regimen may be adjusted to provide the optimum therapeutic response (such as sustained therapeutic effects). For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • “Suboptimal dose” refers to a dose of an active compound which is less than the optimal dose for that compound when used in monotherapy.
  • a “unit dosage form” refers to a unitary, i.e. a single dose, which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active agent(s) as such or a mixture with one or more solid or liquid pharmaceutical excipients, carriers, or vehicles.
  • compositions comprising a compound of the formula I may be formulated as sterile, substantially isotonic, and in full compliance with all Good Manufacturing Practice (GMP) regulations of appropriate regulatory authorities such as the US Food and Drug Administration.
  • the compositions will typically include at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle and the active compound and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, and the like.
  • Carriers, excipients, and vehicles are generally selected based on the intended form of administration, and consistent with conventional pharmaceutical practices.
  • a compound of the formula I may be administered by any of the accepted modes of administration, in particular systemic administration including oral, subdermal, intramuscular, parenteral, and other systemic routes of administration.
  • Any pharmaceutically acceptable form of administration can be used, including solid, semi-solid, or liquid dosage forms, such as for example, tablets, pills, capsules, powders, liquids, suspensions, or the like.
  • Those dosage forms may be in a unit dosage form suitable for administration of precise dosages, or in sustained or controlled dosage forms, such as extended release forms, for the prolonged administration of the compound at a predetermined rate.
  • Parenteral administration is generally characterized by injection, whether subcutaneously or intramuscularly.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspension, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients include, for example, water, saline, aqueous dextrose, glycerol, ethanol or the like.
  • the pharmaceutical compositions may also contain minor amounts of non-toxic substances such as wetting or emulsifying agents, auxiliary pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and the like.
  • a compound of the formula 1 may be administered in substantially pure form as a powder or a powder contained in, for example, a gelatin capsule. It may also be administered in solid compositions with conventional non-toxic carriers, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used.
  • conventional non-toxic carriers for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used.
  • a compound of the formula I may be admixed, encapsulated, conjugated or otherwise associated with molecules to facilitate uptake, distribution and/or absorption of the compound.
  • Various known delivery systems can be used to administer a medicament of the invention, e.g. encapsulation in liposomes, microparticles, microcapsules, and the like.
  • a compound of the formula I may be included in a pharmaceutical composition formulated for slow release, such as in microcapsules formed with biocompatible polymers, polymer coated multiparticulates or in liposomal carrier systems according to methods known in the art.
  • the compositions may also be advantageously administered as bi-layer tablets containing an immediate release component and a delayed release component.
  • a compound of the formula I may be covalently conjugated to a water soluble polymer, such as a polylactide or biodegradable hydrogel derived from an amphipathic block copolymer, as described in U.S. Pat. No. 5,320,840.
  • a compound of the formula I may also be incorporated into a polymer or multi-polymer matrix having properties that release the active compound through diffusion from the matrix, erosion of the matrix or a combination of diffusion and erosion.
  • compositions are advantageously compounded into unit dosage forms containing a predetermined, standard amount of the active pharmaceutical ingredient, to make dosing and patient compliance simpler.
  • Dosage forms including capsules, tablets, liquid or controlled release delivery forms, may be formulated and manufactured to contain, for example, about 0.1 to about 1000 mg, 0.1 to about 500 mg, 0.1 to about 400 mg, 0.1 to about 200 mg, 0.1 to about 100 mg, 1 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 400 mg, 1 mg to about 300 mg, 1 mg to about 200 mg, 1 mg to about 100 mg, 1 mg to about 50 mg, 5 mg to about 500 mg, 5 mg to about 400 mg, 5 mg to about 300 mg, 5 mg to about 200 mg, 5 mg to about 100 mg, 5 mg to about 75 mg, 5 mg to about 50 mg, 10 mg to about 500 mg, 10 mg to about 400 mg, 10 mg to about 300 mg, 10 mg to about 200 mg, 10 mg to about 100 mg, 10 mg to about 75 mg, 10 mg to about 50 mg, 20 mg to
  • a unit dosage form comprises about 0.5 mg to 500 mg, 1 mg to 500 mg, 1 mg to 100 mg, 5 mg to 500 mg, 5 mg to 100 mg, 10 mg to 100 mg or 50 to 500 mg, and in particular 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 25 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 120 mg, 140 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg or 500 mg, more particularly 10 mg, 50 mg, 60 mg, 70 mg, 75 mg, 85 mg, 100 mg, 150 mg, 200 mg, 250 mg, 400 mg or 500 mg of a compound of the formula I.
  • a unit dosage form comprises about 0.1 to 1000 mg/day, 0.1 to 500 mg/day, 0.1 to 400 mg/day, 0.1 to 200 mg/day, 0.1 to 100 mg/day, 1 mg/day to about 1000 mg/day, 1 mg/day to about 500 mg/day, 1 mg/day to about 400 mg/day, 1 mg/day to about 300 mg/day, 1 mg/day to about 200 mg/day, 1 mg/day to about 100 mg/day, 1 mg/day to about 75 mg/day, 1 mg/day to about 50 mg/day, 1 mg/day to about 25 mg/day, 1 mg/day to about 10 mg/day, 5 mg/day to about 500 mg/day, 5 mg/day to about 400 mg/day, 5 mg/day to about 300 mg/day, 5 mg/day to about 200 mg/day, 5 mg/day to 100 mg/day, 5 mg/day to 75 mg/day, 10 mg/day to about 500 mg/day, 10 mg/day to about 400 mg/day, 10 mg/day to about 300 mg/day,
  • the amount of compound of the formula I administered ranges from 1 to 500 mg/day or 5 to 500 mg/day. In embodiments, the amount of compound of the formula I administered ranges from 5 to 100 mg/day. In embodiments, the amount of compound of the formula I administered ranges from 50 to 500 mg/day.
  • the amount of active compound administered will be dependent on the subject being treated, the amount or severity of the condition, the particular disease state being treated, the manner of administration and the judgment of the prescribing physician.
  • an effective dosage of a compound of the formula I may be in the range of about 0.01 to 100 mg/kg body weight, 0.01 to 50 mg/kg body weight, 0.1 to 100 mg/kg body weight, 0.1 to 50 mg/kg body weight, 0.1 to 25 mg/kg body weight, 0.1 to 20 mg/kg body weight, 0.1 to 10 mg/kg body weight, 1 to 100 mg/kg body weight, 1 to 50 mg/kg body weight, 1 to 20 mg/kg body weight, 1 to 10 mg/kg body weight, in particular, about 0.1 to 50 mg/kg body weight, more particularly about 0.1 to 25 mg/kg body weight, and most particularly about 0.1 to 10 mg/kg body weight or 1 to 10 mg/kg body weight.
  • the amount of a compound of the formula I administered to the subject ranges from about 0.1 to 1000 mg, 0.1 to 500 mg, 0.1 to 400 mg, 0.1 to 200 mg, 0.1 to 100 mg, 1 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 400 mg, 1 mg to about 300 mg, 1 mg to about 200 mg, 1 mg to about 100 mg, 1 mg to about 50 mg, 5 mg to about 500 mg, 5 mg to about 400 mg, 5 mg to about 300 mg, 5 mg to about 200 mg, 5 mg to 100 mg, 5 mg to 75 mg, 10 mg to about 500 mg, 10 mg to about 400 mg, 10 mg to about 300 mg, 10 mg to about 200 mg, 10 mg to 100 mg, 10 mg to 75 mg, 10 mg to 50 mg, 20 mg to about 500 mg, 20 mg to about 400 mg, 20 mg to about 300 mg, 20 mg to about 200 mg, 20 mg to 100 mg, 20 mg to 75 mg, 50 mg to about 1000 mg, 50 mg to about 500 mg, 50 mg to about 400 mg, 50 mg to about 100 mg, 1 mg to
  • the duration of treatment can be adapted to the conditions of the patient.
  • a subject may be treated with a compound of the formula I, or a composition, unit dosage form or formulation thereof, on substantially any desired schedule.
  • a compound of the formula I, unit dosage form, formulation or composition of the invention may be administered one or more times per day, in particular 1 or 2 times per day, once per week, once a month or continuously. However, a subject may be treated less frequently, such as every other day or once a week, or more frequently.
  • Daily dosages may be achieved by once a day, twice a day, three times daily or four times daily administration, preferably once a day administration.
  • a compound of the formula I is administered in a single dose, once daily.
  • a compound of the formula I is administered twice daily.
  • a compound of the formula I is administered three times per day.
  • a compound of the formula I is administered four times per day.
  • a compound of the formula I, composition, unit dosage form or formulation of the invention may be administered to a subject for about or at least about 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks to 4 weeks, 1 week to 10 weeks, 1 week to 20 weeks, 1 week to 24 weeks, 1 week to 48 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 15 weeks, 2 weeks to 16 weeks, 2 weeks to 20 weeks, 2 weeks to 24 weeks, 2 weeks to 48 weeks, 2 weeks to 18 months, or 2 weeks to 24 months, periodically, consecutively or continuously.
  • Dosage forms or compositions may be prepared containing a compound of the formula I in the range of 0.25 to 100%, with the balance, when less than 100%, is made up from non-toxic carriers, excipients or vehicles.
  • a pharmaceutically acceptable non-toxic composition is formed, optionally with the incorporation of any of the normally employed pharmaceutical carriers, excipients or vehicles and may contain 1 %-100% active ingredient, preferably 25%-75%.
  • Percentages recited in the compositions herein are weight percentages or w/w.
  • a compound of the formula I or composition of the invention is administered as one or more doses daily, in particular a single dose, intravenously.
  • about 1 to 500 mg/day, in particular about 5 to 400 mg /day, more particularly about 5 to 75 mg/day or 50 to 500 mg/day of a compound of the formula I or composition of the invention is administered once or twice daily.
  • a compound of the formula I may be administered in combination with other medications (such as second therapeutic agents) or other medical procedures to treat the same or other aspects of the disease state being treated.
  • a second therapeutic agent may either be within the same pharmaceutical composition (combination compositions), or the two agents may be administered in separate compositions at substantially the same time or at different times as required in the judgment of the prescribing physician.
  • the second therapeutic agent may be a disease modifying arthritis drug (DMARD).
  • DMARDs examples include immunomodulatory agents (gold sodium thiomalate, auranofin, penicillamine, salazosulfapyridine, bucillamine, lobenzarit, actarit, etc.), immunosuppressive agents (methotrexate, leflunomide, mizoribine, azathioprine, cyclophosphamide, cyclosporine, tacrolimus, etc.), chimeric TNFa monoclonal antibody (infliximab), pegylated anti-TNF agents, soluble TNF receptor fusion protein (etanercept), gold (oral or intramuscular), staphylococcal protein A immunoadsorption, human anti-TNFa monoclonal antibody (adalimumab), IL-1 receptor antagonist, and humanized anti-IL-6 receptor antibody (MRA).
  • immunomodulatory agents gold sodium thiomalate, auranofin, penicillamine, salazosulfapyridine, bucillamine, lobenzarit,
  • a pharmaceutical agent applied to rheumatic diseases such as a non-steroidal anti-inflammatory drug (NSAID) may also be administered in combination.
  • NSAIDs comprise or may be selected from the group consisting of NSAID's (Cox-2 selective or non-selective), Methotrexate, Sulfasalazine, Hydroxychloroquine, Leflunomide (e.g. AravaTM), Minocycline (MinocinTM), Azathioprine, Etanercept (e.g. EnbrelTM), Infliximab (e.g. RemicadeTM), Adalimumab (e.g.
  • HumiraTM HumiraTM
  • Rituximab Abatacept
  • Anakinra e.g. KineretTM
  • cyclosporine e.g. NeoralTM, SandimmuneTM and generics
  • gold sodium thiomalate MyochrysineTM and generics
  • the present invention relates to further administering one or more agents selected from the group consisting of: 6-(5-carboxy-5-methyl-hexyloxy)-2, 2- dimethyl-hexanoic acid calcium salt, non-steroidal anti-inflammatory agents, piroxicam, diclofenac, naproxen, flurbiprofen, fenoprofen, ketoprofen, ibuprofen, mefenamic acid, indomethacin, sulindac, apazone, phenylbutazone, aspirin, celecoxib, parecoxib, valdecoxib, etoricoxib, corticosteroids, hyalgan, and synvisc.
  • osteoarthitic pain may be treated with an anti-IL-6 antibody or an anti-IL-6 receptor antibody.
  • the dose of the second therapeutic agent can be determined according to the dose employed clinically, and having regard to the age and body weight of the subject, condition, administration time, dosage form, administration method, combination and the like.
  • the mode of administration of the second therapeutic agent is not particularly limited.
  • the invention also relates to articles of manufacture and kits containing materials useful for treating a condition disclosed herein.
  • An article of manufacture may comprise a container. Examples of suitable containers include bottles, vials, and test tubes which may be formed from a variety of materials including glass and plastic.
  • a container holds a medicament or formulation of the invention comprising a compound of the formula I or pharmaceutical composition disclosed herein, and optionally a second therapeutic agent which is effective for treating a condition disclosed herein.
  • the container may have a label which indicates that the medicament or formulation is used for treating the condition, and may also indicate directions for use.
  • a medicament or formulation in a container may comprise any of the medicaments or formulations disclosed herein.
  • a kit may additionally include other materials desirable from a commercial end user standpoint, including, without limitation, buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods disclosed herein.
  • a medicament or formulation in a kit of the invention may comprise any of the compounds or compositions disclosed herein.
  • a kit comprising a compound of the formula I or pharmaceutical composition disclosed herein, and optionally one or more second therapeutic agent.
  • the kit can be a package which houses a container which contains a compound of the formula I or pharmaceutical composition disclosed herein, and also houses instructions for administering the compound of the formula I or pharmaceutical composition disclosed herein.
  • Written materials may also be associated with the container such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the labeling, manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • the invention relates to a commercial package comprising a compound of the formula I or pharmaceutical composition disclosed herein together with instructions for simultaneous, separate or sequential use.
  • a label may include amount, frequency, and method of administration.
  • 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine was manufactured using a 4-step synthesis which results in the formation of a hydrochloride salt.
  • the 4-step synthetic route begins with coupling of the starting material, 3-chloro-6-phenyl-pyridazin-4-ol, by displacement of the chloro group with pyrimidyl piperazine to form the backbone of the molecule. This reaction is carried out in a sealed vessel using dimethylacetamide as the solvent.
  • the second step is the conversion of the hydroxy group to a chloro compound using phosphorus oxychloride POCI3 and is followed by a Suzuki coupling of the compound formed in the second step to 4-pyridine using a palladium catalyst.
  • the resulting compound is the free base of the product.
  • the free base of the molecule is treated with a palladium scavenger (Mercapto- functionalized silica gel).
  • the final step of the synthesis is the formation of a hydrochloride salt.
  • the free base is treated with hydrochloric acid (HC1) in isopropyl alcohol (IPA) to yield the drug substance as a hydrochloride salt.
  • IPA isopropyl alcohol
  • the resulting materia] is dried in a drying oven under vacuum to reduce moisture, residual hydrochloride and residual isopropanol.
  • the drug substance has an empirical formula of C23H21N7 and a molecular weight of 395.47 (free-base) and it is a light yellow to orange powder that is slightly hygroscopic and soluble in water.
  • the product is available as a sterile concentrated solution in 0.9% sodium chloride at 2.5 mg base/mL with pH approximately 2.4 which is further diluted prior to intravenous (iv) administration at higher pH.
  • the concentrated drug product may be further diluted with sterile 0.9% sodium chloride to concentrations ranging from 0.1 to 0.4 mg/mL (pH of approximately 3.5 to 3.0) prior to administration to subjects/patients.
  • the shelf life of the drug substance and concentrated drug substance stored between 2 and 8°C is about 2-6 months, in particular 2-4 months, more particularly 2-3 months.
  • Lewis rats were immunized with porcine type II collagen on day 0 and collagen-induced arthritis (CIA) was evident on day 11.
  • a total of 54 rats were randomized to vehicle controls or 2 treatment arms (test compound at lmg/kg or 7 mg/kg). Based on the degree of joint involvement and soft tissue swelling, each limb was scored from 0-4, with a maximum total score of 16.
  • serum was harvested for subsequent cytokine profiles, the left hind limb was fixed for immunochemistry, the right hind limbs were microdissected to obtain pure synovium for gene expression profiles and gene hub, module and network analysis. Hind limbs were also evaluated by high resolution digital radiographic imaging.
  • test compound In stimulated human RAW264.7 macrophages and synovial fibroblasts, increasing concentrations of the test compound dose-dependently inhibited the induction of key cytokines relevant to the pathology of RA including TNFa, IL-6, RANTES and MCP-l/CCL-2.
  • key cytokines relevant to the pathology of RA including TNFa, IL-6, RANTES and MCP-l/CCL-2.
  • Lewis rats virtually all controls developed CIA on day 1 1 but test compound recipients had a delayed arthritis onset (p ⁇ 0.03) (Figure 3).
  • the clinical severity was significantly lower than vehicle controls for test compound (at all doses) within 24 hours of disease onset and this was sustained throughout the study ( Figure 1).
  • the test compound at both doses, markedly inhibited clinical disease (p ⁇ 1 x 10 " '° vs. controls).
  • Radiographic damage was also suppressed (at lmg/kg and 7mg kg, p ⁇ 2 x 10 "6 and p ⁇ 2 x 10 "7 , respectively) ( Figure 2).
  • the test compound inhibited inflammatory cytokine pathways and suppressed CIA.
  • test compound In stimulated mouse RAW264.7 macrophages and human synovial fibroblasts, increasing concentrations of the test compound dose-dependently inhibited the induction of key cytokines relevant to the pathology of RA including TNFa, IL-1 ⁇ , IL-6, RANTES and MCP-l/CCL-2 (See Figures 4 and 5).
  • 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine hydrochloride inhibited inflammatory cytokine pathways in cell lines that are relevant to the development of rheumatoid arthritis.
  • 6-phenyl-4- pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin-l-yl)-pyridazine hydrochloride dose- dependently inhibited the induction of key cytokines relevant to RA pathology including TNF-a, IL-6, and MCP-1.
  • cytokines relevant to RA pathology including TNF-a, IL-6, and MCP-1.
  • the clinical severity of the test agent was significantly lower than vehicle controls with a dose-response benefit (p ⁇ 1 x 10 "6 , p ⁇ 2 x 10 "8 for lmg/kg or 7mg/kg, respectively).
  • hydrochloride suppressed radiographic damage (p ⁇ 7 x 10 " , p ⁇ 2 x 10 " for lmg/kg or 7mg/kg, respectively).
  • Cytokine profiles post-treatment demonstrated that 6- phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-piperazin- 1 -yl)-pyridazine hydrochloride tended to lower circulating TNF-a levels.
  • 6-phenyl-4-pyridin-4-yl-3-(4- pyrimidin-2-yl-piperazin-l -yl)-pyridazine hydrochloride suppressed established CIA and inhibited TNF-a.

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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
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  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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Abstract

L'invention concerne des composés, des compositions, des formulations et des formes galéniques comprenant de la 6-phényl-4-pyridin-4-yl-3-(4-pyrimidin-2-yl-pipérazin-l-yl)- pyridazine ou un sel pharmaceutiquement acceptable de celle-ci, et des méthodes pour traiter l'arthrite chez un patient à l'aide de tels composés, et de telles compositions, formulations et formes galéniques.
PCT/CA2011/000879 2010-07-28 2011-07-28 Composés, compositions et méthodes de traitement de l'arthrite WO2012012890A1 (fr)

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US61/368,423 2010-07-28
US40885310P 2010-11-01 2010-11-01
US61/408,853 2010-11-01

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007127475A2 (fr) * 2006-04-28 2007-11-08 Northwestern University Compositions et traitements contre des maladies démyélinisantes et des troubles de type douleur
WO2007127448A2 (fr) * 2006-04-28 2007-11-08 Northwestern University Sels de composés de pyridazine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007127475A2 (fr) * 2006-04-28 2007-11-08 Northwestern University Compositions et traitements contre des maladies démyélinisantes et des troubles de type douleur
WO2007127448A2 (fr) * 2006-04-28 2007-11-08 Northwestern University Sels de composés de pyridazine

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