US20100093813A1 - Salts 668 - Google Patents

Salts 668 Download PDF

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US20100093813A1
US20100093813A1 US12/526,331 US52633108A US2010093813A1 US 20100093813 A1 US20100093813 A1 US 20100093813A1 US 52633108 A US52633108 A US 52633108A US 2010093813 A1 US2010093813 A1 US 2010093813A1
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salt
ethyl
pharmaceutically acceptable
ethoxy
naphthyl
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Robert Whittock
Jane Withnall
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention concerns new salt forms of N-[2-(diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide, compositions comprising such new salt forms, processes for preparing such salt forms, and the use of such salt forms in the treatment of disease states (such as respiratory disease states, for example asthma or COPD).
  • disease states such as respiratory disease states, for example asthma or COPD.
  • N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide free base and its dihydrobromide and dihydrochloride salts are ⁇ 2 adrenoceptor agonists and are disclosed in PCT/SE2006/000927 (published as WO 2007/018461, see Examples 7, 15 and 16). These compounds show at least 10-fold selectivity for ⁇ 2 adrenoceptor over adrenergic ⁇ 1D, adrenergic ⁇ 1 and dopamine D2.
  • the present invention provides a pharmaceutically acceptable salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide provided it is not the dihydrobromide or dihydrochloride salt.
  • a pharmaceutically acceptable salt includes for example, a trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, citrate, pyruvate, succinate, oxalate, methanesulphonate, p-toluenesulphonate, bisulphate, benzenesulphonate, ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or e
  • a salt of the invention can exist as a solvate (such as a hydrate), and the present invention covers all such solvents.
  • the present invention provides a pharmaceutically acceptable salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide which is a citrate, ditosylate, phosphate, dixinafoate, sulphate, mono-benzoate, fumarate or besylate salt.
  • the present invention provides a mono-citrate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide.
  • the present invention provides a citrate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide having an X-ray powder diffraction (XRPD) pattern containing specific peaks at: 4.4 ( ⁇ 0.1°), 7.2 ( ⁇ 0.1°), 13.7 ( ⁇ 0.1°), 17.4 ( ⁇ 0.1°), 18.7 ( ⁇ 0.1°) and 21.4 ( ⁇ 0.1°) 2 ⁇ .
  • XRPD X-ray powder diffraction
  • a citrate salt can be prepared by adding citric acid to a solution of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide in a suitable aliphatic alcohol (such as methanol), solubilising all material (at elevated temperature if necessary), allowing the solution to cool, whereupon the citrate salt precipitates from the solution and can be collected.
  • a suitable aliphatic alcohol such as methanol
  • the present invention provides a dixinafoate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide.
  • the present invention provides a dixinafoate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide as a di-hydrate having an X-ray powder diffraction pattern containing specific peaks at: 4.8 ( ⁇ 0.1°), 7.7 ( ⁇ 0.1°), 9.1 ( ⁇ 0.1°), 12.2 ( ⁇ 0.1°), 16.1 ( ⁇ 0.1°) and 21.3 ( ⁇ 0.1°) 2 ⁇ .
  • the present invention provides a dixinafoate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide as a Di-Hemi-Hydrate having an X-ray powder diffraction pattern containing specific peaks at: 8.5 ( ⁇ 0.1°), 9.4 ( ⁇ 0.1°), 11.6 ( ⁇ 0.1°), 11.9 ( ⁇ 0.1°), 16.6 ( ⁇ 0.1°), 17.7 ( ⁇ 0.1°) and 22.4 ( ⁇ 0.1°) 2 ⁇ .
  • a xinafoate salt can be prepared by adding 1-hydroxy-2-naphthoic acid to a solution of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide in a suitable aliphatic alcohol (such as methanol), mixing at elevated temperature (such as reflux), and allowing to cool, whereupon the xinafoate salt can be collected.
  • a suitable aliphatic alcohol such as methanol
  • the present invention provides a phosphate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide.
  • the present invention provides a phosphate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide as a di-hemi-hydrate having an X-ray powder diffraction pattern containing specific peaks at: 5.5 ( ⁇ 0.1°), 8.4 ( ⁇ 0.1°), 9.04 ( ⁇ 0.1°), 11.8 ( ⁇ 0.1°), 16.3 ( ⁇ 0.1°) and 20.6 ( ⁇ 0.1°) 2 ⁇ .
  • a phosphate salt can be prepared by adding phosphoric acid to a solution of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide in a suitable aliphatic alcohol (such as methanol), mixing at elevated temperature (such as reflux), and allowing to cool, whereupon the phosphate salt can be collected.
  • a suitable aliphatic alcohol such as methanol
  • the present invention provides a mono-benzoate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide.
  • the present invention provides a crystalline form of the monobenzoate salt of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide having an X-ray powder diffraction pattern containing specific peaks at: 5.6 ( ⁇ 0.1°), 8.3 ( ⁇ 0.1°), 9.5 ( ⁇ 0.1°), 14.8 ( ⁇ 0.1°), 20.1 ( ⁇ 0.1°) and 22.5 ( ⁇ 0.1°) 2 ⁇ .
  • a benzoate salt can be prepared by adding benzoic acid to a solution of N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide in a suitable aliphatic alcohol (such as methanol), mixing (for example at room temperature (such as 10-30° C.)) and then collecting the benzoate salt.
  • a suitable aliphatic alcohol such as methanol
  • the salts of the present invention can be prepared by using or adapting: the methods presented above; the methods presented in the Preparations or Examples below; or, the methods described in the literature.
  • the salts of the invention can be used in the treatment of:
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature
  • osteoarthritides associated with or including osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; osteoarthritis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus
  • arthritides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • polychondritits scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis); 4.
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial; 6.
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; 8.
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female); 9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 10.
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 11.
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins; 14.
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 15.
  • common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 15.
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.
  • the present invention provides a salt as hereinbefore defined for use in therapy.
  • the present invention provides the use of a salt as hereinbefore defined in the manufacture of a medicament for use in therapy (for example a respiratory disease state)
  • the present invention provides a salt as hereinbefore described for the treatment of a respiratory disease state.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a salt as hereinbefore defined.
  • an inflammatory disease or condition including a reversible obstructive airways disease or condition
  • a salt of the present invention may be used in the treatment of adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ( ⁇ g/kg) to 100 micrograms per kilogram body weight ( ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a salt of the invention may be used on its own but will generally be administered in the form of a pharmaceutical composition in which a salt of the invention (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition will for example comprise from 0.05 to 99% w (per cent by weight), such as from 0.05 to 80% w, for example from 0.10 to 70% w, and such as from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a salt as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a salt as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutical composition of the invention can be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of a cream, solution, suspension, heptafluoroalkane (HFA) aerosol or dry powder formulation, for example, a formulation in the inhaler device known as the Turbuhaler®; or systemically, e.g. by oral administration in the form of a tablet, capsule, syrup, powder or granule; or by parenteral administration in the form of a solution or suspension; or by subcutaneous administration; or by rectal administration in the form of a suppository; or transdermally.
  • HFA heptafluoroalkane
  • a dry powder formulation or pressurized HFA aerosol of a salt of the invention may be administered by oral or nasal inhalation.
  • the salt is desirably finely divided.
  • the finely divided compound has, for example, a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C 8 -C 20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a C 8 -C 20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a salt of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
  • a suitable carrier is, for example, a sugar, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; or starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active ingredient with or without a carrier substance, is delivered to the patient.
  • the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • a liquid preparation for oral application may be in the form of a syrup or suspension, for example, a solution containing a salt of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • a liquid preparation may contain a colouring agent, flavouring agent, saccharine and/or carboxymethylcellulose as a thickening agent or another excipient known to those skilled in art.
  • a salt of the invention may also be administered in conjunction with another compound used for the treatment of one or more of the above conditions.
  • the invention therefore further relates to a combination therapy wherein a salt of the invention or a pharmaceutical composition or formulation comprising a salt of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • a salt of the invention may be combined with one of the following agents: non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as
  • the present invention still further relates to the combination of a salt of the invention together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signaling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signaling pathways such as modulators of the SOCS system
  • the invention relates to a combination of a salt of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax I1-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax I1-15.
  • the present invention still further relates to the combination of a salt of the invention, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3 -C family.
  • a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3
  • the present invention further relates to the combination of a salt of the invention, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a salt of the invention, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY ⁇ 1005.
  • the present invention further relates to the combination of a salt of the invention, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4, selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY ⁇ 7195.
  • LT leukotrienes
  • the present invention still further relates to the combination of a salt of the invention, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a salt of the invention, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a salt of the invention, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a salt of the invention, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a salt of the invention, and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride,
  • the present invention further relates to the combination of a salt of the invention, and an anticholinergic agents including muscarinic receptor (M1, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • M1, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention further relates to the combination of a salt of the invention, and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a salt of the invention, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a salt of the invention, with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a salt of the invention, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • anti-IgE for example omalizumab
  • the present invention further relates to the combination of a salt of the invention, and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • a salt of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a salt of the invention, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a salt of the invention, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirap
  • the present invention still further relates to the combination of a salt of the invention, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • the present invention further relates to the combination of a salt of the invention, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropin
  • the present invention still further relates to the combination of a salt of the invention, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agents, paracetamol, or a non-steroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agents for example an opioid or derivative thereof
  • paracetamol for example an opioid or derivative thereof
  • non-steroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a salt of the invention, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a salt of the present invention can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • a hormonal agent such as raloxifene
  • a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a salt of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine/threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogen
  • NKP-608C SB-233412 (talnetant) or D-4418
  • elastase inhibitor such as UT-77 or ZD-0892
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7
  • inhibitor of transcription factor activation such as NFkB, API, or STATS
  • a glucocorticoid receptor agonist a glucocorticoid receptor agonist.
  • tert-Butyl 3-[2-(1-naphthyl)ethoxy]propanoate (6.19 g) was taken up in dichloromethane (30 mL) and treated with trifluoroacetic acid (5 mL). The resulting solution was stirred at room temperature for 2 hours, an additional 1 mL of trifluoroacetic acid was added and the solution stirred overnight. The mixture was concentrated, taken up in 2M sodium hydroxide solution (30 mL) and washed with ether (2 ⁇ 20 mL). The aqueous layer was subsequently acidified (using 1M hydrochloric acid) and extracted with ether (2 ⁇ 30 mL). The combined organics were washed with brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the sub-titled compound (5.66 g) as a clear oil.
  • Oxalyl chloride (0.33 g) was added dropwise to a solution of 3-[2-(1-naphthy)ethoxy]propanoic acid (0.53 g) in dichloromethane (10 mL), dimethylformamide (1 drop) was added and stirring continued at room temperature for 1 hour. The mixture was subsequently concentrated, re-dissolved in dichloromethane (10 mL) and added dropwise to a solution of 2-(2-diethylaminoethylamino)ethanol (0.35 g) and diisopropylethylamine (0.56 g) in dichloromethane (10 mL).
  • Triethylamine (0.29 g) was added and the reaction allowed to warm to room temperature over 1 hour, the mixture was subsequently diluted (dichloromethane 30 mL), the organics washed with sodium bicarbonate (20 mL), brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the sub-titled compound (0.21 g).
  • FIG. 1 XRPD of Amorphous Form of Compound B
  • FIG. 2 XRPD of Polymorph A of Compound A
  • Citric Acid (248.96 mg) was added to a solution of N-[2-(diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide (0.5 g) in methanol (5 mL). Immediately, the clear solution became opaque and orange oil settled out. This mixture was heated at an external temp of 60° C. forming a clear solution, which was then allowed to cool to room temperature and stirred for 48 h. The resulting precipitate was collected by filtration and washed with methanol (1 mL) and diethyl ether (1 mL). The solid was then dried in vacuo at room temperature for 4 h to give the title compound (0.3 g).
  • FIG. 4 XRPD of Di-Hydrate Polymorph A of Citrate Salt of Compound B
  • p-Toluenesulfonic acid monohydrate (667.33 mg) was added in one portion to a solution of N-[2-(diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide (1 g) in methanol (10 mL) producing a clear solution. This was stirred at room temperature for 30 mins then the solvent was removed in vacuo.
  • FIG. 5 XRPD of Amorphous Form of Di-Tosylate Salt of Compound B
  • Phosphoric Acid (199.19 mg) was added to a solution of N-[2-(diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide (1 g) in methanol (10 mL) producing a gum. The mixture was heated to reflux, and on continued stirring gave a mobile solid. The suspension was allowed to cool slowly to room temperature then filtered and the cake was washed with methanol (2 mL). The title compound (0.93 g) was allowed to dry on the filter.
  • FIG. 6 XRPD of Di-Hemi-Hydrate Polymorph A of Phosphate Salt of Compound B
  • FIG. 7 XRPD of Di-Hydrate Polymorph A of Di-Xinafoate Salt of Compound B
  • Example 4A 20 mg of Di-Hydrate Polymorph A (Example 4A) was slurried in water (0.5 ml) for one week. The resulting suspension was centrifuged and the supernatant was separated from the solid material, the latter being left to air dry overnight in a fume hood.
  • FIG. 8 XRPD of Di-Hemi-Hydrate Polymorph A of Di-Xinafoate Salt of Compound B
  • Methyl t-butyl ether (0.5 mL) was then added and the mixture was heated at an external temperature of 60° C. then allowed to room temperature. The mixture was transferred to another flask using methanol to dissolve the mixture and then the solvent was removed in vacuo. Methyl t-butyl ether (10 mL) was added to the residue and the mixture was stirred at room temperature for 16 h. The title compound was collected by filtration and dried on the filter (0.24 g). Solid found to be amorphous.
  • FIG. 9 XRPD of Amorphous form of Sulphate Salt of Compound B
  • Benzoic acid (52.75 mg) was added in one portion to a solution of N-[2-(diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide (0.25 g) in methanol (2.5 mL) producing a clear solution. This was stirred at room temperature for 1 h then the solvent was removed in vacuo.
  • FIG. 10 XRPD of Amorphous form of Mono Benzoate of Compound B
  • FIG. 11 XRPD (FIG. 11) 5.6 (15.8) 7.8 (11.3) 8.3 (10.6) 9.5 (9.3) 12.0 (7.4) 13.7 (6.4) 14.8 (6.0) 15.5 (5.7) 16.0 (5.5) 16.6 (5.3) 16.8 (5.3) 17.4 (5.1) 20.1 (4.42) 20.9 (4.25) 22.1 (4.03) 22.5 (3.96) 24.1 (3.69) 24.3 (3.66) 25.8 (3.45) 26.2 (3.41) 28.1 (3.17) 28.6 (3.12) FIG. 11 : XRPD of Crystalline form of Mono Benzoate of Compound B
  • Fumaric acid (168.31 mg) was added to a solution of N-[2-(diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthy)ethoxy]propanamide (0.84 g) in methanol (2 mL) producing an opaque mixture. The mixture was warmed at an external temperature of 60° C. then allowed to cool to room temperature and stirred for 16 h. The title compound was obtained as an amorphous foam after evaporation to dryness.
  • FIG. 12 XRPD of Amorphous Form of Mono Fumarate Salt of Compound B
  • Benzenesulfonic acid (158.51 mg) was added to a solution of N-[2-(diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide (0.58 g) in methanol (5.8 mL) producing an clear solution. The mixture was stirred at room temperature for 1 h. The title compound was obtained as an amorphous solid after evaporation to dryness.
  • FIG. 13 XRPD of Amorphous Form of Mono Besylate of Compound B
  • H292 cells were grown in 225 cm2 flasks incubator at 37° C., 5% CO 2 in RPMI medium containing, 10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine.
  • Adherent H292 cells were removed from tissue culture flasks by treatment with AccutaseTM cell detachment solution for 15 minutes. Flasks were incubated for 15 minutes in a humidified incubator at 37° C., 5% CO 2 . Detached cells were re-suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.05 ⁇ 10 6 cells per mL. 5000 cells in 100 ⁇ L were added to each well of a tissue-culture-treated 96-well plate and the cells incubated overnight in a humidified incubator at 37° C., 5% CO 2 .
  • the culture media was removed and cells were washed twice with 100 ⁇ L assay buffer and replaced with 50 ⁇ L assay buffer (HBSS solution containing 10 mM HEPES pH7.4 and 5 mM glucose). Cells were rested at room temperature for 20 minutes after which time 25 ⁇ L of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) was added. Cells were incubated with rolipram for 10 minutes after which time test compounds were added and the cells were incubated for 60 minutes at room temperature. The final rolipram concentration in the assay was 300 ⁇ M and final vehicle concentration was 1.6% (v/v) dimethylsulphoxide. The reaction was stopped by removing supernatants, washing once with 100 ⁇ L assay buffer and replacing with 50 ⁇ L lysis buffer. The cell monolayer was frozen at ⁇ 80° C. for 30 minutes (or overnight).
  • cAMP cyclic adenosine monophosphate
  • concentration of cAMP was determined using AlphaScreenTM methodology. The frozen cell plate was thawed for 20 minutes on a plate shaker then 10 ⁇ L of the cell lysate was transferred to a 96-well white plate. 40 ⁇ L of mixed AlphaScreenTM detection beads pre-incubated with biotinylated cAMP, was added to each well and the plate incubated at room temperature for 10 hours in the dark. The AlphaScreenTM signal was measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings. cAMP concentrations were determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations. Concentration response curves for agonists were constructed and data was fitted to a four parameter logistic equation to determine both the pEC 50 and Intrinsic Activity. Intrinsic Activity was expressed as a fraction relative to the maximum activity determined for formoterol in each experiment.
  • Membranes were prepared from human embryonic kidney 293 (HEK293) cells expressing recombinant human ⁇ 1 D receptor. These were diluted in Assay Buffer (50 mM HEPES, 1 mM EDTA, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 50 mM HEPES, 1 mM EDTA, 0.1% gelatin, pH 7.4
  • Assays were performed in U-bottomed 96-well polypropylene plates. 10 ⁇ L [ 3 H]-prazosin (0.3 nM final concentration) and 10 ⁇ L of test compound (10 ⁇ final concentration) were added to each test well. For each assay plate 8 replicates were obtained for [ 3 H]-prazosin binding in the presence of 10 ⁇ L vehicle (10% (v/v) DMSO in Assay Buffer; defining maximum binding) or 10 ⁇ L BMY7378 (10 ⁇ M final concentration; defining non-specific binding (NSB)). Membranes were then added to achieve a final volume of 100 ⁇ L.
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (50 mM HEPES, 1 mM EDTA, pH 7.4) were performed at 4° C. to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-O (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • wash buffer 50 mM HEPES, 1 mM EDTA, pH 7.4
  • B 0 Total specific binding (B 0 ) was determined by subtracting the mean NSB from the mean maximum binding. NSB values were also subtracted from values from all other wells. These data were expressed as percent of B 0 .
  • Compound concentration-effect curves (inhibition of [ 3 H]-prazosin binding) were determined using serial dilutions typically in the range 0.1 nM to 10 ⁇ M. Data was fitted to a four parameter logistic equation to determine the compound potency, which was expressed as pIC50 (negative log molar concentration inducing 50% inhibition of [ 3 H]-prazosin binding).
  • Membranes containing recombinant human adrenergic beta 1 receptors were obtained from Euroscreen. These were diluted in Assay Buffer (50 mM HEPES, 1 mM EDTA, 120 mM NaCl, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 50 mM HEPES, 1 mM EDTA, 120 mM NaCl, 0.1% gelatin, pH 7.4
  • Assays were performed in U-bottomed 96-well polypropylene plates. 10 ⁇ L [ 125 I]-Iodocyanopindolol (0.036 nM final concentration) and 10 ⁇ L of test compound (10 ⁇ final concentration) were added to each test well. For each assay plate 8 replicates were obtained for [ 125 I]-Iodocyanopindolol binding in the presence of 10 ⁇ L vehicle (10% (v/v) DMSO in Assay Buffer; defining maximum binding) or 10 ⁇ L Propranolol (10 ⁇ M final concentration; defining non-specific binding (NSB)). Membranes were then added to achieve a final volume of 100 ⁇ L.
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (50 mM HEPES, 1 mM EDTA, 120 mM NaCl, pH 7.4) were performed at 4° C. to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-O (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • wash buffer 50 mM HEPES, 1 mM EDTA, 120 mM NaCl, pH 7.4
  • B 0 Total specific binding (B 0 ) was determined by subtracting the mean NSB from the mean maximum binding. NSB values were also subtracted from values from all other wells. These data were expressed as percent of B 0 .
  • Compound concentration-effect curves (inhibition of [ 125 I]-Iodocyanopindolol binding) were determined using serial dilutions typically in the range 0.1 nM to 10 ⁇ M. Data was fitted to a four parameter logistic equation to determine the compound potency, which was expressed as pIC 50 (negative log molar concentration inducing 50% inhibition of [ 125 I]-Iodocyanopindolol binding).
  • Membranes containing recombinant human Dopamine Subtype D2s receptors were obtained from Perkin Elmer. These were diluted in Assay Buffer (50 mM HEPES, 1 mM EDTA, 120 mM NaCl, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 50 mM HEPES, 1 mM EDTA, 120 mM NaCl, 0.1% gelatin, pH 7.4
  • Assays were performed in U-bottomed 96-well polypropylene plates. 30 ⁇ L [ 3 H]-spiperone (0.16 nM final concentration) and 30 ⁇ L of test compound (10 ⁇ final concentration) were added to each test well. For each assay plate 8 replicates were obtained for [ 3 H]-spiperone binding in the presence of 30 ⁇ L vehicle (10% (v/v) DMSO in Assay Buffer; defining maximum binding) or 30 ⁇ L Haloperidol (10 ⁇ M final concentration; defining non-specific binding (NSB)). Membranes were then added to achieve a final volume of 300 ⁇ L.
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (50 mM HEPES, 1 mM EDTA, 120 mM NaCl, pH 7.4) were performed at 4° C. to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-O (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • wash buffer 50 mM HEPES, 1 mM EDTA, 120 mM NaCl, pH 7.4
  • B 0 Total specific binding (B 0 ) was determined by subtracting the mean NSB from the mean maximum binding. NSB values were also subtracted from values from all other wells. These data were expressed as percent of B 0 .
  • Compound concentration-effect curves (inhibition of [ 3 H]-spiperone binding) were determined using serial dilutions typically in the range 0.1 nM to 10 ⁇ M. Data was fitted to a four parameter logistic equation to determine the compound potency, which was expressed as pIC 50 (negative log molar concentration inducing 50% inhibition of [ 3 H]-spiperone binding).
  • Dunkin-Hartley guinea-pigs (between 200 g and 300 g on delivery) were supplied by a designated breeding establishment. The guinea-pigs were killed by cervical dislocation and the trachea removed. The adherent connective tissue was removed and each trachea cut into four rings. The tissue rings were then attached to an isometric transducer. The tissues were washed and a force of 1 g was applied to each ring. In all experiments a paired curve design was used. A priming dose of 1 ⁇ M methacholine was applied to the tissues. The tissues were then washed (three times, one minute between washes), the resting tension of 1 g was reapplied and the tissues were allowed to rest for 1 hour to equilibrate.
  • Tissues were then contracted with 1 ⁇ M methacholine and once a steady response was obtained a cumulative concentration response curve to isoprenaline (10 ⁇ 9 M-10 ⁇ 5 M) was constructed.
  • the tissues were then washed (three times, one minute between washes) and left to rest for an hour. At the end of the resting period the tissues were contracted with 1 ⁇ M methacholine and a p[A] 50 concentration of test compound added. Once the tissue had reached maximum relaxation, a 30 ⁇ p[A] 50 concentration of test compound was added. Once the tissue response had reached a plateau, 10 ⁇ M sotalol was added to the bath to confirm that the relaxation was ⁇ 2 mediated
  • E and [A] are the pharmacological effect (% relaxation) and concentration of the agonist respectively; ⁇ , ⁇ , [A] 50 and m are the asymptote, baseline, location and slope parameters, s respectively.
  • the p[A] 50 and IA of each isoprenaline curve was determined from this fit, to determine if the tissue was viable for generating an onset time for the test compounds.
  • the response was calculated as % relaxation of the methacholine-induced contraction.
  • the results were plotted % relaxation against time and the time taken to reach a 90% relaxation value was calculated and recorded.
  • a dose solution of the test compound was prepared using a suitable dose vehicle.
  • the concentration of the compound in the dose solution was assayed by diluting an aliquot to a nominal concentration of 50 ⁇ g ⁇ ml ⁇ 1 and calibrating against duplicate injections of a standard solution and a QC standard at this concentration.
  • Compounds were administered intravenously as a bolus into a caudal vein to groups of three 250-350 g rats (approximately 1 ml ⁇ kg ⁇ 1 ).
  • a separate group of 2 or 3 animals were dosed by oral gavage (3 ml ⁇ kg ⁇ 1 ). Delivered doses were estimated by weight loss. Food was not usually withdrawn from animals prior to dosing, although this effect was investigated if necessary.
  • Blood samples (0.25 ml) were taken into 1 ml syringes from the caudal vein, transferred to EDTA tubes and plasma was prepared by centrifugation (5 min at 13000 rpm) soon after sample collection, before storage at ⁇ 20° C. Typical sampling times were 2, 4, 8, 15, 30, 60, 120, 180, 240, 300 (min) or until the terminal t1 ⁇ 2 was accurately described.
  • the concentration of the analyte(s) were determined in plasma by quantitative mass spectrometry.
  • Standard and quality control stock solutions were prepared at a concentration 1 mg/ml in methanol.
  • a range of standard and QC stocks produced by serial dilution were added to control rat plasma (50 ⁇ l).
  • the range of concentrations covered the range of levels of analyte present in the rat samples.
  • Standards, QCs and samples underwent liquid extraction using 50 ⁇ l of organic solvent and 100 ⁇ l of organic solvent containing an internal standard, chosen to closely resemble the analyte.
  • the samples were then mixed by repeated inversion, stored at ⁇ 20° C. for at least 1 h, and centrifuged at 3500 rpm in a centrifuge for 20 minutes. Aliquots (120 ⁇ l) of each sample were transferred for analysis using LC-MSMS.
  • Standard and quality control samples covering the range of concentrations found in the test samples were within 25% of the nominal concentration.
  • Pharmacokinetic data analysis was achieved using WinNonlin.
  • a standard non-compartmental analysis was used to estimate the parameters such as Tmax, Cmax, Lambda_z, t 1 ⁇ 2_Lambda_z, AUCall, AUCINF(observed), Cl(observed), Vss(observed).

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  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Otolaryngology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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RU2009133254A (ru) 2011-03-20
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MX2009008371A (es) 2009-08-12
AU2008212714A1 (en) 2008-08-14
UY30903A1 (es) 2008-09-30
EP2118084A1 (en) 2009-11-18
CO6241151A2 (es) 2011-01-20
BRPI0807727A2 (pt) 2014-06-03
CL2008000399A1 (es) 2008-10-24
PE20090646A1 (es) 2009-06-26
ECSP099580A (es) 2009-09-29
US20080249145A1 (en) 2008-10-09
CA2675994A1 (en) 2008-08-14
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