MX2008010050A - Benzo (f) isoindol-2-ylphenyl acetic acid derivatives as ep4 receptor agonists - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein, R1R2R3, R4, R5, R6, X and Y are as defined in the specification;a process for preparing such compounds;a pharmaceutical composition comprising such compounds;and the use of such compounds in medicine.

Description

BENZO ACID DERIVATIVES (F) ISOINDOL-2-ILFENILACETICO AS EP4 RECEIVER AGONISTS DESCRIPTIVE MEMORY This invention relates to naphthalene derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. The compounds of the present invention are EP4 receptor agonists. A series of review articles describe the characterization and therapeutic relevance of prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids; From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signaling, 1996, 14, 83-87 and Prostanoids Receptors, Structure, Properties and Function, S. Narumiya et al., Physiological Reviews 1999, 79 (4), 1 193- 126 The EP4 receptor is a receptor of the seven transmembrane domains and its natural ligand is prostaglandin PGE2. PGE2 also has affinity for the other EP receptors (types EP-i, EP2 and EP3). The EP4 prostanoid receptor enters a group of receptors normally associated with the elevation of intracellular monophosphate levels of cyclic adenosine (cAMP). The EP4 receptor is associated with smooth muscle relaxation, intraocular pressure, pain (in particular inflammatory, neuropathic and visceral pain), inflammation, neuroprotection, lymphocyte differentiation, metabolic bone processes, allergic activities, sleep aid, renal regulation, secretion of gastric or enteric mucus and duodenal bicarbonate secretion. The EP4 receptor plays an important role in the closure of the ductus arteriosus, in vasodepression, inflammation and bone restructuring as outlined by Narumiya in Prostaglandins & Other Lipid Mediators 2002, 68-69 557-73. A number of publications have shown that PGE2 acting through the EP receptor subtype, and EP4 agonists alone, can regulate inflammatory cytokines after an inflammatory stimulus. Takayama et al. in Journal of Biological Chemistry 2002, 277 (46), 44147-54 showed that PGE2 modulates inflammation during inflammatory diseases by reducing the production of chemokines derived from macrophages through the EP4 receptor. In Bioorganic & Medicinal Chemistry 2002, 10 (7), 2103-21 10, Maruyama et al. demonstrated that the selective EP4 receptor agonist, (ONO-AE1 -437) reduces LPS-induced TNF-a in whole human blood while increasing IL-10 levels. An article by Anesthesiology, 2002, 97, 1 70-176 suggests that a selective EP receptor agonist (ONO-AE1 -329) effectively inhibited mechanical and thermal hyperalgesia and inflammatory reactions in acute and chronic monoarthritis. .

Two independent articles by Sakuma et al. in Journal of Bone and Mineral Research 2000, 15 (2), 218-227 and Miyaura et al. in Journal of Biological! Chemistry 2000, 275 (26), 19819-23, point out the defective formation of osteoclasts in cultured cells from mice devoid of the EP receptor. Yoshida et al. in Proceedings of the National Academy of Sciences of the United States of America 2002, 99 (7), 4580-4585, by using mice lacking each of the EP subtypes of the PGE2 receptor, identified as the EP4 receptor that mediates bone formation in response to the administration of PGE2. They also demonstrated that a selective EP4 receptor agonist (ONO-4819) consistently induces bone formation in natural mice. Additionally, Terai et al. in Bone 2005, 37 (4), 555-562 have shown that the presence of a selective EP4 receptor agonist (ONO-4819) improved the bone-inducing capacity of rhBMP-2, a therapeutic cytokine that can induce the formation of bone. An additional investigation by Larsen went to. shows the effects of PGE2 on secretion in the second part of the human duodenum that is mediated by the EP4 receptor. { Acta Physiol. Scand. 2005, 185, 133-140). Also, it has been shown that a selective EP4 receptor agonist (ONO-AE1 -329) can protect against colitis in rats (Nitta et al in Scandinavian Journal of Immunology 2002, 56 (1), 66-75). Doré et al. in The European Journal of Neuroscience 2005, 22 (9), 2199-206 have shown that PGE2 can protect neurons against the toxicity of beta-amyloid peptide by acting on EP2 and EP receptors. In addition, Doré has shown in Brain Research 2005, 1066 (1-2), 71-77 that an EP4 receptor agonist (ONO-AE1 -329) protects against neurotoxicity in an acute model of neurotoxicity in the brain. Woodward et al. in Journal of Lipid Mediators 1993, 6 (1-3), 545-53 found that intraocular pressure could be reduced by using selective prostanoid agonists. Two reports from Investigative Ophtalmology & Visual Science has shown that the EP4 prostanoid receptor is expressed in the epithelial cells of human lenses (Mukhopadhyay et al., 1999, 40 (1), 105-12), and suggest a physiological role of the EP prostanoid receptor in modulation. of the flow in the trabecular network of the eye (Hoyng et al., 1999, 40 (11), 2622-6). Compounds exhibiting binding activity with the EP4 receptor and their uses have been described, for example, in W098 / 55468, WO00 / 18744, WO00 / 03980, WO00 / 15608, WO00 / 16760, WO00 / 21532, WO01 / 010426, EP0855389, EP0985663, WO02 / 047669, WO02 / 50031, WO02 / 50032, WO02 / 50033, WO02 / 064564, WO03 / 103604, WO03 / 077910, WO03 / 086371, WO04 / 037813, WO04 / 067524, WO04 / 085430, US04 / 142969, WO05 / 021508, WO05 / 105733, WO05 / 105732, WO05 / 080367, WO05 / 037812, WO05 / 16010 and WO06 / 122403. The indoprofen derivatives such as the sodium salt of [4- (1-oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl) phenyl] -2-propionic acid have been described by Rufer et al. in Eur. J. Med. Chem. - Chimica Therapeutica, 1978, 13, 193. It has been shown that the compounds of the present invention exhibit advantageous activities in vivo and in vitro when analyzed in the biological assays described herein. . It has also been shown that certain compounds of the invention have advantageous pharmacokinetic profiles in the rat. The present invention provides compounds of the formula (I) and / or their pharmaceutically acceptable derivatives, wherein, R1 and R2 independently represent Ci_4 alkyl; R3, R4, R5 and R6 independently represent H or F, with the proviso that at least one of R3 and R4 represents H, at least one of R5 and R6 represents H, and at least one of R3, R4, R5 and R6 represents F; and X and Y independently represent CH2 or C = 0, with the proviso that at least one of X and Y represents C = O.

In one embodiment of the invention, R1 and R2 are the same and represent C1-4 alkyl. In another embodiment of the invention, R1 and R2 are independently selected from the group consisting of ethyl, n-propyl and / or so-propyl. In one embodiment of the invention, R3 represents H and R4 represents F. In another embodiment of the invention, R3 represents F and R4 represents H. In one embodiment of the invention, R5 represents H and R6 represents F. In another embodiment of the invention, invention, R5 represents F and R6 represents H. In one embodiment of the invention, R3 represents F and R4, R5 and R6 represent H. In another embodiment of the invention, R4 represents F and R3, R5 and R6 represent H. In another embodiment embodiment of the invention, R5 represents F and R3, R4 and R6 represent H. In another embodiment of the invention, R6 represents F and R3, R4 and R5 represent H. In one embodiment of the invention, R3 and R5 represent F and R4 and R6 represent H. In one embodiment of the invention, X represents CH2 and Y represents C = O. In another embodiment of the invention, X represents C = O and Y represents CH2. In another embodiment of the invention, both X and Y represent C = O.

In one embodiment of the invention, a subset of compounds of formula (I) or formula (IA) and / or their pharmaceutically acceptable derivatives is provided, (IA) wherein, R 1 and R 2 independently represent C 1 -alkyl.; R3 and R4 independently represent H or F, with the proviso that they are not equal; and X and Y independently represent CH2 or C = O, with the proviso that at least one of X and Y represents C = O. In another embodiment of the invention, there is provided a compound of the formula (I) selected from the group consisting of: acid. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [1,3-dioxo-4,9-bis (propyloxy) -1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [4,9-bis (1-methylethoxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic; acid { 2-fluoro-4- [1 -oxo-4, 9-bis (propyloxy) -, 3-dihydro-2H-benzo [f] isoindol-2-yl] phenyl} -acetic; acid { 4- [4,9-bis (1-methylethoxy) -1 -oxo-, 3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic; acid { 3-fluoro-4- [1 -oxo-4,9-bis (propyloxy) -1,3-dihydro-2H-benzo [f] isoindol-2-yl] phenyl} -acetic; and acid. { 4- [4,9-bis (1-methylethoxy) -1-oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3,5-difluorophenyl} -acetic; acid { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3,5-difluorophenyl} -acetic; and / or one of its pharmaceutically acceptable derivatives. In another embodiment of the invention, there is provided a compound of the formula (I) which is acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic (IB), or one of its pharmaceutically acceptable derivatives. The present invention covers all combinations of the modalities described herein. As used herein, the term "C- alkyl" includes straight-chain and branched-chain alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, p-propyl, / so-propyl, n- butyl e / 'so-butyl. The term "Ci 'alkyl" can be interpreted accordingly As used herein, "F" means fluoro "Pharmaceutically acceptable derivative" is any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of said ester of the compounds of the formula (I), or any other compound which upon administration to the patient is capable of providing (directly or indirectly) a compound of the formula (I) or one of its metabolites or active residues In one embodiment of the invention, a pharmaceutically derivative acceptable means a salt, solvate or ester, or salt or solvate of said ester In another embodiment of the invention, a pharmaceutically acceptable derivative means a salt or ester, or salt of said ester.

It should be appreciated that for pharmaceutical use, the salts mentioned above will be pharmaceutically acceptable salts, but other salts may also be used, for example in the preparation of compounds of the formula (I) and the pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1 -19. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable bases including organic bases and inorganic bases. Salts derived from inorganic bases include the aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium salts, manganous, manganous, potassium, sodium, zinc, and the like salts. Salts derived from pharmaceutically acceptable organic bases include the salts of primary, secondary and tertiary amines; substituted amines including the natural substituted amines; and cyclic amines. Particular pharmaceutically acceptable organic bases include arginine, betaine, caffeine, choline,?,? '-dibencylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethyl-piperidine, glucamine, glucosamine, histidine, hydrabamine, sopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tris (hydroxymethyl) aminomethane, and the like. The salts can also be formed from basic ion exchange resins, for example polyamine resins. In one embodiment of the invention, the sodium salt of the acid is provided. { 4- [4,9-bis (ethyloxy) -1 -oxo-, 3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic. In another embodiment of the invention, the potassium salt of the acid is provided. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic. In another embodiment of the invention, the choline salt of the acid is provided. { 4- [4,9-bis (ethyloxy) -1 -oxo-, 3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic. It should be appreciated that the compounds of the formula (I) can be produced in vivo by metabolism of a suitable prodrug. Such prodrugs can be, for example, esters of the physiologically acceptable metabolically labile compounds of the formula (I). These can be formed by esterification of the carboxylic acid group in the original compound of the formula (I) with prior protection, when appropriate, of any other reactive group present in the molecule followed by deprotection if necessary. Examples of such metabolically labile esters include C1-4 alkyl esters, for example methyl, ethyl or isobutyl esters, C3-6 alkenyl esters, for example the aminoalkyl esters unsubstituted or substituted by allyl ( for example, aminoethyl esters, 2- (N, N-diethylamino) ethyl, or 2- (4-morpholino) ethyl or acyloxyalkyl esters such as acyloxymethyl or 1-acyloxyethyl, for example pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, -acetoxyethyl, 1 - (1-methoxy-1 - methyl) etilcarboniloxietilo, 1 -benzoiloxietilo, isopropoxycarbonyloxymethyl, 1 -isopropoxicarboniloxietilo, cyclohexylcarbonyloxymethyl ester, 1 -ciclohexilcarboniloxietilo, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1 - (4-tetrahydropyranyloxy) carbonyloxyethyl or 1 - (4-tetrahydropyranyl) carbonyloxyethyl I. It should be understood that the present invention encompasses all isomers of the compounds of the formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures). Since the compounds of formula (I) are intended for use in pharmaceutical compositions, it should be understood that each of them is provided in substantially pure form, for example at least 50% purity, at least 75% purity and at least 95% pure (% is expressed on a weight / weight basis). Impure preparations of the compounds of the formula (I) can be used to prepare the purest forms used in the pharmaceutical compositions. Although the purity of the intermediates of the present invention is less critical, it can be easily understood that the substantially pure form is preferred as for the compounds of the formula (I). Whenever possible, the compounds of the present invention are obtained in crystalline form. When any of the compounds of this invention is allowed to crystallize or recrystallize from organic solvents, the crystallization solvent may be present in the crystalline product. This invention it includes within its scope such solvates, including the solvates of the free acid molecule and the solvates of the salts derived from the free acid molecule. Similarly, some of the compounds of this invention can be crystallized or recrystallized from solvents containing water. In such cases, water of hydration can be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing varying amounts of water that can be produced by processes such as lyophilization. This invention also includes within its scope the anhydrous forms of the compounds of the formula (I). In addition, the different crystallization conditions can 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 formula (I). The present invention also includes within its scope all the compounds of the formula (I) isotopically labeled. Such compounds are identical to those detailed above, except for the fact that one or more atoms thereof are replaced by an atom having an atomic mass or a mass number different from the atomic mass or mass number usually found in the nature. Examples of isotopes that can be incorporated into the compounds of the formula (I) and their pharmaceutically acceptable derivatives include the isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as 2H, 3H, C, 13C, 14C, 15N, 170 , 18O and 18F.

The isotopically-labeled compounds of formula (I), for example those to which radioactive isotopes such as 3H or 14C have been incorporated, are useful in drug and / or substrate tissue distribution assays. The tritiated isotopes, that is 3H and the carbon-4 isotopes, that is 1 C, are especially preferred for their ease of preparation and detectability. Isotopes 1C and 18F are particularly useful in PET (positron emission tomography), and are useful in brain imaging. In addition, replacement with heavier isotopes such as deuterium, that is, 2H, may provide certain therapeutic advantages resulting from increased metabolic stability, for example the increase in half-life in vivo or the reduction of dose requirements., and therefore may be preferred in some circumstances. The isotopically-labeled compounds of the formula (I) can be prepared by carrying out the synthetic procedures described in the schemes and / or in the examples that follow, replacing an isotopically non-labeled reagent with an isotopically readily available reagent. The compounds of the formula (I) are EP4 receptor agonists and therefore may be useful in the treatment of diseases mediated by the EP4 receptor. In particular the compounds of the formula (I) may be useful in the treatment of pain, for example chronic joint pain (eg, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and of joint structure protection; musculoskeletal pain; low back pain and neck pain; muscle strains and strains; neuropathic pain; pain maintained by the sympathetic; 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. The compounds of the formula (I) may be particularly useful in the treatment of neuropathic pain and the symptoms associated therewith. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific low back pain; multiple sclerosis pain; fibromyalgia; neuropathy related to HIV; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. Symptoms of neuropathic pain include spontaneous, throbbing, lancinating pain, or burning, continuous pain. In addition, the pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), hypersensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (allodynia dynamic, static or thermal), hypersensitivity include stimuli harmful (thermal hyperalgesia, cold, mechanical), pain sensation continued after the separation of the stimulation (hyperpathia) or an absence or deficit of selective sensory pathways (hypoalgesia). The compounds of the formula (I) may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (eg sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis, and acute ocular tissue injuries (e.g., conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, lung disease of farmers, chronic obstructive pulmonary disease, COPD (for short English); gastrointestinal tract disorders (for example, aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, celiac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal reflux, diarrhea, constipation) disease, organ transplantation; other conditions with an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, myocardial ischemia, pyrexia, systemic lupus systemic erythematosus, tendinitis, bursitis, and s Sjogren's syndrome The compounds of the formula (I) may also be useful in the treatment of immunological diseases such as diseases autoimmune diseases, immune deficiency diseases or organ transplantation. The compounds of the formula (I) may be effective to increase the latency of HIV infection. The compounds of formula (I) may also be useful in the treatment of diseases of excessive or unwanted activation of platelets, such as intermittent claudication, unstable angina, stroke, and acute coronary syndrome (e.g. occlusive vascular diseases). The compounds of the formula (I) may also be useful as a drug with diuretic action, or they may be useful for treating overactive bladder syndrome. The compounds of the formula (I) may also be useful in the treatment of impotence or erectile dysfunction. The compounds of the formula (I) may also be useful in the treatment of bone diseases characterized by metabolism or abnormal bone resorption such as osteoporosis (especially postmenopausal osteoporosis), hypercalcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignant tumors with or without bone metastasis, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, calculosis, lithiasis (especially urolithiasis), gout and ankylosing spondylitis, tendonitis and bursitis.

The compounds of the formula (I) can also be useful in bone restructuring and / or aid in bone generation and / or aid in the consolidation of the fractures. The compounds of the formula (I) may also be useful for attenuating the hemodynamic side effects of the NSAIDs and the COX-2 inhibitors. The compounds of the formula (I) may also be useful in the treatment of cardiovascular diseases such as hypertension or myocardial ischemia; functional or organic venous insufficiency; varicose therapy; hemorrhoids; and shock states associated with a marked fall in blood pressure (for example, septic shock). The compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease and disease). of Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), motor neuron disease); vascular dementia (including dementia for multi-infarcts); as well as the dementia associated with the lesions that occupy the intracranial space; traumatisms; infections and related conditions (including HIV infection); metabolism; toxins; anoxia and vitamin deficiency; and light cognitive impairment associated with aging, particularly the Impairment of Memory Associated with Age.

The compounds of the formula (I) may also be useful in the treatment of neurological disorders and may be useful as neuroprotective agents. The compounds of the invention may also be useful in the treatment of neurodegeneration after a stroke, cardiac arrest, extracorporeal circulation, traumatic brain injuries, spinal cord injury or the like. The compounds of the formula (I) may also be useful in the treatment of complications of Type 1 diabetes (for example, diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma), nephrotic syndrome, aplastic anemia, uveitis, Kawasaki disease and sarcoidosis. The compounds of the formula (I) may also be useful in the treatment of renal dysfunction (nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), hepatic dysfunction (hepatitis, cirrhosis) and gastrointestinal dysfunction (diarrhea). It should be understood that as any reference to treatment is used herein, this includes both the treatment of established symptoms and the prophylactic treatment. According to a further embodiment of the invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine. According to another embodiment of the invention, a compound of the formula (I) or one of its pharmaceutically derivatives is provided acceptable for use in the treatment of a disease that is mediated by the action, or loss of action, of PGE2 on EP receptors. According to a further embodiment of the invention, there is provided a method for treating a human or animal subject suffering from a disease that is mediated by the action, or loss of action, of PGE2 at EP4 receptors > which comprises administering to said subject an effective amount of a compound of the formula (I) or one of its pharmaceutically acceptable derivatives. According to a further embodiment of the invention, there is provided a method for treating a human or animal subject suffering from a pain, or an inflammatory, immunological or bone disease, a neurodegenerative disease or a renal dysfunction, which method comprises administering to said subject a effective amount of a compound of the formula (I) or one of its pharmaceutically acceptable derivatives. According to another embodiment of the invention, there is provided the use of a compound of the formula (I) or of one of its pharmaceutically acceptable derivatives for the manufacture of a medicament for the treatment of a disease that is mediated by action, or loss of action, of PGE2 in EP4 receptors. According to another embodiment of the invention, there is provided the use of a compound of the formula (I) or one of its pharmaceutically acceptable derivatives for the manufacture of a medicament for the treatment or prevention of a disease such as pain or an inflammatory, immunological, bone, neurodegenerative or renal disorder. The compounds of the formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may be conveniently presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients. Thus, in another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Although it is possible that the compounds of the formula (I) or one of their pharmaceutically acceptable derivatives are administered as raw material, it is preferable that they are presented as a pharmaceutical formulation. The formulations of the present invention comprise the compounds of the formula (I) or a pharmaceutically acceptable derivative thereof together with one or more acceptable excipients or diluents thereof and optionally other therapeutic ingredients. The excipient or excipients must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Therefore, in one embodiment the invention provides a pharmaceutical composition comprising a compound of the formula (I) or one of its pharmaceutically acceptable derivatives and a pharmaceutically acceptable excipient or diluent thereof. The formulations include those which are suitable for oral, parenteral (including subcutaneous administration, for example, by injection or by depot, intradermal, intrathecal, intramuscular for example by deposit and intravenous), rectal and topical (including dermal, buccal and sublingual) although the most appropriate route may depend, for example, on the patient's illness and disorder. The formulations can be conveniently presented in a unit dosage form and can be prepared by any of the methods well known in the pharmacy art (see for example the methods described in "Remington - The Science and Practice of Pharmacy", 21 st Edition, Lippincott, Williams &Wilkins, USA, 2005 and the references included there). All methods include the step of bringing into association the compound of the formula (I) or one of its pharmaceutically acceptable derivatives ("active ingredient") with the excipient constituting 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 can be presented as discrete units such as capsules, seals or tablets (for example chewable tablets in particular for pediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or in a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary or paste. A tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can 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 agent, surfactant or dispersing agent. The tablets by molding can be prepared by molding in a suitable machine a mixture of the pulverized compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated in such a way as to provide a slow or controlled release of the active ingredient. Formulations for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes that make 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 can be presented in uni-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored under freeze-drying conditions (lyophilization) which require only the addition of a sterile liquid vehicle, for example water for injection, immediately before use. Extemporaneous solutions and suspensions for injection can be prepared from sterile powders, granules and tablets of the type previously described. Formulations for rectal administration may be presented as suppositories with the usual excipients such as cocoa butter, hardened fats or polyethylene glycol. Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored base such as sucrose and gum arabic or tragacanth, and lozenges comprising the active ingredient in a base such as gelatin and glycerin or sucrose and gum arabic. The compounds of the formula (I) can also be formulated as depot preparations. These long acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the formula (I) can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as moderately soluble derivatives, for example as a salt Moderately soluble In addition to the ingredients especially mentioned above, the formulations may include other agents conventional in the art according to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents. The compounds of the formula (I) can be used in association with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib or parecoxib; 5-lipoxygenase inhibitors; analgesics such as paracetamol; NSAIDs such as diclofenac, indomethacin, nabumetone, naproxen or ibuprofen; leukotriene receptor antagonists; DMARDs such as methotrexate; sodium channel blockers such as lamotrigine; N-type calcium channel antagonists; NMDA receptor modulators, such as glycine receptor antagonists; gabapentin, pregabalin and related compounds; tricyclic antidepressants such as amitriptyline; antiepileptic drugs stabilizing neurons; inhibitors of mono-aminergic absorption such as venfalaxin; opioid analgesics; local anesthetics; 5HT-I agonists, such as triptans, for example sumatriptan, naratriptan, solmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; ligands of the EP-i receptor; ligands of the EP2 receptor; ligands of the EP3 receptor; antagonists ???; EP2 antagonists and EP3 antagonists; cannabinoid receptor agonists; VR1 antagonists. When the compounds are used in association with other therapeutic agents, the compounds sequentially or simultaneously by any convenient route. The invention thus provides, in a further embodiment, an association comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof together with an additional therapeutic agent (s). In one embodiment of the invention, there is provided an association comprising a compound of the formula (I) or one of its pharmaceutically acceptable derivatives and paracetamol. In particular the invention provides an association comprising acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic or one of its pharmaceutically acceptable derivatives and paracetamol. In yet another embodiment of the invention, an association is provided comprising an agonist of the EP4 receptor or one of its pharmaceutically acceptable derivatives and paracetamol. Suitable EP4 receptor agonists include those described herein., including the compounds of the formula (I) and those compounds described in WO02 / 064564, such as the acid. { 4- [4,9-dipropoxy-1 -oxo-, 3-dihydro-2H-benzo [f] isoindol-2-yl] phenyl} -acetic and in WO01 / 10426, such as the acid. { 4- [4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] phenyl} -acetic. The associations mentioned above can be conveniently presented for use in the form of a pharmaceutical formulation and therefore pharmaceutical formulations comprising an association as defined above together with a pharmaceutically acceptable carrier or excipient constitute another aspect of the invention. In particular, a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof, paracetamol and a pharmaceutically acceptable excipient or diluent is provided. In another embodiment, a pharmaceutical composition comprising the acid is also provided. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic or one of its pharmaceutically acceptable derivatives, paracetamol and a pharmaceutically acceptable excipient or diluent. The individual components of said associations can be administered sequentially or simultaneously or separately or in combination pharmaceutical formulations. When a compound of the formula (I) or one of its pharmaceutically acceptable derivatives is used in association with a second therapeutic agent active against the same disease, the dose of each compound may differ from the dose that is administered when the compound is used. alone. The appropriate doses may be readily appreciated by those skilled in the art. In one embodiment of the invention, there is provided a method for treating a human or animal subject suffering from a disease that is mediated by the action, or loss of action, of PGE2 at EP4 receptors, which comprises administering to said subject a effective amount of a compound of the formula (I) or one of its pharmaceutically acceptable derivatives and paracetamol. In another embodiment of the invention, there is provided a method for treating a human or animal subject suffering from a disease that is mediated by the action, or loss of action, of PGE2 at EP4 receptors, which comprises administering to said subject a effective amount of acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic or one of its pharmaceutically acceptable derivatives and paracetamol. A proposed daily dose of the compounds of the formula (I) or their pharmaceutically acceptable salts for the treatment of man varies from 0.001 to 30 mg / kg of body weight per day and more particularly 0.1 to 3 mg / kg of body weight per day , calculated as free acid, which can be administered as a single or divided dose, for example one to four times a day. The dose range for adult humans generally ranges from 0.1 to 1000 mg / day, such as 10 to 800 mg / day, preferably 10 to 200 mg / day, calculated as free acid. An adequate daily dose 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 a day. The exact amount of the compounds of the formula (I) administered to a recipient, particularly a human patient, will be the responsibility of the attending physician. However, the dose used will depend on a number of factors including the age and sex of the patient, the precise disease to be treated and its severity, the route of administration and any possible association therapy that can be performed. The present invention provides a process for preparing the compounds of the formula (I) and their pharmaceutically acceptable derivatives. Thus, in one embodiment of the invention, there is provided a process for preparing a compound of the formula (I) wherein one of X and Y represents C = 0 and the other represents CH2 and R1, R2, R3, R4, R5 and R6 are as defined hereinbefore in relation to formula (I), which process comprises reacting a compound of formula (II), (II) wherein, one of X and Y represents C = O and the other represents CH2; R1, R2, R3, R4, R5 and R6 are as defined hereinbefore in relation to formula (I); and R7 represents Ci-6 alkyl; with a suitable base, such as sodium hydroxide, and optionally then forming a pharmaceutically acceptable derivative of the compound thus formed, and / or converting a compound of the formula (I) into another.

In one embodiment, the aforementioned reaction comprising a compound of the formula (II) is carried out in a suitable solvent, such as ethanol, at reflux. In another embodiment of the invention, there is provided a process for preparing a compound of the formula (I) wherein X and Y represent C = O and R, R2, R3, R4, R5 and R6 are as defined herein above in relation to the formula (I), which process comprises adding a compound of the formula (III), wherein R, R2, R3, R4, R5 and R6 are as defined hereinbefore in relation to formula (I); and R7 represents Ci-6 alkyl; to a suitable acid or mixture of acids, such as glacial acetic acid in the presence of hydrochloric acid, and optionally then forming a pharmaceutically acceptable derivative of the compound thus formed, and / or converting a compound of the formula (I) into another. In one embodiment, the aforesaid reaction comprising a compound of the formula (III) is carried out at a temperature in the range of about 50 to 1 10 ° C, for a period of time in the range of approximately 2 to 70 hours. In one embodiment, the molar ratio of glacial acetic acid to an acid, such as hydrochloric acid, present in the reaction mixture is 1: 1. It will be appreciated that the compounds of the formula (I) wherein one of X and Y represents C = 0 and the other represents CH2 and R1, R2, R3 and R4 are as defined hereinbefore in relation to the formula ( I), can also be prepared using the acid hydrolysis conditions indicated above. The compounds of the formulas (II) and (III) can be prepared according to Scheme 1.

SCHEME 1 (i) R-Br or R-l, K2CO3, acetone; (ii) NaOH / H2O, EtOH; (iii) SOCI2 > CHCl3 or EtOH; (V) CH3CO2H, optionally DMAP; (v) NaBH 4, MeOH / THF; (vi) Et3SiH, TFA or TFA / DCM or DCM; (where R = R1 = R2; and R, R2, R3, R4, R5, R6 and R7 are as defined in relation to formula (II)). The compounds of the formula (2) in which R1? R2 can be prepared by reacting the compound of the formula (1) in steps with an alkyl halide R1X, followed by a second alkyl halide R2X, or vice versa, under the conditions mentioned above. The compound (1) can be prepared from diethyl phthalate according to the method described in International Patent Application, Publication Number WO02 / 064564. The compounds of the formula (5) can be prepared according to Schemes 2, 3 and 4, SCHEME 2 (i) NaH, dry DMF; (I) NH4C02H, EtOH, Pd / C; (where R3, R4, R5, R6 and R7 are as defined in relation to formula (II)). (i) NaH, dry DMF; (ii) NH 4 CO 2 H, EtOH, Pd / C; (iii) NaOH, H2O, EtOH (where R3, R4, R5, R6 and R7 are as defined in relation to formula (II)).

SCHEME 4 (i) Base (eg, K2C03), 50 ° C, dry DMF; (ii) H2, Pd / C; (iii) HCl (aqueous); and (iv) EtOH, HCl (where R3, R4, R5, R6 and R7 are as defined in relation to formula (II)). The compounds of the formula (A) are commercially available or can be prepared according to methods known in the art (for example 2,4-difluoronitrobenzene and 3,4-difluoronitrobenzene can be purchased from Sigma-Aldrich Co. Ltd.).

The compounds of the formula (B) are commercially available or can be prepared according to methods known in the art (for example benzyl malonate and ethyl can be purchased from Sigma-Aldrich Co. Ltd.). The compounds of the formula (D) are commercially available or can be prepared according to methods known in the art (for example, diethyl chloromalonate can be purchased from Sigma-Aldrich Co. Ltd.). The compounds of formula (E) are commercially available or can be prepared according to methods known in the art (for example, diethyl malonate can be purchased from Sigma-Aldrich Co. Ltd.). In another embodiment of the invention, there is provided a process for preparing a compound of the formula (I) or a pharmaceutically acceptable derivative thereof, which process comprises reacting a compound of the formula (3) or a compound of the formula (4). ), as described in Scheme 1, with a compound of the formula (IV), (IV) wherein R3, R4, R5 and R6 are as defined in relation to formula (I) and R 'represents H or Ci.6 alkyl) and optionally then form a pharmaceutically acceptable derivative of the compound thus formed, and / or converting a compound of formula (I) to another. The compounds of the formula (IV) in which R 'represents H can be prepared by the hydrolysis of the compounds of the formula (5). The following Descriptions and Examples illustrate the preparation of the compounds of the formula (I). The Descriptions refer to intermediate compounds.

Abbreviations DCM dichloromethane DMAP 4- (dimethylamino) pyridine DMF dimethylformamide DMSO dimethyl sulfoxide EtOH ethanol EtOAc ethyl acetate HCI hydrochloric acid LC / MS liquid chromatography / mass spectroscopy MeOH methanol MDAP mass-directed automatic preparation NaOH sodium hydroxide TFA trifluoroacetic acid THF tetrahydrofuran LC / MS Analytical Procedures Column Waters Atlantis (4.6 mm x 50 mm). Particle size of the stationary phase, 3 μ? P.

Solvents A: aqueous solvent = water + 0.05% formic acid B: organic solvent = acetonitrile + 0.05% formic acid Method Time / min% B 0 3 0.1 3 4 97 4.8 97 4.9 3 5.0 3 • Flow rate, 3 ml / min • Injection volume, 5 μ ?, • Column temperature, 30 ° C • UV detection interval, 220 to 330 nm. All retention times are measured in minutes. As used here, 'CV means volume of the column.

NMR The H NMR spectra were recorded on a Bruker AVANCE 400 NMR spectrophotometer or on a Bruker DPX250 NMR spectrophotometer. Chemical shifts are expressed in parts per million (ppm, units d). Coupling constants (J) are given in hertz units (Hz). Uncoupling patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quadruplet), dd (double doublet), dt (double triplet), m (multiplet), br ( width).

Purification techniques The purification of the examples can be carried out by conventional methods such as chromatography and / or recrystallization using suitable solvents. Chromatographic methods include column chromatography, flash chromatography, HPLC (high performance liquid chromatography), SFC (supercritical fluid chromatography), and MDAP (automatic mass directed preparation).

The term "Biotage" when used herein refers to cartridges pre-packaged with commercially available silica gel.

Automatic mass-directed preparation (MDAP) Waters Atlantis Column: 19 mm x 100 mm (small scale); and 30 mm x 100 mm (large scale). Particle size of the stationary phase, 5 pm.

Solvents A: aqueous solvent = water + 0.1% formic acid B: organic solvent = acetonitrile + 0.1% formic acid Preparation solvent = methanohage 80:20 Solvent for washing the needle = methanol Methods Five methods were used depending on the analytical retention time of the compound of interest: (1) Large / small scale 1 .0-1 .5 = 5-30% of B (2) Large / small scale 1 .5-2.2 = 15-55% of B (3) Large / small scale 2.2-2.9 = 30-85% of B (4) Large / small scale 2.9-3.6 = 50-99% of B The chromatography time was 13.5 minutes, comprising a 10 minute gradient followed by a 3.5 minute column wash and a rebalancing step. (5) Large / small scale 3.6-5.0 = 80-99% B The chromatography time was 13.5 minutes, comprising a 6-minute gradient followed by a 7.5-minute column wash and a rebalancing step. When indicated, "soft gradient" conditions were employed as follows: Large scale 1.5 to 2.3 min = 13-29% B Large scale 1 .9 to 2.3 min = 25-41% B Large scale 2.3 to 2.6 min = 37-53% of B Large scale 2.6 to 3.1 min = 49-65% of B Large scale 3.1 to 3.6 min = 61 -77% of B Time of chromatography 13.5 minutes, comprising a gradient of 10 minutes followed by a wash of column of 3.5 minutes and a stage of rebalancing.

Flow rate 20 ml / min (small scale) or 40 ml / min (large scale).

DESCRIPTION 1a 1,4-Bis (propyloxy) -2,3-naphthalenedicarboxylate diethyl ester The diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate * (1.1 g, 36.1 mmol) was dissolved in acetone (180 ml) and potassium carbonate (24.9 g, 180.5 mmol) was added and stirred. 1-Bromopropane (13.1 ml, 144.4 mmol) was added and the reaction mixture was heated at reflux (60 ° C) overnight under argon. The reaction was cooled to room temperature and the inorganic solid was filtered off. The solvent was evaporated to give an orange-brown oil. The residue was taken up in toluene and washed with 5% potassium hydroxide solution, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give a brown oil which was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane. The clean fractions were evaporated to give the title compound as a yellow oil (1 1 .45 g, 29.5 mmol). LC / MS: Rt = 3.87, [MH] "389 DESCRIPTION 1 b 1,4-Bis (ethyloxy) -2,3-naphthalenedicarboxylate diethyl ester The diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate * (25 g, 82.2 mmol) was dissolved in acetone (400 ml) and potassium carbonate (34 g, 246.5 mmol) was added. It was stirred for 20 minutes. Ethyl iodide (19.8 ml, 248.5 mmol) was added and the mixture was heated at 60 ° C for 7 hours. It was cooled to room temperature and the solid separated by filtration. The solvent was evaporated to give an orange oil which was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate (x3) and the combined organic extracts were washed with water and dried over MgSO. It was evaporated to give a brown solid (-29 g). The crude material was purified by flash column chromatography eluting with 0-15% ethyl acetate in hexane over 30 CV (2CV hexane, 5% EtOAc / 2CV hexane, 10% EtOAc / 4CV hexane, 12% EtOAc / 2CV hexane, 15% EtOAc / 20CV hexane). The fractions were evaporated to give a pink solid. It was triturated in cold hexane to give the title compound as a white solid (3 lots, total 24.83 g, 68.9 mmol). LC / MS: Rt = 3.52, [MH] + 287.

* Diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate can be prepared according to the method described in International Patent Application, Publication Number WO02 / 064564. The following compound was prepared in a manner similar to 1,4-bis (propyloxy) -2,3-naphthalenedicarboxylate diethyl using the appropriate starting materials.

DESCRIPTION 2a 1,4-Bis (propyloxy) -2,3-naphthalenedicarboxylic acid The diethyl 4-bis (propyloxy) -2,3-naphthalenedicarboxylate (1.45 g, 29.5 mmol) was dissolved in ethanol (70 ml) and treated with sodium hydroxide (3.54 g, 88.5 mmol) dissolved in water (15 mi). It was heated to 60 ° C under argon for 4 hours. It was confirmed that the reaction was complete by LC / MS and thin layer chromatography. The reaction mixture was cooled to room temperature and evaporated to one third of the volume. It was acidified to pH2 with hydrochloric acid (2 N) and extracted with ethyl acetate (3x 100 mL). The combined organic extracts were washed with water, brine and dried over magnesium sulfate. The solvent was evaporated to give the title compound as a yellow solid (8.91 g, 26.8 mmol). LC / MS: Rt = 2.74, [MH] + 333 DESCRIPTION 2b 1,4-bis (ethyloxy) -2,3-naphthalenedicarboxylic acid The diethyl 1,4-bis (ethyloxy) -2,3-naphthalenedicarboxylate (24.8 g, 68.8 mmol) was suspended in ethanol (200 ml) and treated with sodium hydroxide (8.3 g, 206.4 mmol) dissolved in 200 ml. of water. An additional 50 ml of ethanol was added to aid in stirring. It was heated to reflux, 100 ° C. Everything dissolved when heated. It was refluxed for 8 hours. It was cooled to room temperature and kept overnight. The solvent was evaporated to near dryness. Water was added and stirred in a ice. It was acidified with 2 M HCl solution (-150 ml). The white precipitate was filtered, washed with water and dried in a vacuum oven to give the title compound as a white solid (18.77 g, 61.7 mmol). LC / MS: R t = 2.34, [MH] + 305 The following compound was prepared similarly to the acid, 4-bis (propyloxy) -2,3-nhalenedicarboxylic using the appropriate starting materials.

DESCRIPTION 3a 4,9-Bis (propyloxy) nho [2,3-clfuran-1,3-dione Chloroform (80 ml) was suspended in 1,4-bis (propyloxy) -2,3-nhalenedicarboxylic acid (8.91 g, 26.8 mmol) and chloride was added dropwise. of thionyl (20.5 ml, 281.4 mmol) while monitoring the temperature (no significant change). The reaction was heated at 65 ° C for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The yellowish brown solid was azeotropically distilled with chloroform (x3) to give the title compound as a beige solid (8.74 g, 27.8 mmol). LC / MS: Rt = 3.77, [MH] + 315 DESCRIPTION 3b 4,9-Bis (ethyloxy) nho [2,3-c1furan-1,3-dione A 1,4-bis (ethyloxy) -2,3-nhalenedicarboxylic acid (10.3 g, 33.8 mmol) was added to a three-necked flask and chloroform (80 mL) was added and stirred. Thionyl chloride (49.2 ml, 355.4 mmol) was added dropwise from an addition funnel for 25 minutes while monitoring the temperature (no change). The reaction was heated to reflux (65 ° C) overnight. The LC / MS indicated that no starting material remained. The reaction mixture was cooled to room temperature and the solvent was evaporated. The product was distilled azeotropically with chloroform (x2) to Separate the remaining traces of thionyl chloride to give the title compound as a pale yellow solid (9.86 g). LCMS: Rt = 3.48, [MH] + 287 The following compound was prepared in a manner similar to 4,9-bis (ethyloxy) nho [2,3-c] furan-1,3-dione using the appropriate departure.

DESCRIPTION 4 (2-Fluoro-4-nitrophenyl) propane-2-ethyl acetate and phenylmethyl Cool in a bath of benzyl ethyl malonate ice (2.9 g, 12.6 mmol) in dry DMF (20 mL) and monitor the temperature while adding sodium hydroxide (504 mg, 12.6 mmol) in portions. He stirred to room temperature for 10 minutes until evolution of H2 ceased. 3,4-difluoronitrobenzene (2 g, 12.6 mmol) was added under an argon atmosphere and a dark red color change was obtained. The reaction mixture was heated at 100 ° C for 20 hours under argon. It was confirmed that the reaction was complete by thin layer chromatogr (20% ethyl acetate in hexane). The reaction mixture was cooled to room temperature and partitioned between 2N hydrochloric acid (75 ml) and ethyl acetate (75 ml). The aqueous layer was extracted with ethyl acetate (2 x 75 mL) and the combined organic fractions were evaporated to a yellow oil. Purification by chromatogr on silica gel eluting with 0-20% ethyl acetate in hexane gave the title compound as a yellow oil (3.86 g, 10.6 mmol). LCMS: Rt = 3.40, [MH] + 362 The following compound was prepared in a manner similar to ethyl (2-fluoro-4-nitrophenyl) propanedioate and phenylmethyl using the appropriate starting materials.

DESCRIPTION 5 (4-Amino-2-fluorophenyl) ethyl acetate It was treated with ammonium formate (6.7 g, 10.6 mmol) under argon, ethyl (phenylmethyl) (2-fluoro-4-nitrophenyl) propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol (50 mL). Palladium paste 10% on charcoal (380 mg) was added and the reaction was stirred under reflux for 3 hours (60 ° C). The reaction was cooled to room temperature and the catalyst was removed by filtration through celite. The solvent was removed to give a brown oil. The crude material was purified by chromatogr on silica gel eluting with 0-50% ethyl acetate in hexane (1.1) over 45 minutes. The fractions were evaporated to give the title compound as a yellow oil (1.26 g, 6.4 mmol). LCMS: Rt = 2.10, [MH] + 198 The following compound was prepared in a manner similar to ethyl (4-amino-2-fluorophenyl) acetate using the appropriate starting materials.

DESCRIPTION 6 Diethyl chloro (3-fluoro-4-nitrophenyl) propanedioate and diethyl (3-fluoro-4-nitropheni-propanediodate) Ice 2,4-difluoronitrobenzene (31.5 ml, 287 mmol) and diethyl chloromalonate (46.5 ml, 287 mmol) dissolved in dry DMF (300 ml) were cooled in an ice bath. Sodium hydroxide crushed in portions was added over 20 minutes. The reaction mixture was stirred at room temperature overnight. The reaction was cooled again in an ice bath and acidified with 2N HCl (-400 ml). It was extracted with ethyl acetate (2 x 400 mL, 1 x 200 mL), the organic extracts were washed with water and dried over MgSO4. They were evaporated to give an orange oil (-89 g). The material was loaded on a 1.5 kg Si cartridge and purified on CombiFlash® Companion ™ XL eluting with 0-20% ethyl acetate in hexane over 10 column volumes. The fractions were evaporated to give diethyl chloro (3-fluoro-4-nitrophenyl) propanedioate as a yellow oil (9.09 g), diethyl (3-fluoro-4-nitrophenyl) propanedioate as a yellow oil (24.7 g), and a mixture of the 2 as a yellow oil that crystallized at rest (1.7 g).

Chloro (3-fluoro-4-nitrophenyl) diethyl propanedioate LC / MS: Rt = 3.18; H NMR (CDCl 3) d ppm: 1.32 (6H, t, J = 7.8Hz), 4.35 (4H, m), 7.64 (1 H, dd, J = 1 1 .9, 2.1 Hz), 7.56 (1 H, ddd, J = 8.9, 2.1, 1 .1 Hz), 8.08 (1 H, dd, J = 8.7, 7.6 Hz). (3-Fluoro-4-nitrophenyl) diethyl propanedioate LC / MS: R t = 2.96, MH + = 300; 1 H NMR (CDCl 3) d ppm: 1.29 (6H, t, J = 7.1 Hz), 4.25 (4H, m), 4.67 (1 H, s), 7.45 (1 H, dd, J = 1 1 .5, 1 .8 Hz), 7.35 (1 H, ddd, J = 8.6, 1.5, 0.8 Hz), 8.06 (1 H, dd, J = 8.4, 7.9Hz).

DESCRIPTION 7 (4-Amino-3-fluorophenyl) diethyl propanedioate A mixture of diethyl chloro (3-fluoro-4-nitrophenol) propanedioate and diethyl (3-fluoro-4-nitrophenyl) propanedioate (1.7 g, -5.7 mmol) suspended in ethanol was treated with 5-10 my ethyl acetate until it dissolved. This solution was treated with 10% Pd / C (slurry) (170 mg) under argon and then ammonium formate (1.8 g, 5 equivalents) was added. It was stirred for 1 hour under reflux under argon. It was cooled to room temperature and the Pd was separated by filtration through celite, under argon. Evaporated to a brown oil -1 .7 g. Purified by flash chromatography, 40 + ™ M Si cartridge, eluting with 5-40% ethyl acetate in hexane over 10 column volumes. The fractions were evaporated to give the title compound as a yellow oil (722 mg). LCMS: Rt = 2.65, MH + = 270.

DESCRIPTION 8 (4-Amino-3-fluorophenyl) ethyl acetate Diethyl (4-amino-3-fluorophenyl) propanedioate (1.85 g, 44.1 mmol) was dissolved in ethanol (80 mL) and treated with NaOH (2.6 g, 1.5 eq.) Dissolved in 18 mL of water to give a pink solution. This was heated at 90 ° C for one hour until it was complete. Heating was continued for an additional 1 hour, and then cooled to room temperature. The solvent was evaporated and acidified with 2 N HCl. Extraction with ethyl acetate (3 x 100 mL). The organic extracts were washed with brine and dried over MgSO4. They were evaporated to give the title compound as a yellow oil which crystallized slowly at rest (6.6 g). LC / MS: R t = 2.28, MH + = 198.

DESCRIPTION 9. { 4-14, 9-Bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-ill-3-fluorophenyl} ethyl acetate 4,9-Bys (ethyloxy) naphtho [2,3-c) furan-1,3-dione (0.100 g, 0.35 mmol) in acetic acid (5 ml) was treated with DMAP (0.013 g, 0. 1 mmol) was then added with ethyl (4-amino-3-fluorophenyl) acetate (0.138 g, 0.70 mmol) and heated to reflux (120 ° C) under argon overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated to give an orange brown oil which was diluted in DCM and washed with saturated NaHCO 3 and then with 2N HCl. The organic extracts were dried over MgSO 4 and evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0-20%) in hexane over 30 minutes. The evaporated fractions were triturated with hexane to give the title compound as a solid (0.1 10 g, 0.24 mmole, 69%). LCMS: Rt = 3.74, [MH] + 466 The following compounds were prepared in a similar manner to. { 4- [4,9-bis (ethyloxy) -, 3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} ethyl acetate using the appropriate starting materials.

DESCRIPTION 10. { 4-? 4, 9-Bis (ethyloxy) -1,3-dioxo- 1, 3-dihydro-2H-benzorf] isoindol-2-Ul-2-fluorofeniftacetato of ethyl 1,4-Bis (ethyloxy) -2,3-naphthalenedicarboxylic acid (18.77 g, 61.7 mmol) was added to ethyl (4-amino-2-fluorophenyl) acetate (13.88 g, 67.9 mmol) in acetic acid (190 ml). ), and heated to reflux. The LC / MS performed at 5 o'clock indicated that the reaction was incomplete. More (4-amino-2-fluorophenyl) ethyl acetate (4 g, 20 mmol) was added and heating continued. After 3 hours of additional heating, more (4-amino-2-fluorophenyl) ethyl acetate (3 g, 15 mmol) was added and heating continued. After a further 2 hours of heating, more (4-amino-2-fluorophenyl) ethyl acetate (3 g, 15 mmol) was added and heating continued for a further 6 hours. The reaction mixture was then cooled and the product separated from the solution by crystallization. It was diluted with water (200 ml) and more precipitate formed. The solid was filtered and washed with additional acetic acid (500 ml) to remove as much color as possible, and then washed with water (500 ml). The solid was dried in a vacuum oven overnight to give a slightly brown solid (12.01 g). The aqueous solution was filtered again and the solid was washed with more acetic acid and water, and dried to give a slightly brown solid (1.4 g). The acidic solution from the above was filtered again and the solid was washed with more acetic acid and water, and dried to give a slightly brown solid (6.12 g). All acidic filtrates were concentrated in vacuo (-250 ml) and cooled. The solid which had crystallized was filtered, washed with more acetic acid (50 ml) and water, and dried to give a white solid (2.19 g). In the filtrate, additional solid crystallized, which was filtered, washed with more acetic acid (50 ml) and water, and dried to give a brown solid (3.76 g, ~ 60% purity = 2.27 g of product). Total yield of the compound of the epigraph, 24 g. LC / MS: Rt = 3.81, [MH] + 466 EXAMPLE 1 Acid Í4-Í4, 9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H'benzoff1isoin dol-2-ill-3-fluorophenyl) acetic acid It dissolved. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} ethyl acetate (0.050 g, 0.1 1 mmol) in glacial acetic acid (2 mL) and 2N hydrochloric acid (2 mL) was added resulting in a precipitate. The reaction mixture was heated to 100 ° C under argon (the precipitate was redissolved) for 2 hours. The reaction mixture was cooled to room temperature and water was added, with stirring for 5 minutes. A solid precipitate formed which was filtered, washed with water, and collected to give the title compound as a yellow solid. The product was dried overnight in a vacuum oven (0.024 g, 0.05 mmol). LCMS: Rt = 3.27, [MH] + 438 The following compounds were prepared in a manner similar to acid. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} acetic using the appropriate starting materials.

DESCRIPTION 11. { 4-l4,9-Bis (ethyloxy) -1-hydroxy-3-oxo-1,3-dihydro-2H-be fluorophenyl} ethyl acetate It was suspended in methanol (2 ml),. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isindol-2-yl] -3-fluorophenyl} ethyl acetate (0.1 12 g, 0.24 mmol) and tetrahydrofuran (3 mL) was added to dissolve the reactant. The reaction mixture was cooled to 0 ° C in an ice bath and sodium borohydride (0.027 g, 0.72 mmol) was added in portions. Stirred under argon for 2-3 hours at 0 ° C. More sodium borohydride was added to the reaction to force it to complete. The reaction mixture was evaporated to a solid and partitioned between EtOAc and (saturated) ammonium chloride. The aqueous layer was extracted with EtOAc (x2) and the combined organic extracts were washed with brine and dried over MgSO. The solvent was evaporated to give the title compound as a gummy residue, which was triturated with hexane to give a solid (0.11 1 g, 0.23 mmole). LCMS: Rt = 3.29, [MH] + 468 The following compounds were prepared in a similar manner to. { Ethyl 4- [4,9-bis (ethyloxy) -1-hydroxy-3-oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl-acetic acid ester using the appropriate starting materials .

DESCRIPTION 12. { 4- [4.9-Bis (ethyloxy) -1-hydroxy-3-oxo-1,3-dhydro-2H-benzo [flisoin fluorophenyl] ethyl acetate It was suspended. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} ethyl acetate (24 g, 51.6 mmol) in methanol (75 ml) and tetrahydrofuran (200 ml) and cooled to 5 ° C in an ice bath. Some of the solid remained without dissolving. Sodium borohydride (2 g, 51.6 mmoles) was added in portions over 2 minutes (effervescence). The solid that had not dissolved dissolved slowly and the color cleared from dark brown to light brown. The LC / MS after 5 minutes and 30 minutes indicated that the reaction had not been completed. Therefore, after 30 minutes, more sodium borohydride (1 g, 26.3 mmol) was added in one portion (effervescence). The LC / MS after another 30 minutes showed that no starting material remained. The mixture was concentrated in vacuo to give a brown oil which was partitioned between ethyl acetate (300 ml) and water (500 ml). The aqueous layer was then extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the title compound as a brown solid (26 g).

LC / MS: Rt = 3.47, [MH] + 468 DESCRIPTION 13. { 4- [4,9-Bis (ethyloxy) -1-oxo-1,3-dihydro-2H-benzofflisoindol-2-ill-3-fluorophenyl} ethyl acetate It dissolved. { 4- [4,9-bis (ethyloxy) -1-hydroxy-3-oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} ethyl acetate (0.1 1 1 g, 0.24 mmol) in trifluoroacetic acid (5 ml) [orange flash solution] and cooled to 0 ° C in an ice bath. It was treated dropwise with triethylsilane (0.06 ml, 0.36 mmol) and stirred at 0 ° C under argon. The reaction was complete after 30-60 minutes. The trifluoroacetic acid was evaporated to give a yellow oil which was purified directly by chromatography on silica gel eluting with ethyl acetate (0-20%) in hexane for 30 minutes. The fractions were evaporated to a colorless gum, which by trituration with hexane gave a white solid (0.072 g, 0.16 mmol). LCMS: Rt = 3.65, [MH] + 452. The following compounds were prepared in a similar manner to. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} ethyl acetate using the appropriate starting materials.

DESCRIPTION 14. { 4-! 4,9-Bis (ethyloxy) -1-oxo-1,3-dihydro-2H-benzoyl-fluorophenyl} ethyl acetate It dissolved. { 4- [4,9-bis (ethyloxy) -1-hydroxy-3-oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} ethyl acetate (approximately 51.6 mmol) in CH2Cl2 (50 mL) and cooled to 0 ° C and TFA (50 mL) was added. Thetilsilane (12.3 ml, 77 mmol) was added in one portion to give a brown solution. The solution was concentrated in vacuo to give an ocher solid. This was recrystallized from hot isopropanol (550 ml), cooled, filtered, washed with isopropanol, and dried in a vacuum oven to give the title compound as dirty white crystals (20.2 g). LC / MS: Rt = 3.89, [MH] + 452.

EXAMPLE 4 Acid (4-Í4, 9-bis (ethyloxy) -1-oxo-1,3-dihydro-2H-benzorflisoindol-2-in-3-fluorophenyl) acetic acid It was suspended in ethanol (2 ml),. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} ethyl acetate (0.072 g, 0.16 mmol) and treated with 2N sodium hydroxide (6 mL). It was heated to reflux at 100 ° C under argon for 1 hour. By LC / MS the reaction was seen to be complete. The reaction mixture was cooled and the solvent was evaporated to dryness. Water and 2N HCl were added to acidify. It was extracted with ethyl acetate (x2), dried over magnesium sulfate and evaporated to a solid which was dried overnight in a vacuum oven to give the title compound (0.038 g, 0.09 mmol). LC / MS: R t = 3.14, [MH] + 424. The following compounds were prepared in a manner similar to acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] issoindol-2-yl] -3-fluorophenyl} acetic using the appropriate starting materials.

EXAMPLE 9 Acid. { 4-f4,9-bis (ethyloxy) -1-oxo-1,3-dihydro-2H-benzorf1isoindol-2-ill-2-fluoropheniQacetic It was suspended in ethanol (450 ml),. { 4- [4,9-bis (ethyloxy) -1-oxo-1, 3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} ethyl acetate (20.2 g, 44.8 mmol) and treated with 2N sodium hydroxide (150 ml). The mixture was heated at reflux for 1 hour, then cooled and concentrated in vacuo to -200 ml, and then acidified with 2N hydrochloric acid. The white solid was collected by filtration, washed with water (500 ml) and dried in a vacuum oven to give the title compound as a creamy solid (18.45 g, 43.6 mmol). LCMS: R t = 3.35, [MH] + 424. 1 H NMR (DMSO) 512.49 (1 H, br, s), 58.32 (1 H, d, J = 8 Hz), 58.19 (1 H, d, J = 8Hz), 57.96 (1 H, dd, J = 13.2Hz), 57.74 (1 H, dd, J = 9.2Hz), 57.71 (1 H, t, J = 8Hz), 57.64 (1 H, t, J = 8Hz), 57.41 (1 H, t, J = 9Hz), 55.19 (2H, s), 54.39 (2H, q, J = 7Hz), 54.32 (2H, q, J = 7Hz), 53.63 (2H, s ), 51.48 (3H, q, J = 7Hz), 51.46 (3H, q, J = 7Hz).

DESCRIPTION 15 (Diethyl 3,5-difluoro-4-nitrophenyl) propanedioate To a solution of 1,3-nitrobenzene (3.0 g, 16.95 mmol) and diethyl chloropropanedioate (3.3 g, 16.95 mmol) in DMF (20 ml) cooled in an ice bath was added crushed sodium hydroxide (1.36). g, 33.90 mmol) in portions. This resulted in a bright red solution. The reaction was stirred at room temperature overnight. It was then acidified with 2N HCl (50 ml) and extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography eluting with 5-40% ethyl acetate in hexane. The cleanest fractions were evaporated to give the title compound as a yellow solid (2.08 g, 6.56 mmoles). LC / MS: Rt = 3.06, [MH] + 318.

DESCRIPTION 16 (diethyl 4-amino-3,5-difluorophenyl) propanedioate Diethyl (3,5-difluoro-4-nitrophenyl) propanedioate (2.08 g, 6.56 mmol) was added to ethanol (100 mL). Then 10% palladium on carbon (slurry) (0.208 g) was added under a stream of argon. It was treated with ammonium formate (2.07 g, 32.80 mmol) and the reaction was heated to reflux for 30 minutes. Once cooled to room temperature, the mixture was filtered through celite and washed with ethanol. This was evaporated to a brown oily solid. By triturating with DCM insoluble impurities were separated. Volatiles were evaporated and then purified by chromatography eluting with 5-40% ethyl acetate in hexane. The clean fractions were evaporated to give the title compound as a light brown oil (0.774 g, 2.70 mmol). LC / MS: R t = 2.69, [MH] + 288.

DESCRIPTION 17 (4-Amino-3,5-difluorophenyl) ethyl acetate Diethyl (4-amino-3,5-difluorophenyl) propanedioate (0.770 g, 2.68 mmol) was dissolved in ethanol (50 ml) and treated with sodium hydroxide (0.107 g, 2.68 mmol) in water (1.5 ml). ). It was heated at 90 ° C for 55 minutes. Additional sodium hydroxide (0.016 g, 0.40 mmol) was added to the reaction and heating continued for 15 minutes. The mixture was cooled to room temperature and evaporated. It was then acidified with 2N HCl (20 mL) and extracted x2 with ethyl acetate (25 mL). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound as a light brown oil (0.610 mg, 2.84 mmol,> 100%). LC / MS: Rt = 2.52, [MH] + 216.

EXAMPLE 10 Acid. { 4-14, 9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [flisoindol-2-ill-3,5-difluorophenyl) acetic acid y. { 4-Í4, 9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzoff] isoindol-2-ill-3,5-difluorophenyl} ethyl acetate To a solution of acid, 4-bis (ethyloxy) -2,3-naphthalenedicarboxylic acid * (0.389 g, 1.28 mmol) in acetic acid (5 mL), (4-amino-3,5-difluorophenyl) acetate was added. of ethyl (0.55 g, 2.56 mmoles) and DMAP (0.047 g, 0.38 mmoles). The reaction was heated at 120 ° C for two days. Water (50 ml) was added to the mixture and the resulting creamy solid was collected by filtration and washed with water. It was dried in a vacuum oven. The crude mixture was purified using reverse phase chromatography. The more polar fractions were pooled to give two batches of the acid, Example 10, acid. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H- benzo [f] isoindol-2-yl] -3,5-d-fluoro-phenyl} acetic acid (0.131 g, 0.29 mmol). LCMS: Rt = 3.30, [MH] + 456 and (0.05 g, 0.1 1 mmol). LC / MS: R t = 3.30, [MH] + 456. The less polar fractions were combined as a mixture of the acid and the ethyl ester. This mixture was evaporated and purified using normal phase chromatography eluting with 7-60% ethyl acetate in hexane. The fractions were evaporated to give two batches of the ethyl ester as a pale yellow solid. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3,5-difluorophenyl} ethyl acetate (0.172 g, 0.36 mmol). LCMS: Rt = 3.90, [MH] + 484 and (0.072 g, 0.15 mmoles). LC / MS: R t = 3.72, [MH] + 484. * 1,4-Bis (ethyloxy) -2,3-naphthalenedicarboxylic acid can be prepared according to the method described in the International Patent Application, Publication Number WO02 / 064564.

DESCRIPTION 18 (4-G4, 9-Bis (ethyloxy) -1-hydroxy-3-oxo-1,3-dihydro-2H-benzoff1isoindol-2-ill-3,5-difluorophenyl} ethyl acetate To an agitated solution of. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] soindol-2-yl] -3,5-difluorophenyl} Ethyl acetate (0.240 g, 0.50 mmol) in THF (10 mL) and methanol (5 mL), sodium borohydride (0.019 g, 0.50 mmol) was added slowly under argon atmosphere. It was stirred at room temperature for 15 minutes and then 0.057 g (1.50 mmoles) plus sodium borohydride was added to complete the reaction. After 1.5 hours the reaction was evaporated and quenched with an aqueous solution of ammonium chloride. X2 was extracted with ethyl acetate (25 mL) and the combined extracts were washed with brine. The organic layer was then dried over magnesium sulfate, filtered and evaporated to give the title compound as a yellow oily solid (0.240 g, 0.49 mmol). LC / MS: Rt = 3.42 and 3.46, [MH] + 486.

DESCRIPTION 19. { 4-G4.9-Bis (ethyloxy) -1-oxo-1,3-dihydro-2H-benzoyl-isoindol-2-ylh3, ethyl 5-difluorophenic acid acetate To an agitated solution of. { 4- [4,9-bis (ethyloxy) -1-hydroxy-3-oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3,5-difluorophenyl} Ethyl acetate (0.240 g, 0.495 mmol) in TFA (3 mL) at 0 ° C, triethylsilane (0.118 mL, 0.742 mmol) was added dropwise. The bright red solution turned light yellow with the addition. The mixture was evaporated and then purified by MDAP. The fractions were evaporated to give a yellow solid (0.049 g, 0. 0 mmol). LC / MS: Rt = 3.62, [MH] + 470.

EXAMPLE 11 Acid. { 4-4,49-bis (ethyloxy) -1-oxo-1,3-dihydro-2H-benzoylphlisoindol-2-in-3,5-difluorophenyl} acetic TO . { 4- [4,9-bis (ethyloxy) -1-oxo-1,3-d, 2-dH-benzo [f] y sool-2-yl] -3,5-difluorophenyl} ethyl acetate (0.045 g, 0.096 mmol) were added acetic acid (3 mL) and 2N hydrochloric acid (3 mL). The mixture was heated at 100 ° C for 1 hour. The heating was stopped and the reaction was cooled to room temperature, water was added and the resulting yellow solid was collected by filtration and dried in a vacuum oven. It was purified by MDAP (mild gradient). The clean fraction was evaporated to give the title compound as a clear vitreous compound (0.08 g, 0.04 mmol). LCMS: Rt = 3.16, [MH] + 442. The acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} acetic acid (Example 9) was also prepared according to the following procedures.

Stage 1 1, 4-Dihydroxy-2,3-naphthalenedicarboxylate diethyl To a stirring suspension of sodium ethoxide (95%, 750 g, . 2 moles) in toluene (7.2 liters, azeotropically distilled to remove water), diethyl phthalate (1513 ml, 7.6 moles) was added under a nitrogen atmosphere. The resulting suspension was heated to 70 ° C followed by the dropwise addition of diethyl succinate (800 ml, 5.07 moles) over a period of one hour. The reaction mixture was then stirred at 70 ° C under a nitrogen atmosphere for 18 hours, monitoring the consumption of diethyl succinate by TLC analysis (silica, dichloromethane). The reaction mixture was cooled to 5 ° C, water (7.2 L) was added dropwise and the suspension was stirred for 5 minutes before stopping the stirring and allowing the layers to separate. The aqueous layer was collected and adjusted to pH 4.5 by dropwise addition of concentrated hydrochloric acid (-600 ml) at 5 ° C *. The precipitated solid was isolated by filtration, washed with water (2 L) and dried by freezing to give the pure product as a yellow solid (0.049 g, 34% yield).

* The aqueous mixture should be acidified as soon as possible to avoid hydrolysis of the desired product.

Stage 2 1,4-Bis (ethyloxy) -2,3-naphthalenedicarboxylate diethyl ester A suspension of potassium carbonate (1728 g, 12.5 moles) in acetone (1 L) was stirred at 40 ° C for two hours, and then allowed to cool to 20 ° C. To the reaction mixture were added 1,4-bis (ethyloxy) -2,3-naphthalenedicarboxylate diethyl ester (1087 g, 3.57 mol) and ethyl bromide * (800 ml, 10.7 mol). This was followed by heating to reflux for 18 hours. 1 H NMR spectroscopy indicated a predominant mono-alkylation so that the reaction mixture was allowed to cool to -30 ° C, ethyl iodide (470 ml, 5.88 moles) was added and the mixture was then heated under reflux for 24 hours. more hours The reaction mixture was cooled to room temperature, filtered and the inorganic solids were washed with acetone (3 L). Removal of the solvent from the combined filtrates under reduced pressure obtained the desired product as a dark red solid (1343 g, quantitative yield). * Ethyl iodide can also be used in this reaction and may be preferable on a large scale due to the low boiling point of ethyl bromide.

Stage 3 1, 4-bis (ethyloxy) -2,3-naphthalenedicarboxylic acid To a stirred solution of diethyl 1,4-bis (ethyloxy) -2,3-naphthalenedicarboxylate (1343 g, 3.73 mol) in ethanol (5.5 L), 2M sodium hydroxide solution (5.5 L, 1. 0 moles). The reaction mixture was heated at reflux for 8 hours, monitoring the progress of the reaction by H NMR spectroscopy. The mixture was then cooled to 0 ° C for 18 hours before isolating the crystallized solid by filtration, washing with ethanol (5 L) and drying in a vacuum oven at 60 ° C to constant weight, whereby the product was obtained desired as a white solid (903.7 g, remains ~ 1 1% water determined by Karl-Fischer, 62% yield).

Stage 4a (4-Amino-2-fluorophenyl) ethyl acetate Thionyl chloride (986 mL, 8.51 mol) was added dropwise to a stirred suspension of 2- (4-amino-2-fluorophenyl) acetic acid (960 g, 5.68 mol) in ethanol (10 L) at 0 °. C in a nitrogen atmosphere. The reaction mixture was then heated at 40 ° C for 48 hours, monitoring the progress of the reaction by 1 H NMR spectroscopy. The reaction mixture was evaporated to dryness and the residue was redissolved in a mixture of dichloromethane (8 L) and saturated sodium hydrogencarbonate solution (5 L). More sodium hydrogen carbonate solution (~ 8 L) was added until the aqueous phase became basic. The layers were separated and the organic phase was washed with saturated sodium hydrogencarbonate solution (4 L), dried over magnesium sulfate and the solvent was removed under reduced pressure, whereby the product was obtained desired, (4-amino-2-fluorophenyl) ethyl acetate, as an orange solid (1042 g, 93% yield), which may crystallize at rest.

Stage 4b . { 4-G4, 9-Bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzoylisoindindol-2-ill-2-fluorophenyl) ethyl acetate A mixture of the sodium salt of 1,4-bis (ethyloxy) -2,3-naphthalenedicarboxylic acid (526 g, 1.51 mol) and ethyl (4-amino-2-fluorophenyl) acetate (539 g, 2.73 moles) in glacial acetic acid (5100 ml), was heated to reflux for 6 hours, monitoring the progress of the reaction by 1 H NMR spectroscopy. The reaction mixture was allowed to cool to room temperature, stirred for 18 hours, diluted with water (14 L) and stirred for a further 30 minutes. The product was isolated by filtration, washed with water (5 L) and dried in a vacuum oven to give the desired product as a dirty white solid (587 g, 84% yield), Stage 5a (4- [4.9-Bis (ethyloxy) -1-hydroxy-3-yl-1,3-dihydro-2H-benzo [flisoindol-2-ill-2-fluorophenyl] ethyl acetate Sodium borohydride (45 g) was added, 1 .19 moles) in portions over 45 minutes, to a suspension under stirring of. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} ethyl acetate (542 g, 1.16 moles) in a mixture of methanol (1.63 L) and tetrahydrofuran (4.34 L) between -5 and 0 ° C under nitrogen atmosphere. After stirring for a further 60 minutes at 0 ° C, additional portions of sodium borohydride (a total of 25 g, 0.66 mole) were added until no observable starting material remained by TLC analysis (silica, hexane: ethyl acetate , 70:30). At this point, the reaction mixture was quenched by the dropwise addition of saturated ammonium chloride solution (-2700 ml) to ~ pH 9. Ethyl acetate (2 L) was added and the mixture was stirred for 5 minutes. . Agitation was stopped and the layers separated. The aqueous phase was extracted with another portion of ethyl acetate (2 x 4 L). The combined organic phases were washed with brine (6 L), dried over magnesium sulfate and filtered. The material was combined with that of another lot processed in a similar manner and evaporated to dryness. HE The residue was redissolved in dichloromethane (5 L), dried over sodium sulfate, filtered and evaporated to dryness. It was suspended in isopropyl alcohol (2 L) and dried by dissolving in DCM (5 L) and evaporating to dryness three times to give the desired product as a dirty white solid (929 g, 89% yield), Stage 5b . { 4-Í4, 9-Bis (ethyloxy) -1-oxo-1, 3-dihydro-2H-benzo [f] isoindol-2-ill-2-fluorophenyl-ethyl acetate acetate Trifluoroacetic acid (1900 ml) was added to a stirred solution of. { 4- [4,9-bis (ethyloxy) -1-hydroxy-3-oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} ethyl acetate (898 g, 1.92 mol) in dichloromethane (1900 ml) at 0 ° C under nitrogen atmosphere. Triethylsilane (465 ml, 2.92 moles) was added dropwise to the dark red solution ensuring that the temperature was maintained below 3 ° C. The reaction mixture was then stirred at 0 ° C for 45 minutes, at which time the solution turned yellow and it was seen that all of it had been consumed. { 4- [4,9-bis (ethyloxy) -1-hydroxy-3-yl-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} ethyl acetate, by TLC analysis (silica, dichloromethane: methanol, 99: 1). The reaction mixture was evaporated to dryness under reduced pressure, suspended in hexane (2 x 2.5 L) and then isopropanol (2.5 L) at 40 ° C and dried in vacuo to give the desired product as a white solid (821 g. , 95% yield).

Stage 6a Acid { 4- [4,9-bis (ethyloxy) -1-oxo-1,3-dihydro-2H-benzoyl] isoindol-2-yl] -2-fluorophenyl} acetic A suspension of. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} Ethyl acetate (70.0 g, 155 mmol) in a mixture of glacial acetic acid (650 ml) and hydrochloric acid (6 M, 250 ml) was heated to reflux under a nitrogen atmosphere, monitoring the progress of the reaction by analysis of TLC (silica, dichloromethane: methanol, 99: 1). After 60 minutes, the reaction mixture was cooled to 0 ° C. The precipitated solid was isolated by filtration, washed with water (500 ml), suspended in glacial acetic acid (350 ml) at 50 ° C and dried in the air to give the desired product, acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2- fluorophenylacetic, as a dirty white solid (57.7 g, 88% yield). During this reaction procedure, all the solid will dissolve, followed by precipitation of the product from the reaction mixture after about 30 minutes. A small increase in the ratio of acetic acid to hydrochloric acid can be used to ensure that the products of the reaction remain in solution from the beginning to the end.

Stage 6b Acid { 4- [4,9-bis (ethyloxy) -1-oxo-1,3-dihydro-2H-benzo [fl isoindol-2-ill-2-fluorophenyl]} acetic A suspension of. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} Ethyl acetate (200.0 g, 443 mmol) in a mixture of glacial acetic acid (2080 ml) and hydrochloric acid (2 M, 700 ml), was heated to reflux under a nitrogen atmosphere, monitoring the progress of the reaction by analysis of TLC (silica, dichloromethane: methanol, 99: 1). After 60 minutes, the reaction mixture was cooled to 0 ° C. The precipitated solid was isolated by filtration, washed with water (1400 ml), and dried by freezing to give the desired product as a dirty white solid (163.4 g, 87% yield). The final batch of the product was obtained by a suspension in ethyl acetate (3 L) of five batches made as above (total weight, 555 g), then freeze drying and oven drying at 70 ° C to give the desired product, acid { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} acetic acid as a dirty white solid (510.6 g, 82% yield for hydrolysis and suspension).

Biological data In vitro cAMP assay Studies were performed using HEK-293 (T) cells expressing the recombinant human EP4 prostanoid receptor (HEK-EP4 cells). The cells were cultured as a monolayer culture in DMEM-F12 / F12 containing glutamax II (Gibco) and supplemented with 10% fetal bovine serum and 0.4 mg / ml of 1 G418. The HEK-EP4 cells were pre-treated 24 hr and 30 mins before the experiment with indomethacin 10 μ? and were collected using Verseno containing indomethacin 10 μ ?. The cells were resuspended in assay buffer (DMEM: F12indomethacin 10 μ? and IBMX 200 μ?) at 1 x 106 cells per ml and incubated for 20 min at 37 ° C.

Then, 50 μ? of cells at 50 μ? of agonist (compound of the formula (I)) and incubated at 37 ° C for 4 minutes before stopping the reactions with 100 μl of 1% triton X-100. The cAMP levels in the cell lysates were determined using a competition binding assay. In this assay the ability of the cell lysates to inhibit the binding of 3 H-cAMP (Amersham) to the binding subunit of protein kinase A was measured and the cAMP levels were calculated from a standard curve. The data for each compound were expressed as% of the response at a maximum concentration of 10 nM of the standard PGE2 agonist. For each compound, the maximum response and the concentration of the compound causing 50% of its maximum response were calculated. Intrinsic activity is expressed in relation to the maximum response to PGE2. Unless otherwise indicated, all reagents were purchased commercially from Sigma. The Examples of the present invention were tested in the aforementioned assay and presented an average of the pEC50 values of 6.8 or higher, and a mean of the intrinsic activities of 50% or higher. For example, Example 9 had a mean value of pEC50 of 7.4 and an average intrinsic activity of 68% when tested in the above-mentioned assay (n = 24).

In vivo test - Effect of the acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} acetic acid ('Example 9') in an association with ED2o and a fixed dose association with paracetamol on the FCA-induced hypersensitivity in the rat Objective of the study To determine whether combining Example 9 and acetaminophen at dose ED20 or as a fixed dose association will produce synergy in reducing the hypersensitivity induced by established ACF.

Methods FCA and reading of the weight carp • At the beginning of the study, the readings of the weight loads without treatment were taken. Hypersensitivity to pain was measured using the incapacitance analyzer in the rat (Linton Instruments). • All the male rats (strain RH, 180-120 g) then received an intraplantar injection of 100 μ? of FCA (Freund's complete adjuvant) in the left hind leg. The FCA had been sonicated for 15 minutes before use. • 24 hours after the administration of the FCA, the pre-treatment readings of the weight loads were taken. All the animals were then sorted and randomly distributed for treatment according to their FCA interval (difference in grams in the pretreatment - difference in grams without treatment). Rats with an ACF interval less than 30 were excluded from the study. • The animals were then orally dosed according to their classification and random distribution. Two studies were conducted as follows: • In the first study the ED2o doses of Example 9 and paracetamol were associated using the following protocol, (1) Vehicle (1% methylcellulose) p.o. (2) Paracetamol (60 mg / kg) po * (3) Example 9 (0.1 mg / kg) po * (4) Example 9 (0.1 mg / kg) + Paracetamol (60 mg / kg) po ** (5) Celecoxib (10 mg / kg) po * ED2o dose ** Example 9 was initially administered followed by paracetamol 30 minutes later.

In the second study an association was completed with a fixed dose ratio, of Example 9 and paracetamol using the following protocol, (1) Vehicle (1% methylcellulose) p.o. + Vehicle (1% methylcellulose) p.o. (2) Example 9, 0.003 mg / kg p.o. + Paracetamol, 1.8 mg / kg p.o. (3) Example 9, 0.01 mg / kg p.o. + Paracetamol, 6 mg / kg p.o. (4) Example 9, 0.03 mg / kg p.o. + Paracetamol, 18 mg / kg p.o. (5) Example 9, 0.1 mg / kg p.o. + Paracetamol, 60 mg / kg p.o. (6) Vehicle (1% methylcellulose) p.o. + Celecoxib, 10 mg / kg p.o. The animals were evaluated in the weight-bearing apparatus 1 hour after the administration of the dose of paracetamol. The study was blinded and randomized using the FCA interval using a Latin square method.

Preparation details • All the compounds were crushed using a mortar with their hand before adding to the vehicle (1% methylcellulose). The dose volume was 5 ml / kg. • All doses were sonicated and shaken before administration. • In this study, a positive control (Celecoxib) was also tested. If the positive control did not produce a significant reduction of the FCA-induced hypersensitivity (> 60%) the experiment was not considered valid and the study was repeated.

Statistical analysis •% of reductions were calculated using the values without treatment, pre-treatment and post-treatment as follows:% reduction = [(pre-treatment - post-treatment) / (pre-treatment - no treatment)] x 100.

• Graphics and ED50 values were calculated using Prism3. • The statistical analysis was carried out using ANOVA and the Fischer LSD test of the statistical program Statistica 6.

• Synergy was calculated statistically using the synergy macro. The logED50 values and errors Standards for the study of the individual molecules and the association are obtained with Statistica 6 and put in the macro. The fixed dose ratio is specified and then the macro calculates whether the association is statistically synergistic. Compare the data of the association with the theoretical addition of the individual compounds.

Results Percentage of the reduction in hypersensitivity induced by established ACF: Significant activity was demonstrated. The reduction of hypersensitivity equivalent to a dose of maximum efficacy of celecoxib occurred with associations of low doses of Example 9 and paracetamol which are ineffective when administered alone (Figure 1). It has been shown that the observed effect is synergistic in nature (Figure 2). When administered alone at 3 mg / kg in the same model, Example 9 has an EC50 of 0.6 μ? and advantageously produced an 80% reduction in hypersensitivity induced by eFCA. Example 9 also exhibited an oral pharmacokinetic half-life of 7.6 hours in the rat.

Figure 1 illustrates the effect of combining Example 9 (0.1 mg / kg) and paracetamol (60 mg / kg) alone and in association on FCA-induced hypersensitivity. Figure 2 illustrates a theoretical additive dose-response curve against the actual dose-response curve observed for an association of Example 9 + paracetamol.

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS 1 .- A compound of the formula (I) or one of its pharmaceutically acceptable derivatives, (I) wherein, R1 and R2 independently represent alkyl of d. 4; R3, R4, R5 and R6 independently represent H or F, with the proviso that at least one of R3 and R4 represents H, at least one of R5 and R6 represents H, and at least one of R3, R4, R5 and R6 represents F; and X and Y independently represent CH2 or C = O, with the proviso that at least one of X and Y represents C = O.
2. 2. The compound of the formula (I), according to claim 1, further characterized in that R and R2 are the same and represent C-4 alkyl. 3. - The compound of the formula (I), according to claim 1, further characterized in that R1 and R2 are independently selected from the group consisting of ethyl, n-propyl and / so-propyl. 4. The compound of the formula (I), according to any of claims 1 to 3, further characterized in that both X and Y represent C = 0. 5. The compound of the formula (I), according to any of the preceding claims, further characterized in that R3 represents F and R4, R5 and R6 represent H. 6.- The compound of the formula (I), in accordance with any of claims 1 to 4, further characterized in that R4 represents F and R3, R5 and R6 represent H. 7. The compound of the formula (I), according to any of claims 1 to 4, further characterized in that R3 and R5 represent F and R4 and R6 represent H. 8. The compound according to claim 1, of the formula (IA), or one of its pharmaceutically acceptable derivatives, (IA) wherein, R 1 and R 2 independently represent C 1 -alkyl.; R3 and R4 independently represent H or F, with the proviso that they are not equal; and X and Y independently represent CH2 or C = O, with the proviso that at least one of X and Y represents C = O. 9. The compound of the formula (I), according to claim 1, selected from the group consisting of: acid. { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dhydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [1,3-dioxo-4,9-bis (propyloxy) -1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [4,9-bis (1-methylethoxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [fjisoindol-2-yl] -2-fluorophenyl} -acetic; acid { 2-fluoro-4- [1 -oxo-4, 9-bis (propyloxy) -1,3-dihydro-2H-benzo [f] isoindol-2-yl] phenyl} -acetic; acid { 4- [4,9-bis (1-methylethoxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic; acid { 3-fluoro-4- [1 -oxo-4, 9-bis (propyloxy) -1,3-dihydro-2H-benzo [f] isoindol-2-yl] phenyl} -acetic; and acid. { 4- [4,9-bis (1-methylethoxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3-fluorophenyl} -acetic; acid { 4- [4,9-bis (ethyloxy) -1,3-dioxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -3,5-difluorophenyl} -acetic; acid { 4- [4,9-bis (ethyloxy) -1 -oxo-, 3-dihydro-2H-benzo [f] isoindol-2-yl] -3,5-difluorophenyl} -acetic; or one of its pharmaceutically acceptable derivatives. 10.- The acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic, or one of its pharmaceutically acceptable derivatives. 1 1 .- A procedure to prepare a compound of the formula (I) or one of its pharmaceutically acceptable derivatives according to claim 1, wherein one of X and Y represents C = O and the other represents CH2 and R1, R2, R3, R4, R5 and R6 are as defined in claim 1, which process comprises reacting a compound of the formula (II), (II) wherein, one of X and Y represents C = O and the other represents CH2; R1, R2, R3, R4, R5 and R6 are as defined in relation to formula (I); and R7 represents alkyl of d.6; with a suitable base, and optionally then forming a pharmaceutically acceptable derivative of the compound thus formed, and / or converting a compound of the formula (I) into another. 12. - A process for preparing a compound of the formula (I) or one of its pharmaceutically acceptable derivatives, in accordance with the claim 1, further characterized in that X and Y represent C = O and R1, R2, R3, R4, R5 and R6 are as defined in claim 1, The process comprises adding a compound of the formula (III), (III) wherein, R1, R2, R3, R4, R5 and R6 are as defined in claim 1; and R7 represents C- | 6 alkyl; to a suitable acid or mixture of acids, and optionally then forming a derivative pharmaceutically acceptable compound of the compound thus formed, and / or convert a composed of the formula (I) in another. 13. - A process for preparing a compound of the formula (I) or one of its pharmaceutically acceptable derivatives, in accordance with the claim 1, which method comprises reacting a compound of the formula (3), (IV) wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 1, and R 'represents H or Ci_6 alkyl, and optionally then forming a pharmaceutically acceptable derivative of the compound thus formed, and / or converting a compound of the formula (I) into another. 14. A process for preparing a compound of the formula (I) or a pharmaceutically acceptable derivative thereof, according to claim 1, which process comprises reacting a compound of the formula (4), (4) with a compound of the formula (IV), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 1, and R 'represents H or C6 alkyl, and optionally then form a pharmaceutically acceptable derivative of the compound thus formed, and / or converting a compound of the formula (I) into another. 15. A compound of the formula (I), according to claim 1, for use in human or veterinary medicine. 16. A compound of the formula (I), according to claim 1, for use in the treatment of a disease that is mediated by the action, or loss of action, of the PGE2 at the EP4 receptors. 17. - The use of a compound of the formula (I), as claimed in claim 1, for the manufacture of a medicament useful for the treatment of a disease that is mediated by the action, or loss of action, of the PGE2 in EP4 receivers. 18. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof according to claim 1, and a pharmaceutically acceptable excipient or diluent thereof. 19. - The pharmaceutical composition according to claim 17, further characterized in that it comprises one or more additional therapeutic agents. 20. An association comprising an EP4 receptor agonist or one of its pharmaceutically acceptable derivatives and paracetamol. twenty-one . An association comprising a compound of the formula (I) or one of its pharmaceutically acceptable derivatives according to claim 1, and paracetamol. 22. The association according to claim 20, further characterized in that it comprises acid. { 4- [4,9-bis (ethyloxy) -1 -oxo-1,3-dihydro-2H-benzo [f] isoindol-2-yl] -2-fluorophenyl} -acetic or one of its pharmaceutically acceptable derivatives and paracetamol.