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WO2009147165A1 - Nouveaux composés agonistes des récepteurs ep4 - Google Patents

Nouveaux composés agonistes des récepteurs ep4 Download PDF

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Publication number
WO2009147165A1
WO2009147165A1 PCT/EP2009/056789 EP2009056789W WO2009147165A1 WO 2009147165 A1 WO2009147165 A1 WO 2009147165A1 EP 2009056789 W EP2009056789 W EP 2009056789W WO 2009147165 A1 WO2009147165 A1 WO 2009147165A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
chloro
amino
carbonyl
oxy
Prior art date
Application number
PCT/EP2009/056789
Other languages
English (en)
Inventor
Alessandra Gaiba
Mark Patrick Healy
Helen Susanne Price
Steven James Stanway
Martin Edward Swarbrick
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2009147165A1 publication Critical patent/WO2009147165A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring

Definitions

  • This invention relates to benzamide derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • the compounds of the present invention are EP 4 receptor agonists.
  • the EP 4 receptor is a 7-transmembrane receptor and its natural ligand is the prostaglandin PGE 2 .
  • PGE 2 also has affinity for the other EP receptors (types EP 1 , EP 2 and EP 3 ).
  • the prostanoid EP 4 receptor falls into a group of receptors normally associated with elevation of intracellular cyclic adenosine monophosphate (cAMP) levels.
  • the EP 4 receptor is associated with smooth muscle relaxation, intraocular pressure, pain (in particular inflammatory, neuropathic and visceral pain), inflammation, neuroprotection, lymphocyte differentiation, bone metabolic processes, allergic activities, promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion.
  • EP 4 receptor agonists may be useful for the treatment of pain, inflammation and other conditions associated with the EP 4 receptor.
  • the EP 4 receptor also plays an important role in closure of the ductus arteriosus, vasodepression, inflammation and bone remodeling as reviewed by Narumiya in Prostaglandins & Other Lipid Mediators 2002, 68-69 557-73.
  • indoprofen such as [4-(1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl)phenyl]-2-propionic acid, sodium salt have been described by Rufer et. al. in Eur. J. Med. Chem. - Chimica Therapeutica, 1978, 13, 193.
  • the present invention provides a compound selected from the group consisting of: (3-chloro-4- ⁇ [(5-chloro-2- ⁇ [(2- chlorophenyl)methyl]oxy ⁇ phenyl)carbonyl]amino ⁇ phenyl)acetic acid;
  • pharmaceutically acceptable derivative any pharmaceutically acceptable salt or ester, or salt of such ester of the compounds of the invention, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention or an active metabolite or residue thereof.
  • salts referred to above will be the pharmaceutically acceptable salts, but other salts may find use, for example in the preparation of compounds of the invention and the pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; and cyclic amines.
  • Particular pharmaceutically acceptable organic bases include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropyl amine, tris(hydroxymethyl)aminomethane, and the like. Salts may also be formed from basic ion exchange resins, for example polyamine resins.
  • the compounds of the invention may be produced in vivo by metabolism of a suitable prodrug.
  • suitable prodrug may be for example physiologically acceptable metabolically labile esters of compounds of the invention. These may be formed by esterification of the carboxylic acid group in the parent compound of the invention with, where appropriate, prior protection of any other reactive groups present in the molecule followed by deprotection if required.
  • metabolically labile esters include C 1-4 alkyl esters e.g. methyl ethyl or t-butyl esters esters, C 3 . 6 alkenyl esters e.g. allyl substituted or unsubstituted aminoalkyl esters (e.g.
  • pivaloyloxymethyl 1-pivaloyloxyethyl, acetoxymethyl, 1- acetoxyethyl,1-(1-methoxy-1 - methyl)ethylcarbonyloxyethyl, 1 - benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1- isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1- cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1- cyclohexyloxycarbonyloxyethyl, 1-(4-tetrahydropyranyloxy)carbonyloxyethyl or 1-(4- tetrahydropyranyl)carbonyloxyethyl.
  • the present invention encompasses all isomers of the compounds of the invention and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
  • the compounds of the invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of the invention may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of the invention. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
  • solvent of crystallisation may be present in the crystalline product.
  • This invention includes within its scope such solvates, including solvates of the free acid molecule and solvates of salts derived from the free acid molecule.
  • some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products.
  • This invention includes within its scope all polymorphic forms of the compounds of the invention.
  • the present invention also includes within its scope all isotopically-labelled compounds of the invention. Such compounds are identical to those recited above except that one or more atoms therein are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, chlorine and fluorine, such as 2H, 3H, 11 C, 13C, 14C, 15N, 170, 180, 36Cl and 18F.
  • Isotopically-labelled compounds of the invention for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 1 1 C and 18F isotopes are particularly useful in PET (positron emission tomography), and are useful in brain imaging.
  • lsotopically labelled compounds of the invention may be prepared by carrying out the synthetic procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds of the invention are EP 4 receptor agonists and may therefore be useful in treating EP 4 receptor mediated diseases. These diseases include those mediated by the action, or loss of action, of PGE 2 at EP 4 receptors.
  • the compounds of the invention may be useful in the treatment of pain, for example, chronic articular pain (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
  • chronic articular pain e.g. rheumatoid arthritis, osteoarthritis, rheumatoid
  • the compounds of the invention may be particularly useful in the treatment of neuropathic pain and symptoms associated therewith.
  • Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • Symptoms of neuropathic pain include spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • pain associated with normally non-painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation
  • hypoalgesia or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • the compounds of the invention may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, COPD; gastrointestinal tract disorders (e.g.
  • an inflammatory component such as vascular disease, migraine, periarteritis nod
  • the compounds of the invention may also be useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • the compounds of the invention may also be effective in increasing the latency of HIV infection.
  • the compounds of the invention may also be useful in the treatment of diseases of excessive or unwanted platelet activation such as intermittent claudication, unstable angina, stroke, and acute coronary syndrome (e.g. occlusive vascular diseases).
  • the compounds of the invention may also be useful as a drug with diuretic action, or may be useful to treat overactive bladder syndrome.
  • the compounds of the invention may also be useful in the treatment of impotence or erectile dysfunction.
  • the compounds of formula (I) may also be useful in the treatment of various Bone Disorders as hereinbelow defined, which includes the treatment of bone fractures, bone injury or bone defects.
  • the compounds of the invention may be useful in enhancement of bone formation i.e. osteogenesis, such as increasing bone mass, bone volume, osteoblast number or osteoblast survival.
  • the compounds of formula (I) may therefore be useful in the treatment of bone disease, including genetic disorders, that are characterised by abnormal bone metabolism or resorption such as osteoporosis (especially postmenopausal osteoporosis, glucocorticoid induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilisation-induced osteoporosis, heparin-induced osteoporosis and immunosuppressive-induced osteoporosis as well as long term complications of osteoporosis such as curvature of the spine, loss of height and prosthetic surgery), abnormally increased bone turnover, hyper-calcemia (including humoral hypercalcemia), hyperparathyroidism, Paget's bone diseases, osteolysis (including periprosthetic osteolysis), hypercalcemia of malignancy with or without bone metastases, hypercalcemia of fracture healing, rheumatoid arthritis, osteoarthritis (including disease modifying in osteoarthristis such as cartilage/bone repair), ostealgia, osteo
  • the compounds of formula (I) may also be useful in bone remodelling and/or promoting bone generation and/or promoting fracture healing.
  • the compounds of the present invention may be useful in fracture healing e.g. long bone fractures and fractures of other bones.
  • the compounds of the present invention may also be useful in healing fractures of the head, face and neck caused e.g. by injury.
  • the compounds of the present invention may also be useful in bone grafting including replacing bone graft surgery entirely, enhancing the rate of successful bone grafts, bone healing following facial reconstruction, maxillary reconstruction, mandibular reconstruction, craniofacial reconstruction e.g. of craniofacial defects such as orofacial defects at birth (including orofacial clefts such as cleft palate), prosthetic ingrowth, vertebral synostosis, long bone extension, spinal fusion, and sternotomy.
  • the compounds of the invention may also be useful in treating bone defects that might evolve around defects that occur during war.
  • the compounds of the invention may also be useful in periodontal indications such as periodontal disease (periodontitis), tooth loss, and peridontal augmentation e.g. in preparation for tooth implants.
  • the compounds of the present invention may also be useful in facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation and repairing damage caused by metastatic bone disease.
  • the compounds of the invention may also be useful for attenuating the hemodynamic side effects of NSAIDs and COX-2 inhibitors.
  • the compounds of the invention may also be useful in the treatment of cardiovascular diseases such as hypertension or myocardial ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • cardiovascular diseases such as hypertension or myocardial ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • the compounds of the invention may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins;
  • the compounds of the invention may also be useful in the treatment of neurological disorders and may be useful as neuroprotecting agents.
  • the compounds of the invention may also be useful in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • the compounds of the invention may also be useful in the treatment of complications of Type 1 diabetes (e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease and sarcoidosis.
  • Type 1 diabetes e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy
  • the compounds of the invention may also be useful in the treatment of kidney dysfunction (nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis, cirrhosis) and gastrointestinal dysfunction (diarrhoea).
  • kidney dysfunction nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome
  • liver dysfunction hepatitis, cirrhosis
  • gastrointestinal dysfunction diarrhoea
  • any reference to treatment includes both treatment of established symptoms and prophylactic treatment.
  • a compound of the invention or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.
  • a compound of the invention or a pharmaceutically acceptable derivative thereof for use in the treatment of a Bone Disorder there is provided a compound of the invention or a pharmaceutically acceptable derivative thereof for use in the treatment of a Bone Disorder.
  • a method of treating a human or animal subject suffering from a condition which is mediated by the action, or by loss of action, of PGE 2 at EP 4 receptors which comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof.
  • a method of treating a human or animal subject suffering from a Bone Disorder which comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof.
  • a method of treating a human or animal subject suffering from a pain, or an inflammatory, immunological, neurodegenerative or renal disorder comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof.
  • a compound of the invention or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a condition which is mediated by the action, or loss of action, of PGE 2 at EP 4 receptors.
  • a compound of the invention or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a Bone Disorder.
  • a compound of the invention or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment or prevention of a condition such as a pain, or an inflammatory, immunological, neurodegenerative or renal disorder.
  • compositions are conveniently administered in the form of pharmaceutical compositions.
  • Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or diluents.
  • a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. While it is possible for the compounds of the invention or a pharmaceutically acceptable derivative thereof to be administered as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the formulations of the present invention comprise the compounds of the invention or a pharmaceutically acceptable derivative thereof together with one or more acceptable carriers or diluents therefore and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the invention provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or diluent therefore.
  • Administration of the compounds of this invention can be via any method which delivers a compound of this invention systemically and/or locally.
  • the formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot, intradermal, intrathecal, intracapsular, intraspinal, intrasternal, intraarticular, intramuscular e.g. by depot, intravenous and intranasal), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy (see for example methods disclosed in 'Remington - The Science and Practice of Pharmacy', 21 st Edition, Lippincott, Williams & Wilkins, USA, 2005 and references therein). All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by injection (for example intramuscular or intra-articular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • Local application e.g., to the site of bone fracture, intra-articular
  • local application may be achieved by applying a solution or dispersion of the compound in a suitable carrier or diluent onto the surface of, or incorporating it into, solid or semisolid implants conventionally used in orthopedic surgery.
  • the present invention can also be administered using an injectable, flowable composition that provides sustained release at the local site of the injection by forming a biodegradable solid or gel depot, matrix or implant.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib or parecoxib
  • 5-lipoxygenase inhibitors such as paracetamol
  • NSAI D's such as diclofenac, indomethacin, nabumetone, naproxen or ibuprofen
  • leukotriene receptor antagonists leukotriene receptor antagonists
  • DMARD's such as methotrexate
  • sodium channel blockers such as lamotrigine
  • N-type calcium channel antagonists such as NMDA receptor modulators, such as glycine receptor antagonists
  • gabapentin, pregabalin and related compounds tricyclic antidepressants such as amitriptyline
  • neurone stabilising antiepileptic drugs such as venlafaxine
  • opioid analgesics such as venlafaxine
  • 5HT 1 agonists such as tript
  • the compounds of the invention may also be used in combination with known agents useful for treating or preventing the bone disorders described above.
  • the present invention therefore includes combinations of the presently disclosed compounds with other agents including the following: Progestins (such as algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyproge
  • the invention thus provides, in a further embodiment, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
  • a combination comprising an EP 4 receptor agonist of the invention or a pharmaceutically acceptable derivative thereof and paracetamol.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or diluent comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • a method of treating a human or animal subject suffering from a condition which is mediated by the action, or by loss of action, of PGE 2 at EP 4 receptors which comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof and paracetamol.
  • a method of treating a human or animal subject suffering from a Bone Disorder which comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof and paracetamol.
  • a proposed daily dosage of compounds of the invention or their pharmaceutically acceptable salts for the treatment of man is from 0.001 to 30 mg/kg body weight per day and more particularly 0.1 to 3 mg/kg body weight per day, calculated as the free acid, which may be administered as a single or divided dose, for example one to four times per day.
  • the dose range for adult human beings is generally from 0.1 to 1000 mg/day, such as from 10 to 800 mg/day, preferably 10 to 200 mg/day, calculated as the free acid.
  • a suitable daily dosage of paracetamol is up to 4000 mg per day.
  • Suitable unit doses include 200, 400, 500 and 1000 mg, one, two, three or four times per day.
  • the precise amount of the compounds of the invention administered to a host, particularly a human patient, will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors including the age and sex of the patient, the precise condition being treated and its severity, the route of administration, and any possible combination therapy that may be being undertaken.
  • ester intermediates of the compounds of the invention are novel and form an aspect of the invention.
  • the ester intermediates are: Ethyl (3-chloro-4- ⁇ [(5-chloro-2- ⁇ [(3- chloropheny ⁇ methyljoxyjpheny ⁇ carbonyljaminojpheny ⁇ acetate, ethyl ⁇ 4-[( ⁇ 5-chloro-2-[(phenylmethyl)oxy]phenyl ⁇ carbonyl)amino]phenyl ⁇ acetate, ethyl ⁇ 3-chloro-4-[( ⁇ 5-chloro-2-
  • the present invention provides processes for the preparation of the compounds of the invention and pharmaceutically acceptable derivatives thereof.
  • a process for preparing a compound of the invention comprising reacting an ester intermediate with a suitable base, such as sodium hydroxide, and optionally thereafter forming a pharmaceutically acceptable derivative of the compound so formed, and/or converting one compound of formula (I) to another.
  • the above-mentioned reaction comprising an ester intermediate is performed in a suitable solvent, such as ethanol, under reflux.
  • the following examples illustrate the preparation of the compounds the invention.
  • the examples show the preparation of intermediates ("Intermediates") and compounds of the invention ("Examples").
  • the starting material for the preparation of intermediates may not necessarily have been prepared from the batch referred to unless expressly indicated.
  • the intermediates for the preparation of the examples may not necessarily have been prepared from the batch referred to unless expressly indicated.
  • Chromatographic methods include column chromatography, flash chromatography, HPLC (high performance liquid chromatography), SFC (supercritical fluid chromatography), SCX (strong cation exchange chromatography) and MDAP (mass directed autopreparation).
  • Biotage when used herein refers to commercially available pre-packed silica gel cartridges.
  • Aqueous solvent Water + 0.1% Formic Acid
  • Runtime 13.5 minutes, comprising 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.
  • Runtime 13.5 minutes, comprising 6-minute gradient followed by a 7.5 minute column flush and re-equilibration step.
  • methyl 5- chloro-2-hydroxybenzoate, ethyl 4-aminophenylacetate, 2- [(phenylmethyl)oxy]benzoic acid and methyl 2-hydroxybenzoate may be obtained from Alfa Aesar; 5-chlorosalicylic acid, methyl 2-amino-5-chlorobenzoate and 6- chloro-2H-3,1-benzoxazine-2,4(1 H)-dione may be obtained from Aldrich; 2-amino-6- (methyloxy)benzoic acid may be obtained from Fluorochem.
  • N-chlorosuccinimide (1 eq, 7.45g, 55.8mmol) was added to a solution of ethyl A- aminophenylacetate (10g, 55.8mmol) in chloroform (20OmIs). The reaction mixture was stirred at room temperature, under argon, for 15 minutes.
  • Example 1 (3-chloro-4- ⁇ [(5-chloro-2- ⁇ [(3- chlorophenyl)methyl]oxy ⁇ phenyl)carbonyl]amino ⁇ phenyl)acetic acid
  • Step 1
  • Benzyl bromide (2.79ml, 23.5mmol) and potassium carbonate (4.87g, 35.3mmol) were added to 5-chlorosalicylic acid (2.03g, 1 1.8mmol) in DMF (20ml) and stirred at room temperature for 16 hours.
  • LCMS indicated a mixture of mono and dialkylated material.
  • the mixture was then heated at 6O 0 C for 1 hour giving a ratio of 10:1 , dkmono alkylated product.
  • the mixture was cooled, diluted with water (150ml) and extracted with EtOAc (x3). The organics were washed with water (x2), brine, dried (MgSO 4 ) and concentrated in vacuo to yield a yellow oil that was used immediately in the next step.
  • Example 8 ⁇ 4-[( ⁇ 5-chloro-2- [(phenylmethyljaminojpheny ⁇ carbonyljaminolpheny ⁇ acetic acid
  • Example 10 (4- ⁇ [(5-chloro-2- ⁇ [(3- chlorophenyl)methyl]amino ⁇ phenyl)carbonyl]amino ⁇ phenyl)acetic acid.
  • Lithium hydroxide monohydate (25mg, 0.599mmol) was added to a solution of ethyl ⁇ 4-[( ⁇ 2-chloro-6-[(phenylmethyl)oxy]phenyl ⁇ carbonyl)amino]phenyl ⁇ acetate (169mg, 0.399mmol) in dioxane (4ml) and water (2ml) and the reaction was stirred at room temperature for 2 hrs. The solvent was evaporated and the residue dissolved in water. Acidification (cone. HCI, pH ⁇ 1 ) afforded a colourless solid which was collected by filtration and dried invacuo to give the title compound (154mg, 98%). MS (ES+) m/z 396 [M+H + ] (C 22 H 18 35 CINO 4 ).
  • Example 13 (4- ⁇ [(2-chloro-6- ⁇ [(3- chlorophenyl)methyl]oxy ⁇ phenyl)carbonyl]amino ⁇ phenyl)acetic acid.
  • Lithium hydroxide monohydate (27mg, 0.64mmol) was added to a solution of ethyl (4- ⁇ [(2-chloro-6- ⁇ [(3-chlorophenyl)methyl]oxy ⁇ phenyl)carbonyl]amino ⁇ phenyl)acetate (194mg, 0.424mmol) in dioxane (4ml) and water (2ml) and the reaction was stirred at room temperature for 18 hrs. The solvent was evaporated and the residue dissolved in water. Acidification (cone. HCI, pH ⁇ 1 ) afforded a colourless solid which was collected by filtration and dried invacuo to give the title compound (180mg, 99%).
  • HEK-293(T) cells expressing the recombinant human prostanoid EP 4 receptor were grown as a monolayer culture in DMEM-F12/F12 containing glutamax IITM (a source of L-Glutamine) (Gibco) and supplemented with 10% foetal bovine serum (Gibco) and 0.4mg.ml-1 G418.
  • HEK- EP 4 cells were pre-treated 24hr and 30mins prior to the experiment with 10 ⁇ M indomethacin and harvested using VerseneTM (EDTA) containing 10 ⁇ M indomethacin.
  • the cells were resuspended in assay buffer (DMEM:F12, 10 ⁇ M indomethacin and 200 ⁇ M IBMX) at 1 ⁇ 10 6 cells per ml and incubated for 20min at 37 0 C. Thereafter, 50 ⁇ l of cells were added to 50 ⁇ l test compound (compound of the invention) and incubated at 37°C for 4 minutes before stopping reactions with 10O ⁇ l of 1 % Triton ® X-100 (non-ionic surfactant). cAMP levels in the cell lysates were determined using a competition binding assay.
  • assay buffer DMEM:F12, 10 ⁇ M indomethacin and 200 ⁇ M IBMX
  • the Examples of the present invention were tested in the above-mentioned assay and exhibited average pEC 50 values of 6.0 or higher, and average intrinsic activities of 20% or higher.

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Abstract

L'invention porte sur un composé choisi dans le groupe constitué par : l'acide (3-chloro-4-{[(5-chloro-2-{[(2-chlorophényl)méthyl]oxy}phényl)carbonyl]amino}phényl)acétique ; l'acide {4-[({5-chloro-2-[(phénylméthyl)oxy]phényl}carbonyl)amino]phényl}acétique ; l'acide {3-chloro-4-[({5-chloro-2-[(phénylméthyl)oxy]phényl}carbonyl)amino]phényl}acétique ; l'acide (3-chloro-4-{[(5-chloro-2-{[(3-chlorophényl)méthyl]oxy}phényl)carbonyl]amino}phényl)acétique ; l'acide {4-[({2-[(phénylméthyl)oxy]phényl}carbonyl)amino]phényl}acétique ; l'acide (4-{[(5-chloro-2-{[(3-chlorophényl)méthyl]oxy}phényl)carbonyl]amino}-2-fluorophényl)acétique ; l'acide {3-chloro-4-[({2-[(phénylméthyl)oxy]phényl}carbonyl)amino]phényl}acétique ; l'acide (3-chloro-4-{[(2-{[(3-chlorophényl)méthyl]oxy}phényl)carbonyl]amino}phényl)acétique ; l'acide {4-[({2-chloro-6-[(phénylméthyl)oxy]phényl}carbonyl)amino]phényl}acétique ; l'acide (4-{[(2-chloro-6-{[(3-chlorophényl)méthyl]oxy}phényl)carbonyl]amino}phényl)acétique ; l'acide {4-[({5-chloro-2-[(phénylméthyl)amino]phényl}carbonyl)amino]phényl}acétique ; l'acide (4-{[(5-chloro-2-{[(3-chlorophényl)méthyl]amino}phényl)carbonyl]amino}phényl)acétique ; et l'acide (4-{[(5-chloro-2-{[(2-chlorophényl)méthyl]amino}phényl)carbonyl]amino}phényl)acétique, ou des sels pharmaceutiquement acceptables de ceux-ci, sur des compositions pharmaceutiques comprenant de tels composés et sur l'utilisation de tels composés en médecine.
PCT/EP2009/056789 2008-06-05 2009-06-03 Nouveaux composés agonistes des récepteurs ep4 WO2009147165A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021508A1 (fr) * 2003-09-03 2005-03-10 Pfizer Inc. Composes de phenyle ou de pyridyle amide utiles comme antagonistes de la prostaglandine e2
WO2005080367A1 (fr) * 2004-02-12 2005-09-01 Pharmagene Laboratories Limited Agonistes des recepteurs ep2
WO2005116010A1 (fr) * 2004-05-26 2005-12-08 Merck Frosst Canada Ltd. Agoniste du recepteur ep4, compositions et methodes associees ep4 receptor agonist, compositions and methods thereof
WO2008071736A1 (fr) * 2006-12-15 2008-06-19 Glaxo Group Limited Utilisation de dérivés du benzamide comme agonistes des récepteurs ep4

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021508A1 (fr) * 2003-09-03 2005-03-10 Pfizer Inc. Composes de phenyle ou de pyridyle amide utiles comme antagonistes de la prostaglandine e2
WO2005080367A1 (fr) * 2004-02-12 2005-09-01 Pharmagene Laboratories Limited Agonistes des recepteurs ep2
WO2005116010A1 (fr) * 2004-05-26 2005-12-08 Merck Frosst Canada Ltd. Agoniste du recepteur ep4, compositions et methodes associees ep4 receptor agonist, compositions and methods thereof
WO2008071736A1 (fr) * 2006-12-15 2008-06-19 Glaxo Group Limited Utilisation de dérivés du benzamide comme agonistes des récepteurs ep4

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