MXPA05001534A - Therapeutic use of aryl amino acid derivatives. - Google Patents

Abstract

The compounds of formula (I) are useful in the treatment of faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, neuropathological disorders and sleep disorders. Processes for the preparation of the final products and intermediates useful in the process are included. Pharmaceutical compositions containing one or more of the compounds are also included.

Description

THERAPEUTIC USE OF ARILO DERIVATIVES OF AMINO ACIDS This invention relates to new aryl derivatives of amino acids useful as pharmaceutical agents, to processes for their production, to pharmaceutical compositions containing them and to their use for the treatment of the disease states mentioned below.

BACKGROUND OF THE INVENTION Gabapentin (Neurontin®) is an anticonvulsant agent that is useful in the treatment of epilepsy and has recently been shown to be a possible treatment for neurogenic pain. It is l- (aminomethyl) -cyclohexylacetic acid of structural formula: Gabapentin is one of a series of compounds of formula H2 ^^ < ^ C02R (CH2) n in which R is hydrogen or a lower alkyl radical and n is 4, 5 or 6. These compounds are described in US-A-4024175 and its divisional patent US-A-4087544. Its described uses are: protection against cramps induced by thiosemicarbazide; protection against cardiazol cramps; brain diseases, epilepsy, fainting, hypokinesia and cranial trauma; and improve brain functions. The compounds are useful in geriatric patients. The descriptions of the two prior patents are incorporated herein by reference. WO 95/31 194, the disclosure of which is incorporated herein by reference, discloses aminobenzoic acid derivatives and analogs of formula (A) where n = 0-10; R = H, OH, C1-10 alkoxy, Ci-10 aminoalkyl, S03H, C- -I alkyl; R, R2 = H, OH, Me and its salts, esters and amides, in combination with another medicament for the treatment of inflammation, useful for the clinical treatment of chronic inflammatory diseases including arthritis, ileitis and colitis and other inflammatory disorders, as well as traumatisms derived from ischemia and the consequent reperfusion.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides aryl derivatives of amino acids and their prodrugs, and pharmaceutically acceptable salts and solvates useful in the treatment of a variety of disorders including fainting, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, sleep and neuropathological disorders. The compounds provided may also be useful in the treatment of premenopausal syndrome. Thus, the invention provides the use of compounds of formula (I) or one of its pharmaceutically acceptable salts in the manufacture of a medicament for the treatment of a disease selected from fainting, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, sleep disorders and neuropathological disorders: Formula (I) wherein R1 is H, Ci-C6 alkyl or C3-C8 cycloalkyl; X is - (CH2) n-C (R7) (R8) -; And it is a direct bond or - (CH2) m-C (R) (R10) -; R7, R8, R9 and R10 are, independently, H or Ci-C6 alkyl; or R8 and R1 may be taken together with the nitrogen to which R1 is attached to form a 4- to 8-membered heterocycloalkyl ring; or R 10 and R can be taken together with the nitrogen to which R 1 is attached by forming a 4 to 8 membered heterocycloalkyl ring; or R8 and R10 can be taken together with the carbons to which they are attached forming a carbocyclic ring of 4 to 8 members; n is 0.1 or 2; m is 0, 1 or 2; R2, R3, R4 and R5 are independently selected from H, alkyl C1-C6, Ci-C6 alkoxy, hydroxy, halogen, hydroxycarbonyl, d-C6 alkoxycarbonyl, cyano, sulphonyl, (Ci-C6 alkyl) sulfonyl, thio, (Ci-Ce alkyl) thio, sulfonamide, perfluoro (C 1 - alkyl) Ce,), perfluoro (C-pCe alkoxy), C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl, amino, (Ci-C6 alkyl or C6-dialkyl) amino, aminocarbonyl, (C1-C6 alkyl or CrC6 dialkyl) aminocarbonyl , acylamino CrC6, (N-alkyl CrC6) acylamino C C6, phenyl or monocyclic heteroaryl, monocyclic phenyl and heteroaryl being optionally substituted by C- | -C6 alkyl, Ci-C6 alkoxy] hydroxy, halogen, hydroxycarbonyl, C- | - alkoxycarbonyl C6 or C1-C6 perfluoroalkoxy; or any one or two of CR2, CR3, CR4 and CR5 may be replaced with a nitrogen; or R2 and R3 or R3 and R4 or R4 and R5 can be taken together with the carbon atoms to which they are attached by forming a fused C5-C-8 cycloalkyl ring, 4- to 8-membered heterocycloalkyl, phenyl or monocyclic heteroaryl; or R1 and R2 can be taken together with the nitrogen to which R1 is attached to form a 4 to 8 membered heterocycloalkyl ring; or R8 and R2 may be taken together with the carbon atoms to which they are attached to form a carbocyclic ring or 4 to 8 membered heterocycloalkyl; and R6 is hydroxycarbonyl or a carboxylic acid bioster or one of its prodrugs. According to formula (I), R1 is, appropriately, H. According to formula (I), Y is, appropriately, a direct link. According to formula (I), X is, suitably -C (R7) (R8) -, or R7 is, suitably H and R8 is, suitably H or Ci-C6 alkyl, for example, methyl, or R8 and R2 suitably form a 4- to 8-membered carbocyclic ring, preferably a 5-membered carbocyclic ring, for example, cyclopentyl or R8 and R1 suitably form a 4- to 8-membered heterocycloalkyl ring, preferably a 5-membered heterocycloalkyl ring , for example, a tetrahydropyran ring. According to formula (I), R2, R3, R4 and R5 are independently selected, suitably, from H and halogen, for example, bromine or chlorine. According to formula (I), R6 is preferably hydroxycarbonyl, tetrazole or oxazolidinone, most preferably hydroxycarbonyl. A preferred subgroup according to the present invention is represented by a compound of formula (II): Formula (II) wherein R7 and R8 are independently H or C 1 -C 6 alkyl, and R 2, R 3, R 4 and R 5 are independently selected from H, alkyl Ci-C6, Ci-C6 alkoxy, hydroxy, halogen, hydroxycarbonyl, C6 alkoxycarbonyl, cyano, (CrC6 alkyl) sulfonyl, perfluoroC1-C6 perfluoroalkyl, CrC6 perfluoroalkoxy, C3-C8 cycloalkyl and 4 to 8 membered heterocycloalkyl; or R8 and R2 can be taken together with the carbon atoms to which they are attached to form a carbocyclic or heterocycloalkyl ring of 4 to 8 members. Particularly preferred examples of the compounds of formula (I) are; 2-aminomethyl-5-chloro-benzoic acid; 2-aminomethyl-4,5-dichloro-benzoic acid; 2-aminomethyl-3-bromo-benzoic acid; 2-aminomethyl-6-chloro-benzoic acid; 2- (1-aminoethyl) -benzoic acid; 2,3-dihydro-1 H-isoindol-4-carboxylic acid; and 3- (2-aminomethyl-5-chloro-phenyl) -4H- [1, 2,4] oxadiazol-5-one; or one of its pharmaceutically acceptable salts.

It will be appreciated that certain compounds of formula (I) are new and these compounds, or one of their pharmaceutically acceptable salts, solvates, polymorphs or prodrugs, form a further aspect of the present invention. The invention also relates to pharmaceutical compositions comprising the compounds and their use as a medicament. In the above definitions, halo means fluoro, chloro, bromo or iodo. Alkyl and alkoxy, groups containing the necessary number of carbon atoms, except where indicated, may be unbranched or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Example alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. 4- to 8-membered heterocycloalkyl, when used herein refers to a saturated or partially unsaturated single ring system containing at least one ring heteroatom selected independently from O, S and N. Suitable heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl , dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, , 3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 2-tetrahydrodiazin-2-yl, 1, 3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl and the like.

"Monocyclic heteroaryl", when used herein, refers to a simple aromatic ring containing at least one ring heteroatom selected independently of O, S and N. Suitable heteroaryl groups include furyl, thienyl, thiazoyl, pyrazolyl, isothiazolyl, oxazolyl, soxazolyl, pyrrolyl, triazolyl, tetrazolyl, midazolyl, 1, 3,5-oxadiazolyl, 1,4-oxadiazolyl, 1,3-oxadiazolyl, 1, 3,5-thiadiazolyl 1,2,3-thiadiazolyl, 1,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl and the like . C3-C8 cycloalkyl, as used herein, refers to a single saturated or partially unsaturated carbocyclic ring. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. "Carboxylic acid biosteroid," when used herein, refers to a group functionally equivalent to a carboxylic acid. Suitable bioisosters include tetrazolyl, oxazolidinonyl, sulfonic acid, sulfinic acid, phosphoric acid, phosphinic acid, hydantoinyl, pyrrolidionyl and 3-isoxazolyl. The present compounds can exist in unsolvated forms, as well as in solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, which may contain isotopic substitutions (eg, D20, d6-acetone, d6-DMSO) are equivalent to unsolvated forms and are included in the scope of the present invention.

Some of the compounds of the present invention possess one or more chiral centers and each center may exist in the R (D) or S (L) configuration. The present invention includes all enantiomeric and epimeric forms, as well as appropriate mixtures thereof. The separation of diastereoisomers or of cis and trans isomers can be achieved by conventional techniques, for example, by fractional crystallization, chromatography or HPLC of a mixture of stereoisomers of a compound of the invention or a suitable salt or derivative thereof. A single enantiomer of a compound of the invention can also be prepared from the corresponding optically pure intermediate or by resolution, such as by HPLC of the corresponding racemate using a suitable chiral support or by fractional crystallization of the diastereomeric salts formed by reaction of the corresponding racemate. with an appropriate optically active acid or base as appropriate. The present invention also includes all suitable isotopic variations of a compound of the invention or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as that in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 170, 180 , 3 P, 32 P, 35 S, 18 F and 36 C, respectively. Certain isotopic variations of the compounds of the invention and their pharmaceutically acceptable salts, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in studies of drug distribution and / or substrate tissues. The isotopes of tritium, i.e., 3H, and carbon 14, i.e., 4C, are particularly preferred for their ease of preparation and detection. In addition, substitution with isotopes such as deuterium, i.e., H, can provide certain therapeutic advantages derived from increased metabolic stability, eg, increased in vivo half-life or lower dosage requirements and, therefore, preferred in some circumstances. The isotopic variations of the compounds of the invention and the pharmaceutically acceptable salts of this invention can be prepared generally by conventional methods such as by the illustrative methods or by the preparations described in the Examples and Preparations below, using isotopic variations of the suitable reactants. Since the amino acids are amphoteric, pharmacologically compatible salts can be salts of appropriate non-toxic inorganic acids or bases. Suitable acid addition salts are the hydrochloride / chloride, hydrobromide / bromide, iodide / iodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, fumarate, aspartate, besylate, bicarbonate / carbonate, camsylate, D and L-lactate salts , D and L-tartrate, edisilate, mesylate, malonate, orotate, gluceptate, methylsulfate, stearate, glucuronate, 2-napsylate, tosylate, hybienate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, saccharate, benzoate, esylate and pamoato. Suitable base salts are formed from bases which form non-toxic salts and are examples of sodium, potassium, aluminum, calcium, magnesium, zinc, choline, diolamine, olamine, arginine, glycine, tromethamine, benzathine, lysine, meglumine salts. and diethylamine. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyoammonium ion. The compounds of the invention can also be formed as bipolar ions. A suitable salt of compounds of the present invention is the hydrochloride salt. A review of suitable salts can be found in Berge et al. J. Pharm. ScL, 66,1-19,1977. Also included in the present scope of the compounds of the invention are the polymorphs thereof. Prodrugs of the above compounds are included in the scope of the present invention. The efficacy of a drug administered orally depends on the efficient transport of the drug through the mucosal epithelium and its stability in the enterohepatic circulation. Drugs that are effective after parenteral administration but less effective orally, or whose half-life in plasma is considered too short, can be chemically modified to a prodrug form. A prodrug is a drug that has been chemically modified or may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other processes in vivo to the main bioactive form. This chemically modified drug, or prodrug, will have a pharmacokinetic profile different from the main compound, allowing easier absorption through the mucosal epithelium, a better formulation in the form of salt and / or solubility, better crystalline stability (to increase plasma half-life , for example). These chemical modifications can be (1) Ester or amide derivatives which can be cleaved, for example, by esterases or lipases. For the ester derivatives, the ester is obtained from the carboxylic acid moiety of the drug molecule by known means. For amide derivatives, the amide can be obtained from the carboxylic acid moiety or the amine moiety of the drug molecule by known means. (2) Peptides that can be recognized by specific or non-specific proteinases. A peptide can be coupled to the drug molecule by forming an amide linkage with the amine or carboxylic acid moiety of the drug molecule by known means. (3) Derivatives that accumulate in a site of action by membrane selection in a prodrug form or modified prodrug form. (4) Any combination of 1 to 3. It will be appreciated by those skilled in the art that certain residues known to those skilled in the art as "prorests", for example, as described in "Design of Prodrugs" by H Bundgaard (Elsevier ) 1985, can be placed in appropriate functional groups when such functional groups are present in compounds of the invention also forming a "prodrug". In addition, certain compounds of the invention can act as prodrugs of other compounds of the invention. All protected denudates and prodrugs of the compounds of the invention are included in the scope of the invention. Research has shown that the oral absorption of certain drugs can be increased by the preparation of "soft" quaternary salts. Quaternary salt is called a "soft" quaternary salt since, unlike normal quaternary salts, for example, R-N + (CH3) 3, it can release the active drug when hydrolyzed. The "soft" quaternary salts have useful physical properties compared to the basic drug or its salts. The solubility in water can be increased compared to other salts, such as the hydrochloride, but more importantly, there can be greater absorption of drug from the intestine. The greater absorption is possibly due to the fact that the "soft" quaternary salts have surfactant properties and are capable of forming micelles and un ionized ion pairs with bile acids and the like which can penetrate the intestinal epithelium more efficiently. The prodrug, after absorption, is rapidly hydrolysed with release of the active major drug. Aminoacyl-glycolic and lactic esters are known as amino acid prodrugs (Wermuth C.G., Chemistry and Industry, 1980: 433-435). The carbonyl group of the amino acids can be esterified by known means. Prodrugs and soft drugs are known in the art (Palomino E., Drugs of the Future, 1990; 15 (4): 361-368). The last two citations are incorporated herein by reference. The invention also relates to the therapeutic use of the present compounds as agents for treating or alleviating the symptoms of neurodegenerative disorders. Such neurodegenerative disorders include, for example, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. The present invention also covers the treatment of neurodegenerative disorders called acute brain injury. This includes, but is not limited to: cranial trauma and asphyxia. Other incidents are head injury, spinal cord injury or injury from general hypoxia, hypoxia, hypoglycaemia, hypotension, as well as similar injuries seen during embolism, hyperfusion, and hypoxia procedures. The present invention will be useful in a variety of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia and in cardiac arrest. The compounds of the invention are also useful for the treatment of acute and chronic pain. Acute pain is usually of short duration and is associated with hyperactivity of the sympathetic nervous system. Examples are postoperative pain, such as after a tooth extraction, migraine, headache, trigeminal neuralgia and allodynia. Chronic pain is usually defined as pain that lasts from 3 to 6 months and includes somatogenic pain and psychogenic pain. Examples of chronic pain include pain associated with musculoskeletal disorders such as fibromyalgia, ankylosing spondylitis, seronegative (non-rheumatoid) arthropathies, non-articular rheumatism and periarticular disorders and pain associated with cancer, peripheral neuropathy and postherpetic neuralgia. Another pain is nociceptive. Another pain is caused by injury or infection of the peripheral sensory nerves. It includes, although it is not limited to them, pain due to peripheral nervous trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation and vasculitis. Neuropathic pain is also caused by nerve damage resulting from chronic alcoholism, infection by human immunodeficiency virus, hypothyroidism, uremia or vitamin deficiencies. Neuropathic pain includes, but is not limited to, pain caused by nerve injury such as, for example, diabetic pain, psychogenic pain that occurs without an organic origin such as low back pain, atypical facial pain and chronic headaches. Other types of pain are: trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legs syndrome, acute herpetic and postherpetic neuralgia, causalgia, brachial plexus avulsion, occipital neuralgia, gout, phantom limb, burns and other forms of neuralgia, neuropathy and idiopathic pain syndrome. The compounds of formula (I) are preferably used for the treatment of neuropathic pain.

The compounds of the invention are expected to be useful in the treatment of depression. Depression can be the result of organic disease, secondary to stress associated with personal loss or of idiopathic origin. There is a strong tendency to the familiar appearance of some forms of depression that suggest a metabolic cause for at least certain forms of depression. The diagnosis of depression is mainly made by quantifying the alterations in the mood of the patient. These mood assessments are usually carried out by a physician or quantified by a neuropsychologist using validated rating scales, such as the Hamilton Depression Rating Scale or the Summary Psychiatric Rating Scale. Numerous additional scales have been developed to quantify and measure the degree of mood alterations in patients with depression, such as insomnia, difficulty concentrating, lack of energy, feelings of worthlessness and guilt. The norms for the diagnosis of depression as well as the psychiatric diagnosis are included in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) cited as DSM. As an alternative aspect of the invention, there is provided a method for treating a disease selected from fainting, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, sleep disorders and neuropathological disorders, comprising administering a therapeutically amount effective of a compound of formula (I) to a mammal in need of said treatment. The biological activity of the compounds of the invention can be measured in a radioligand binding assay using [3H] gabapentin and the c¾¾ subunit derived from porcine brain tissue (Gee NS, Brown JP, Dissanayake VUK, Offord J., Thurlow R ., Woodruff GN, J. Biol. Chem., 1996; 271: 5776-5879). The results can be expressed in terms of μ? or nM binding affinity The compounds of the present invention can be administered in combination, either separately, simultaneously or sequentially, with one or more other pharmacologically active agents. Suitable agents, in particular for the treatment of neuropathic pain include: (i) opioid analgesics, for example, morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorfan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine; (ii) non-steroidal anti-inflammatory drugs (NSAIDs), for example, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, buprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin , phenylbutazone, piroxicam, sulindac, tolmetin, zomepyra and its pharmaceutically acceptable salts; (iii) barbiturate sedatives, for example, amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, teamilal, thiopental and their pharmaceutically acceptable salts; (V) benzodiazepines having sedative action, for example, chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts; (v) Hi antagonists with sedative action, for example, diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts; (vi) various sedatives such as glutethimide, meprobamate, metaqualone, dichloralphenazone and their pharmaceutically acceptable salts; Skeletal muscle relaxants, for example, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orfrenadine and their pharmaceutically acceptable salts; (vii) NMDA receptor antagonists, for example, dextromethorphan ((+) - 3-hydroxy-N-methylmorphinan) and its metabolite dextrorphan ((+) - 3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone and cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid and their pharmaceutically acceptable salts; (viii) active alpha-adrenergic compounds, for example, doxazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1, 2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline; (ix) tricyclic antidepressants, for example, desipramine, imipramine, amitriptyline and nortriptyline; (x) anticonvulsants, for example, carbamazepine, gabapentin, pregabalin and valproate; (xi) serotonin reuptake inhibitors, eg, fluoxetine, paroxetine, citalopram and sertraline; (xii) mixed inhibitors of serotonin-noradrenaline reuptake, eg, milnacipran, venlafaxine and duloxetine; noradrenaline reuptake inhibitors, for example, reboxetine; (xiii) tachykinin (NK) antagonists, in particular NK-3, NK-2 and NK-1, for example, antagonists (aR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8, 9 0 1-tetrahydro-9-methyl-5- (4-methyl-phenyl) -7H- [1,4] diazocino [2 g] [1,7] naphthyridine-6-13-dione (TAK-637), 5- [[(2R, 3S) -2 - [(1 R) -1- [3,5-bis (trifluoromethyl] pheny1] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] methyl] -1, 2-dihydro-3H, 2,4-triazol-3-one (MK-869), lanepitant, dapitant and 3 - [[2-methoxy-5- (trifluoromethoxy) phenyl] methylamino] -2-phenyl-piperidine (2S , 3S) (xiv) muscarinic antagonists, for example, oxybutyn, tolterodine, propiverine, tropsium chloride and darifenacin; (xv) PDEV inhibitors such as sildenafil, vardenafil and Cialis ™; (xvi) COX-2 inhibitors, for example, celecoxib, rofecoxib and valdecoxib; (xvii) non-selective COX inhibitors (preferably with Gl protection), for example, nitroflurbiprofen (HCT-1026); (xviii) analgesics Coaltar (or coal tar), in particular, acetaminophen; (xix) neuroleptics, such as droperidol; (xx) vanilloid receptor antagonists, for example, resinferatoxin; (xxi) beta-adrenergic compounds such as propranolol; (xxii) local anesthetics such as mexiletine; (xxiii) corticosteroids such as dexamethasone (xxiv) agonists and serotonin receptor antagonists; cholinergic (nicotinic) analgesics and (xxv) various agents such as Tramadol®. Combinations of the compounds of the present invention and other therapeutic agents can be administered separately, sequentially or simultaneously. Thus, the present invention extends to a kit comprising a compound of formula (I), one or more other therapeutic agents, such as those listed above, and a suitable container. The compounds of formula (I) can be administered alone although, in general, they will be administered in admixture with suitable excipient (s), diluent (s) or pharmaceutical carrier (s) selected with respect to the desired route of administration and pharmaceutical practice. conventional. If appropriate, auxiliary materials can be added. The auxiliary materials are preservatives, antioxidants, flavorings or colorants. The compounds of the invention can be administered in a composition of the immediate, delayed, modified, sustained, pulsatile or controlled release type. The compounds of formula (I) can be administered, for example, but without being limited thereto, by the following routes: oral, buccal or sublingual in the form of tablets, capsules, in the form of multi-and nanoparticles, gels, films (including mucoadhesives), powders, ovules, elixirs, tablets (including liquid-filled ones), gums, solutions, suspensions and sprays. The compounds of formula (I) can also be administered as an osmotic dosage form, or in the form of a high energy dispersion or as coated or rapidly dissolving particles, rapid disintegrating dosage forms as described in Ashley Publications, 2001 by Liang and Chen. The compounds of formula (I) can be administered as crystalline or amorphous, freeze-dried or spray-dried products. Suitable formulations of the compounds of formula (I) may be in a hydrophilic or hydrophobic matrix, an ion exchange resin complex, in coated or uncoated form and in other types as described in US 6,106,864 as desired . Such pharmaceutical compositions, for example tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn starch, potato or tapioca), mannitol, disintegrants such as sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), triglycerides, hydroxypropylcellulose (HPC), bentonite sucrose, sorbitol, gelatin and gum arabic. In addition, lubricating agents can be added to solid compositions such as magnesium stearate, stearic acid, glyceryl behenate, PEG and talc, or wetting agents, such as sodium lauryl sulfate. In addition, polymers such as carbohydrates, phospholipids and proteins can be used. The dispersion or rapid dissolution (FDDF) dosage formulations may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavor, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol or xylitol. The terms dispersion or dissolution, as used herein to describe FDDF, depend on the solubility of the pharmacological substance used, ie, when the drug substance is insoluble, a fast dispersing dosage form can be prepared and when the Pharmacological substance is soluble a fast dissolving dosage form can be prepared. The solid dosage form, such as tablets, is manufactured by a conventional process, for example, by direct compression or in a wet, dry or melt granulation process, by melt-freezing or by extrusion. The tablet cores, which may be mono or multi-stratified may be coated with appropriate coverage layers known in the art. Solid compositions of a similar type can be employed as fillers in gelatin capsules such as gelatin capsules, starch or HPMC. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. Liquid compositions can be employed as fillers in hard or soft capsules such as gelatin capsules. For aqueous or oily suspensions, solutions, syrups and / or elixirs, the compounds of the invention can be combined with various sweetening or flavoring agents, coloring materials or pigments, with emulsifying and / or suspending agents and with diluents such as water, ethanol , propylene glycol, methylcellulose, alginic acid or sodium alginate, glycerin, hydrocolloid agents and combinations thereof. On the other hand, formulations containing these compounds and excipients may be presented as a dry product for constitution with water or other suitable vehicle before use. Liquid form preparations include solutions, suspensions and emulsions, for example, solutions in water or aqueous propylene glycol. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. The compounds for use in the present invention can also be administered by injection, i.e., intravenously, intramuscular, intracutaneous, intraduodenal or intraperitoneal, intraarterial, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramedullary or subcutaneous, or can be administered by infusion, needleless injectors or implant injection techniques. For such parenteral administration, these are best used in the form of a solution, suspension, emulsion or sterile system (including micelles), which may contain other substances known in the art, for example, salts or sufficient carbohydrates such as glucose to make the solution isotonic with blood The aqueous solutions can be suitably buffered (preferably at a pH of 3 to 9) if necessary. For some forms of parenteral administration, these may be used in the form of a non-aqueous sterile system such as fixed oils, including mono- or diglycerides and fatty acids, including oleic acid. The preparation of suitable parenteral formulations under sterile conditions, for example lyophilization, is carried out in a simple manner by conventional pharmaceutical techniques well known to those skilled in the art. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use. In addition, the compounds of the present invention can be administered intranasally or by inhalation. These are conveniently released in the form of a dry powder (alone or as a mixture, for example, a dry mixture with lactose, or a mixed component particle, for example, with phospholipids) from a dry powder inhaler or an aerosol spray presentation. of a pressurized container, pump, sprayer, atomizer (preferably an atomizer using the electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1, 1, 1, 2, -tetrafluoroethane (HFA 134A ™) or 1, 1, 1, 2,3,3,3, -heptafluoropropane (HFA 227E ™), carbon dioxide, other perfluorinated hydrocarbon such as Perflubron ™ or another suitable gas. In the case of a pressurized aerosol, the dose unit can be determined by providing a valve that releases a measured quantity. The pressurized container, pump, sprayer, atomizer or nebulizer may contain a solution or suspension of the active compound, for example, using a mixture of ethanol (optionally aqueous ethanol) or a suitable agent to disperse, solubilize or prolong the release and propellant. as a solvent, which may also contain a lubricant, for example sorbitan trioleate. Capsules, blister packs and cartridges (made, for example, in gelatin or HPMC) can be formulated for use in an inhaler or insufflator containing a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a behavioral modifier such as l-leucine, mannitol or magnesium stearate. Before use in a dry powder formulation or suspension formulation for inhalation, the compound for use in the invention will be micronized to a suitable size to be released by inhalation (typically considered to be less than 5 micrometers). Micronization can be achieved by a series of processes, for example, spiral jet milling, fluid bed jet milling, use of crystallization in supercritical fluids or by spray drying. A solution formulation suitable for use in an atomizer that uses electrohydrodynamics to produce a fine mist may contain from 1 μg to 10 mg of the compound for use in the invention by actuation and the actuation volume may vary from 1 μ? at 100 μ ?. A typical formulation may comprise a compound for use in this invention, propylene glycol, sterile water, ethanol and sodium chloride. Other solvents can be used instead of propylene glycol, for example, glycerol or polyethylene glycol. Alternatively, the compounds for use in the invention can be administered topically on the skin, mucosa, dermally or transdermally, for example, in the form of a gel, hydrogel, lotion, solution, cream, ointment, extemporaneously applied powder, apposite, foam, film, skin patch, wafers, implant, sponge, fibers, bandages, microemulsions and combinations thereof. For such applications, the compounds for use in the invention may be suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene-polyoxypropylene compound, emulsifying wax , fixed oils, including synthetic mono- or diglycerides and fatty acids, including oleic acid, water, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, ethanol. Alternatively penetration enhancers may be used. The following can also be used: polymers, carbohydrates, proteins, phospholipids in the form of nanoparticles (such as niosomes or liposomes) or suspended or dissolved. In addition, these can be released using iontophoresis, electroporation, phonophoresis and sonophoresis. Alternatively, the compounds for use in the invention can be administered rectally, for example, in the form of a suppository or pessary. These are also administered vaginally. For example, although not limited to the following presentations, these compositions can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at normal temperatures but which liquefy and / or dissolve in the cavity releasing the drug.

The compounds of the invention can also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in sterile saline with adjusted pH or, preferably, as solutions in isotonic saline with adjusted pH. A polymer such as crosslinked poly (acrylic acid), polyvinyl alcohol, hyaluronic acid, a cellulosic polymer (e.g., hydroxypropylmethyl cellulose, hydroxyethylcellulose, methyl cellulose), or a heteropolysaccharide polymer (e.g., gelatin gum) may be added. . Alternatively, they can be formulated into an ointment such as petrolatum or mineral oil, incorporated into degradable implants (for example silicon), wafers, drops, lenses or released through particulate or vesicular systems such as niosomes or liposomes. The formulations may optionally be combined with a preservative such as benzalkonium chloride. They can also be released using iontophoresis. These can also be administered in the ear, using for example, but without being limited to the same, drops. The compounds of the invention can also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. The formation of a drug-cyclodextrin complex can modify the solubility, rate of dissolution, mask the taste, bioavailability and / or stability of a drug molecule. The drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiy additive, for example, as a carrier, diluent or solubilizer. Alpha-, beta- and gamma-cyclodextrins are the most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148. The term "administered" includes the release by viral or non-viral techniques. Viral delivery mechanisms include, but are not limited to, adenoviral vectors, adeno-associated viral vectors (AAV), herpes virus vectors, retroviral vectors, lentivirus vectors, and vaculovirus vectors. Non-viral delivery mechanisms include lipid-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFA), and combinations thereof. The routes for such release mechanisms include, but are not limited to, the mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes. The pharmaceutical preparation is preferably in the form of a unit dose. In such form the preparation is subdivided into unit doses containing appropriate quantities of active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, lozenge or tablet itself or may be an appropriate number of any of these in packaged form. The amount of active component in a unit dose preparation can vary or adjust from 0.1 mg to 1 g depending on the particular application and the pharmacological potency of the active component. In medical use, the drug can be administered three times a day as, for example, capsules of 100 or 300 mg. In therapeutic use, the compounds used in the pharmaceutical process of this invention are administered at the initial dose of about 0.01 mg to about 100. mg / kg per day. A daily dose range of about 0.01 mg to about 100 mg / kg is preferred. However, the doses may vary depending on the requirements of the patient, the intensity of the disease state being treated and the compound used. The determination of the appropriate dosage for a particular situation is within the expert's knowledge. As usual, the treatment starts with smaller doses that are less than the optimum dose of the compound. Next, the dosage is increased by small increments until the optimum effect is obtained in each circumstance. For convenience, the total daily dose can be divided and administered in portions during the day. The pharmaceutical composition according to the present invention can, if desired, also contain one or more other compatible therapeutic agents. In particular, the composition can be combined with any one or more compounds useful in the treatment of pain, such as those listed above. Thus, the present invention features a pharmaceutical composition comprising a compound of formula (I) or (II), one or more additional pharmacologically active agents and one or more pharmaceutically acceptable carriers. It will be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.

General Procedures According to a first method A, when Y is a direct bond, R1 is H and R6 is C02H, a compound of formula (I) can be prepared by ring opening of a lactam of formula (III); ID wherein PG is H or a suitable protecting group such as tert-butoxycarbonyl, by acid hydrolysis using a suitable acid such as hydrochloric acid in a suitable solvent such as dioxane or by base-mediated ring opening using a hydroxide source, such as hydroxide of lithium, in a suitable solvent such as tetrahydrofuran, followed by deprotection of any protecting group present by procedures known in the art, for example, treatment with an acid such as hydrochloric acid in a suitable solvent such as diethyl ether or dioxane.

According to a second method B, when Y is a direct bond and R1 is H, a compound of formula (i) can be prepared by deprotection of a compound of formula (IV) by procedures known in the art; wherein PG is a suitable protective group. Typically, when PG is tert-butoxycarbonyl, deprotection can be carried out by treatment with an acid such as hydrochloric acid in a suitable solvent such as diethyl ether or dioxane. According to third and fourth procedures C and D, when R1 is H, Y is a direct bond, R2, R3, R4 and R5 are not cyano, thio or amino and R6 is tetrazole or an oxazolidinone, a compound of formula can be prepared (IV) from a compound of formula (V) according to Scheme 1.

SCHEME 1 Typical reaction conditions; (i) Treatment of (V) with a suitable azide source such as sodium azide with NH4CI or trimethylsilyl azide in a suitable solvent such as DMF at reflux, (i) Treatment of (V) with a suitable hydroxylamine source such as hydroxylamine hydrochloride and an acid acceptor such as triethylamine in a suitable solvent such as absolute ethanol at elevated temperatures. (iii) Treatment of (VII) with a suitable carbonyl source such as carbonyl diimidazole in a suitable solvent such as tetrahydrofuran at elevated temperatures. According to a fifth process E, when R1 is H, R2 and R8 form a carbocyclic ring of 5 members, R3, R4 and R5 are not cyano, thio or amino and Y is a direct bond, a compound of formula (I) can be prepared ) from a compound of formula (IX) according to Scheme 2.

SCHEME 2 Typical reaction conditions. (i) Treatment of (IX) with a suitable hydroxylamine source such as hydroxylamine hydrochloride and an acid acceptor such as triethylamine in a suitable solvent such as methanol or ethanol at room temperature. (ii) Reduction of (X) using a suitable proton source such as glacial acetic acid or hydrochloric acid or sodium, zinc or hydrogen amalgam with catalytic palladium in a suitable solvent such as methanol at elevated temperatures. According to a sixth method F, when R1 and R2 form a 5-membered carbocyclic ring, R3, R4 and R5 are not cyano, thio or amino and Y is a direct bond, a compound of formula (I) can be prepared from a compound of formula (XI) according to Scheme 3.

SCHEME 3 (XI) (XII) (I) Typical reaction conditions. (i) Treatment of (XI) with benzylamine in a suitable solvent such as ethanol, ciorobenzene or toluene at room temperature or elevated temperatures. (ii) Deprotection using a debenzylating agent such as palladium catalyst and hydrogen in a suitable solvent at room temperature or chloroethyl chloroformate in a suitable solvent such as dichloromethane or methanol at elevated temperatures, followed by hydrolysis using a suitable hydroxide source such as lithium hydroxide in a suitable solvent such as methanol and tetrahydrofuran at room temperature. When R2, R3, R4 and R5 are not cyano, thio or amino, a lactam of formula (III) can be prepared from a compound of formula (XIII); (XIII) by treatment with a reducing agent such as sodium borohydride with cobalt chloride hexahydrate in an alcohol solvent such as methanol at 0-25 ° C. When R2, R3, R4 and R5 are not uncle, a lactam of formula (III) can be prepared from a compound of formula (XIV); (XIV) by lactam formation using a source of ammonia suitable as ammonium hydroxide in a suitable solvent such as tetrahydrofuran or ethanol at 0-25 ° C When R2, R3, R4 and R5 are not thio or amino, a lactam can be prepared of formula (III) from a compound of formula (XV); by treating (XV) with a suitable hydroxylamine source such as hydroxylamine hydrochloride and base such as pyridine in a suitable solvent such as methanol or ethanol at elevated temperatures to form a benzo [d] [1,2] oxain-1-one , followed by ring opening and lactam formation by treatment with a suitable reducing agent such as zinc in an acid such as glacial acetic acid or hydrochloric acid at elevated temperatures. With reference to the above general procedures, it will be readily appreciated by those skilled in the art that when protecting groups are present, they will generally be interchangeable by other protecting groups of a similar nature, for example, when an amine is described as being protected with a The ferc-butoxycarbonyl group can be easily exchanged with any suitable amine protecting group. It will be appreciated by one skilled in the art that the particular steps in the general methods presented herein may be conveniently combined in any other way not shown to provide a compound according to the present invention. A pharmaceutically acceptable salt of a compound of the invention can be readily prepared by mixing together solutions of a compound of the invention and the desired acid or base, as appropriate. The salt can precipitate in the solution and be collected by filtration or can be recovered by evaporation of the solvent. Thus, in summary, the invention provides: (i) a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof; (ii) a pharmaceutical composition that includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof together with a pharmaceutically acceptable excipient, diluent or carrier; (iii) the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, prodrug or composition thereof for the manufacture of a medicament for the treatment of any of the pathological conditions mentioned hereinbefore; (iv) the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, prodrug or composition thereof for the manufacture of a medicament for the treatment of any of the disease conditions mentioned hereinbefore; (v) a method of treating a mammal to treat any of the disease states cited hereinabove including treating said mammal with an effective amount of a compound of formula (I) or a salt thereof, solvate, polymorph or prodrugs or pharmaceutically acceptable compositions; (vi) a method for the treatment of any of the pathological conditions mentioned hereinabove, which comprises administering to a patient in need of said treatment, either simultaneously, separately or sequentially, a combination of a compound of formula ( I) and another agent for pain; (vii) use of a combination of a compound of formula (I) and another therapeutic agent for the manufacture of a medicament for the treatment of any of the disease states mentioned hereinbefore; and (vii) a product containing a compound of formula (I) and another therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of any of the disease states mentioned hereinbefore. The present invention is illustrated by the following examples and non-limiting intermediates.

EXAMPLE 1 2-aminomethyl-5-chloro-benzoic acid hydrochloride salt A mixture of 6-chloro-2,3-dihydro-isoindol-1-one (0.1 15 g, 0.68 mmol) and 6M hydrochloric acid (8 mL) in dioxane (1 mL) was heated at 110 ° C for 18 hours. After cooling to room temperature, the solid was separated by filtration and dried in vacuo to give the title compound (0.0055 g, 4%) as a beige solid. NMR of H (400 MHz, DMSO): d = 4.30 (broad s, 2H), 7.58 (dd, 1 H), 7.76 (dd, 1 H), 8.22 (broad s, 3H). LRMS (Electrospray): m / z [H +] 86. Microanalysis: Found: C, 43.13; H, 4.05; N, 6.18.

C8H8N02CI-HCI requires C, 43.26; H, 4.08; N, 6.31%.

EXAMPLE 2 2-aminomethyl-4,5-dichloro-benzoic acid hydrochloride salt The above compound was synthesized (0.159 g, 46%) as a gold solid using a procedure similar to Example 1. 1 H NMR (400 MHz, DMSO): d = 4.32 (s, 2 H), 7.9 (s, 1 H) , 8.12 (s, 1 H), 8.28 (broad s, 3H). LRMS (Electrospray): m / z [M] + 220. Microanalysis: Found: C, 36.98; H, 3.06; N, 5.21. C8H8NO2CI-HCI-0.1 H2O requires C, 37.20; H, 3.20; N, 5.42%.

EXAMPLE 3 2-aminomethyl-3-bromo-benzoic acid hydrochloride salt A mixture of 2- (ferc-butoxycarbonylamino-methylene) -3-bromo-benzoic acid (0.188 g, 0.57 mmol) in 2M HCl in diethyl ether (10 mL) was stirred at room temperature for 18 hours. The solvent was removed by evaporation under reduced pressure. The solid was diluted with ethyl acetate / dioxane (1: 1) (10 mL) and stirred at room temperature for 1.5 hours. The solid was separated by filtration and dried to give the title compound (0.02 g, 13%) as a white solid. 1 H NMR (400 MHz, DMSO): d = 4.40 (s, 2H), 7.44 (t, 1 H), 8.0 (m, 2H), 8.1 (broad s, 3H). LRMS (Electrospray): m / z [M] + 230. Microanalysis: Found: C, 35.09; H, 3.39; N, 5.12. C8H8N02Br- 1.2 HCI requires C, 35.24; H, 3.41; N, 4.87%.

EXAMPLE 4 2-aminomethyl-6-chloro-benzoic acid hydrochloride salt The above compound was synthesized (0.0051 g, 11%) as a white solid using a procedure similar to Example 3. H NMR (400 MHz, DMSO): d = 4.0 (s, 2H), 7.51 (m; 3H) , 8.4 (broad s, 3H). LRMS (Electrospray): m / z [M - H] + 184.

EXAMPLE 5 2- (1-Amino-ethyl) -benzoic acid hydrochloride salt The above compound was synthesized (0.006 g, 8%) as a white solid using a procedure similar to Example 3. H NMR (400 MHz, D SO): d = 1.58 (d, 3H), 5.22 (broad s) , 1 H), 7.50 (t, 1 H), 7.72 (t, 1 H), 7.78 (d, 1 H), 7.92 (d, 1 H), 8.42 (broad s, 3H). LRMS (Electrospray): m / z [M-H] + 166. Microanalysis: Found: C, 52.84; H, 5.98; N, 6.74. CgHuNCVHCI requires C, 52.65; H, 5.94; N, 6.82%.

EXAMPLE 6 2,3-Dihydro-1 H-isoindol-4-carboxylic acid To a suspension of the hydrochloride salt of the acid methyl ester, 3-dihydro-1 H-isoindole-4-carboxylic acid (0.18 g, 0.83 mmol) in 25% MeOH THF (4 mL) was added lithium hydroxide (0.08 g). , 3.32 mmol) dropwise in water (1 ml), followed by the addition of water (2 ml) and the clear solution was stirred at room temperature under nitrogen for 5 hours. The solution was acidified with aqueous HCl and purified by ion exchange resin (DOWEX ™ 50WX2-100) eluting with a solvent gradient of ammonia: water (5:95) to give the title compound (0.0059 g, 4%) as a white solid. 1 H NMR (400 MHz, D20): d = 4.6 (s, 2H), 4.82 (s, 2H), 7.43 (m, 2H), 7.72 (d, 1 H). LRMS (APCI): m / z [M + H] + 164.

EXAMPLE 7 3- (2-aminomethyl-5-chloro-phenyl) -4-H-ri, 2,41-oxadiazol-5-one hydrochloride salt The mixture was stirred at 0 ° C and then a mixture of [4-chloro-2- (5-oxo-4,5-dihydro- [1,2, -3-] -butyl tert-butyl ester was heated to room temperature for 18 hours. 4] oxadiazolyl-3-yl] -dicarobamic acid (0.2875 g, 0.68 mmol) in 4M HCl in dioxane (8 mL) The solid was filtered and washed with dichloromethane (5 mL) and diethyl ether (50 mL). The dark beige was suspended in 6M hydrochloric acid and washed with dichloromethane (3 x 10 mL) and ethyl acetate (3 x 10 mL) The HCl solution was evaporated under reduced pressure and the resulting solid was dried under reduced pressure to give the compound of the heading (0.028 g, 16%) as a beige solid.1 H-NMR (400 MHz, CD3OD): d = 4.41 (s, 2H), 7.68 (dd, 1 H), 7.74 (dd, 1 H), 7.82 (d, 1 H). LRMS (APCI): m / z [M + H] + 226.

PREPARATION 1 2-Chloro-6-amino-benzoic acid methyl ester1 Methyl iodide (0.47 mL, 7.58 mmol) was added dropwise to 2-amino-6-chloro-benzoic acid (1 g, 5.83 mmol) and potassium carbonate (1.21 g, 8.74 mmol) in DMF (15 mL) and The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (150 ml). The aqueous phase was extracted with diethyl ether (3 x 50 mL), dried over magnesium sulfate. The mixture was filtered and the solvent was removed by evaporation under reduced pressure to give an orange residue. The residue was dissolved in a minimum amount of dichloromethane and purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (3: 1) to give the title compound (0.61 g, 56%) as an orange oil 1 H NMR (400 MHz, CDCl 3): d = 3.92 (s, 3 H), 4.8 (broad s, 2 H), 6.48 (dd, 1 H), 6.72 (dd, 1 H), 7.4 (m, 1 H) . LRMS (Electrospray): m / z [M + H + Na] + 208. Microanalysis: Found: C, 51.69; H, 4.34; N, 7.46. C8H8N02CI. requires C, 51 .77; H, 4.34; N, 7.55%. In a similar way it was prepared; PREPARATION 2 3-Chloro-6-amino-benzoic acid methyl ester The above compound was synthesized (0.33 g, 15%) as a white solid. NMR from H (400 MHz, CDCl 3): d = 3.89 (s, 3H), 5.65 (broad s, 2H), 6.60 (dd, 1 H), 7.20 (dd, 1 H), 7.82 (m, 1 H) . LRMS (Electrospray): m / z [M-H] + 184. Microanalysis: Found: C, 51.84; H, 4.32; N, 7.49. C8H8N02CI. Requires C, 51.77; H, 4.34; N, 7.55%. 1. I fell, Sui Xiong: Zhou, Zhang-Lin: Huang, Jin-Cheng; Whittermore, Edward R; Egbuwoku, Zizi O; J. Med. Chem .; 39, 17, 1996, 3248-3255. 2. Available commercially from Sigma Aldrich.

PREPARATION 3 3-Chloro-6-cyano-benzoic acid methyl ester Water (5 ml) was added to a stirred suspension of 2-amino-5-chloromethyl benzoate (0.33 g, 1.77 mmole) in concentrated hydrochloric acid (1.1 ml) at 0 ° C. A solution of sodium nitrite (0.12 g, 1.77 mmoles) in water (1 ml) was added dropwise and the solution was stirred until complete dissolution. The diazonium salt was brought to pH 6.0 with saturated sodium bicarbonate. In a separate flask was added dropwise a solution of CUS04-5H20 (0.53 g, 2.12 mmoies) in water (2 ml) to a stirred solution of potassium cyanide (0.53 g, 8.13 mmoies) in water (2 ml) at 0 ° C. Toluene (3 mL) was added and the resulting brown mixture was stirred and heated to 60 ° C. The diazonium solution prepared above was added to Cu (I) CN at 60 ° C for a period of 30 minutes. The reaction mixture was heated at 70 ° C for a further hour, then cooled to room temperature. The brown mixture was diluted with ethyl acetate (70 ml), filtered through a pad of Celite ™, washed with ethyl acetate (3 x 20 ml), the combined organic phases were washed with brine (50 ml) , dried over magnesium sulfate, filtered and the solvent was removed by evaporation under reduced pressure to give a dark orange solid. The solid was dissolved in a minimum of dichloromethane and purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (3: 1) to give the title compound (0.23 g, 65%) as a whitish solid. R N of 1H (400 MHz, CDCl 3): d = 4.0 (s, 3H), 7.62 (dd, 1 H), 7.72 (dd, 1 H), 8.12 (d, 1 H). LRMS (Electrospray): m / z [M + Hf 2 8. Microanalysis: Found: C, 55.16; H, 3.09; N, 7.08. C9H6N02CI requires C, 55.26; H, 3.09; N, 7.16%. In a similar way it was prepared; PREPARATION 4 Methyl ester of 2-chloro-6-cyano-benzoic acid3 The above compound was synthesized (0.34 g, 64%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3): d = 4.02 (s, 3 H), 7.50 (dd, 1 H), 7.66 (m, 2 H). LRMS (Electrospray): m / z [M + Na + f 218. Microanalysis: Found: C, 55.24; H, 3.07; N, 7.19. C9H6N02CI requires C, 55.26; H, 3.09; N, 7.16%. 3. Patent; CIBA-GEIGY; DE 2525587; 1975; Chem. Abstr .; 84; 91648 PREPARATION 5 6-Chloro-2,3-dihydro-isoindol-1 Sodium borohydride (CAUTION WITH EXOTHERMIA) was added in several portions to a stirred solution of 3-chloro-6-cyano-benzoic acid methyl ester (0.22 g, 1.12 mmol) and hexahydrated cobalt chloride (0.54 g, 2.24 mmol) ) in methanol (18 ml). The black mixture was stirred at room temperature under nitrogen for 1 hour. The mixture was quenched with 5% HCl (aqueous, 10 mL), diluted with water (10 mL) and concentrated ammonium hydroxide (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent was removed by evaporation under reduced pressure to give a brown solid. The solid was purified by flash chromatography on silica gel eluting with a solvent gradient of ethyl acetate to give the title compound (0.1 16 g, 61%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3): d = 4.42 (d, 2H), 6.6 (broad s, 1 H), 7.4 (dd, 1 H), 7.54 (dd, 1 H), 7.84 (d, 1 H) ). LRMS (Electrospray): m / z [M + H + Na] + 190. They were similarly prepared; PREPARATION 6 7-Chloro-2,3-dihydro-isoindol-1 The above compound was synthesized (0.17 g, 62%) as a yellow solid using a procedure similar to Preparation 3. 1 H NMR (400 MHz, CDCl 3): d = 4.41 (s, 2 H), 7.08 (broad s, 1 H), 7.36 (dd, 1 H), 7.4 (dd, 1 H), 7.48 (dd, 1 H). LRMS (Electrospray): m / z [M - H] + 166.

PREPARATION 7 5,6-Dichloro-2,3-dihydro-isoindol-1 -one The above compound was synthesized (0.37 g, 25%) as orange. 1 H-NMR (400 MHz, CDCl 3): d = 4.42 (s, 2 H), 6.24 (broad s, 1 H), 7.6 (d, 1 H), 7.86 (d, 1 H). LRMS (Electrospray): m / z [M-2H] + 200. 4. Anderson, P.S. et. to the. J. Org. Chem; 44, 9, 1979,1519-1533. 5. Hennige, Hans; Kreher, Richard P .; Konrad, Michael; Jeliito, Frank; Chem Ber, 121, 1988, 243-252.

PREPARATION 8 3-Bromo-2-bromomethyl-benzoic acid methyl ester6 A mixture of 3-bromo-2-methylbenzoic acid methyl ester (2.4 g, 10.29 mmol), NBS (1.83 g, 10.29 mmol) and AIBN (4 mg) was heated to 80 ° C under nitrogen for 18 hours. chlorobenzene (40 ml). The mixture was cooled in an ice bath, filtered and the solvent was removed by evaporation under reduced pressure. The orange residue was purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (40: 1) to give the title compound (2.74 g, 86%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3): d = 3.88 (s, 3 H), 5.06 (s, 2 H), 7.22 (dd, H), 7.68 (d, H), 7.89 (d, H). Microanalysis: Found: C, 35.21; H, 2.67; N, 0.00 requires C, 35.10; H, 2.62; N, 0.00%. 6. Tasaka, Akihiro, Kaku, Tomohiro, Kusaka, Masami; PCT international application (2001) WO 0130764.

PREPARATION 9 4-Bromo-2,3-dihydro-isoindol-1 -ona7 30% aqueous ammonia (10 mL) was added to a solution of 3-bromo-2-bromomethyl-benzoic acid methyl ester (2.74 g, 8.88 mmol) in tetrahydrofuran (70 mL) at 0 ° C and the mixture was stirred at room temperature under nitrogen for 18 hours. The solvent was removed by evaporation under reduced pressure. The white residue was partitioned between ethyl acetate (50 ml) and 2M citric acid (50 ml). The ethyl acetate was dried over magnesium sulfate, filtered and the solvent was removed by evaporation under reduced pressure. The orange oil was dissolved in a minimum of dichloromethane and purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane / methanol (9: 1) to give the title compound (1.5 g, 80%) as a solid. White. NMR of? (400 MHz, DMSO): d = 4.29 (s, 2H), 7.44 (t, 1 H), 7.69 (d, 1 H), 7.80 (d, 1 H), 8.68 (broad s, 1 H). LRMS (Electrospray): m / z [M + 2H] + 214. Microanalysis: Found: C, 45.20; H, 2.90; N, 6.67. C8H6NOBr requires C, 45.31; H, 2.85; N, 6.60%. 7. Tasaka, Akihiro; Kaku, Tomohiro; Kusaka, Masami; PCT international application (2001). WO 0130764 PREPARATION 10 4-Bromo-1-oxo-1,3-dihydro-isoindole-2-carboxylic acid ferric-butyl ester A mixture of 4-bromo-2,3-dihydro-isoindol-1-one (0.159 g, 0.749 mmol), di-fer-butyl dicarbonate (0.33 g, 1.5 mmol) was stirred at room temperature under nitrogen for 18 hours. , triethylamine (0.1 ml, 0.75 mmol) and DMAP (0.092 g, 0.75 mmol) in dichloromethane (7 ml). The yellow solution was purified by flash chromatography on silica gel eluting with a solvent gradient of heptane / ethyl acetate (3: 1) to give the title compound (0.23 g, 99%) as a colorless residue. R N of H (400 MHz, CDCl 3): d = 1.6 (s, 9H), 4.64 (s, 2H), 7.4 (t, 1 H), 7.74 (d, 1 H), 7.84 (d, 1 H). LRMS (Electrospray): m / z [M + 2H + Na] + 336. Microanalysis: Found: C, 50.45; H, 4.72; N, 4.38. Ci3Hi N03Br requires C, 50.02; H, 4.52; N, 4.49%. In a similar way they were prepared; PREPARATION 11 7-Chloro-1-oxo-1,3-dihydro-isoindol-2-carboxylic acid tert-butyl ester The above compound was synthesized (0.064 g, 80%) as a colorless foam. R N of 1H (400 MHz, CDCl 3): d = 1.62 (s, 9H), 4.65 (s, 2H), 7. 34 (dd, 1 H), 7.42 (dd, 1 H), 7.52 (t, 1 H). LR S (Electrospray): m / z [M + Na] + 289. Microanalysis: Found: C, 58.64; H, 5.43; N, 5.09. Ci3H14N03CI requires C, 58.33; H, 5.27; N, 5.23%.

PREPARATION 12 1-methyl-3-oxo-1,3-dihydro-isoindol-2-tert-butyl ester The above compound was synthesized (0.12 g, 72%) as a colorless oil from 3-methyl-2,3-dihydro-isoindol-1 -one8 using a procedure similar to Preparation 6. 1 H NMR (400 MHz, CDCI3): d = 1.6 (broad s, 12H), 5.06 (c, H), 7.44 (m, 2H), 7.64 (t, 1 H), 7.89 (d, 1 H). LRMS (Electrospray): m / z [M + Na 269. Microanalysis: Found: C, 67.52; H, 6.93; N, 5.60. C14Hi7N03 requires C, 67.99; H, 6.93; N, 5.66%. 8. Kreher, Richard P .; Hennige, Hans; Konrad, Michael; Uhrig, Juergen; Ciemens, Andrea; Z. Naturforsch. B; 46, 6, 1991, 809-828.

PREPARATION 13 2- (tert-Butoxycarbonylamino-methyl) -3-bromo-benzoic acid To a stirred solution of 4-bromo-1-oxo-1,3-dihydro-isoindol-2-carboxylic acid tert-butyl ester (0.206 g, 0.66 mmol) in tetrahydrofuran (10 mL) was added dropwise. aqueous lithium hydroxide (1M, 2 ml, 1.98 mmol) and the mixture was stirred at room temperature under nitrogen for 18 hours. The mixture was diluted with diethyl ether (30 ml) and washed with 1 M HCl (10 ml). The aqueous phase was extracted with diethyl ether (2 x 20 mL) and the combined organic extracts were dried over magnesium sulfate, filtered and the solvent was removed by evaporation under reduced pressure to give the title compound (0.188 g, 86%) like a white waxy solid. LRMS (Electrospray): m / z [M] + 330. In the same way they were prepared; PREPARATION 14 2- (Ferric-butoxycarbonylamino-methyl) -6-chloro-benzoic acid The above compound was synthesized (0.064 g, 94%) as a white solid. 1 H NMR (400 MHz, CDCl 3): d = 1.42 (s, 9H), 4.28 (s, 2H), 7.29-7.4 (m, 3H). LRMS (Electrospray): m / z [M-H] + 284. Microanalysis: Found: C, 54.51; H, 5.91; N, 4.54. C13H16N04CI requires C, 54.65; H, 5.64; N, 4.90%.

PREPARATION 15 2- (tert-Butoxycarbonylamino-ethyl) -benzoic acid The above compound was synthesized (0.1 1 g, 86%) as a white solid. 1 H NMR (400 MHz, CD3OD): d = 1.40 (s, 12H), 5.5 (m, 1 H), 7.3 (m, 1 H), 7.51 (m, 2H), 7.89 (dd, 1 H). LRMS (Electrospray): m / z [M -H] + 264.

PREPARATION 16 3-hydroxyimino-indan-4-carboxylic acid A mixture of 3-oxo-indan-4-carboxylic acid 9 (1 g, 5.68 mmol), potassium carbonate (0.81 g, 5.85 mmol), hydroxylamine hydrochloride (0.39 g, 5.68 mmol) was stirred at room temperature under nitrogen for 18 hours. ) in methanol (25 ml). The solvent was removed by evaporation under reduced pressure and the residue was suspended in ethyl acetate (30 ml) and washed with water (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 30 mL), the combined organic extracts were dried over magnesium sulfate, filtered and the solvent was removed by evaporation under reduced pressure to give the title compound (0.95 g, 87% ) as a pale yellow solid. NMR of H (400 Hz, CD3OD): d = 3.04 (t, 2H), 3.19 (t, 2H), 7.54 (t, 1 H), 7.64 (d, 1 H), 8.2 (d, 1 H). LRMS (APCI): m / z [M + H] + 192. Microanalysis: Found: C, 62.89; H, 4.71; N, 7.05. C10H9NO3 requires C, 62.82; H, 4.74; N, 7.33%. 9. Panetta, Charles A; Dixit, Ajjit S; Synthesis; 1, 1981, 59-60.

PREPARATION 17 3-amino-indan-4-carboxylic acid A mixture of 3-hydroxyimino-indan-4-carboxylic acid (0.45 g, 2.35 mmol), zinc powder (0.72 g) in 1 M HCl (10 ml) and glacial acetic acid was heated at 90 ° C for 18 hours. 3 mi). The mixture was cooled to room temperature, the solid was removed by filtration and the solvent was removed by evaporation under reduced pressure. The residue was diluted with water (5 ml) and extracted with dichloromethane (3 x 10 ml) and ethyl acetate (50 ml). The aqueous fraction was purified by ion exchange column (DOWEX ™ 50WX2-100) eluting with a solvent gradient of ammonia: water (5:95) to give the title compound (0.142 g, 34%) as a white solid. 1 H NMR (400 MHz, CD3OD): d = 2.1 1 (m, 1 H), 2.6 (m, 1 H), 3.01 (m, 1 H), 3.21 (m, 1 H), 4.93 (m, 1 H), 7.38 (d, 2H), 7.83 (m, 1 H). LRMS (APCI): m / z [M-H] + 176. Microanalysis: Found: C, 64.81; H, 6.34; N, 7.53. CioHnN02. 0.15 NH4CI requires C, 64.85; H, 5.99; N, 7.56%.

PREPARATION 18 2-Benzyl-2,3-dihydro-1H-isoindol-4-carboxylic acid methyl ester A solution of 2,3-bis-bromomethyl benzoic acid methyl ester10 (1.20 g, 3.74 mmol) was added to a mixture of benzylamine (0.71 ml, 6.52 mmol), 10 M NaOH, n-tetrabutyl ammonium chloride (0.12 g, 0.42 mmole) and the mixture was stirred at room temperature under nitrogen for 18 hours. The mixture was poured into water (50 ml). The aqueous fraction was extracted with ethyl acetate (10 ml), the combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate, filtered and the solvent was removed by evaporation under reduced pressure to give an orange oil. . The oil was suspended in a minimum amount of dichloromethane and purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (3: 1) to give the title compound (0.57 g, 57%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3): d = 3.87 (s, 3 H), 3.95 (s, 4 H), 4.34 (s, 2 H), 7.27 (m, 3 H), 7.35 (m, 2 H), 7.42 (m , 2H), 7.85 (d, 1 H). LRMS (APCI): m / z [M + Hf 268. Microanalysis: Found: C, 75.83; H, 6.40; N, 5.20. C17Hi7N02-0.1 H20 requires C, 75.87; H, 6.37; N, 5.20%. 10. Neubeck, H. K. Montash. Chem; 127, 2, 1996, 201-217.

PREPARATION 19 Hydrochloride salt of 2,3-dihydro-1H-isoindol-4-carboxylic acid methyl ester A-chloroethyl chloroformate (0.16 mL, 1.46 mmol) was added dropwise to a solution of 2-benzyl-2,3-dihydro-1 H-isoindole-4-carboxylic acid methyl ester (0.3 g, 1.12 mmol) in dichloromethane (4 ml) at -10 ° C, and stirred at -10 ° C for 30 minutes. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in methanol (5 ml) and heated to 90 ° C for 40 minutes. The solution was cooled to room temperature and the solvent was removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate (30 ml), extracted into saturated NaOH solution to give a hygroscopic solid and used without further purification. 1 H NMR (400 MHz, crude CD3OD): d = 3.9 (s, 3H), 4.6 (broad s, 2H), 4.92 (broad s, 2H), 7.51 (d, 1 H), 7.61 (d, 1 H ), 8.0 (d, 1 H). LRMS (APCI): m / z [M + Hf 178.

PREPARATION 20 (4-Chloro-2-cyano-benzyl) -dicarobamic acid ferric-butyl ester A solution of 2-bromomethyl-5-chloro-benzonitrile (10 g, 43.39 mmol) in anhydrous tetrahydrofuran (35 mL) was added to a suspension of sodium hydride (1.91 g, 47.72 mmol) in anhydrous tetrahydrofuran (30 mL). at room temperature under nitrogen, followed by the addition, dropwise, of di-ert-butyl iminodicarboxylate (10.37 g, 47.72 mmol) in anhydrous tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 28 hours under nitrogen. The reaction was quenched with water (50 ml) and the solvent was removed under reduced pressure. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvent was removed by evaporation under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (4: 1) to give the title compound (13.45 g, 84%) as a pale yellow solid. NMR from H (400 MHz, CDCl 3): d = 1.46 (s, 18H), 4.98 (s, 2H), 7.28 (d, 1 H), 7.53 (d, 1 H), 7.61 (d, 1 H). LRMS (APCI): m / z [M + H] + 389.

Microanalysis: Found: C, 59.37; H, 6.47; N, 7.09.

C18H23N204CI requires C, 58.93; H, 6.32; N, 7.64%. 11. Ando, Kazuo; Tokoroyama, Takshi; Kubota, Takshi; Bull Chem. Soc. Jpn., 53, 10, 1980, 2885-2890.

PREPARATION 21 f4-Chloro-2- (A / -hydroxycarbamimidoyl) -benzyl-dicarbamic acid tert-butyl ester A mixture of hydroxylamine hydrochloride (1.33 g, 19.08 mmol) and triethylamine (2.9 ml, 20.99 mmol) was stirred at room temperature in absolute ethanol (200 ml) for 30 minutes. To this mixture was added ester (4-chloro-2-cyano-benzyl) dicarbamic acid (7 g, 19.08 mmol) and heated to 85 ° C for 18 hours. The ethanol was removed by evaporation under reduced pressure and then diluted with water (100 ml). The aqueous phase was extracted with ethyl acetate (3 x 75 mL), the combined organic extracts were dried over magnesium sulfate, filtered and the solvents were removed by evaporation under reduced pressure to give a yellow residue. The residue was dissolved in a minimum of dichloromethane and purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (4: 1) to give the title compound (1.03 g, 13%) as a pale yellow foam. 1 H NMR (400 MHz, CDCl 3): 6 = 1.45 (s, 18 H), 4.84 (s, 2 H), 5.70 (s broad, 2 H), 7.22 (d, 1 H), 7.36 (m, 3 H). LRMS (APCI): m / z [- H] + 398. Microanalysis: Found: C, 54.26; H, 6.60; N, 10.20. C18H2oN305CI requires C, 54.07; H, 6.55; N, 10.51%.

PREPARATION 22 Ferric-butyl ester of r4-chloro-2- (5-oxo-4,5-dihydro-r, 2,41-oxadiazolyl-3-in-dicarbamic acid Carbonyl diimidazole (0.52 g, 3.19 mmol) was added to a solution of [4-chloro-2- (A / -hydroxycarbamimidodo) -benzyl] -dicarobamic acid ester (0.85 g, 2.13 mmol) in tetra The id was not anhydrous (100 ml) and the mixture was stirred and heated to 90 ° C for 18 hours under nitrogen. The mixture was cooled to room temperature and the solvent was removed by evaporation under reduced pressure. The brown residue was dissolved in a minimum of dichloromethane and purified by flash chromatography eluting with a solvent gradient of heptane: ethyl acetate (4: 1) to (1: 1) to ethyl acetate to dichloromethane: methanol (9: 1) giving the title compound (0.3105 g, 34%) as a brown vitreous solid. 1 H NMR (400 Hz, CDCl 3): d = 1.50 (s, 18H), 4.75 (s, 2H), 7.52 (s, 1H), 7.52 (s broad 2H), 7.64 (s, 1 H) . LRMS (APCI): m / z [M - Hf 424.

Examples of pharmaceutical compositions In the following Examples, the active compound may be any compound of formula (I) and / or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. (i) Compositions of tablets The following compositions A and B can be prepared by wet granulation of ingredients (a) to (c) and (a) to (d) with a solution of povidone, followed by the addition of stearate. magnesium and compression.

Composition A mg / tablet mg / tablet (a) Active ingredient 250 250 (b) Lactose, F.B. * 210 26 (c) Sodium glycolate starch 20 12 (d) Povidone, F.B. 15 9 (e) Magnesium stearate 5 3 500 300 * Pharmacopoeia of the United Kingdom Composition B mg / tablet mg / tablet (a) Active ingredient 250 250 (b) Lactose 150 50 (c) Avicel PH 101 60 26 (d) Sodium glycolate starch 20 12 (e) Povidone, F.B. 15 9 (f) Magnesium stearate 5 3 500 300 Composition C mg / tablet Active ingredient 100 Lactose 200 Starch 50 Povidone 5 Magnesium stearate 4 359 The following compositions D and E can be prepared by direct compression of the mixed ingredients. The lactose used in the Formulation E is of the direct compression type.

Composition D mg / tablet Active ingredient 250 Magnesium stearate 4 Pregelatinised starch 15 146 400 Composition E mg / tablet Active ingredient 250 Magnesium stearate 5 Lactose 145 Avicel 100 500 Composition F mg / tablet (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose 1 12 (ethocel K4M Premium) (c) Lactose, F.B 53 (d) Povidone, F.B. 28 (e) Magnesium Stearate 7 700 The composition can be prepared by wet granulation of ingredients (a) to (c) with a povidone solution, followed by the addition of magnesium stearate and compression.

Composition G (Enteric coated tablet) Enteric coated tablets of Composition C can be prepared by coating the tablets with 25 mg / tablet of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate or anionic acid polymers methacrylic or methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers will include 10% (by weight with respect to the amount of polymer used) of a plasticizer to prevent membrane cracking during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

Composition H (Enteric coated controlled release tablet) Enteric coated tablets of Composition F can be prepared by coating the tablets with 50 mg / tablet of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate or polymers anionic acid methacrylic acid or methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers will include 10% (by weight with respect to the amount of polymer used) of a plasticizer to prevent membrane cracking during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. (i) Capsule compositions Composition A Capsules can be prepared by mixing the ingredients of the Composition D above and filling two-piece hard gelatin capsules with the resulting mixture. Composition B (infra) can be prepared from a similar way.

Composition B m / capsule (a) Active ingredient 250 (b) Lactose, F. B. 143 (c) Sodium glycolate starch 25 (d) Magnesium stearate 2 420 Composition C m / capsule (a) Active ingredient 250 (b) Macrogol 4000, F. B. 350 600 Capsules can be prepared by melting the Macrogol 4000 FB, dispersing the active ingredient in the melt and filling capsules of hard gelatin of two pieces with it.

Composition D m / capsule Active ingredient 250 Lecithin 100 Peanut oil 100 450 Capsules can be prepared by dispersing the active ingredient in the lecithin and the peanut oil and filling soft elastic gelatin capsules with the dispersion.

Composition E (Controlled release capsule) m / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose, FB 125 (d) Ethyl cellulose 13 513 The controlled release capsule formulation can be prepared by extruding the mixed ingredients (a) to (c) using an extruder, then spheronizing and drying the extrudate. The dried granules are coated with a controlled release membrane (d) and filled into two-piece hard gelatin capsules.

Composition F (Enteric capsule) m / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose, FB 125 (d) Cellulose acetate phthalate 50 (e) Diethyl phthalate 5 555 The controlled release capsule formulation can be prepared by extruding the mixed ingredients (a) to (c) using an extruder, then spheronizing and drying the extrudate. The dried granules are coated with a controlled release membrane (d) containing a plasticizer (e) and filled into two-piece hard gelatin capsules.

Composition G (Enteric coated controlled release capsule) Enteric capsules of Composition E can be prepared by coating the controlled release granules with 50 mg / capsule of an enteric polymer such as cellulose acetate phthalate., polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate or anionic polymers of methacrylic acid or methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers will include 10% (by weight with respect to the amount of polymer used) of a plasticizer to prevent membrane cracking during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin (iü) Intravenous Injection Composition active ingredient 0.200 g Sterile phosphate buffer free of pyrogens (pH 9.0), c.s.p. 10 ml The active ingredient dissolves in most of the buffer phosphate at 35-40 ° C, then brought to volume and filtered through sterile 10 ml glass vials with microporous filter (Type 1) that are sealed with sterile plugs and seals. (iv) Composition of intramuscular injection Active ingredient 0.20 g Benzyl alcohol 0.10 g Glycofurol 75 1.45 g Water for injection, c.s.p. 3.00 ml The active ingredient dissolves in glycofurol. The benzyl alcohol is then added and dissolved, and water is added to 3 ml. The mixture is then filled through a sterile micropore filter and sealed in 3 ml glass vials (Type 1). (v) Syrup composition Active ingredient 0.25 g Sorbitol solution 1.50 g Glycerol 1.00 g Sodium benzoate 0.005 g Aroma 0.0125 ml Purified water, c.s.p 5.0 ml Sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution is added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and brought to the required volume with the purified water. (vi) Suppository composition mq / suppository Active ingredient 250 Hard fat, FB (Witepsol H15 - Dynamit NoBel) 1770 2020 One fifth of Witepsol H15 is melted in a steam jacketed container at 45 ° C. The active ingredient is screened through a 200 Im sieve and added to the molten base with mixing using a Silverson equipped with a cutting head until a homogeneous dispersion is achieved. The mixture is maintained at 45 ° C, the rest of Witepsol H15 is added to the suspension which is stirred to ensure a homogeneous mixture. The whole suspension is passed through a stainless steel mesh of 250 lm and, with continuous agitation, it is allowed to cool to 40 ° C. At a temperature of 38 to 40 ° C, aliquots of 2.02 g of the mixture are filled into suitable plastic molds and allowed to cool to room temperature. (vii) Composition of pessary mg / pesa Active ingredient (63 Im) 250 Dextrose anhydrous 380 Potato starch 363 Magnesium stearate 7 1000 The above ingredients are mixed directly to prepare loamies by compression of the resulting mixture. (viiO Transdermal composition Active ingredient 200 mg Alcohol, pharmacopoeia USA 0.1 mi Hydroxyethylcellulose The active ingredient and alcohol of the US pharmacopoeia are gelled with hydroxyethylcellulose and packaged in a transdermal device with a surface area of 10 cm2.

Biological Data The compounds of the invention were tested in the radioligand binding assay described herein and found to have the following union affinities: EXAMPLE 2d 1 100 nM 5 270 nM 2 435 nM 4 383 nM

Claims (8)

1. NOVELTY OF THE INVENTION
2. CLAIMS use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the curative, palliative or prophylactic treatment of a disease selected from attacks of fainting, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety , panic, neuropathic pain, sleep disorders and neuropathological disorders:
3. Formula (I) wherein R1 is H, C6 alkyl, or C3-C8 cycloalkyl; X is - (CH2) n-C (R7) (R8) -; Y is a direct bond or - (CH2) m-C (R9) (R10) -; R7, R8, R ° and R10 are, independently, H or CrC6 alkyl; or R8 and R1 can be taken together with the nitrogen to which R is attached by forming a 4- to 8-membered heterocycloalkyl ring; or R 0 and R 1 can be taken together with the nitrogen to which R 1 is attached by forming a 4 to 8 membered heterocycloalkyl ring; or R8 and R10 can be taken together with the carbons to which they are attached forming a carbocyclic ring of 4 to 8 members; n is 0.1 or 2; m is 0, 1 or 2; R2, R3, R4 and R5 are independently selected from H, C1-C6 alkyl, CI-C6 alkoxy, hydroxy, halogen, hydroxycarbonyl, alkoxycarbonyl CrC6, cyano, sulfonyl, (C6 alkyl) sulfonyl, thio, (Ci-C6 alkyl) ) thio, sulfonamide, perfluoro (Ci-C6 alkyl), perfluoro (CrC6 alkoxy), C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl, amino, (C 1 -C alkyl or C 6 alkyl) amino, aminocarbonyl, (C 1 alkyl) -C6 or dialkyl C- | -C6) aminocarbonyl, C6-acylamino, (C-C6-N-alkyl) C- | -C6-acylamino, phenyl or monocyclic heteroaryl, phenyl and monocyclic heteroaryl being optionally substituted with C-1 alkyl C6, Cr C6 alkoxy, hydroxy, halogen, hydroxycarbonyl, C1-C6 alkoxycarbonyl or perfluoroalkoxy CrC6; or any one or two of CR2, CR3, CR4 and CR5 may be replaced with a nitrogen; or R2 and R3 or R3 and R4 or R4 and R5 can be taken together with the carbon atoms to which they are attached to form a Cs-Cs fused cycloalkyl ring, 4- to 8-membered heterocycloalkyl, phenyl or monocyclic heteroaryl; or R and R2 may be taken together with the nitrogen to which R1 is attached to form a 4- to 8-membered heterocycloalkyl ring; or R8 and R2 may be taken together with the carbon atoms to which they are attached to form a carbocyclic ring or 4 to 8 membered heterocycloalkyl; and R6 is hydroxycarbonyl or a carboxylic acid biosteroid or one of its prodrugs. 2 - The use as claimed in claim 1, wherein the disease is neuropathic pain. 3. The use of a compound as claimed in claim 1 or 2, wherein Y is a direct link.
4. 4. - The use of a compound as claimed in any one of claims 1 to 3, wherein R7 is H and R8 is H, methyl, or R8 and R2 are taken together with the carbon atoms to which they are attached forming a 5-membered carbocyclic ring, or R8 and R1 are taken together with the nitrogen atom to which R is bonded to form a 5-membered heterocycloalkyl ring.
5. 5. The use of a compound as claimed in any one of claims 1 to 4, wherein R2, R3, R4 and R5 are independently selected from H and halogen.
6. 6. The use of a compound as claimed in any one of claims 1 to 5, wherein R6 is hydroxycarbonyl, tetrazole or oxazolidinone.
7. 7. The use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the curative, palliative or prophylactic treatment of a disease selected from fainting, hypokinesia, cranial disorders, neurodegenerative disorders, depression , anxiety, panic, neuropathic pain, sleep disorders and neuropathological disorders: Formula (II) wherein R7 and R8 are independently H or CrC6 alkyl; and R2, R3, R4 and R5 are independently selected from H, C1-C6 alkyl, Ci-C6 alkoxy, hydroxy, halogen, hydroxycarbonyl, Ci-C6 alkoxycarbonyl, cyano, (Ci-C6 alkyl) sulfonyl, perfluoroalkyl C-1 C6, C1-C6 perfluoroalkoxy, C3-C8 cycloalkyl and 4- to 8-membered heterocycloalkyl; or R8 and R2 can be taken together with the carbon atoms to which they are attached by forming a carbocyclic ring or 4- to 8-membered heterocycloalkyl.
8. 8. The use as claimed in claim 1, wherein the compound is selected from the group consisting of: 2-aminomethyl-5-chloro-benzoic acid; 2-aminomethyl-4,5-dichloro-benzoic acid; 2-aminomethyl-3-bromo-benzoic acid; 2-aminomethyl-6-chloro-benzoic acid; 2- (1-aminoethyl) -benzoic acid; 2,3-dihydro-1 H-isoindol-4-carboxylic acid; and 3- (2-aminomethyl-5-chloro-phenyl) -4H- [1, 2,4] oxadiazol-5-one; or one of its pharmaceutically acceptable salts. SUMMARY OF THE INVENTION The compounds of formula (I) are useful in the treatment of fainting, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, neuropathological disorders and sleep disorders. Processes for the preparation of end products and intermediates useful in the process are included. Also included are pharmaceutical compositions containing one or more of the compounds. Formula (I) wherein R1 is H, C6 alkyl, or C3-C8 cycloalkyl; X is - (CH2) n-C (R7) (R8) -; Y is a direct bond or - (CH2) m-C (R9) (R10) -; R7, R8, R9 and R10 are, independently, H or Ci-C6 alkyl; or R8 and R can be taken together with the nitrogen to which R1 is attached by forming a 4- to 8-membered heterocycloalkyl ring; or R 10 and R 1 can be taken together with the nitrogen to which R is attached by forming a 4 to 8 membered heterocycloalkyl ring; or R8 and R10 can be taken together with the carbons to which they are attached forming a carbocyclic ring of 4 to 8 members; n is 0.1 or 2; m is 0, 1 or 2; R2, R3, R4 and R5 are independently selected from H, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, halogen, hydroxycarbonyl, CI-C6 alkoxycarbonyl, cyano, sulfonyl, (CrC6 alkyl) sulfonyl, thio, ( Ci-C6 alkyl) thio, sulfonamide, perfluoro (Ci-C6 alkyl), perfluoro (CrC6 alkoxy), C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl, amino, (C6 alkyl or Ci-C6 dialkyl) amino, aminocarbonyl , (CrC6 alkyl or CrC6 dialkyl) aminocarbonyl, CrC6 acylamino, (Ccyl N-alkyl) Ccy6 acylamino, phenyl or monocyclic heteroaryl, monocyclic phenyl and heteroaryl being optionally substituted with C- | -C6 alkyl, CiC-6 alkoxy, hydroxy, halogen, hydroxycarbonyl, alkoxycarbonyl CiC-6 or perfluoroalkoxy Ci-C6; or any one or two of CR2, CR3, CR4 and CR5 may be replaced with a nitrogen; or R2 and R3 or R3 and R4 or R4 and R5 can be taken together with the carbon atoms to which they are attached by forming a fused C5-C-8 cycloalkyl ring, 4- to 8-membered heterocycloalkyl, phenyl or monocyclic heteroaryl; or R1 and R2 can be taken together with the nitrogen to which R1 is attached to form a 4 to 8 membered heterocycloalkyl ring; or R8 and R2 may be taken together with the carbon atoms to which they are attached to form a carbocyclic ring or 4 to 8 membered heterocycloalkyl; and Re is hydroxycarbonyl or a carboxylic acid biosteroid or one of its prodrugs. PFIZER P05 / 12F