RU2472785C2 - NOVEL 951 COMPOUNDS: BIPHENYLOXYPROPANOIC ACID AS CRTh2 RECEPTOR MODIFIER AND INTERMEDIATE COMPOUNDS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I)

: in form of a mixture of (2S)-2-({3'-chloro-4'-[(2,2-dimethylpyrrolidin-1-yl)carbonyl]-5-fluorobiphenyl-2-yl}oxy)propanoic acid and (2R)-2-({3'-3-chloro-4'-[(2,2-dimethylpyrrolidin-1-yl)carbonyl]-5-fluorobiphenyl-2-yl}oxy)propanoic acid or pharmaceutically acceptable salts thereof. Described are methods of producing said compounds, crystalline forms of the compounds and intermediate compounds. Compounds of formula I are CRTH2 receptor modulators.

EFFECT: improved method.

18 cl, 4 ex, 3 dwg

Description

The present invention relates to certain phenoxyacetic acids and their salts and solvates, useful as pharmaceutical compounds for the treatment of respiratory disorders, pharmaceutical compositions containing them and methods for their preparation. Crystalline forms are also disclosed.

WO 2004/089885 and WO 2006/021759 disclose a number of compounds including amide-based compounds that are active against the Th2-type chemokine receptor (CRTh2) and are considered useful in the treatment of various respiratory diseases, including asthma and chronic obstructive disease lungs (COPD).

The present invention has found that biarylamide not disclosed in these applications is active against the CRTh2 receptor and exhibits particularly useful biological properties. The compound of this invention combines high efficacy against CRTh2 with a useful long half-life and low metabolic conversion rate as measured in human hepatocytes.

Thus, in a first aspect of this invention, there is provided a compound of formula (I):

as a mixture of (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid and (2R) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid, or their solvates, or their pharmaceutically acceptable salts or solvates of pharmaceutically acceptable salts.

In one embodiment of this invention, compound (I) is substantially in the form of an (S) enantiomer. In one embodiment of this invention, compound (I) is at least 90% (S) enantiomer, in another embodiment it is at least 95% (S) enantiomer, and in yet another embodiment it is at least 99% (S) -enantiomer.

Thus, an additional embodiment of this invention includes a compound of formula (I):

or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt solvate thereof.

As indicated above, the compound of formula (I) is able to exist in other stereoisomeric forms. Other isomers, including tautomers and mixtures thereof, also form an aspect of the present invention. It should be understood that other isomers of the compounds of formula (I), in particular (2R) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2 -yl} oxy) propanoic acid, should be considered as exhibiting activity against CRTh2, as well as a mixture of (R) - and (S) -isomers.

The compound of the above formula (I) may be converted into a solvate, a pharmaceutically acceptable salt, or a solvate of the salt. In one embodiment of this invention, the compound is in the form of a base addition salt. Base addition salts include salts derived from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, aluminum, calcium, lithium, potassium, magnesium, sodium, zinc, and other metals. Salts derived from pharmaceutically acceptable non-toxic bases include salts of primary, secondary or tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins such as arginine, betaine, benzathine, caffeine, choline, chlorprocaine , cycloprocaine, N'N'-dibenzylethylenediamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, lisidopine, hydropine n, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, tertiary butylamine (2-methylpropan-2-amine), theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like, ethanolamine and the like, as well as salts non-toxic cations of ammonium and quaternary ammonium, including, without limitation, ammonium, tetramethylammonium, tetraethylammonium.

In one embodiment of this invention, the compound of formula (I) is in the form of a 2-methylpropan-2-amine salt. Solvates, including hydrates, form an additional aspect of this invention, as are solvate salts, such as solvate salts of 2-methylpropan-2-amine.

The compounds of this invention can be obtained in accordance with the methods presented below in the examples. Alternatively, the compound can be obtained as a mixture of enantiomers, which can then be separated and purified using methods known in the art to give a pure or substantially pure (S) isomer, for example, using chromatography. As an additional alternative, isomers of intermediates such as compound (1e) can be separated before deesterification. The intermediates of formulas (1a), (1c), (1g) and (1e), as defined herein in the examples, are new, and each of them forms one embodiment of the invention. In an additional aspect of this invention, a method for producing a compound of formula (I), including:

the interaction of the compounds of formula (1g):

with a compound of formula (1e):

,

,

in which R represents an ester forming group, followed by deesterification of the resulting derivative and possibly the formation of a pharmaceutically acceptable salt, solvate or solvate of the salt. The ester group R is typically C _1-6 alkyl, preferably methyl. This reaction is suitably carried out in a suitable solvent at an elevated temperature, in one embodiment, using the conditions indicated in the examples here.

The crystalline forms of the compounds of formula (I) and their salts / solvates form an additional aspect of this invention. One of the embodiments of this invention relates to crystalline forms of the compounds of formula (I) in the form of a free acid and in the form of a salt of 2-methylpropan-2-amine, as defined and illustrated here.

The compound of this invention or its pharmaceutically acceptable salt / solvate and crystalline forms, as defined here, can be used in the treatment of the following:

1) airways: obstructive airways diseases, including: asthma, including bronchial, allergic, hereditary, acquired, exercise-induced, drug-induced (including induced by aspirin and non-steroidal anti-inflammatory drugs) and dust asthma, as intermittent, so and persistent, and any severity, and other causes of hypersensitivity of the respiratory tract; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer’s lung and related diseases; hypersensitive pneumonitis; pulmonary fibrosis, including cryptogenic fibrous alveolitis, idiopathic interstitial pneumonia, fibrosis complicating anti-cancer treatment, and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the vascular system of the lungs, and pulmonary hypertension; antitussive activity, including the treatment of chronic cough associated with inflammatory and secretory conditions of the respiratory tract, and iatrogenic cough; acute and chronic rhinitis, including drug rhinitis and vasomotor rhinitis; year-round and seasonal allergic rhinitis, including nervous rhinitis (hay fever); polyposis of the nasal cavity; acute viral infection, including the common cold, and infection caused by respiratory syncytial virus, influenza virus, coronavirus (including SARS) and adenovirus;

2) bones and joints: rheumatic and arthritic skin lesions associated with osteoarthritis / osteoarthrosis or including them, both primary and secondary, for example, congenital hip dysplasia; cervical and lumbar spondylitis and pain in the lower back and neck; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infection-related arthropathies and bone diseases such as tuberculosis, including Pott disease and Ponce syndrome; acute and chronic crystal-induced synovitis, including gout, a disease consisting of calcium pyrophosphate deposition, and inflammation of the tendon, joint bag, or synovial cavity associated with calcium apatite; 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 dermatomyositis and polymyositis; rheumatic polymyalgia; juvenile arthritis, including idiopathic inflammatory rheumatic and arthritic skin lesions, regardless of the spread to the joints and associated syndromes, and rheumatic fever and its systemic complications; vasculitic skin lesions, including giant cell arteritis, Takayasu arteritis, Charge-Strauss syndrome, nodosa polyarteritis, microscopic polyarteritis and vasculitis skin lesions associated with viral infection, hypersensitivity reactions, cryoglobulins and paraproteins; pain in the lower back; hereditary Mediterranean fever, Michael Wells syndrome and hereditary Irish fever, Kikuchi disease; iatrogenic arthralgia, tendonitis and myopathy;

3) pain and remodeling of the connective tissue in musculoskeletal disorders due to damage (e.g. sports) or disease: rheumatic and arthritic skin lesions (e.g. rheumatoid arthritis, osteoarthritis, gout or crystal-induced arthropathy), other joint disease (such as degeneration of the intervertebral discs or degeneration of the temporomandibular joint), a disease representing bone remodeling (such as osteoporosis, Paget's disease or osteonecrosis), polychondritis, scleroderma, cm another disorder of connective tissue, spondylarthropathy, 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; seborrheic dermatitis, herpetiform dermatitis, lichen planus, sclerosis and atrophic lichen, gangrenous pyoderma, cutaneous sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, bullous epidermolysis, urticaria, skin lesions, vasculitis, oesculitis, oesculitis, vasculitis male pattern baldness, Sweet syndrome, Weber-Christian syndrome, erythema multiforme; cellulite, both infectious and non-infectious; panniculitis; skin lymphomas, non-melanoma skin cancer, and other dysplastic pathological changes; iatrogenic disorders, including fixed drug rashes;

5) eyes: blepharitis; conjunctivitis, including year-round and spring allergic conjunctivitis; iritis; front and rear uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmia, including sympathetic ophthalmia; sarcoidosis; infections, including viral, fungal and bacterial;

6) the gastrointestinal tract: glossitis, gingivitis, periodontitis; esophagitis, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, including ulcerative colitis, proctitis, anal itching; celiac disease, irritable bowel syndrome, and food allergies that may have effects remote from the intestines (e.g., migraine, rhinitis, or eczema);

7) internal organs: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8) the genitourinary system: nephritis, including interstitial nephritis and glomerulonephritis; nephrotic syndrome; cystitis, including acute and chronic (interstitial) cystitis and chronic bladder 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 after, for example, transplantation of a kidney, heart, liver, lung, bone marrow, skin or cornea, or after blood transfusion; or chronic disease, graft versus host;

10) CNS: Alzheimer's disease and other dementia, including Creutzfeldt-Jakob disease and its new version; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; severe myasthenia gravis; acute and chronic pain (acute, intermittent, or persistent, of both central and peripheral origin), including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain due to cancer and tumor invasion neuropathic pain syndromes, including diabetic, postherpetic and HIV-associated neuropathies; neurosarcoidosis; complications of malignant, infectious or autoimmune processes in the central and peripheral nervous system;

11) other autoimmune and allergic disorders, including Hashimoto's thyroiditis, Graves disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, high IgE level syndrome, antiphospholipid syndrome;

12) other disorders with an inflammatory or immunological component, including acquired immunodeficiency syndrome (AIDS), leprosy, Cesari syndrome and paraneoplastic syndromes;

13) cardiovascular system: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and autoimmune cardiomyopathies, including myocardial sarcoid; damage due to reperfusion after ischemia; endocarditis, valvulitis and aortitis, including infectious forms (e.g. syphilitic); cutaneous manifestations of vasculitis; 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 tumors of the prostate, breast, lung, ovaries, pancreas, colon and colon, stomach, skin and brain, and malignant lesions of the bone marrow (including leukemia) and lymphoproliferative systems such as Hodgkin and non-Hodgkin lymphoma; including the prevention and treatment of metastatic disease and relapse of the tumor and paraneoplastic syndromes; and

15) the gastrointestinal tract: celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, colitis of unknown etiology, irritable bowel syndrome, irritable bowel syndrome, non-inflammatory diarrhea, food allergies that have long-term effects from the intestines, such as migraine, rhinitis, and eczema;

16) diseases associated with elevated levels of prostaglandin D2 (PGD ₂ ) or its metabolites.

Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined hereinabove, for use in treatment.

Preferably, the compounds of this invention are used to treat diseases in which the chemokine receptor belongs to the CRTh2 receptor subfamily.

Specific conditions that can be treated with the compounds of this invention are asthma, rhinitis, COPD and other diseases in which levels of PGD ₂ or its metabolites are elevated. Preferably, the compound of this invention is used to treat asthma, rhinitis or COPD.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined hereinabove, in the manufacture of a medicament for use in treatment.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined hereinabove, in the manufacture of a medicament for use in treatment in combination with medications used to treat asthma, rhinitis or COPD ( such as inhaled and oral steroids, inhaled β2 receptor agonists and oral leukotriene receptor antagonists).

This invention further relates to combination therapies, wherein a compound of this invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or preparation containing a compound of this invention is administered simultaneously or sequentially or as a combined preparation with another therapeutic agent or agents for treating one or more than one specified state.

In particular, for the treatment of inflammatory diseases such as (but not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel disease, the compounds of this invention can be combined with the agents listed below .

Nonsteroidal anti-inflammatory drugs (hereinafter NSAIDs) including non-selective COX-1 / COX-2 cyclooxygenase inhibitors applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, phenoprofen, ketoprofen and fenbuprofen and ketoprofen and 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); cyclooxygenase inhibiting nitric oxide donors (CINOD); glucocorticosteroids (administered by local, oral, intramuscular, intravenous or intraarticular route); methotrexate; leflunomide; hydroxychloroquin; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intraarticular therapeutic agents, such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof together with a cytokine or an agonist or antagonist of cytokine function (including agents that act on cytokine signaling pathways, such as SOCS modulators (cytokine signal suppressors)), including alpha, beta and gamma interferons; type 1 insulin-like growth factor (IGF-1); interleukins (IL), including interleukins from IL-1 to IL-17 and interleukin antagonists or inhibitors such as anakinra; tumor necrosis factor alpha inhibitors (TNF-α), such as anti-TNF monoclonal antibodies (e.g. infliximab; adalimumab and CDP-870) and TNF receptor antagonists, including immunoglobulin molecules (such as etanercept) and low molecular weight agents such as pentoxifylline .

In addition, this invention relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a monoclonal antibody against B lymphocytes, such as against CD20 (rituximab), MRA-alLI6R, and T lymphocytes, CTLA4-lg, HuMax II-15.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a modulator of chemokine receptor function, such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for family CC); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the family of C-X-C) and CX ₃ CR1 for the family of C-X ₃ -C.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with matrix metalloprotease (MMP) inhibitors, namely stromelysins, collagenases and gelatinases, as well as agricanases; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 ( MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor, or 5-lipoxygenase activating protein (FLAP) antagonist, such as: zileuton; ABT-761; fenleyton; tepoxaline; Abbott-79175; Abbott-85761; N- (5-substituted) -thiophen-2-alkylsulfonamide; 2,6-di-tert-butylphenol-hydrazones; methoxytetrahydropyranes such as Zeneca ZD-2138; compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene, a compound such as L-739010; A 2-cyanoquinoline compound such as L-746530; or an indole or quinoline compound, such as MK-591, MK-886 and BAY × 1005.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a leukotriene (LT) B4, LTC4, LTD4 and LTE4 receptor antagonist selected from the group consisting of phenothiazines-3-1, such as L-651392; amidine compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, ralukast (CGP 45715A) and BAY × 7195.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a phosphodiesterase inhibitor (PDE) such as methylxanthanine, including theophylline and aminophylline; a selective PDE isoenzyme inhibitor, including a PDE4 inhibitor, a PDE4D isoform inhibitor, or a PDE5 inhibitor.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a type 1 histamine receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocarbastine, chlorpheniramine, promethazine, cyclizine or orally, topically or parenterally.

The present invention further relates to a combination of a compound of this invention or a pharmaceutically acceptable salt thereof with a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a type 4 histamine receptor antagonist.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a vasoconstrictive sympathomimetic agent, which is an alpha-1 / alpha-2 type adrenergic agonist such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethyl norepinephrine hydrochloride.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with anticholinergic agents, including a muscarinic receptor antagonist (M1, M2 and M3) such as atropine, hyoscine, glycopyrrolate, ipratropium bromide, tiotropium bromide, oxytropium bromide, pirenzepine or telenzepine.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a beta adrenergic receptor agonist (including beta receptors of subtypes 1-4), such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate or pirbuterol or its chiral enantiomer.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a chromone, such as sodium chromoglycate or sodium non-chromium.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, cyclesonide or mometasone furoate.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with an agent that modulates nuclear hormone receptors, such as a peroxisome proliferator activated receptor (PPAR).

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with immunoglobulin (Ig) or an Ig preparation or an antagonist or antibody that modulates Ig function, such as anti-IgE (e.g. omalizumab).

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with another systemic or locally applied anti-inflammatory agent, such as thalidomide or a derivative thereof, retinoid, dithranol or calcipotriol.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide and olsalazine, and immunomodulatory agents such as thiopurines and corticosteroids such as budesonide.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with an antibacterial agent such as a penicillin derivative, tetracycline, macrolide, beta-lactam, fluoroquinolone, metronidazole, inhaled aminoglycoside; an antiviral agent, including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a cardiovascular agent such as a calcium channel blocker, beta adrenergic receptor blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as statin or fibrate; a blood cell morphology modulator such as pentoxifylline; a thrombolytic agent or an anticoagulant, such as a platelet aggregation inhibitor.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with an agent acting on the central nervous system, such as an antidepressant (such as sertraline), a drug against parkinsonism (such as deprenyl, L-DOPA, ropinirole, pramipexole, a monoamine oxidase inhibitor B such as selegiline and rasagiline, a cMP inhibitor such as tasmar, A-2 inhibitor, dopamine reuptake inhibitor, N-methyl-D-aspartate antagonist (NMDA), nicotinic agonist, dopamine agonist or non-dopamine agonist ronalnoy nitric oxide synthase), or a drug against Alzheimer's disease such as donepezil, rivastigmine, tacrine, COX-2 inhibitor, propentofylline or metrifonate.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with an agent for the treatment of acute or chronic pain, such as a central or peripheral analgesic (e.g., an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitriptyline or other antidepressants, paracetamol or a non-steroidal anti-inflammatory agent.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a parenterally or topically applied (including inhalation) local anesthetic, such as lignocaine or a derivative thereof.

The compound of the present invention or a pharmaceutically acceptable salt thereof may also be used in combination with an anti-osteoporosis agent, including a hormonal agent, such as raloxifene, or a bisphosphonate, such as alendronate.

The present invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof together with: (1) a tryptase inhibitor; (2) a platelet activating factor (PAF) antagonist; (3) an interleukin converting enzyme (ICE) inhibitor; (4) an inosine monophosphate dehydrogenase inhibitor (IMPDH); (5) adhesion molecule inhibitors, including a VLA-4 antagonist; (6) cathepsin; (7) a kinase inhibitor such as a tyrosine kinase inhibitor (such as Btk, Itk, Jak3 or MAP, for example gefitinib or imatinib mesylate), serine / threonine kinase (such as a MAP kinase inhibitor such as p38, JNK, protein kinase A, B or C or IKK) or a kinase involved in the regulation of the cell cycle (such as cyclin-dependent kinase); (8) a glucose-6-phosphate dehydrogenase inhibitor; (9) an antagonist of the kinin-B receptor subtype 1 or kinin-B subtype 2; (10) an anti-gout agent, for example colchicine; (11) a xanthine oxidase inhibitor, for example, allopurinol; (12) an anti-uricosuria agent, for example, probenecid, sulfinpyrazone or benzbromarone; (13) a stimulator of growth hormone secretion; (14) transforming growth factor (TGFβ); (15) platelet growth factor (PDGF); (16) a fibroblast growth factor, for example, a major fibroblast growth factor (bFGF); (17) granulocyte macrophage colony stimulating factor (GM-CSF); (18) capsaicin cream; (19) an NK subtype 1 or NK subtype 3 tachykinin receptor antagonist, such as NKP-608C, SB-233412 (talnetant) or D-4418; (20) an elastase inhibitor such as UT-77 or ZD-0892; (21) an TNF-alpha converting enzyme inhibitor (TACE); (22) an inhibitor of inducible nitric oxide synthase (iNOS); (23) a P38 inhibitor; (24) a Toll-like receptor (TLR) modulating agent; (25) an agent modulating the activity of purinergic receptors, such as P2X7; or (26) an inhibitor of the activation of transcription factors such as NFκB, API, or STATS.

The compound of the invention or a pharmaceutically acceptable salt thereof may also be used in combination with an existing therapeutic agent for treating cancer, for example, suitable agents include:

(1) an antiproliferative / antineoplastic drug or combinations thereof, as used in medical oncology, such as an alkylating agent (e.g. cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan or nitrosourea); antimetabolite (for example, an antifolate such as fluoropyrimidine such as 5-fluorouracil or tegafur, altitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumor antibiotic (e.g., anthracycline, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mitramycin); 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 (e.g., epipodophyllotoxin, such as etoposide, teniposide, amsacrine, topotecan or camptothecin);

(2) a cytostatic agent such as an anti-estrogen (e.g. tamoxifen, toremifene, raloxifene, droloxifene or iodoxifene), a negative regulator of estrogen receptor expression (e.g. fulvestrant), antiandrogen (e.g. bicalutamide, flutamide, nilutamide or cyproterone histone HN,) (e.g. goserelin, leuprorelin or buserelin), a progestogen (e.g. megestrol acetate), an aromatase inhibitor (e.g. anastrozole, letrozole, brazole or exemestane) or a 5α-reductase inhibitor such as finasteride;

(3) an agent that inhibits cancer cell invasion (for example, a metalloproteinase inhibitor such as marimastat or an inhibitor of urokinase function as an activator of plasminogen receptor);

(4) an inhibitor of growth factor function, for example: an anti-growth factor antibody (e.g., an anti-erbb2 antibody trastuzumab or an anti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, or a serine / threonine kinase inhibitor, an epidermal growth factor family inhibitor (e.g. an EGFR family tyrosine kinase inhibitor such as N - (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) -quinazolin-4-amine (gefitinib), N - (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) -quinazolin-4-amine (erlotinib) or 6-acrylamido- N - (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (Cl 1033)), an inhibitor of a family of platelet growth factors or an inhibitor of a family of hepatocyte growth factors;

(5) an antiangiogenic agent, such as an agent that inhibits the effects of vascular endothelial growth factor (e.g., an antibody against vascular endothelial cell growth factor bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354 ) or a compound that acts by a different mechanism (e.g. linomid, αvβ3 integrin function inhibitor, or angiostatin);

(6) a vascular damage 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;

(7) an agent used in antisense treatment, for example, one that targets one of the targets listed above, such as ISIS 2503, an antisense anti-ras agent;

(8) an agent used in gene therapy, for example, approaches consisting in replacing aberrant genes, such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzymatic prodrug therapy), for example, using cytosine deaminase, thymidine kinase or bacterial nitroreduct enzyme , and in approaches to increase patient tolerance to chemotherapy or radiotherapy, such as gene therapy of multiple drug resistance; or

(9) an agent used in an immunotherapeutic approach, for example, ex-vivo and in-vivo approaches to increase the immunogenicity of a patient’s tumor cells, such as transfection with cytokines, such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, in approaches to reduce T cell energy, methods using transfected immune cells, such as cytokine-transfected dendritic cells, in approaches using cytokine-transfected tumor cell lines, and in approaches using a tiidiotipicheskie antibody.

In yet a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined hereinabove, in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of CRTh2 receptor activity is useful.

In the context of the present description, the term "treatment" also includes "prophylaxis", unless specifically indicated otherwise. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

The invention further provides a method of treating diseases mediated by PGD2 or its metabolites, wherein the prostanoid binds to its receptor (especially CRTh2), comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined here above.

The invention also provides a method for treating an inflammatory disease, especially psoriasis, in a patient suffering from or at risk of the disease, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined hereinabove.

For these therapeutic applications, the dosage administered will, of course, vary depending on the compound used, the route of administration, the treatment desired and the disorder indicated.

A compound of formula (I), prodrug forms thereof, and pharmaceutically acceptable salts and solvates thereof may be used as such, but should usually be administered in the form of a pharmaceutical composition in which the compound / salt / solvate (active ingredient) of formula (I) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the method of administration, the pharmaceutical composition will preferably contain from 0.05 to 99 wt.% (Percent by weight), more preferably from 0.05 to 80 wt.%, Even more preferably from 0.10 to 70 wt.%, and even more preferably from 0.10 to 50% by weight of the active ingredient, where all percentages by weight are based on the total weight of the composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined hereinabove, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (for example, to the lung and / or respiratory tract or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, for example, 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 rectal administration in the form of suppositories, or transdermally. Preferably, the compound of the invention is administered orally.

This invention will now be illustrated by the following non-limiting examples, in which, unless otherwise indicated:

(1) the compounds indicated in the headings and subheadings of the examples and methods are named using the ACD labs / name program (version 8.0) from Advanced Chemical Development Inc, Canada;

(2) unless otherwise indicated, reverse phase preparative HPLC (RP-HPLC) was carried out using a Symmetry, NovaPak or Ex-Terra reverse phase silica column;

(3) flash column chromatography refers to normal phase silica chromatography;

(4) the solvents were dried using MgSO ₄ or Na ₂ SO ₄ ;

(5) evaporation was carried out by rotary evaporation in vacuo, and the processing procedures were carried out after removing the remaining solids, such as drying agents, by filtration;

(6) unless otherwise indicated, the operations were carried out at ambient temperature, which is in the range from 10 ° C to 40 ° C, and in an atmosphere of an inert gas such as argon or nitrogen;

(7) the outputs are given for illustration only and do not necessarily represent achievable highs;

(8) the structures of the final products of formula (I) are confirmed by nuclear (usually proton) magnetic resonance (NMR) and mass spectrometric methods; peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, wide; q, quartet; quin, quintet. ¹ H-NMR data are given in the form of delta values for the main diagnostic protons, indicated in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard;

(9) intermediate compounds are characterized by thin layer chromatography (TLC), high performance liquid chromatography (HPLC), mass spectrometry (MS), infrared (IR) or NMR analysis;

(10) mass spectra (MS): if given, usually only ions are indicated that show the mass of the starting material; MM = multimodal;

(11) the following abbreviations were used:

EtOAc Ethyl acetate DMF N, N-Dimethylformamide Nmp N-methylpyrrolidinone MgSO ₄ Magnesium sulfate Thf Tetrahydrofuran K.T. Room temperature DCM Dichloromethane Mecn Acetonitrile

Example 1: (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) -carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid

a) 3-Chloro-5'-fluoro-2'-methoxybiphenyl-4-carboxylic acid

4-Bromo-2-chlorobenzoic acid (1.1 g) and 5-fluoro-2-methoxyphenylboronic acid (0.94 g) were suspended in toluene (20 ml) and ethanol (20 ml). An aqueous 2 M solution of sodium carbonate (16 ml) and tetrakis (triphenylphosphine) palladium (0) (0.14 g) were added, and this reaction mixture was heated at 95 ° C for 20 hours. The mixture was diluted with water and extracted with diethyl ether (discarded). . The aqueous layer was acidified with aqueous 2M hydrochloric acid, extracted with ethyl acetate, dried (MgSO ₄ ) and concentrated under reduced pressure to obtain the product indicated in the subtitle as a cream solid (1.25 g).

MS: APCI (-ve) (mass spectrometry with chemical ionization at atmospheric pressure): 279.

b) 2,2-Dimethylpyrrolidine hydrochloride salt

5,5-Dimethyl-1-pyrroline-N-oxide (2 g) in ethanol (40 ml) containing 10% palladium on carbon (0.5 g) was stirred in a hydrogen atmosphere (4 bar (400 kPa) ) during the night. The mixture was purged with nitrogen, filtered through Celite, and the filtrate was treated with 4 M HCl in dioxane (5 ml). The solution was concentrated under reduced pressure and subjected to azeotropic distillation with toluene (× 2) to obtain the product indicated in the subtitle as an off-white solid (2.10 g).

1 H NMR: δ (CDCl ₃ ) 9.52 (2H, bs), 3.46-3.37 (2H, m), 2.15-2.01 (2H, m), 1.91-1.85 (2H, t), 1.55 (6H, s).

c) 1 - [(3-Chloro-5'-fluoro-2'-methoxybiphenyl-4-yl) carbonyl] -2,2-dimethylpyrrolidine

The product from step (a) (1.25 g) in DCM (20 ml) was treated with oxalyl chloride (0.44 ml) and a drop of DMF. The mixture was stirred at rt. for 1 h and concentrated under reduced pressure to obtain an oil which was subjected to azeotropic distillation with toluene. This acid chloride was dissolved in DCM (10 ml) and treated with the product from (b) (0.60 g) and then triethylamine (0.4 ml), and this reaction mixture was stirred at rt. during the night. The organic layer was diluted with DCM and washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure to obtain the subtitle product as a cream solid (0.6 g).

MS: APCl (+ ve) 362.

d) 3'-Chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-ol

The product from step (c) (0.6 g) in DCM (10 ml) was treated with 1.0 M boron tribromide in DCM (5 ml) and the reaction mixture was stirred at rt. during the night. The reaction mixture was diluted with DCM and washed with ice water, dried (MgSO ₄ ) and concentrated under reduced pressure to obtain the product indicated in the subtitle as a solid (0.5 g).

MS: APCl (-ve) 346.

1 H-NMR (300 MHz, D6-DMSO) δ 7.69 (1H, d), 7.59 (1H, dd), 7.34 (1H, d), 7.19 (1H, dd), 7.05 (1H, td), 6.95 (1H , dd), 3.17 (2H, t), 1.87-1.71 (4H, m), 1.52 (6H, s).

d) Methyl- (2R) -2 - {[(4-methylphenyl) sulfonyl] oxy} propanoate

2-Hydroxy-propanoic acid methyl ester (6.66 g) was dissolved in MeCN (34 ml) and the solution was cooled to 5 ° C. Triethylamine (9.8 ml) and then trimethylamine hydrochloride (0.62 g) were added. A solution of para-toluenesulfonyl chloride (11.6 g) in MeCN (34 ml) was added over 20 min (sonicated until complete dissolution), keeping the temperature of this reaction mixture below 5 ° C. This reaction mixture was filtered through Celite and washed with additional MeCN. The filtrate was concentrated almost to dryness (bath, 30 ° C.) and partitioned between diethyl ether and water. The organic layer was separated, dried (MgSO ₄ ) and the solvents were removed to obtain the product indicated in the subtitle as a yellow oil, which solidified in the refrigerator (13.71 g).

1 H NMR: δ (CDCl ₃ ) 7.82 (2H, d), 7.35 (2H, d), 4.95 (1H, q), 3.67 (3H, s), 2.45 (3H, s), 1.51 (3H, d) .

f) Methyl- (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) -carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoate

The intermediate compound from step (g) (2.83 g) was dissolved in MeCN (30 ml). The product from step (e) (2.11 g) and potassium carbonate (2.25 g) were added and the mixture was heated to 65 ° C. for 16 hours. The mixture was cooled to rt. and extracted with diethyl ether (× 2), dried (MgSO ₄ ) and concentrated under reduced pressure to give an oil. The oil was purified by flash column chromatography on silica using a 3: 1 mixture of isohexane and ethyl acetate as an eluent to give the product indicated in the subtitle as a colorless oil (2.29 g).

MS: APCI (+ ve) 434.

g) (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} hydroxy) propanoic acid

The product from step (e) was treated with an aqueous 2 M sodium hydroxide solution (10 ml) and tetrahydrofuran (10 ml) and stirred for 1 h. The mixture was diluted with water and extracted with diethyl ether (discarded). The aqueous layer was acidified with 2 M hydrochloric acid, extracted with ethyl acetate, dried (MgSO ₄ ) and concentrated under reduced pressure to give an oil. The oil was purified by reverse phase preparative HPLC (Xterra column using a gradient of 25-95% MeCN in 0.2% aqueous TFA as eluent) to give the title product as a white solid (1.70 g) .

MC: APCI (-ve) 418.

1 H NMR: δ (D6-DMSO) 7.81 (1H, s), 7.66-7.63 (1H, d), 7.42-7.14 (3H, m), 7.01-6.96 (1H, m), 4.93-4.86 (1H, q), 3.19-3.15 (2H, m), 1.86-1.73 (4H, m), 1.52 (6H, s), 1.45-1.42 (3H, d).

Example 2: salt of (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid with 2- methylpropan-2-amine

The product from step (g) of Example 1 (1.20 g) was dissolved in ethyl acetate, tert-butylamine (1 equiv.) Was added and the volatiles removed in vacuo. The resulting solid was recrystallized from MeCN (30 ml) to give the title product as a crystalline white solid (0.51 g).

MC: APCI (-ve) 418.

1 H NMR: δ (D6-DMSO) 8.04 (1H, bm), 7.73 (1H, d), 7.32 (1H, d), 7.18 (1H, dd), 7.07 (1H, td), 6.88 (1H, dd ), 4.42-4.40 (1H, q), 3.18 (2H, t), 1.84-1.75 (4H, m), 1.51 (6H, s), 1.33 (3H, d), 1.19 (9H, s).

Example 3: Large-scale Synthesis of (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} hydroxy) propanoic acid salt with 2-methylpropan-2-amine

a) 3-Chloro-5'-fluoro-2'-methoxybiphenyl-4-carboxylic acid

4-Bromo-2-chlorobenzoic acid (205 g) and 5-fluoro-2-methoxy-phenylboronic acid (161 g) were dissolved in toluene (2 L) and ethanol (2 L) in a 10 L reaction vessel. Sodium carbonate (2 L of a 2 M aqueous solution) was added and then tetrakis (triphenylphosphine) palladium (0) (15.39 g). This reaction mixture was heated at 75 ° C. for 16 hours. The reaction mixture was diluted with water (2.5 L) and TBME (2 L) and stirred. Additional water (0.5 L) was added and this mixture was stirred for an additional 5 minutes until the solid was completely dissolved. The aqueous layer was separated, filtered through a layer of celite and cooled to 15 ° C. The solution was acidified to pH 1 over 1 h by adding concentrated HCl (532 ml, final pH 1). The solid was filtered and washed with cold ice water (400 ml) to give a light brown solid. It was dried for 72 hours in a vacuum chamber at 45 ° C over CaCl ₂ to give the product indicated in the subtitle (237 g).

MS: APCI (-ve) 279.

1 H NMR: δ (D6-DMSO) 7.84 (d, 1H), 7.66 (d, 1H), 7.56 (dd, 1H), 7.21-7.30 (m, 2H), 7.14-7.18 (m, 1H), 3.78 (s, 3H).

This process was repeated on the same scale to give an additional 228 g (465 g total).

b) 2,2-dimethylpyrrolidine

2,2-Dimethyl-3,4-dihydro-2H-pyrrole-1-oxide (0.31 L) was dissolved in EtOAc (3 L) and Pd / C (32 g) was added. This reaction mixture was stirred under a hydrogen atmosphere (4 bar (400 kPa)) for 16 hours. The mixture was filtered through celite. Fresh Pd / C catalyst (32 g) was added and hydrogenation was continued for an additional 24 hours. The mixture was filtered through celite. Fresh Pd / C catalyst (32 g) was added and hydrogenation was continued for another 24 hours. The mixture was filtered through celite. Fresh Pd / C catalyst (32 g) was added and hydrogenation was continued for an additional 24 hours. The mixture was filtered through celite. Fresh Pd / C catalyst (32 g) was added and hydrogenation was continued for another 24 hours. The mixture was filtered through celite. Fresh Pd / C catalyst (32 g) was added and hydrogenation continued for an additional 24 hours. The mixture was filtered through celite to give a solution of the product indicated in the subtitle in EtOAC (3.17 L), which was used without further manipulation.

Analysis of an aliquot by NMR showed that the solution had a concentration of 0.74 M. GC-MS analysis confirmed the complete use of the starting material.

GC-MS: molecular weight 99 (100%).

1 H NMR d (CDCl ₃ ) 2.90 (t, 2H), 1.74 (quintet, 2H), 1.46 (t, 2H), 1.09 (s, 6H).

c) 1 - [(3-Chloro-5'-fluoro-2'-methoxybiphenyl-4-yl) carbonyl] -2,2-dimethylpyrrolidine

Thionyl chloride (0.177 L) was added to a suspension of the product from step (a) (453 g) in toluene (4 L) and this reaction mixture was heated at 75 ° C for 16 hours. Volatiles were evaporated and the residue was subjected to azeotropic distillation with toluene (1 k) to obtain a beige solid. It was dissolved in ethyl acetate (1 L) and added dropwise over 30 minutes to a mixture of triethylamine (0.45 L) in ethyl acetate (0.5 L) and the product from step (b) (2.62 L) at 10 ° C. . The temperature of this reaction mixture increased to 17 ° C during the addition. The reaction mixture was stirred at 23 ° C for 1 h, then washed with water (2 L), 1 N. HCl (2 L), saturated aqueous NaHCO ₃ (2 L) and brine (2 L). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was evaporated to obtain, after drying, the product indicated in the subtitle as a colorless solid (550 g).

MS: APCI (+ ve) 362/364.

d) 3'-Chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-ol

The product from step (c) (550 g) was suspended in 48% hydrobromic acid (4.5 L) and heated at 95 ° C for 12 hours, then cooled to 23 ° C and stirred for 72 hours. Solid filtered and washed with water (4 L) and then dried to constant weight to obtain 527 g of a solid. This solid was suspended in water (5 L) and vigorously stirred overnight. The solid was filtered and washed with water until the pH of the filtrate reached 7. The filter cake was washed with isohexane and dried in a vacuum chamber at 45 ° C for 72 hours to obtain the product indicated in the subtitle (496 g).

MS: APCI (+ ve) 348.

1 H NMR δ (D6-DMSO) 9.77 (s, 1H), 7.69 (s, 1H), 7.59 (d, 1H), 7.35 (d, 1H), 7.19 (dd, 1H), 7.05 (td, 1H) 6.95 (dd, 1H), 3.17 (t, 2H), 1.75-1.85 (m, 4H), 1.52 (s, 6H).

d) Methyl- (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) -carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoate

The product from step (g) (206.4 g) was dissolved in NMP (1 L) and potassium tert-butoxide (65.9 g) was added portionwise (6 × 10 g and 1 × 5.9 g). The temperature during the addition increased to 35 ° C. This reaction mixture was stirred at K.T. over 30 minutes and then added dropwise over 3 hours to a solution of methyl- (2R) -2 - {[(4-methylphenyl) sulfonyl] oxy} propanoate (Example 1e, 169 g) in NMP (1 L), maintaining the temperature at 20 ° C. This reaction mixture was halved and each half was independently added to water (10 L) and extracted with diethyl ether (5 L). Each aqueous phase was salted (1.5 kg of NaCl was added) and the extraction with diethyl ether was repeated. The combined organic phases were dried (Na ₂ SO ₄ ), and evaporation of the solvent gave a crude product (~ 300 g). This crude product was combined with an additional batch of crude product obtained by re-synthesis (~ 310 g) and purified by large-scale preparative HPLC (Kromasil silica 10 μm 60 Å, 25 cm × 150 mm, 20% ethyl acetate in isohexane, 100 ml / min, run time 20 min, 280 nm) to give the title product (307 g).

MS: APCI (+ ve) 434.

f) (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid as a crystalline free acid

To an intensely stirred solution of the product from step (d) (307 g) in THF (3 L) was added a solution of lithium hydroxide (148 g) in water (0.6 L) and this reaction mixture was stirred at K.T. within 45 minutes An aqueous 20% brine solution (2.5 L) was added and the layers were separated. The organic fraction was concentrated in vacuo, the residue was redissolved in water (6 L) and the stirred mixture was acidified to pH 1 with concentrated HCl. The resulting precipitate was filtered and washed with portions of water until the pH of the filtrate reached 6. Isohexane was passed through the filter cake to remove excess water and the solid was dried in a vacuum chamber for 48 h at 40 ° C to obtain the title product in crude form (259 g).

MS: APCI (+ ve) 420.

MeCN (1.3 L) was added and this mixture was heated to 74.5 ° C (internal temperature) for 22 minutes until a clear solution was obtained. The mixture was maintained at this temperature for 10 minutes, then linearly cooled to 20 ° C. over 1 hour, and then stirred for another 1 hour at 20 ° C. The resulting solid was filtered, washed with MeCN (250 ml) and isohexane (500 ml) and dried at 40 ° C. in vacuo for 72 hours to give the product indicated under the subtitle (216 g).

MS: APCI (+ ve) 420.

1 H NMR δ (D6-DMSO) 13.12 (s, 1H), 7.81 (s, 1H), 7.64 (d, 1H), 7.36 (d, 1H), 7.28 (dd, 1H), 7.18 (td, 1H) , 6.99 (dd, 1H), 4.90 (q, 1H), 3.17 (t, 2H), 1.94-1.66 (m, 4H), 1.52 (s, 6H), 1.44 (d, 3H).

g) Salt (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) -carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid with 2- methylpropan-2-amine

To a suspension of the free acid product from step (e) (215.4 g), stirred in MeCN (1.5 L) at K.T., tert-butylamine (0.054 L) in MeCN (1 L) was added in one portion . The temperature increased from 23 ° C to 28 ° C. A homogeneous solution was obtained immediately before precipitation of the solid. The mixture was stirred for 1 hour, then combined with additional batches (36 g) of the product indicated in the title of Example 2 (salt with tert-butylamine), and the mixture was stirred for 16 hours. The solid was then filtered off and washed with ice-cold MeCN ( 500 ml) and dried to constant weight at 40 ° C in vacuo to give the title product (280 g).

MS: APCI (+ ve) 420.

1 H NMR δ (D6-DMSO) 8.17 (s, 2H), 8.06 (s, 1H), 7.73 (d, 1H), 7.32 (d, 1H), 7.18 (td, 1H), 7.07 (td, 1H) , 6.89 (dd, 1H), 4.44 (q, 1H), 3.18 (t, 2H), 1.89-1.69 (m, 4H), 1.49 (s, 6H), 1.33 (d, 3H), 1.18 (s, 9H )

Example 4: (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid in the form of crystalline free acid

To a solution of the product from step (e) of Example 3 (21.4 g) in THF (200 ml) was added a solution of lithium hydroxide (10.35 g) in water (40 ml) with vigorous stirring. After 45 minutes, a 20% aqueous solution of brine (160 ml) was added and the layers were separated. The organic fraction was concentrated in vacuo, the residue was again dissolved in water (400 ml) and acidified to pH 2 with concentrated HCl with stirring. The obtained precipitate was filtered and washed with portions of water until the pH of the filtrate reached 6. Isohexane was passed through the precipitate on the filter to remove excess water and the solid was dried in a vacuum chamber at 40 ° С to obtain the title product in crude form (~ 20 g). A portion of this solid (1 g) was recrystallized by heating to reflux in MeCN (5 ml) until it dissolved, followed by cooling to KT, stirring for 16 hours and collecting the resulting solid and drying in vacuum with obtaining the product indicated in the title (0.759 g).

MS: APCI (+ ve) 420.

1 H NMR δ (D6-DMSO) 13.13 (s, 1H), 7.81 (s, 1H), 7.64 (d, 1H), 7.36 (d, 1H), 7.28 (dd, 1H), 7.23-7.13 (m, 1H), 6.99 (td, 1H), 4.90 (q, 1H), 3.17 (t, 2H), 1.89-1.70 (m, 4H), 1.52 (s, 6H), 1.44 (d, 3H).

Physical Data

Description of graphic materials

Figure 1: X-ray diffraction pattern on a polymorph A powder of the compound of Example 2 (salt with 2-methylpropan-2-amine).

Figure 2: X-ray diffraction pattern on a polymorph A powder of the compound of Example 4 (free acid).

Figure 3: Pattern of x-ray diffraction on the polymorph B powder of the compound of Example 4 (free acid).

Detailed description of tool equipment:

X-ray powder diffraction (XRPD) data was obtained using either a PANalytical CubiX PRO instrument or a Philips X-Pert MPD instrument.

XRPD - PANalytical CubiX PRO

Data was obtained using a PANalytical CubiX PRO instrument in the θ-θ configuration in the 2θ scan range from 2 ° to 40 ° at a 100-second exposure in increments of 0.02 °. X-ray radiation was generated by a long-focus copper tube operating at 45 kV and 40 mA. The X-ray wavelength from copper was 1.5418 Å. Data was collected on zero background holders on which approximately 2 mg of the compound was placed. The holder was made of monocrystalline silicon, which was cut along a diffraction-free plane, and then polished on an optically neutral finish. The occurring x-ray radiation on this surface was leveled by Bragg scattering.

Philips X-Pert MPD

Data was collected using a Philips X-Pert MPD instrument in θ-θ and θ-2θ configurations in a 2θ scan range of 2 ° to 40 ° at 100 second exposure in increments of 0.03 °. X-ray radiation was generated by a long-focus copper tube operating at 45 kV and 40 mA. The wavelengths of x-ray radiation from copper were 1.5405 Å (K _α1 ) and 1.5444 Å (K _α2 ). Data was collected on zero background holders on which approximately 2 mg of the compound was placed. The holder was made of monocrystalline silicon, which was cut along a diffraction-free plane, and then polished on an optically neutral finish.

Differential scanning calorimetry (DSC) thermograms were determined using a TA Q1000 differential scanning calorimeter with aluminum cuvettes and perforated shutters. Sample weights ranged from 0.5 to 5 mg. The procedure was carried out at a nitrogen gas flow rate (50 ml / min) and the temperature was studied from 25 ° to 300 ° C at a constant temperature increase rate of 10 ° C per minute.

Gravimetric vapor sorption profiles (GVS) were determined using a DVS-1 dynamic vapor sorption apparatus. A solid sample of about 1-5 mg was placed in a glass vessel and the mass of the sample was recorded by a double step cycle method (from 40 to 90 to 0 to 90 to 0% relative humidity (RH), in increments of 10% RH).

The specialist should be clear that the values of 2-theta may vary slightly depending on the instrument used and the exact nature of the experiment. This invention encompasses crystalline forms having 2-theta values substantially the same as defined herein.

Analysis of the compound of Example 2: polymorph A salts (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) - propanoic acid with 2-methylpropan-2-amine

A sample of polymorph A of the compound of Example 2 was obtained by the method described in example 2 and analyzed by XRPD, DSC and GVS.

The melting point of polymorph A of the compound of Example 2, when determined by DSC, was 157-165 ° C. with a water absorption of 0.6% at 0 to 80% OB, measured by GVS. The XRPD diffraction pattern of polymorph A of the compound of Example 2 is shown in FIG.

The polymorphic form obtained by the large-scale method (example 3g) was identical to polymorph A of the compound of this example 2 in accordance with XRPD.

Experiments with suspensions in 10 solvents at room temperature for 7 days yielded crystals of the above polymorph A. The following solvents were studied: acetone, acetonitrile, dichloromethane, 1,4-dioxane, ethanol, ethyl acetate, n-heptane, cyclohexane, toluene and water .

Analysis of the compound of Example 4: polymorph A (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propane acid free acid

A polymorph A sample of the compound of Example 4 was obtained by the method described in example 4 and analyzed by XRPD, DSC and GVS.

The melting point of polymorph A of the compound of Example 4 when determined by DSC showed a single endothermic event at 180 ° C (± 2 ° C) with a water absorption of 0.7% at OB from 0% to 80%, as measured by GVS. The XRPD diffraction pattern of polymorph A of the compound of Example 4 is shown in FIG. 2.

The polymorphic form obtained by the large-scale method (example 3e) was identical to polymorph A of the compound of this example 4, in accordance with XRPD.

Experiments with suspensions in ethyl acetate, MeCN and n-heptane at K.T. and ethyl acetate at 50 ° C. for 9 days gave crystals of the above polymorph A.

Obtaining and analysis of the compound of Example 4: polymorph B (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} -oxy a) propanoic acid in the form of a free acid

Experiments with a suspension of polymorph A of the compound of Example 4 in water at K.T. and in water and MeCN at 50 ° C for 9 days gave crystals of polymorph B. Polymorph B was also formed after slow evaporation of ethanol suspension at K.T.

The melting point of polymorph B of the compound of Example 4, when determined by DSC, showed the only endothermic event occurring at 188 ° C (± 2 ° C).

Physical Data

Figure 1 is a powder X-ray diffraction pattern for the compound of Example 2, polymorph A.

Figure 2 is a powder X-ray diffraction pattern for the compound of Example 4, polymorph A.

Figure 3 is a powder X-ray diffraction pattern for the compound of Example 4, polymorph B.

Pharmacological data

Ligand Binding Assay

[ ³ H] PGD ₂ with a specific activity of 100-210 Ci / mmol was purchased from Perkin Elmer Life Sciences. All other chemicals were of analytical quality.

Human embryonic kidney (HEK) cells expressing rhCRTh2 / Gα16 were continuously maintained in Dulbecco's modified Eagle’s medium (DMEM) containing 10% fetal bovine serum (HyClone), 1 mg / ml geneticin, 2 mM L-glutamine and 1 % replaceable amino acids. To obtain membranes, adhesive transfected HEK cells were grown to confluency in bilayer tissue culture systems (Fisher, catalog number TKT-170-070E). Maximum receptor expression levels were induced by the addition of 500 mM sodium butyrate in the last 18 hours of culture. Adhesive cells were washed once with phosphate-buffered saline (PBS, 50 ml per cell system) and decoupled by adding ice-cold membrane homogenization buffer [20 mM HEPES (pH 7.4), 0.1 mM dithiothreitol, 1 mM ethylenediaminetetraacetic acid (EDTA) ), 0.1 mM phenylmethylsulfonyl fluoride and 100 μg / ml bacitracin] in an amount of 50 ml per cell system. Cells were pelleted by centrifugation at 220 g for 10 minutes at 4 ° C, resuspended in half the initial volume of fresh membrane homogenization buffer and dispersed with a Polytron homogenizer for two 20-second sessions, keeping the tubes in ice all the time. Undamaged cells were removed by centrifugation at 220 g for 10 minutes at 4 ° C and the membrane fraction was precipitated by centrifugation at 90,000 g for 30 minutes at 4 ° C. The final pellet was resuspended in 4 ml of membrane homogenization buffer on the cell system used and the protein content was determined. Membranes were stored at -80 ° C in suitable aliquots.

All assays were performed in white 96-well Corning NBS clear-bottom plates (Fisher). Before analysis, HEK cell membranes containing CRTh2 were applied onto SPA PVT WGA granules (Amersham). For application, membranes were incubated with granules, in typical cases, at 25 μg of membrane protein per 1 mg of granules, at 4 ° C with constant stirring overnight. (Optimum application concentrations were determined for each batch of membranes.) Granules were pelleted by centrifugation (800 g for 7 minutes at 4 ° C), washed once with assay buffer (50 mM HEPES at pH 7.4, containing 5 mM magnesium chloride) and finally resuspended in assay buffer at a granule concentration of 10 mg / ml.

Each analysis included 20 μl of 6.25 nM [ ³ H] PGD ₂ , 20 μl of membrane-saturated SPA beads, both in the assay buffer and in 10 μl of a solution of the compound or 13.14-dihydro-15-ketoprostaglandin D ₂ (DK-PGD ₂ , for determination of non-specific binding, Cayman Chemical Company).

Compounds and DK-PGD _{2 were} dissolved in DMSO and diluted in the same solvent to 100 times the desired final concentration. An assay buffer was added to obtain a final concentration of 10% DMSO (the compounds were at 10 times the desired final concentration), and it was a solution added to an assay plate. An assay plate was incubated at K.T. for 2 hours and counted on a Wallac Microbeta liquid scintillation counter (1 minute per well).

The compound of formula (I) has a pIC50 of 8.4.

Determination of intrinsic metabolic clearance (CL _int ) using human hepatocytes

Stock solutions of the compounds in dimethyl sulfoxide were obtained at a 100-fold incubation concentration (100 μM). 10 μl of this 100 μM stock solution was added to a vial containing 490 μl hepatocyte suspension buffer (without serum). A vial containing human hepatocytes at a concentration of 2 million viable cells per ml was preincubated for 5 min in a shaken (80 cycles / min) water bath at 37 ° C together with a vial containing a mixture of drug / buffer.

Interactions were initiated by adding 500 μl of a suspension of hepatocytes to 500 μl of the drug / buffer mixture (to give a final substrate concentration of 1 μM at 1% dimethyl sulfoxide v / v). Aliquots (40 μl) were taken at 5, 15, 30, 45, 60, 75, 90, and 120 minutes, and interactions were quenched in 80 μl of ice-cold methanol.

The samples were then frozen for 1 h at -20 ° C and then centrifuged at 2000 g for 20 min at 4 ° C. Supernatants were removed and analyzed by tandem mass spectrometry (MS / MS) and Cl _int was evaluated by the slope of the graph of the natural logarithm of the response in MS / MS over time.

Based on physiological correction factors for calculating human hepatocellularity and liver mass (Ito and Houston, 2004), clearance in the bloodstream of the liver (Clh) was predicted using the technique described in Riley et al., 2005. Typical acidic drugs showing intrinsic clearance in In this assay, less than 2 μl / min / e of ⁶ cells show approximate elimination half-lives from the human body corresponding to once-daily administration intervals. Example 1: Cl _int ≤1 μl / min / e ⁶ (n = 3).

Claims (18)

1. The compound of formula (I):

as a mixture of (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid and (2R) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid or their pharmaceutically acceptable salts. 2. The mixture according to claim 1, in which (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy ) propanoic acid is present in an amount of at least 95%. 3. The mixture according to claim 1 or 2, in which (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl } oxy) propanoic acid and (2R) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid are in salt form with 2-methylpropan-2-amine. 4. The compound of formula (I):

or a pharmaceutically acceptable salt thereof. 5. The salt of the compounds of formula (I), as defined in claim 4, with an amine. 6. The salt of claim 5, which is a salt of (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} hydroxy) propanoic acid with 2-methylpropan-2-amine:

7. The crystalline salt form of the compound (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid with 2-methylpropan-2-amine, characterized by a powder X-ray diffraction pattern with peaks at least one of the following 2-theta values measured using a CuKα radiation source: 11.6, 14.6 and 21.1. 8. The crystalline salt form of the compound (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid with 2-methylpropan-2-amine, characterized by a pattern of x-ray diffraction on the powder, essentially the same as shown in Fig.1. 9. The crystalline form of the compound (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid (form A), characterized by a powder X-ray diffraction pattern with peaks at least one of the following 2-theta values measured using a CuKα radiation source: 17.6, 21.4 and 29.4. 10. The crystalline form of the compound (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid (form A), characterized by a pattern of x-ray diffraction on the powder, essentially the same as shown in Figure 2. 11. The crystalline form of the compound (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid (form C) characterized by a powder X-ray diffraction pattern with peaks at least one of the following 2-theta values measured using a CuKα radiation source: 10.6, 13.2 and 20.5. 12. The crystalline form of the compound (2S) -2 - ({3'-chloro-4 '- [(2,2-dimethylpyrrolidin-1-yl) carbonyl] -5-fluorobiphenyl-2-yl} oxy) propanoic acid (form B) characterized by a powder X-ray diffraction pattern substantially the same as that shown in FIG. 3. 13. The compound of formula (I) according to any one of claims 1 to 12 for use as modulators of CRTh2 receptors. 14. The compound of formula (1A):

15. The compound of formula (1B):

16. The compound of formula (1g):

17. The compound of formula (1e):

18. A method of obtaining a compound of formula (I), including:
the interaction of the compounds of formula (1g):

with a compound of formula (1e):

in which R represents an ester forming group, followed by deesterification of the resulting derivative and possibly the formation of a pharmaceutically acceptable salt.

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