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WO2008100202A1 - A 2-f luorobenzoate salt and a 2, 6-dif luorobenzoate salt of n-{5-chloro-2- [ ( (2s) -3-{ [1- (4-chlorobenzyl)piperidin-4- yl ] amino } - 2 - hydroxy- 2 -me t hylpr opyl ) oxy] - 4 - hydroxyphenyl } acetamide - Google Patents

A 2-f luorobenzoate salt and a 2, 6-dif luorobenzoate salt of n-{5-chloro-2- [ ( (2s) -3-{ [1- (4-chlorobenzyl)piperidin-4- yl ] amino } - 2 - hydroxy- 2 -me t hylpr opyl ) oxy] - 4 - hydroxyphenyl } acetamide Download PDF

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Publication number
WO2008100202A1
WO2008100202A1 PCT/SE2008/000118 SE2008000118W WO2008100202A1 WO 2008100202 A1 WO2008100202 A1 WO 2008100202A1 SE 2008000118 W SE2008000118 W SE 2008000118W WO 2008100202 A1 WO2008100202 A1 WO 2008100202A1
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Prior art keywords
salt
compound according
disease
hydroxy
oxy
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PCT/SE2008/000118
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French (fr)
Inventor
Julien Giovannini
Bo-Göran Josefsson
Marguerite Mensonides-Harsema
Håkan SCHULZ
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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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to a 2-fluorobenzoate salt and a 2,6-difluorobenzoate salt of N- ⁇ 5-chloro-2-[((2 1 S)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide and polymorphic forms thereof, to pharmaceutical compositions containing said salts.
  • the present invention further relates to processes for the preparation of said salts and polymorphic forms.
  • the invention also related to the use of salts and polymorphic forms in the treatment in therapy.
  • Chemokine Receptor 1 is highly expressed in tissues affected in different autoimmune, inflammatory, proliferative, hyper proliferative and immunologically mediated diseases, e.g. asthma, chronic obstructive pulmonary disease, multiple sclerosis and rheumatoid arthritis. Therefore, inhibiting CCRl -mediated events with the salt of the invention, e.g. by cell activation and migration, is expected to be effective in the treatment of such conditions.
  • the active compound In the manufacture of pharmaceutical compositions, it is important that the active compound is in a form in which it can be conveniently handled and processed in order to obtain a commercially-viable manufacturing process.
  • the chemical stability and the physical stability of the active compound are important factors.
  • the active compound, and compositions containing it, must be capable of being effectively stored over appreciable periods of time, without exhibiting any significant change in the physico- chemical characteristics (e.g. chemical composition, density, hygroscopicity and solubility) of the active compound.
  • the active compound is to be incorporated into a composition for pulmonary administration, e.g., via a dry powder inhaler such as the Turbuhalere ® device, it is desirable if the active compound can be readily micronised to yield a powder with good flow properties and comprising a high fine crystalline particle fraction (i.e. a fraction in which the active compound particles have a mass median aerodynamic diameter of less than 10 ⁇ m (micrometer)). Such a fraction is capable of being earned deep into the lungs leading to faster and increased absorption of the active compound.
  • a dry powder inhaler such as the Turbuhalere ® device
  • Patent application PCT/SE2006/000918 generally discloses piperidinyl derivatives and, in particular, the compound TV- ⁇ 5-chlor ⁇ -2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4- yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4-hy droxyphenyl ⁇ acetamide and pharmaceutically acceptable salts or solvates thereof. These compounds have activity as CCRl antagonists. Salts of said compound specifically disclosed in the application are the benzoate salt and the furoate salt.
  • Patent applications PCT/SE2006/000920 and PCT/SE2006/000921 disclose the benzoate and furoate salts of 4-( ⁇ (2S)-3-[2-(acetylamino)-5-hydroxyphenoxy]-2-hydroxy-2- methyl ⁇ ropyl ⁇ ammonio)-l-(4-chlorobenzyl)piperidine.
  • the melting points for the benzoate salts of both polymorphs A and B of iV- ⁇ 5-chloro-2-[((25)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]ammo ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide are lower then those of 4-( ⁇ (2 ⁇ S r )-3-[2-(acetylamino)-5- hydroxyphenoxy]-2-hydroxy-2-methylpropyl ⁇ ammonio)-l-(4-chlorobenzyl)piperidine.
  • the melting points for the furoate salts of both polymorphs A and B of JV- ⁇ 5-Chloro-2- [((2S)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide are higher then those of 4-( ⁇ (2iSl-3-[2-(acetylamino)-5- hydroxyphenoxy]-2-hydroxy-2-methylpropyl ⁇ ammonio)-l-(4-chlorobenzyl)piperidine.
  • the low melting point of the benzoate salts has implications for its developability as an ingredient of a composition for pulmonary administration as the crystals may melt upon micronisation.
  • substituted benzoic acid salts of the compound/V- ⁇ 5-chloro-2- [((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide can be prepared, which have good physico-chemical properties, and which may be formulated in a dry powder composition for pulmonary administration.
  • the 2-fluorobenzoate salt of N- ⁇ 5- chloro-2-[((2iS)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide hereinafter referred to as "the 2- fluorobenzoate salt”
  • the 2,6-difhiorobenzoate salt of JV- ⁇ 5-chloro-2-[((2S>-3- ⁇ [l-(4- chlorobenzyI)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide hereinafter referred to as "the 2.6-difluorobenzoate salt”).
  • the invention also provides solvates (including hydrates) as well as cocrystals of the 2- fluorobenzoate and 2,6- difluorobenzoate salts.
  • the 2-fluorobenzoate and 2,6- difluorobenzoate salts are anhydrous.
  • the 2-fiuorobenzoate and 2,6- difluorobenzoate salts are in non-solvated form.
  • the 2-fluorobenzoate and 2,6- difluorobenzoate salts or solvates thereof have crystalline properties and are preferably at least 50% crystalline, more preferably at least 60% crystalline, still more preferably at least 70% crystalline and most preferably at least 80% crystalline, Crystallinity can be estimated by conventional X- ray diffractometry techniques.
  • the 2-fluorobenzoate and 2,6- difluorobenzoate salts or solvates thereof are from 50%, 60%, 70%, 80% or 90% to 95%, 96%, 97%, 98%, 99% or 100% crystalline.
  • the 2-fluorobenzoate and 2,6- difluorobenzoate salts are believed to be polymorphic.
  • One embodiment of the invention relates to polymorphic forms of said salts.
  • one polymorph of the 2-fruorobenzoate (hereinafter referred to as Form A, 2-fiuorobenzoate salt) exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
  • One embodiment relates to Form A, 2-fluorobenzoate salt exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks: 12.7, 14.2, 16.6, 18.8 and 19.1.
  • XRPD characteristic X-ray powder diffraction
  • one polymorph of the 2,6-difhiorobenzoate exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089): (1) 5.6, 9.1 and 11.2, or
  • Form A 2,6-difluorobenzoate salt exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks: 12.6, 14.2, 18.4, 16.7, 17.4 and 23.4.
  • XRPD characteristic X-ray powder diffraction
  • Both Forms A may be prepared substantially free of other physical forms by a process comprising the following steps:
  • ⁇ r - ⁇ 5-chloro-2-[((25)-3- ⁇ [l-(4-chlorobenz ⁇ 4)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide dissolved in a suitable solvent or mixture of solvents e.g. an organic solvent such as a polar solvent, including but not restricted to alcohols (e.g. methanol), cyanides (e.g. acetonitrile), acetone and ethyl acetate), with
  • a heated solution at a temperature range of form 40 to 8O 0 C e.g. 60 0 C
  • a suitable solvent or mixture of solvents e.g. an organic solvent such as a polar solvent, including but not restricted to alcohols (e.g. methanol), cyanides (e.g. acetonitrile), acetone and ethyl acetate), to obtain a mixture
  • solvents e.g. an organic solvent such as a polar solvent, including but not restricted to alcohols (e.g. methanol), cyanides (e.g. acetonitrile), acetone and ethyl acetate
  • One embodiment relates to a process for the preparation of Form A, 2-fluorobenzoate salt or Form A 5 2,6-difhiorobenzoate salt: comprising the steps of; (i) contacting a solution at a temperature range of form 40 to 8O 0 C of 7 ⁇ r - ⁇ 5-chloro-2-
  • organic solvent used in steps (i) and/or (ii) is acetonitrile.
  • Forms A being substantially free of other physical forms (or substantially pure)
  • the compounds of the invention are useful as modulators of CCRl or MIP-Ia chemokine receptor activity.
  • ⁇ /' - ⁇ 5-chloro-2-[((2iS0-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2- hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide ditrifluoroacetate has an IC50 of below 5 nM in the Human CCRl binding assay as described in PCT/SE2006/O0O918, and may be administered to a mammal, including man, for the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases.
  • a compound 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 NS AID-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 vascula
  • 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; 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, mixed connective
  • arthitides 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 such as osteoporosis, Paget'
  • 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; panniculitisjcutaneous lymphomas, non-melanoma skin
  • 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;
  • 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;
  • 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; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • 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;
  • 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;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain rumors 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.
  • Combination therapies further relates to combination therapies wherein a compound of the invention, or a pharmaceutical composition or composition comprising a compound 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.
  • NSAIDs non-steroidal anti-inflammatory agents
  • COX-I / COX-2 inhibitors whether applied topically or systemically
  • 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 compound of the invention, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl 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 signalling pathways such as modulators of the SO
  • the invention relates to a combination of a compound of the invention, with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab). MRA-aIL16R and T-Lymphocytes, CTLA4-Ig ; HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab). MRA-aIL16R and T-Lymphocytes, CTLA4-Ig ; HuMax 11-15).
  • the present invention still further relates to the combination of a compound of the invention, with a modulator of chemokine receptor function such as an antagonist of CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRI l (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX 3 CRl for the C-X 3 -C family.
  • a modulator of chemokine receptor function such as an antagonist of CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRI l (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX 3 CRl for the
  • the present invention further relates to the combination of a compound of the invention, with an inhibitor of matrix metalloprotease (Tv-IMPs) 5 i.e., the stromefysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP- I) 5 collagenase-2 (MMP -8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP -9 and MMP- 12, including agents such as doxycycline.
  • Tv-IMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound 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-butyl ⁇ henolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-213S; 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 x 100
  • the present invention farther relates to the combination of a compound of the invention, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecatboximidamides 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 x 7195.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the
  • the present invention still further relates to the combination of a compound 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 still further relates to the combination of a compound of the invention, and an endothelin antagonist such as Tezosentan, Bosentan, Enrasentan, and Sixtasentan.
  • an endothelin antagonist such as Tezosentan, Bosentan, Enrasentan, and Sixtasentan.
  • the present invention still further relates to the combination of a compound of the invention, and an angiotensin II antagonist such as Azilzartan, Losartan, Valsartan, Candesartan, and Telmisartan.
  • an angiotensin II antagonist such as Azilzartan, Losartan, Valsartan, Candesartan, and Telmisartan.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a dual antagonists for both angiotensin II and endothelin A receptors (DARAs) such as disclosed in WO2000001389 and WO2001044239.
  • DARAs angiotensin II and endothelin A receptors
  • the present invention further relates to the combination of a compound of the invention, and an adenosine A2a agonist such as CGS-21680 and/or an adenosine A3 agonist such as IB-MECA and/or an adenosine A2b antagonist.
  • the present invention further relates to the combination of a compound 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.
  • the present invention still further relates to the combination of a compound 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 compound of the invention, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, and an alpha- l/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 ethy norepinephrine hydrochloride.
  • an alpha- l/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 compound of the invention, and an anticholinergic agents including muscarinic receptor (Ml 5 M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml 5 M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention still further relates to the combination of a compound of the invention, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • beta receptor subtypes 1-4 such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
  • the present invention further relates to the combination of a compound of the invention, and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • a chromone such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, betamethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound 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 compound 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
  • anti-IgE for example omalizumab
  • the present invention further relates to the combination of a compound 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 compound 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 compound 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 compound 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, nelf ⁇ navir, 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 nevi
  • the present invention still further relates to the combination of a compound 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 compound 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, ropinirole,
  • the present invention still further relates to the combination of a compound 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 agent-s, 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 agent-s 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 compound of the invention, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound 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 compound 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, INK, protein kinase A, B or C, or inhibitors of kappaB kinases, such as IKKl 5 IKK2 or IKK3), or a kinase involved in cell cycle regulation (such
  • - or B.sub2. -receptor antagonist for example colchicine;
  • anti-gout agent for example colchicine;
  • xanthine oxidase inhibitor for example allopurinol;
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone;
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor (GM-CSF);
  • capsaicin cream for example tachykinin KK.
  • NKP-608C sub 1. or NK.sub3.
  • receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-441S;
  • elastase inhibitor such as LT-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; or
  • inhibitor of transcription factor activation such as NFkB, API, or STATS.
  • a compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
  • an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fiuorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vin
  • OSI-774 or 6-acrylamido-N-(3- chloro-4-fiuorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;
  • an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354
  • a compound that works by another mechanism for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin
  • a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or
  • an agent used in an immunotherapeutic approach for example ex-vivo and in-vivo approaches to increase the in
  • the compounds of the invention can be combined with one or more agents for the treatment of such a condition.
  • the one or more agents is selected from the list comprising:
  • a PDE4 inhibitor including an inhibitor of the isoform PDE4D
  • adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline. orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
  • a muscarinic receptor antagonist for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist
  • a muscarinic receptor antagonist such as a Ml, M2 or M3 antagonist, such as a selective M3 antagonist
  • ipratropium bromide such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine
  • a steroid such as budesonide
  • neutrophil serine proteases • an inhibitor of neutrophil serine proteases, most preferably neutrophil elastase or proteinase 3.
  • the compounds of the invention can be administered by inhalation or by the oral route and the other agent can be administered by inhalation or by the oral route.
  • the compounds of the invention and the other agent may be administered together. They may be administered sequencially. Or they may be administered separately.
  • the present invention provides JV- ⁇ 5-chloro-2-[((2 ⁇ S)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide 2-fluorobenzoate or iV- ⁇ 5-chloro-2-[((25)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide 2,6-difluorobenzoate or solvates thereof, Form A, 2- fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt for use in therapy
  • the present invention provides iV- ⁇ 5-chloro-2-[((2 ⁇ S)-3- ⁇ [l-(4 ⁇ chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide 2-fluorobenzoate or jV- ⁇ 5-chlol ⁇ -2-[((2 ⁇ S)-3- ⁇ [l-(4- chlorobenzyl)piperidm-4-yl]ammo ⁇ -2-hydroxy-2-memylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide 2,6-difluorobenzoate or solvates thereof, Form A, 2- fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt for use in treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma.
  • the present invention provides the use of iV- ⁇ 5-chloro-2-[((2S)-3- ⁇ [l-(4- chlorobenzyl)piperidm-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide 2-fluorobenzoate or 7V- ⁇ 5-chloro-2-[((25 r )-3- ⁇ [l-(4- chIorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide 2,6-difluorobenzoate or solvates thereof, in the manufacture of a medicament for treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma.
  • an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma.
  • the present invention provides the use of Form A, 2-fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt, in the manufacture of a medicament for treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma.
  • the invention also provides a method of treating an airway disease, respirator ⁇ ' disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of JV- ⁇ 5-chloro-2-[((2SV3- ⁇ [l-(4-chlorobenzyl ⁇ )piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide 2-fluorobenzoate or N- ⁇ 5-chloro-2-[((25)-3- ⁇ [l-(4- chlorobenzyl)pi ⁇ eridin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide 2,6-difluorobenzoate or solvates thereof, Form A, 2- fluorobenzoate salt or Form A, 2.6-difluorobe
  • the dosage administered will, of course, vary with the mode of administration, the treatment desired and the disorder indicated but may typically be in the range from 0.001 mg/kg to 30 mg/kg.
  • 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.
  • compositions also provides a pharmaceutical composition comprising N- ⁇ 5- chloro-2-[((2iS)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide 2-fluorobenzoate or 7V- ⁇ 5-chloro-2-[((2 ⁇ )- 3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide 2,6-difluorobenzoate or solvates thereof, Form A, 2- fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the compounds of the invention may be used on its own but will generally be administered in the form of a pharmaceutical composition in which the compounds 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 compositions are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 198S.
  • the pharmaceutical composition may comprise from 0.01 to 100 %w (per cent by weight), more preferably from 0.01 to 80 %w, still more preferably from 0.05 to 70 %w, and even more preferably from 0.05 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing JV- ⁇ 5-chloro-2-[((2S)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide
  • 2-fluorobenzoate oriV- ⁇ 5-chloro-2-[((25)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide 2,6-difluorobenzoate or solvates thereof, Form A.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder compositions, for example, compositions in the inhaler device known as the Turbuhaler* device (Model 0, 1, 2, or 3) or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • Turbuhaler* device Model 0, 1, 2, or 3
  • the 2-fluorobenzoate salt or 2,6-difluorobenzoate salt of the invention is administered by inhalation.
  • the 2- fluorobenzoate salt or 2,6-difluorobenzoate salt of the invention is 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.
  • the dose of the compounds of the invention may generally be in the range of from 0.1 ⁇ g to 10000 ⁇ g, 0.1 to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 5 ⁇ g to 5000 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 200 ⁇ g, 5 to 100 ⁇ g, 5 to 50 ⁇ g, 10 to 5000 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 200 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 5000 ⁇ g ; 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 200 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 5000 ⁇ g, 50 to 1000 ⁇ g, 50 to 500 ⁇ g, 50 to 200 ⁇ g, 50 to 1000 ⁇ g,
  • Dry powder compositions and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has 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 2O 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 2O 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 carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyoL
  • Suitable carriers are sugars, for example, lactose, glucose, raffmose, melezitose, lactitol. maltitol, trehalose, sucrose, mannitol; and 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 ® device (Model 0, 1, 2, or 3) in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • Turbuhaler ® device Model 0, 1, 2, or 3
  • 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 compositions of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein the compounds of the invention or a pharmaceutical composition comprising said compounds 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.
  • X-ray powder diffraction (XRPD) analyses may be performed on samples prepared according to standard methods (see for example Giacovazzo et a!., eds., Fundamentals of Crystallography, Oxford University Press (1992); Jenkins & Snyder, eds., Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York (1996); Bunn. ed. 5 Chemical Crystallography, Clarendon Press, London (1948); and Khig & Alexander eds., X-ray Diffraction Procedures, John Wiley & Sons, New York (1974)).
  • a Bragg-Brentano parafocusing powder X-ray diffractometer using monochromatic CuKa radiation (45 kV and 40 mA) was used for the analyses.
  • the primary optics contained soller slits and an automatic divergence slit.
  • Flat samples were prepared on zero background plates that were rotated during the meausurements,
  • the secondary optics contained soller slits, an automatic anti scatter slit, a receiving slit and a monochromator.
  • the diffracted signal was detected with a proportional xenon-filled detector.
  • Diffraction patterns were collected between 2° ⁇ 2 ⁇ (theta) ⁇ 40° in a continous scan mode with a step size of 0.016° 20 at a rate of 4° 2 ⁇ per minute.
  • Raw data were stored electronically. Evaluation was performed on raw or smoothed diffraction patterns.
  • a Panalytical X'pert PRO MPD ⁇ - ⁇ diffractometer in reflection mode was used for the above-mentioned measurements.
  • a person skilled in the art can set up instrumental parameters for a powder X-ray diffractometer so that diffraction data comparable to the data presented can be collected.
  • Form A, 2-fluorobenzoate salt exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 29) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia. 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
  • Form A, 2,6-difluorobenzoate salt exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X- Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeia! Convention; 2002:2088-2089):
  • DSC onset and peak temperatures may vary due to the purity of the sample and instrumental parameters, especially the temperature scan rate.
  • a person skilled in the art can use routine optimization/calibration to set up instrumental parameters for a differential scanning calorimeter so that data comparable to the data presented here can be collected.
  • the melting temperature for a typical sample of the anhydrous Form A, 2-fluorobenzoate salt (example 1) was found to be 138 0 C ⁇ 2 0 C (onset).
  • the melting temperature for a typical sample of the anhydrous Form A, 2,6- difluorobenzoate salt (example 2) was found to be 14O 0 C ⁇ 2 0 C (onset).

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Abstract

The invention provides a 2-fluorobenzoate salt and a 2,6-difluorobenzoate salt of N-{5-chloro-2-[((2S)-3-{[1-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide or a solvate and polymorhpic forms thereof, pharmaceutical compositions containing the salts or solvates and use thereof in therapy.

Description

A 2-fluorobenzoate salt and a 2, 6-difluorobenzoate salt of N-{5-chloro-2- [ ( (2S) -3-{ [1- (4-chlorobenzyl)piperidin-4- yl] amino} -2-hydroxy-2-methylpropyl) oxy] -4- hydroxyphenyl }acetamide
FIELD OF THE INVENTION
The present invention relates to a 2-fluorobenzoate salt and a 2,6-difluorobenzoate salt of N-{5-chloro-2-[((21S)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl} acetamide and polymorphic forms thereof, to pharmaceutical compositions containing said salts. The present invention further relates to processes for the preparation of said salts and polymorphic forms. The invention also related to the use of salts and polymorphic forms in the treatment in therapy.
BACKGROUND OF THE INVENTION
Chemokine Receptor 1 (CCRl) is highly expressed in tissues affected in different autoimmune, inflammatory, proliferative, hyper proliferative and immunologically mediated diseases, e.g. asthma, chronic obstructive pulmonary disease, multiple sclerosis and rheumatoid arthritis. Therefore, inhibiting CCRl -mediated events with the salt of the invention, e.g. by cell activation and migration, is expected to be effective in the treatment of such conditions.
In the manufacture of pharmaceutical compositions, it is important that the active compound is in a form in which it can be conveniently handled and processed in order to obtain a commercially-viable manufacturing process. In this connection, the chemical stability and the physical stability of the active compound are important factors. The active compound, and compositions containing it, must be capable of being effectively stored over appreciable periods of time, without exhibiting any significant change in the physico- chemical characteristics (e.g. chemical composition, density, hygroscopicity and solubility) of the active compound.
Furthermore, if the active compound is to be incorporated into a composition for pulmonary administration, e.g., via a dry powder inhaler such as the Turbuhalere® device, it is desirable if the active compound can be readily micronised to yield a powder with good flow properties and comprising a high fine crystalline particle fraction (i.e. a fraction in which the active compound particles have a mass median aerodynamic diameter of less than 10 μm (micrometer)). Such a fraction is capable of being earned deep into the lungs leading to faster and increased absorption of the active compound.
Patent application PCT/SE2006/000918 generally discloses piperidinyl derivatives and, in particular, the compound TV- {5-chlorσ-2-[((25)-3-{[l-(4-chlorobenzyl)piperidin-4- yl] amino} -2-hydroxy-2-methylpropyl)oxy]-4-hy droxyphenyl} acetamide and pharmaceutically acceptable salts or solvates thereof. These compounds have activity as CCRl antagonists. Salts of said compound specifically disclosed in the application are the benzoate salt and the furoate salt.
Patent applications PCT/SE2006/000920 and PCT/SE2006/000921 disclose the benzoate and furoate salts of 4-({(2S)-3-[2-(acetylamino)-5-hydroxyphenoxy]-2-hydroxy-2- methylρropyl}ammonio)-l-(4-chlorobenzyl)piperidine. However, the melting points for the benzoate salts of both polymorphs A and B of iV-{5-chloro-2-[((25)-3-{[l-(4- chlorobenzyl)piperidin-4-yl]ammo}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide, are lower then those of 4-({(2ιSr)-3-[2-(acetylamino)-5- hydroxyphenoxy]-2-hydroxy-2-methylpropyl}ammonio)-l-(4-chlorobenzyl)piperidine. The melting points for the furoate salts of both polymorphs A and B of JV-{5-Chloro-2- [((2S)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl} acetamide are higher then those of 4-({(2iSl-3-[2-(acetylamino)-5- hydroxyphenoxy]-2-hydroxy-2-methylpropyl}ammonio)-l-(4-chlorobenzyl)piperidine. The low melting point of the benzoate salts has implications for its developability as an ingredient of a composition for pulmonary administration as the crystals may melt upon micronisation.
It has now been found that substituted benzoic acid salts of the compound/V-{5-chloro-2- [((25)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl} acetamide can be prepared, which have good physico-chemical properties, and which may be formulated in a dry powder composition for pulmonary administration.
DETAILED DESCRIPTION OF THE INVENTION The structure of iV-{5-Chloro-2-[((25)-3-{[l-(4-chlorobenzyl)ρiperidin-4-yl]amino}-2- hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide is shown below.
Figure imgf000004_0001
In one embodiment of the invention, there is provided the 2-fluorobenzoate salt of N- {5- chloro-2-[((2iS)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl}acetamide (hereinafter referred to as "the 2- fluorobenzoate salt") and the 2,6-difhiorobenzoate salt of JV-{5-chloro-2-[((2S>-3-{[l-(4- chlorobenzyI)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide (hereinafter referred to as "the 2.6-difluorobenzoate salt").
The invention also provides solvates (including hydrates) as well as cocrystals of the 2- fluorobenzoate and 2,6- difluorobenzoate salts. In one embodiment the 2-fluorobenzoate and 2,6- difluorobenzoate salts are anhydrous. In another embodiment the 2-fiuorobenzoate and 2,6- difluorobenzoate salts are in non-solvated form.
In an embodiment of the invention, the 2-fluorobenzoate and 2,6- difluorobenzoate salts or solvates thereof have crystalline properties and are preferably at least 50% crystalline, more preferably at least 60% crystalline, still more preferably at least 70% crystalline and most preferably at least 80% crystalline, Crystallinity can be estimated by conventional X- ray diffractometry techniques.
In another embodiment of the invention, the 2-fluorobenzoate and 2,6- difluorobenzoate salts or solvates thereof are from 50%, 60%, 70%, 80% or 90% to 95%, 96%, 97%, 98%, 99% or 100% crystalline.
Without being bound to any particular theory, the 2-fluorobenzoate and 2,6- difluorobenzoate salts are believed to be polymorphic. One embodiment of the invention relates to polymorphic forms of said salts. In another embodiment one polymorph of the 2-fruorobenzoate (hereinafter referred to as Form A, 2-fiuorobenzoate salt) exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
(1) 5.6, 9.2 and 11.2, or
(2) 5.6, 10.4 and 12.4, or
(3) 9.2, 10.4, 11.2, 12.4, 14.2 and 15.0 or
(4) 5.6, 10.4, 12.7, 13.6, 14.2, 15.0, 17.5 and 1S.8 or
(5) 5.6, 9.2, 11.2, 12.4, 12.7, 13.6, 14.2, 15.0, 16.8, 17.7 and 19.1 or (6) 9.2, 10.4, 11.2, 12.4, 13.6, 14.2, 15.0, 16.6, 18.8, 19.1 and 19.5 or
(7) 5.6, 9.2, 10.4, 12.4, 13.6, 14.2, 15.0, 16.8, 17.5, 18.8, 19.5 and 20.6 or
(8) 9.2, 10.4, 11.2, 12.4, 13.6, 14.2, 15.0, 16.6, 17.5, 17.7, 19.1, 19.5, 21.0, 22.6 and 25.2 or
(9) 5.6, 9.2, 10.4, 11.2, 12.4, 13.6, 14.2, 16.6, 16.S, 17.5, 18.8, 19.1, 19.5, 20.5, 21.0, and 22.6
One embodiment relates to Form A, 2-fluorobenzoate salt exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks: 12.7, 14.2, 16.6, 18.8 and 19.1.
In yet another embodiment one polymorph of the 2,6-difhiorobenzoate (hereinafter referred to as Form A, 2,6-difluorobenzoate salt) exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089): (1) 5.6, 9.1 and 11.2, or
(2) 5.6, 10.3 and 12.6, or
(3) 9.1, 10.3, 11.2, 12.3, 14.9 and 16.7 or
(4) 5.6, 10.3, 12.6, 13.5, 14.2, 14.9, 17.4 and 19.0 or (5) 5.6, 9.1, 11.2, 12.6, 13.5, 14.2, 16.7, 18.4, 18.7, 19.0 and 20.S or
(6) 9.1, 10.3, 11.2, 12.3, 13.5, 14.2, 14.9, 16.7, 17.4, 18.7 and 19.0 or
(7) 5.6, 9.1, 10.3, 12.3, 13.5, 14.2, 14.9, 16.7, 17.4, 18.4, 19.5 and 20.3 or
(8) 9.1, 10.3, 11.2, 12.3, 13.5, 14.2, 14.9, 16.7, 17.4, 1S.4, 18.7, 19.0, 20.3, 21.0 and 22.6 or (9) 5.6, 9.1, 10.3, 11.2, 12.3, 13.5, 14.2, 16.7, 17.4, 18.7, 19.0, 19.5, 20.3, 20.8, and 23.4
One embodiment relates to Form A, 2,6-difluorobenzoate salt exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks: 12.6, 14.2, 18.4, 16.7, 17.4 and 23.4.
Both Forms A may be prepared substantially free of other physical forms by a process comprising the following steps:
(i) contacting a heated solution at a temperature range of form 40 to 80cC (e.g. 60 0C) of
Λr-{5-chloro-2-[((25)-3-{[l-(4-chlorobenz}4)piperidin-4-yl]amino}-2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl}acetamide dissolved in a suitable solvent or mixture of solvents (e.g. an organic solvent such as a polar solvent, including but not restricted to alcohols (e.g. methanol), cyanides (e.g. acetonitrile), acetone and ethyl acetate), with
(ii) a heated solution at a temperature range of form 40 to 8O0C (e.g. 60 0C) of 2- fhxorobenzoic acid or 2,6-difiuorobenzoic acid dissolved in a suitable solvent or mixture of solvents (e.g. an organic solvent such as a polar solvent, including but not restricted to alcohols (e.g. methanol), cyanides (e.g. acetonitrile), acetone and ethyl acetate), to obtain a mixture,
(iii) allowing the mixture to cool to ambient temperature (e.g. 2O0C) to yield a precipitate of Form A of iV-{5-chloro-2-[((2S)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2- hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl} acetamide 2-fiuorobenzoate or Form A of-V-{5-chloro-2-[((2S)-3-{[l-(4-chlorobenzyl)piρeridin-4-yl]amino}-2- hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide 2,6-difluorobenzoate, and (iv) separating the precipitate from the mixture.
One embodiment relates to a process for the preparation of Form A, 2-fluorobenzoate salt or Form A5 2,6-difhiorobenzoate salt: comprising the steps of; (i) contacting a solution at a temperature range of form 40 to 8O0C of 7\r-{5-chloro-2-
[((21S0-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]- 4-hydroxyphenyl}acetamide dissolved in an organic solvent, with (ii) a solution at a temperature range of form 40 to 8O0C of 2-fluorobenzoic acid or 2,6- difluorobenzoic acid dissolved in an organic solvent, to obtain a mixture, (iii) allowing the mixture to cool to ambient temperature to yield a precipitate of Form A ofiV-{5-chloro-2-[((25)-3-{[l-(4-chlorobenzyl)pipeπdin-4-yl]amino}-2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl}acetamide 2-fluorobenzoate or Form A of-V-{5-chloro-2-[((2y)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]ammo}-2- hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide 2,6-difluorobenzoate, and (iv) separating the precipitate from the mixture.
In another embodiment the organic solvent used in steps (i) and/or (ii) is acetonitrile.
Where reference is made in this specification to Forms A being substantially free of other physical forms (or substantially pure), this means that at least 90% by weight, e.g. 90, 91, 92, 93, 94, 95, 96, 91, 98, 99 or 100 %w, of either the 2-fluorobenzoate salt or the 2,6- difluorobenzoate salt is present in that physical form.
The term 'compounds of the invention' as used in this specification, means the 2- fluorobenzoate salt and 2,6- difluorobenzoate salt, or solvates thereof, as well as the Form A, 2-fluorobenzoate and the Form A, 2,6-difluorobenzoate salt in any degree of crystallinity.
Medical use The compounds of the invention are useful as modulators of CCRl or MIP-Ia chemokine receptor activity. Λ/'-{5-chloro-2-[((2iS0-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2- hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide ditrifluoroacetate has an IC50 of below 5 nM in the Human CCRl binding assay as described in PCT/SE2006/O0O918, and may be administered to a mammal, including man, for the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases.
A compound of the invention, can be used in the treatment of:
1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NS AID-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, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
2. bone and joints: arthritides 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; 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, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;
3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthitides (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; panniculitisjcutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; 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. genitourinary: 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; vulvovaginitis; 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. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;
12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes; 13. 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 rumors 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.
Combination therapies The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutical composition or composition comprising a compound 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.
In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below; non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-I / 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 meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine. The present invention still further relates to the combination of a compound of the invention, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) 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.
In addition the invention relates to a combination of a compound of the invention, with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab). MRA-aIL16R and T-Lymphocytes, CTLA4-Ig; HuMax 11-15).
The present invention still further relates to the combination of a compound of the invention, with a modulator of chemokine receptor function such as an antagonist of CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRI l (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX3CRl for the C-X3-C family.
The present invention further relates to the combination of a compound of the invention, with an inhibitor of matrix metalloprotease (Tv-IMPs)5 i.e., the stromefysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP- I)5 collagenase-2 (MMP -8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP -9 and MMP- 12, including agents such as doxycycline.
The present invention still further relates to the combination of a compound 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-butylρhenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-213S; 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 x 1005.
The present invention farther relates to the combination of a compound of the invention, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecatboximidamides 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 x 7195.
The present invention still further relates to the combination of a compound 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.
The present invention still further relates to the combination of a compound of the invention, and an endothelin antagonist such as Tezosentan, Bosentan, Enrasentan, and Sixtasentan.
The present invention still further relates to the combination of a compound of the invention, and an angiotensin II antagonist such as Azilzartan, Losartan, Valsartan, Candesartan, and Telmisartan.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a dual antagonists for both angiotensin II and endothelin A receptors (DARAs) such as disclosed in WO2000001389 and WO2001044239.
The present invention further relates to the combination of a compound of the invention, and an adenosine A2a agonist such as CGS-21680 and/or an adenosine A3 agonist such as IB-MECA and/or an adenosine A2b antagonist. The present invention further relates to the combination of a compound 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.
The present invention still further relates to the combination of a compound of the invention, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
The present invention further relates to the combination of a compound of the invention, and an antagonist of the histamine type 4 receptor.
The present invention still further relates to the combination of a compound of the invention, and an alpha- l/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 ethy norepinephrine hydrochloride.
The present invention further relates to the combination of a compound of the invention, and an anticholinergic agents including muscarinic receptor (Ml5 M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
The present invention still further relates to the combination of a compound of the invention, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
The present invention further relates to the combination of a compound of the invention, and a chromone, such as sodium cromoglycate or nedocromil sodium. The present invention still further relates to the combination of a compound of the invention, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, betamethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
The present invention further relates to the combination of a compound 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 compound 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).
The present invention further relates to the combination of a compound 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 compound 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.
The present invention further relates to the combination of a compound 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, nelfϊnavir, 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 nevirapine or efavirenz.
The present invention still further relates to the combination of a compound 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.
The present invention further relates to the combination of a compound 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.
The present invention still further relates to the combination of a compound 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 agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
The present invention further relates to the combination of a compound of the invention, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
A compound 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.
The present invention still further relates to the combination of a compound 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, INK, protein kinase A, B or C, or inhibitors of kappaB kinases, such as IKKl5 IKK2 or IKK3), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subl. - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin KK. sub 1. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-441S; (xx) elastase inhibitor such as LT-77 or ZD-0892; (xxϊ) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.
A compound of the invention, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fiuorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere): or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ϋ) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, fhitamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or biiserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-rnethoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZDl 839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib. OSI-774) or 6-acrylamido-N-(3- chloro-4-fiuorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;
(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);
(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the inimunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells,, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. For example, for the treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma, the compounds of the invention can be combined with one or more agents for the treatment of such a condition. Where such a combination is to be administered by inhalation, then the one or more agents is selected from the list comprising:
• a PDE4 inhibitor including an inhibitor of the isoform PDE4D;
• a selective β.sub2. adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline. orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
• a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; • a steroid (such as budesonide);
• an inhibitor of p38 kinase function;
• an inhibitor of matrix metalloproteases, most preferably targeting MMP-2, -9 or MMP-12; or,
• an inhibitor of neutrophil serine proteases, most preferably neutrophil elastase or proteinase 3.
In another embodiment of the invention where such a combination is for the treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma, the compounds of the invention, can be administered by inhalation or by the oral route and the other agent can be administered by inhalation or by the oral route. The compounds of the invention and the other agent, may be administered together. They may be administered sequencially. Or they may be administered separately.
Thus, the present invention provides JV-{5-chloro-2-[((2<S)-3-{[l-(4- chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide 2-fluorobenzoate or iV-{5-chloro-2-[((25)-3-{[l-(4- chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide 2,6-difluorobenzoate or solvates thereof, Form A, 2- fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt for use in therapy
In one aspect, the present invention provides iV- {5-chloro-2-[((2ιS)-3-{[l-(4~ chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide 2-fluorobenzoate or jV-{5-chlol^-2-[((2^S)-3-{[l-(4- chlorobenzyl)piperidm-4-yl]ammo}-2-hydroxy-2-memylpropyl)oxy]-4- hydroxyphenyl}acetamide 2,6-difluorobenzoate or solvates thereof, Form A, 2- fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt for use in treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma.
In a further aspect, the present invention provides the use of iV-{5-chloro-2-[((2S)-3-{[l-(4- chlorobenzyl)piperidm-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide 2-fluorobenzoate or 7V-{5-chloro-2-[((25r)-3-{[l-(4- chIorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide 2,6-difluorobenzoate or solvates thereof, in the manufacture of a medicament for treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma.
In a further aspect, the present invention provides the use of Form A, 2-fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt, in the manufacture of a medicament for treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma.
The invention also provides a method of treating an airway disease, respirator}' disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of JV-{5-chloro-2-[((2SV3- {[l-(4-chlorobenzyl<)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide 2-fluorobenzoate or N- {5-chloro-2-[((25)-3-{[l-(4- chlorobenzyl)piρeridin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide 2,6-difluorobenzoate or solvates thereof, Form A, 2- fluorobenzoate salt or Form A, 2.6-difluorobenzoate salt or a pharmaceutical composition cmprising said compounds.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the mode of administration, the treatment desired and the disorder indicated but may typically be in the range from 0.001 mg/kg to 30 mg/kg.
In the context of the present specification, 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.
Pharmaceutical composition The present invention also provides a pharmaceutical composition comprising N- {5- chloro-2-[((2iS)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl}acetamide 2-fluorobenzoate or 7V-{5-chloro-2-[((2^)- 3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide 2,6-difluorobenzoate or solvates thereof, Form A, 2- fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The compounds of the invention may be used on its own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 198S. Depending on the mode of administration, the pharmaceutical composition may comprise from 0.01 to 100 %w (per cent by weight), more preferably from 0.01 to 80 %w, still more preferably from 0.05 to 70 %w, and even more preferably from 0.05 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing JV-{5-chloro-2-[((2S)-3-{[l-(4- chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide 2-fluorobenzoate oriV-{5-chloro-2-[((25)-3-{[l-(4- chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide 2,6-difluorobenzoate or solvates thereof, Form A. 2- fluorobenzoate salt or Form A, 2,6-difluorobenzoate salt, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder compositions, for example, compositions in the inhaler device known as the Turbuhaler* device (Model 0, 1, 2, or 3) or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
In an embodiment of the invention, the 2-fluorobenzoate salt or 2,6-difluorobenzoate salt of the invention is administered by inhalation. In a further embodiment, the 2- fluorobenzoate salt or 2,6-difluorobenzoate salt of the invention is 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.
When administered via inhalation the dose of the compounds of the invention may generally be in the range of from 0.1 μg to 10000 μg, 0.1 to 5000 μg, 0.1 to 1000 μg, 0.1 to 500 μg, 0.1 to 200 μg, 0.1 to 200 μg, 0.1 to 100 μg, 0.1 to 50 μg, 5 μg to 5000 μg, 5 to 1000 μg, 5 to 500 μg, 5 to 200 μg, 5 to 100 μg, 5 to 50 μg, 10 to 5000 μg, 10 to 1000 μg, 10 to 500 μg, 10 to 200 μg, 10 to 100 μg, 10 to 50 μg, 20 to 5000 μg; 20 to 1000 μg, 20 to 500 μg, 20 to 200 μg, 20 to 100 μg, 20 to 50 μg, 50 to 5000 μg, 50 to 1000 μg, 50 to 500 μg, 50 to 200 μg, 50 to 100 μg, 100 to 5000 μg, 100 to 1000 μg or 100 to 500 μg.
Dry powder compositions and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 μm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C2O 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.
One possibility is to mix the finely divided compound of the invention with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyoL Suitable carriers are sugars, for example, lactose, glucose, raffmose, melezitose, lactitol. maltitol, trehalose, sucrose, mannitol; and starch. Alternatively 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.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® device (Model 0, 1, 2, or 3) in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient.
For oral administration 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. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, 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. Also liquid or semisolid compositions of the compound of the invention may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
The invention therefore further relates to combination therapies wherein the compounds of the invention or a pharmaceutical composition comprising said compounds 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.
Detailed description of the drawings
Figure 1. X-ray powder diffraction pattern of N-{5-chloro-2-[((25')-3-{[l-(4- chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl} acetamide 2-fluorobenzoate (Form A, 2-fluorobenzoate salt).
Figure 2. X-ray powder diffraction pattern of N-{5-chloro-2-[((25)-3-{[l-(4- chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl} acetamide 2,6-difluorobenzoate (Form A, 2,6-difluorobenzoate salt). Examples
The present invention will now be farther explained by reference to the following illustrative examples.
General Methods
1H NMR spectra were recorded at 298K on a Varian Unity Inova 400 MHz (software : VKMR 6.1C and VNMRJ 1.1D; probe: Xalorac 5mm DG400-5AT) or a Varian Mercury - VX 300 MHz (software: VNMR 6.1C; probe: Varian 5mm AutoSW PFG) instrument. The central peaks of acetone-^ or dimethylsulphoxide (DMSO)-Ck were used as internal references.
The following method was used for LC/MS analysis: MS Instrument: Agilent 1100 series, equipped with APCI interface LC instrument: Agilent 1100 series, equipped with UV-detector VWD, autosampler
ALS, binary pump and degasser
LC-column: Chromolith Speed ROD, RP-C 18, ø 4.6 x 50 mm
Eluant: Solvent A: water + 0.1% trifluoroacetic acid (TFA); Solvent B: acetonitrile + 0.1% TFA Conditions LC: flow 2.5 ml/minute; 5 to 95% B in gradient; run time 3.6 minutes: UV 220 nm
MS: positive detection: capillary voltage 3 kV
Example 1 Preparation ofiV-{5-chloro-2-[((2iS)-3-{[l-(4-chIorobenzyl)piperidin-4-yl]amino}-2- hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyI}acetamide 2-fIuorobenzoate (1:1 salt), Form A, 2-fluorobenzoate salt
Hot solutions (60 0C) of7V-{5-chloro-2-[((25)-3-{[l-(4-chlorobenzyl)piperidin-4- yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide (99 mg, 0.2 mmol), which may be prepared by processes described in patent application
PCT/SE2006/000918, or by processes analogous to those disclosed in WO 01/98273, in acetonitrile (2 ml) and 2-fluorobenzoic acid (60 mg, 0.4 mmol) in acetonitrile (2 ml) were mixed. The resulting mixture was left to cool down from 60 0C to ambient temperature (2O0C) in a closed vial. The solution was then filtered and subsequently seeded with Λr-{5- chloro-2-[((25)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl}acetamide benzoate, polymoiph B (described in patent application PCT/SE2006/000918). A white precipitate was formed without turbidity. After standing at ambient temperature overnight the precipitate obtained was filtered, washed with acetonitrile (3 x 1 ml) and dried in vacuo at 6O0C overnight to give the titled salt as an off-white solid (89 mg, 70%).
1H NMR (400 MHz5 DMS(M;) δ 9.02 (s, IH)5 7.76-7.72 (m, 2H)5 7.51-7.45 (m, IH)5 7.37-7.35 (ni, 2H)5 7.30-7.28 (m, 2H)5 7.22-7.16 (m, 2H), 6.65 (s, IH)5 3.823.77 (m, 2H)5 3.42 (s5 2H)5 2.93-2.74 (m5 5H)5 1.99 (s5 3H)5 1.97-1.86 (m5 4H)5 1.43-1.40 (m, 2H)5 1.23 (S5 3H); APCI-MS: m/z 496 [MH+]; density 1.349 g/cm3. The stoichiometry, base to acid, of 1 : 1 was confirmed by NMR.
Example 2 Preparation of jV-{5-chloro-2-[(i(25)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2- hydroxy~2-methylpropyl)oxy]-4-hydroxyphenyI}acetamide 2,6-difluorobenzoate (1:1 salt), Form A, 2,6-difluorobenzoate salt
The 2,6-difluorobenzoate salt was prepared in a similar fashion and scale as described for Example 1, to give the titled salt as an off-white solid (89 mg; 68%). 1H NMR (400 MHz, DMSO-^6) δ 9.05 (s, IH)5 7.76 (s5 IH)5 7.39-7.37 (m5 2H)5 7.31-7.22 (m, 3H), 7.00-6.95 (m, 2H)5 6.67 (s, IH)5 3.85-3.79 (m, 2H)5 3.46 (s, 2H)5 3.14-2.81 (m, 5H), 1.96 (s, 3H), 1.99-1.93 (m, 4H)5 1.63-1.53 (m, 2H)5 1.30 (s, 3H); APCI-MS: m/z 496 [MKT]; density 1.385 g/cm3.
The stoichiometry, base to acid, of 1 : 1 was confirmed by NMR
Example 3
X-Ray Powder Diffraction Analyses
General Procedures X-ray powder diffraction (XRPD) analyses may be performed on samples prepared according to standard methods (see for example Giacovazzo et a!., eds., Fundamentals of Crystallography, Oxford University Press (1992); Jenkins & Snyder, eds., Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York (1996); Bunn. ed.5 Chemical Crystallography, Clarendon Press, London (1948); and Khig & Alexander eds., X-ray Diffraction Procedures, John Wiley & Sons, New York (1974)).
X-ray powder diffraction patterns of the Forms A salt described in Examples 1 and 2 above (in anhydrous form) were obtained as described below:
A Bragg-Brentano parafocusing powder X-ray diffractometer using monochromatic CuKa radiation (45 kV and 40 mA) was used for the analyses. The primary optics contained soller slits and an automatic divergence slit. Flat samples were prepared on zero background plates that were rotated during the meausurements, The secondary optics contained soller slits, an automatic anti scatter slit, a receiving slit and a monochromator. The diffracted signal was detected with a proportional xenon-filled detector. Diffraction patterns were collected between 2° ≤ 2Θ (theta) < 40° in a continous scan mode with a step size of 0.016° 20 at a rate of 4° 2θ per minute. Raw data were stored electronically. Evaluation was performed on raw or smoothed diffraction patterns.
A Panalytical X'pert PRO MPD θ-θ diffractometer in reflection mode was used for the above-mentioned measurements. A person skilled in the art can set up instrumental parameters for a powder X-ray diffractometer so that diffraction data comparable to the data presented can be collected.
The results obtained are shown in figure 1 and figure 2.
Form A, 2-fluorobenzoate salt exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 29) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia. 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
(1) 5.6, 9.2 and 11.2, or
(2) 5.6, 10.4 and 12.4, or
(3) 9.2, 10.4, 11.2, 12.4, 14.2 and 15.0 or
(4) 5.6, 10.4, 12.7, 13.6, 14.2, 15.0, 17.5 and 18.8 or (5) 5.6, 9.2, 11.2, 12.4, 12.7, 13.6, 14.2, 15.0, 16.8, 17.7 and 19.1 or
(6) 9.2, 10.4, 11.2, 12.4, 13.6, 14.2, 15.0, 16.6, 18.8, 19.1 and 19.5 or
(7) 5.6, 9.2, 10.4, 12.4, 13.6, 14.2, 15.0, 16.8, 17.5, I S.8, 19.5 and 20.6 or
(8) 9.2, 10.4, 11.2, 12.4, 13.6, 14.2, 15.0, 16.6, 17.5, 17.7, 19.1, 19.5, 21.0, 22.6 and 25.2 or
(9) 5.6, 9.2, 10.4, 11.2, 12.4, 13.6, 14.2, 16.6, 16.8, 17.5, 18.8, 19.1, 19.5, 20.5, 21.0, and 22.6
Form A, 2,6-difluorobenzoate salt exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X- Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeia! Convention; 2002:2088-2089):
(1) 5.6, 9.1 and 11.2, or
(2) 5.6, 10.3 and 12.6, or
(3) 9.1, 10.3, 11.2, 12.3, 14.9 and 16.7 or
(4) 5.6, 10.3, 12.6, 13.5, 14.2, 14.9, 17.4 and 19.0 or (5) 5.6, 9.1, 11.2, 12.6, 13.5, 14.2, 16.7, 18.4, 18.7, 19.0 and 20.8 or
(6) 9.1, 10.3, 11.2, 12.3, 13.5, 14.2, 14.9, 16.7, 17.4, 18.7 and 19.0 or
(7) 5.6, 9.1, 10.3, 12.3, 13.5, 14.2, 14.9, 16.7, 17.4, 18.4, 19.5 and 20.3 or
(8) 9.1, 10.3, 11.2, 12.3, 13.5, 14.2, 14.9, 16.7, 17.4, 18.4, 18.7, 19.0, 20.3, 21.0 and 22.6 or (9) 5.6, 9.1, 10.3, 11.2, 12.3, 13.5, 14.2, 16.7, 17.4, 18.7, 19.0, 19.5, 20.3, 20.8, and 23.4
Example 4
Differential Scanning Calorimetry (DSC)
Using standard methods, for example those described in Hδhne, G. W. H. et al (1996), Differential Scanning Calorimetry, Springer, Berlin, the calorimetric response of a test sample to increasing temperature was investigated using a QlOOO Modulated Temperature Differential Scanning Calorimeter (MTDSC) in "heat only" mode with a ramp rate of 50C per minute. Approximately 2 to 5 mg of test sample was placed in aluminium cups with lids (no crimping) under a nitrogen atmosphere.
It is well known that the DSC onset and peak temperatures may vary due to the purity of the sample and instrumental parameters, especially the temperature scan rate. A person skilled in the art can use routine optimization/calibration to set up instrumental parameters for a differential scanning calorimeter so that data comparable to the data presented here can be collected.
The melting temperature for a typical sample of the anhydrous Form A, 2-fluorobenzoate salt (example 1) was found to be 1380C ± 20C (onset).
The melting temperature for a typical sample of the anhydrous Form A, 2,6- difluorobenzoate salt (example 2) was found to be 14O0C ± 20C (onset).
Example 5 Hygroscopicity Determination
The weight change of a test sample at room temperature (250C) and at 80% relative humidity (RH) were investigated by recording adsoprtion-desoprtion isotherms using a symmetric vapor-sorption analyser SGA-100 (VTI Corporation) using different methods, the main features being: a single sorption/desorption cycle from 0 to 90% RH in 10% RH steps with a dm/dt trigger value of 0.002%, (dm/dt = change in mass with time - when the balance stability is within this value the next step is automatically started, however, if those conditions are not achieved there is a default maximum time for each step of 6 hours). Approximately 2 to 10 mg of the test sample was placed in a sample holder and exposed to different relative humidities.
Test Sample Water Uptake (% w/w) at 80% RH
Anhydrous Form A, 2-fluorobenzoate salt < 0.7
Anhydrous Form A, 2.6-difiuorobenzoate salt < 0.7

Claims

1. A 2-fluorobenzoate salt of iV-{5-chloro-2-[((25)-3-{[l-(4-chlorobenzyl)piperidin-4- yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide or a solvate thereof.
2. A 2,6-difluorobenzoate salt of iV-{5-chloro-2-[((25}-3-{[l-(4-chlorobenzyl)piperidin- 4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide or a solvate thereof.
3. The compound according to claim 1 or 2, which is anhydrous.
4. The compound according to claim 1 or 3, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ): 12.7, 14.2, 16.6, 18.8 and 19.1.
5. The substantially pure compound according to claim 4 having an X-ray powder diffraction pattern substantially the same as that shown in figure 1.
6. The compound according to claim 2 or 3, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ): 12.6, 14.2, 18.4, 16.7, 17.4 and 23.4.
7 The substantially pure compound according to claim 6 having an X-ray powder diffraction pattern substantially the same as that shown in figure 2.
8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
9. The compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in combination with a dry powder inhaler.
10. The compound according to any one of claims 1 to 7 for use in therapy.
11. Use of the compound according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor 1 (CCRl) activity is beneficial.
12. Use of the compound according to any one of claims 1 to 7 in the manufacture of a medicament for treatment of airway disease, respiratory disease and/or an inflammatory disease.
13. Use of the compound according to any one of claims 1 to 7 in the manufacture of a medicament for treatment of asthma.
14. Use of the compound according to any one of claims 1 to 7 in the manufacture of a medicament for treatment of chronic obstructive pulmonary disease.
15. A method of treating a airway disease, respiratory disease and/or an inflammatory disease such as chronic obstructive pulmonary disease and asthma in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim S.
16. A combination of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8, and one or more agents selected from the list comprising: • a PDE4 inhibitor;
• a selective β.sub2. adrenoceptor agonist;
• a muscarinic receptor antagonist;
• a steroid;
• an inhibitor of p3 S kinase function; • an inhibitor of matrix metalloproteases; or,
• an inhibitor of neutrophil serine proteases.
17. A process for the preparation of Form A, 2-fluorobenzoate salt or Form A, 2.6- difluorobenzoate salt: comprising the steps of;
(i) contacting a solution at a temperature range of form 40 to 8O0C of N-(S-ChI oro-2-
[((25)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-meth3'lpropyl)oxy]- 4-hydroxyphenyl}acetamide dissolved in an organic solvent, with
(ii) a solution at a temperature range of form 40 to 8O0C of 2-fluorobenzoic acid or 2,6- difiuorobenzoic acid dissolved in an organic solvent, to obtain a mixture, (iii) allowing the mixture to cool to ambient temperature to yield a precipitate of Form A ofN-{5-chloro-2-[((25)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl}acetamide 2-fluorobenzoate or
Form A ofN-{5-chloro-2-[((26)-3-{[l-(4-chlorobenzyl)piperidin-4-yl]amino}-2- hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl} acetamide 2,6-difluorobenzoate, and (iv) separating the precipitate from the mixture.
PCT/SE2008/000118 2007-02-14 2008-02-13 A 2-f luorobenzoate salt and a 2, 6-dif luorobenzoate salt of n-{5-chloro-2- [ ( (2s) -3-{ [1- (4-chlorobenzyl)piperidin-4- yl ] amino } - 2 - hydroxy- 2 -me t hylpr opyl ) oxy] - 4 - hydroxyphenyl } acetamide Ceased WO2008100202A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2125728A4 (en) * 2007-02-23 2011-06-22 Astrazeneca Ab Novel combination of compounds to be used in the treatment of airway diseases, especially chronic obstructive pulmonary disease (copd) and asthma

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015666A1 (en) * 2005-08-02 2007-02-08 Astrazeneca Ab New salt i
WO2007015664A1 (en) * 2005-08-01 2007-02-08 Astrazeneca Ab Novel piperidine derivatives as chemokine receptor modulators useful for the treatment of respiratory diseases.
WO2007015667A1 (en) * 2005-08-02 2007-02-08 Astrazeneca Ab New salt ii

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015664A1 (en) * 2005-08-01 2007-02-08 Astrazeneca Ab Novel piperidine derivatives as chemokine receptor modulators useful for the treatment of respiratory diseases.
WO2007015666A1 (en) * 2005-08-02 2007-02-08 Astrazeneca Ab New salt i
WO2007015667A1 (en) * 2005-08-02 2007-02-08 Astrazeneca Ab New salt ii

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2125728A4 (en) * 2007-02-23 2011-06-22 Astrazeneca Ab Novel combination of compounds to be used in the treatment of airway diseases, especially chronic obstructive pulmonary disease (copd) and asthma

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