MXPA05001643A

MXPA05001643A - Therapeutic use of fused bicyclic or tricyclic amino acids.

Info

Publication number: MXPA05001643A
Application number: MXPA05001643A
Authority: MX
Inventors: Kistom Stephen Bryans
Original assignee: Pfizer
Priority date: 2002-08-15
Filing date: 2003-08-06
Publication date: 2005-04-25
Also published as: AU2003250481A1; BR0313432A; WO2004016260A8; WO2004016260A1; CA2494811A1; JP2005539092A; EP1545491A1

Abstract

The compounds of the instant invention are bicyclic or tricyclic amino acids useful in the treatment of fibromylagia. Pharmaceutical compositions containing one or more of the compounds for use in the treatment of fibromyalgia are also included.

Description

THERAPEUTIC USE OF CONCENTRATED BICYCLIC OR TR1CYCLIC AMINO ACIDS FIELD OF THE INVENTION This invention relates to the use of new cyclic amino acids in the treatment of fibromyalgia. 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 potential treatment for neurogenic pain. It is the 1- (aminomethyl) -cyclohexylacetic acid of structural formula: Gabapentin is one of the series of compounds of formula ¾N-C¾-C-C¾-COOR1 wherein Ri is hydrogen or a lower alkyl radical and n is 4, 5 or 6. These compounds are described in US-A-4024175 and in their divisional document US-A-4087544. Its described uses are: protection against spasm induced by thiosemicarbazides; protection against cardiac spasms; brain diseases epilepsy, faintness attacks, hypokinesia and cranial traumas; and improvement of brain functions. The compounds are useful in geriatric patients. The descriptions of the two prior patents are incorporated by reference to the present specification. WO 99/2 824, the disclosure of which is also incorporated by reference, discloses additional cyclic amino acids which are useful in the treatment of epilepsy, fainting fits, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders. , gastrointestinal disorders such as intestinal irritation syndrome (IBS) and inflammation, especially arthritis. The disclosed compounds include those of the formula: and its salts, wherein: R is hydrogen or a lower alkyl; and R1 to R are each independently selected from hydrogen, linear or branched alkyl of 1 to 6 carbon atoms, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, -CO2H, -C02R15, -CH2CO2H, -CH2CO2R15, -OR15 wherein R15 is linear or branched alkyl of 1 to 6 carbon atoms, phenyl or benzyl, and R1 to R8 are not simultaneously hydrogen. The publication of the international patent application 0128978, corresponding to the U.S. patent application. No. US 60/160725, describes a series of novel bicyclic amino acids, their pharmaceutically acceptable salts and their prodrugs of the formula: wherein n is an integer from 1 to 4, in which there are este-reocentros, and each center can be independently R or S, and the preferred compounds are those of formulas I-IV above in which n is a number whole number from 2 to 4. The compounds are described as being useful in the treatment of a variety of disorders including epilepsy, fading attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders and sleep disorders. The patent application number EP 01400214.1 describes the use of compounds of formula I to IV above for preventing and treating visceral pain and gastrointestinal disorders. International patent application PCT / IB02 / 01146, unpublished on the priority date of the present invention, discloses the use of compounds of the invention of formula (I) - (XXV), below, for a certain number of disorders. Fibromyalgia is not specifically cited as an adequate utility. The description of the document PCT / IB02 / 01146 is incorporated herein by reference in its entirety to the present specification.

Farrar et al., In the publication Pain 94, 149-158 (2001), refers to and uses data from an unpublished clinical study that illustrates the efficacy of an additional alpha-2-delta ligand, pregabalin, in the treatment of fibromyalgia SUMMARY OF THE INVENTION The present invention provides the use of a compound selected from the compounds (I) - (XXV), or a pharmaceutically acceptable salt, solvate or prodrug thereof, (III) (IV) (V) (VI) (VII) (VIII) (X) (XI) (XII) XVIII XIX XX XX XX XXII XXIV xxv in which R1 and R2 are each independently selected from H, linear or branched alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl and benzyl, with a condition that, except in the case of a tricyclooctane compound of formula (XVII), R and R2 are not simultaneously hydrogen, in the manufacture of a medicament for the treatment of fibromyalgia. Suitable compounds (including salts, solvates and prodrugs thereof) are: ((1 R, 5S) -3-aminomethyl-1, 5-dimethyl-bicyclo- [3.2.0] hept-3-yl) -acetic acid; ((1 S, 5R) -3-aminomethyl-1, 5-dimethyl-bicyclo- [3.2.0] hept-3-yl) -acetic acid; Acid ((1 R.SSJ-S-aminomethyl-ee-dimethyl-bicyclo-fS.1.0] hex-3-yl) acetic acid ((1 S, 5R) -3-aminomethyl-6,6-dimethyl-bicyclo - [3 .0] hex-3-yl) -acetic acid ((1 S, 2S, 5R) -2-aminomethyl-6,6-dimethyl-bicyclo- [3.1.0] hex-2-yl) -acetic acid ((1 R, 2S, 5S) -2-amnomethyl-6,6-dimethyl-b- cyclo- [3.1.0] hex-2-yl) -acetic acid ((1S, 2R) , 5R) -2-aminomethyl-6,6-dimethyl-cyclo- [3.1.0] hex-2-yl) -acetic acid ((1R, 2R, 5S) -2-aminomethyl-6 , 6-dimethyl-bicyclo- [3.1.0] hex-2-yl) -acetic acid ((1 R, 5R, 6S) -6-aminomethyl-bicyclo [3.2.0] hept-6-yl) -acetic acid; ((1S, 5S, 6S) -6-aminomethyl-bicyclo [3.2.0] hept-6-yl) -acetic acid; ((1R, 5R, 6R) -6-aminomethyl-bicyclo [3.2.0] hept-6-yl) -acetic; ((1S, 5S, 6R) -6-aminomethyl-bicyclo [3.2.0] hept-6-yl) -acetic acid; Cis ((1S, 2R, 4S, 5R) -3-aminomethyl-2,4-dimethyl-bicyclo [3.2.0] hept-3- (l) -acetic acid; trans - ((1S, 2R, 4S, 5R) -3-aminomethyl-2,4-dimethyl-bicyclo [3.2.0] hept-3-yl * -acetic acid ((IS.SR.eSJRJ-S-aminomethyl-ej-dimethyl-bicyclo-P ^. Olhept-Si!] - acetic acid ((1S, 5R, 6R7S) -3-aminornetyl-6,7-dimethyl-bicyclic- [3.2.0] hept-3-yl) -acetic acid; , 58) -7-3 ????? G? T ??? - 3.3 ^ ??? T ??? -? P ??? - [3.3.0.0] ??? - 7-?) -acetic acid ((1R, 6R, 7S) -7-aminomethyl-bicyclo [4.2.0] oct-7-yl) -acetic acid: ((1S, 6S, 7S) -7-aminomethyl-bicyclo [4.2. 0] oct-7-yl) -acetic acid ((1 R, 6R, 7R) -7-aminomethyl-bicyclo [4.2.0] oct-7-yl) -acotic acid: ((1S, 6S, 7R) -7-aminomethyl-bicyclo [4.2.0] oct-7-yl) -acetic acid ((1R, 7R, 8S) -8-aminomethyl-bicyclo [5.2.0] non-8-ii) -acetic; ((1S, 7S, 8S) -8-aminomethyl-bicyclo [5.2.0] non-8-yl) -acetic acid; ((1 R, 7R, 8R) -8-aminomethyl-bicyclo [5.2.0] ] non-8-yl) -acetic acid and ((1S, 7S, 8R) -8-aminomethyl-bicyclo [5.2.0] non-8-yl) -acetic acid The preferred compounds (including ales, solvates and prodrugs thereof) are: Acid [(IR.SR.eSJ-e-íaminometi biciclofS ^ .OJhept-e-ilJacetic; [(1S, 5S, 6R) -6- (aminomethyl) bicyclo [3.2.0] hept-6-l3-acetic acid; Acid [(1 RS, 5RS, 6RS) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid; Acid [(1 RS, 6RS, 7SR) -7- (aminomethyl) bicyclo [4.2.0] oct-7-yl] acetic acid; and Acid [(1 RS, 6RS, 7RS) -7- (aminomethyl) bicyclo [4.2.0] oct-7-yl] acetic acid. A particularly preferred compound (including the salts, solvates and prodrugs thereof) is [(1 R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] actic acid. 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 (e.g., D20, d6-acetone, d6-D SO) are equivalent to unsolvated forms and are encompassed within the scope of the present invention. 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 their appropriate mixtures. The separation of diastereomers or cis and trans isomers can be achieved by conventional techniques, for example, by fractional crystallization, chromatography or HPLC of a stereoisomeric mixture of a compound of the invention or a suitable salt or derivative thereof. An individual enantiomer of a compound of the invention can also be prepared from a corresponding optically pure intermediate or by resolution, 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 a suitable optically active acid or base, to the appropriate extent. Since the amino acids are amphoteric, the pharmacologically compatible salts can be salts of appropriate non-toxic inorganic or organic acids or bases. Suitable acid addition salts are the salts of hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, fumarate, aspartate, besilate, bicarbonate / carbonate, camsylate, D - and L-lactate, D- and L-tartrate, edisi-lato, mesylate, malonate, orotate, gluceptate, methylsulfate, stearate, glucuro-nate, 2-napsylate, tosylate, hybienate, nicotinate, isethionate, malate, maleate, citrate , gluconate, succinate, saccharate, benzoate, mesylate and pamoate. Suitable base salts are formed from bases that form non-toxic salts and examples thereof are the salts of sodium, potassium, aluminum, calcium, magnesium, zinc, choline, diolamine, olamine, arginine, glycine, tromethamine, benzathine. , lysine, meglumine and diethylamine. The salts with quaternary ammonium ions can also be prepared, for example, with the tetra-methyl-ammonium ion. The compounds of the invention can also be formed in the form of a hybrid ion. A suitable salt of the compounds of the present invention is the hydrochloride salt. For an examination of suitable salts see the publication by Berge et al., J. Pharm. Sci., 66, 1-19, 1977. Its poimorphisms are also included within the scope of the compounds of the invention. 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 entero-hepatic circulation. Drugs that are effective after parenteral administration but less effective orally, or whose half-life in plasma is considered to be too short, can be clinically modified into a prodrug form. A prodrug is a drug that has been chemically modified and that may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymes or other procedures in vivo to the parental bioactive form. This chemically modified drug, or prodrug, must have a pharmacokinetic profile different from the parental one, making possible an easier absorption through the mucosal epithelium, better formulation and / or salt solubility, improved systemic stability (for an increase of the semi -Life in plasma, for example). These chemical modifications can be (1) Derivatives of esters or amides that can be cleaved, for example, by esterases or lipases. For ester derivatives, the ester is derived from the carboxylic acid moiety of the drug molecule by known means. For amide derivatives, the amide can be derived 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 through the formation of an amide bond with the amine or carboxylic acid moiety of the drug molecule by known means. (3) Derivatives that accumulate in a site of action through membrane selection of a prodrug form or a modified prodrug form. (4) Any combination of 1 to 3. It will be further appreciated by those skilled in the art that certain moieties known to those skilled in the art as "pro-moieties", for example, as described in the "Design of Prodrugs" publication. of H. Bundgaard (Elsevier) 1985, can be placed in appropriate functionalities when these functionalities are present in compounds of the invention to also form a "prodrug". Additionally, certain compounds of the invention can act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of the compounds of the invention are included within 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. The quaternary salt is referred to as a "soft" quaternary salt since, unlike normal quaternary salts, for example, R-N + (CH3) 3, the active drug was released by hydrolysis. The "soft" quaternary salts have useful physical properties compared to the basic drug or its salts. The solubility in water can be increased in comparison with other salts, such as the hydrochloride, but more importantly there can be an increased absorption of the drug in the intestine. The increased absorption is probably due to the fact that the "blan-da" quaternary salt has tensioactive properties and is capable of micelles and ion pairs not ionized with bile acids, etc., which are able to penetrate more efficiently in the intestinal epithelium. . The prodrug, after absorption, is rapidly hydrolyzed with release of the active parental 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 as reference to the present descriptive memory. The biological activity of the compounds of the invention can be measured in a radioligand binding assay using [H3] -gabapentin and the 0028 subunit derived from porcine brain tissue (Gee NS, Brown JP, Dissanayake VUK, Offord J., Thurlow R. ., Woodruff GN, ADVAN-CEADVANCE J. Biol. Cherra., 1996; 271: 5879-5776). The results can be expressed in terms of binding affinity (2d μm or nM) The therapeutic compounds can be administered, for example, but without limitation, by the following routes: oral, buccal or sublingual in the form of tablets, capsules, multi- and nano-particles, gels, films (including muco-adhesives), powders, ovules, elixirs, pills (including liquid-filled ones), chewing gums, solutions, suspensions and sprays The compounds of the invention can be administered also in the form of osmotic dosage, or in the form of a high energy dispersion or in the form of coated or rapidly dissolving particles or a rapid disintegrating dosage form as described in Ashley Publi-cations, 2001 by Liang and Chen. The therapeutic compounds can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, intra-duodenal or intraperitoneal, intraarter ial, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intraspinal or subcutaneous, or can be administered by infusion, needle-free injectors or implant injection techniques. Also, the therapeutic compounds can be administered intranasally or by inhalation. Alternatively, the therapeutic compounds can be administered topically to the skin, mucosa, dermally or transdermally, for example, in the form of a gel, hydrogel, lotion, solution, cream, ointment, fine powder, dressing, foam, film, skin patch, seals, implants, sponges, fibers, bandage, microemulsions and their combinations. Alternatively, the therapeutic compounds may be administered rectally, for example, in the form of a suppository or pessary.

They can also be administered vaginally. The therapeutic compounds can also be administered by the ocular route. They can also be administered in the ear by the use, for example, but without limitation, of drops. The therapeutic compounds can also be used in combination with a cyclodextrin. 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 delivery by viral or non-viral techniques. Viral delivery mechanisms include, but are not limited to, adenoviral vectors, associated adenoviral vectors (AAV), viral vectors of herpes, retroviral vectors, lentiviral vectors and baculoviral vectors. Non-viral delivery mechanisms include lipid-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFA), and combinations thereof. The routes for these delivery mechanisms include, but are not limited to, the mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes. The pharmaceutical preparation of the therapeutic compounds is preferably in a unit dosage form. In this form, the pre-portion is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, in which the package contains discrete quantities of preparation, such as packaged tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be capsule, tablet, seal or tablet itself, or it can be the appropriate number of any of these in packaged form. The amount of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 1 g depending on the particular application and the potency of the active component. In a medical use, the drug can be administered three times a day in the form, for example, of capsules of 100 or 300 mg. In a therapeutic use, the compounds used in the pharmaceutical method of this invention are administered at the initial dosage 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 dosages can be varied depending on the patient's requirements, the severity of the condition being treated and the compound being used. The determination of the appropriate dosage for a particular situation is within the knowledge of the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Subsequently, the dosage is increased in small increments until the optimum effect is reached under the circumstances. For reasons of convenience, the total daily dosage can be divided and administered in parts during the day if desired. The pharmaceutical composition according to the present invention may also contain, if desired, one or more other compatible therapeutic agents, in particular, the composition may be combined with one or more compounds useful in the treatment of pain, such as those mentioned above. Thus, the present invention features a pharmaceutical composition comprising a compound selected from the formulas (I) - (XXV), one or more other pharmacologically active agents and one or more pharmaceutically acceptable carriers. GENERAL METHODS The above compounds can be synthesized from the following ketones (1) - (12), wherein R1 and R2 have the same meanings as given above: (11) (12) The intermediates of formulas (1) to (6) above are believed to be new and constitute a further aspect of the present invention. Particularly suitable intermediate ketones according to the present invention are selected from: Various methods for synthesizing the above ketones are set forth below: A. Ketone synthesis 1-12 (1) Synthesis of ketones of type (1) For example: (a) The known diester (13) is reduced to diol (14), for example, by means of lithium-aluminum hydride in an organic solvent, for example, tetrahydrofuran or diethyl ether at a temperature of 0 ° C at of reflux. (b) The diol (14) is added to methylsulfonyl chloride in pyridine or triethylamine in dichloromethane from -60 ° C to 40 ° C to produce a dimesylate of formula (15). (c) The dimesylate (15) is added to a solution of lithium-aluminum hydride in a solvent such as tetrahydrofuran or diethyl ether at a temperature of 0 ° C to reflux to produce an alkane of formula (16) . (d) The above alkene (16) is added to a mixture of carbon tetrachloride or ethyl acetate and acetonitrile to which water, sodium periodate, and ruthenium chloride (III) are added, and stirred to a temperature of -40 ° C to 80 ° C to produce the carboxylic acid of formula (17); or • to a mixture of potassium permanganate in water and dichloromethane in the presence of a phase transfer catalyst such as tetrabutylammonium bromide to produce (17). (e) The carboxylic acid (17) is added to a mixture of an alcohol such as methanol and a concentrated acid such as sulfuric acid or hydrochloric acid at a temperature from room temperature to that of reflux to produce the diester of formula (18). (f) The above diester (18) is added to a strong base such as sodium hydride or potassium tert-butoxide in a solvent such as tetrahydrofuran at the reflux temperature to provide the ketone (19). (g) The above ketone (19) is added to a mixture of dimethyl sulfoxide and water at a temperature of 00-180 ° C to produce the ketone of formula (20). (2) Synthesis of ketones of type (4) v (5) For example: (a) The known alkene (21), see BD Kramer, PD Bartlett, J. Am. Chem. Soc, 1972, 94, 3934, is mixed with an organoborane such as disiamylborane, hexyl borane or 9-BBN in a solvent such as diethyl ether. ether or tetrahydrofuran at a temperature of 0 ° C at room temperature. The resulting organoborane is mixed with a solution of concentrated sodium hydroxide and hydrogen peroxide to provide an alcohol of formula (22). (b) The alcohol (22) is oxidized, for example, with an oxidizing agent such as chromium trioxide, pyridinium dichromate or pyridinium chlorochromate in a solvent such as dichloromethane or acetone to provide the keto-na of formula (23). A similar procedure can be used for the ketone (25) with the exception that the starting material is the known alkene (24), see B. D. Kramer, P. D. Bartlett, supra. (3) Synthesis of ketones of type (3) For example: 27 28 (a) The known ketone (27) see the US patent application 60/160725, is added to a strong base such as lithium diisopropylamide or lithium hexamethyldisilazide followed by a methylating agent such as methyl iodide in a solvent such as tetrahydrofuran or diethyl ether at a temperature between -00 ° C and room temperature to provide lacetone of formula (28). (b) The ketone of formula (46) above is further methylated with a methylating agent such as methyl iodide in the presence of a strong base such as lithium diisopropylamide or lithium hexamethyldisilazide in a solvent such as tetrahydrofuran or diethyl ether at a temperature between -100 ° C and room temperature to provide the ketone product of formula (29). (4) Synthesis of ketones of type (9) v (10) These ketones are known compounds, see L. Y. Chen, L. Ghosez, Tetrahedron Letters, 1990, 31, 4467; C. Houge, AM Frisque-Hesbain, A. Mockel, L. Ghosez, JP Declercq, G. Germain, M. Van Meerss-che, J. Am. Chem. Soc, 1982, 104, 2920. These ketones can be prepared also from the known nonsaturated ketone of the general formula (76) ° (76) by reduction by hydrogenation with a suitable catalyst such as Pd / C in a suitable solvent such as ethyl acetate. (5) Synthesis of ketones of type (2) For example: 30 31 32 MeO-C 35 34 33 36 37 (a) The known carbamate (30), see W. Von der Saal, R. Reinhardt, H. M. Seidenspinner, J. Stawitz, H. Quast, Liebigs Ann. Chem., 1989,703; Z. Cekovic, R. atovic, J. Serb. Chem. Soc, 1988, 53, 595, is reused using lithium-aluminum hydride in a solvent such as tetrahydrofuran or diethylether at a temperature of 0 ° C to reflux to provide the diol (31). (b) The diol (31) is added to methylsulfonyl chloride in pyridine or triethylamine in dichloromethane at a temperature of -60 ° C to 40 ° C to produce the dimesylate of formula (32). (c) The dimesylate (32) is added to sodium or potassium cyanide in a solvent such as tetrahydrofuran, diethyl ether, dimethylsulfoxide or dimethylformamide at a temperature of 0 ° C to reflux to provide the structure dicyanide. (33). (d) The dicyanide (33) is added to a concentrated solution of potassium or sodium hydroxide at a temperature of 50 ° C at reflux to provide the diacid (34). (e) The diacid (34) is esterified to the diester (35) by the addition: • to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene or 1,4-dioxane to which a base is added as 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), triethylamine or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) at a temperature from -40 ° C to 110 ° C; or • to a mixture of methanol and a concentrated acid such as sulfuric acid or hydrochloric acid at a temperature ranging from 0 ° C to 100 ° C; or 'to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature of -40 ° C to 100 ° C; or • to diazomethane in a solvent such as benzene, toluene or dichloromethane at a temperature of -40 ° C to 40 ° C. (0) The diester (35) is added to a strong base such as sodium hydride or potassium tert-butoxide in a solvent such as tetrahydrofuran at the reflux temperature to provide the ketone (36). (G) The ketone (36) above is added to a mixture of dimethyl sulfoxide and water at a temperature of 100-180 ° C to produce lacetone of formula (37). (6) Synthesis of ketones type 7 and 8 Ketones of this type can be prepared using ruthenium complexes, see SAN. Park, J-H. Son, S-G. Kim, K. H. Ahn, Tetrahedron: Asymmetry, 1999.10, 1903. For example: (i) wherein L-ligand The known alkene (38), see H. Nishiyama, Y. Itoh, H. Mat-sumoto, SB Park, K. Itoh, J. Am. Chem. Soc, 1994,116, 2223 , was stirred with a ruthenium catalyst such as Cl2 u (pybox-ip) (CH2 = CH2) in a solvent such as dichloromethane or chloroform at a temperature of 0 ° C at room temperature to provide the ketone of structure (39). (ü) 40 41 42 (a) The known alcohol (40), see M. Asami, Bull. Chem. Soc. Jpn. , 1990, 63, 721; T. Sato, Y. Gotoh, Y. Wakabayashi, T. Fujisawa, Tetrahedron Letters, 1983, 24, 4123, is mixed with diiodomethane and alkyl zinc such as dimethyl-zinc or diethyl-zinc or a pair of zinc-copper in a solvent such as toluene or benzene at a temperature of -60 ° C to reflux to provide an alcohol of formula (41). (b) The alcohol of formula (41) is added to an oxidizing agent such as chromium trioxide, depridinium dichromate or pyridinium chlorochromate in a solvent such as dichloromethane or acetone to provide the ketone of formula (42). (7) Synthesis of ketones of type (6) 6 For example: 43 44 The known ketone (43), see W. A. Wilczak, D. I. Schuster, Tetrahedro Letters, 1986,27, 5331; D. I. Schuster, J. Eriksen, J. Org. Chem, 1979.44, 4254, is mixed with diiodomethane and an alkyl-zinc such as dimethyl-zinc or diethyl-zinc or a pair of zinc-copper in a solvent such as toluene or benzene at a temperature of 60 ° C at reflux to provide the structure ketone (44). (8) Synthesis of ketones of type (11) and (12) dD (12) The preparation of (11) can be found in the following references: • Ogino, Toshio. Preparation of bicyclo [4.2. 0] octan-7-ones. Niigata Daigaku Kyoikugakubu Kiyo, Shizen Kagaku Hen (1973), 15 26- 33. • Marko, Istvan; Ronsmans, Bruno; Hesbain-Frisque, Anne Marie; Dumas, Stephane; Ghosez, León; Ernst, Beat; Greuter, Hans. Intramolecular [2 + 2] cycloadditions of ketenes and keteniminium salts to olefins. J. Am. Chem. Soc. (1985), 107 (7), 2192-4. • Chen, Lian Yong; Ghosez, León. Study of chiral auxiliaries for the intramolecular [2 + 2] cycloaddition of a keteniminium salt to an olefinic double bond. A new asymmetric synthesis of cyclobutanones. Tetrahedron Lett. (1990), 31 (31), 4467-70. The preparation of (12) can be found in Marko et al., Supra .. B. Conversion of ketone starting materials to amino acids of the invention The above ketones can be transformed into amino acids using one of the following general methods A to E , as illustrated below for lacetone (1) in which R1 = R2 = methyl.

Method A: (a) The ketone (20) is converted to an unsaturated ester (45a) by reaction with a trialkyl phosphonoacetate such as triethyl phosphonoacetate in the presence of a base. Suitable bases include sodium hydride, potassium hydride, lithium hexamethyldisilazide, sodium or potassium, butyl lithium or potassium tert-butoxide. The reaction can be carried out in a polar aprotic organic solvent such as tetrahydrofuran, dimethylphoramide, diethyl ether or dimethyl sulfoxide at a temperature in the range of -78 ° C to 100 ° C. (b) Nitromethane is added to the unsaturated ester (45a) by a Michael addition reaction in the presence of a base and in a polar aprotic organic solvent at a temperature of -20 ° C to 100 ° C to provide the nitroester (45b) . Suitable bases include tetrabutylammonium fluoride, tetramethylguanidine, 1,5-diazabicyclo- [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, a sodium or potassium alkoxide as potassium tert-butoxide, potassium carbonate, sodium hydride or potassium fluoride. Suitable organic solvents include tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, dichloromethane, chloroform or tetrachloromethane. (c) Reduction of the nitro-ester (45b) and ring closure by reaction of the resulting amino group with the ester group provides the cyclic lac-tama (45c). The hydrogenation can be in the presence of a catalyst such as Raney nickel, palladium on carbon or a rhodium catalyst or other catalyst containing nickel or palladium in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, acetic acid, 1, 4 -dioxane, chloroform or diethyl ether at a temperature in the range of 20 ° C to 80 ° C. (d) Hydrolysis of the cyclic lactam (45c, for example, using aqueous hydrochloric acid at a concentration of 0.01 to 12 M and optionally in the presence of a solvent such as 1,4-dioxane, acetic acid or water) the amino acid (46) Method B: (a) The ketone (20) is condensed with an alkyl cyanoacetate, for example, ethyl cyanoacetate, in an organic solvent selected from toluene, benzene, xylenes or n-heptane to which are added acetic acid and β-alanine or ammonium acetate, or pyridine. The mixture is stirred at a temperature of 0 ° C to 150 ° C with water separation by using, for example, a Dean-Stark separator or activated molecular sieves, to produce the cyanoester of formula (47). (b) The cyanoester (47) is converted to the dicyanide (48) by treatment with potassium cyanide or sodium cyanide in water and ethanol or methanol. The mixture is brought to reflux and water is removed, for example, by the use of a Dean Stark separator. (c) The cyanomethyl group of the dicyanide (48) is converted to an ethoxycarbonylmethyl group by reaction with ethanol in toluene or benzene saturated with gaseous hydrochloric acid. The reaction temperature can be -30 ° C to 40 ° C. (d) The cyano group of the resulting cyanoester (49) is reduced by hydrogenation in methanol, ethanol or ethyl acetate using a catalyst such as nickel, palladium, platinum or rhodium at a temperature of 15 ° C to 60 ° C, then whereof the ring closure provides the lactam (50). (e) The hydrolysis of the lactam (50) using, for example, aqueous hydrochloric acid at a concentration of 0.01 M to 12 M and, optionally, in the presence of a solvent such as 1,4-dioxane, acetic acid or water produces the amino acid (51). Method C: (a) The cyanoester (47) is added to a mixture of chloride, bromide or benzylmagnesium iodide, in a dry solvent, for example, tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl- ether or tert-butyl methyl ether at a temperature of -100 ° C to 110 ° C giving the cyanoester of formula (52). (b) The cyano group of the cyanoester (52) is separated by means of a base, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or cesium hydroxide in a solvent, for example, ethylene glycol, 2-methoxyethyl ether, 1,4-dioxane or diethylene glycol. The mixture is stirred at a temperature of 25 ° C to 250 ° C to produce the carboxylic acid of formula (53). (c) The carboxylic acid group of the acid (53) is protected by the conversion of its alkyl group to an ester of 1-6 carbon atoms, for example, its methyl ester (54). For this purpose the acid (53) can be added to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene or 1,4-dioxane to which a base such as 1,8-diazabicyclo [5.4. 0] undec-7-ene (DBU), triethylamine or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and is stirred at a temperature of -40 ° C to 110 ° C; or • to a mixture of methanol and a concentrated acid such as sulfuric acid or hydrochloric acid at a temperature ranging from 0 ° C to 100 ° C; or • to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature of -40 ° C to 100 ° C; or • to diazomethane in a solvent such as benzene, toluene or dichloromethane at a temperature of -40 ° C to 40 ° C. (D) The phenyl group of the resulting ester (54) is oxidized to an acid group carboxylic acid by treatment with sodium periodate and ruthenium (III) chloride in a mixture of carbon tetrachloride or ethyl acetate and ace-tonitrilo which Water is added. The mixture is stirred at a temperature of -40 ° C to 80 ° C to provide the carboxylic acid (55). (E) The carboxylic acid (55) acid group is converted to iso-cyanate by addition • a mixture of a base selected from triethylamine or dii- sopropiletilamina and a solvent selected from toluene, benzene, xylenes, tetrahydrofuran, diethyl ether or n-heptane to which diphenyphosphoryl azide (DPPA) is added and stirred at a temperature of 0 ° C to 150 ° C to produce the isocyanate of formula (26); or • to ethyl chloroformate or isobutyl chloroformate and a base as triethylamine or diisopropylethylamine in tetrahydrofuran or acetone or diethyl ether at a temperature of -40 ° C to 78 ° C followed by addition of sodium azide in water and tetrahydrofuran or acetone followed by the addition of toluene or benzene and bring to reflux. (f) The isocyanate and ester groups of the compound (56) are simultaneously hydrolyzed to amino and carboxylic acid groups, for example, by means of aqueous hydrochloric acid at a concentration of 0.01 M to 12 optionally in the presence of a solvent as, 4-dioxane, acetic acid or water to produce the amino acid (57). Method D: (a) As a first step in the protection of the carboxylic acid group of the acid (53), it is converted to its chloride (58) by reaction at a temperature of -40 ° C to 110 ° C with, for example, oxalyl chloride or thionyl chloride in an aprotic organic solvent, for example, dichloromethane, chloroform, diethyl ether, toluene or tert-butyl methyl ether to which 0.01 mole percent to 10 mole percent? is added, ? -dimethylformamide (DMF). (b) The chloride (58) is converted to its tert-butyl ester, for example, by reaction with tert-butyl alcohol in an aprotic organic solvent, for example, dichloromethane, chloroform, diethyl ether, toluene or tert-butyl- methyl-ether to which is added?,? - diisopropylletllamine (DIPEA) or triethylamine. The reaction mixture is stirred at a temperature of -40 ° C to 110 ° C to produce the ester of formula (59). (c) The phenyl group of the ester (59) is oxidized to a carboxylic acid group by reaction with sodium periodate and ruthenium (III) chloride in a mixture of carbon tetrachloride or ethyl acetate and acetonitrile to which water is added . The reaction mixture is stirred at a temperature of -40 ° C to 80 ° C to produce the carboxylic acid of formula (60). (d) The carboxyl group of the acid (60) is converted to an ester group by addition to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene or 1,4-dioxane to which a base is added. as 1, 8-dlazabicyclo [5.4.0] undec-7-ene (DBU), triethylamine or, 5-diazabicyl [4.3.0] non-5-ene (DBN) and is stirred at a temperature of -40 ° C at 110 ° C to produce the ester of formula (61); or • to a mixture of methanol and a concentrated acid such as sulfuric acid or hydrochloric acid at a temperature ranging from 0 ° C to 100 ° C; or • to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature of -40 ° C to 100 ° C; or • to diazomethane in a solvent such as benzene, toluene or dichloromethane at a temperature of -40 ° C to 40 ° C. (e) The tert-butoxy group is separated from the diester (61) by reaction with trifluoroacetic acid in a solvent, for example, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether or tert-butyl-methyl. -ether. The reaction mixture is stirred at a temperature of -40 ° C to 110 ° C to provide the carboxylic acid of formula (62). (f) The ester group of the acid (62) is converted to isocyanate (63) by addition to a mixture of a base selected from triethylamine or diisopropylethylamine and a solvent selected from toluene, benzene, xylenes, tetrahydrofuran, diethyl- ether or n-heptane to which diphenyl phosphoryl azide (DPPA) is added and stirred at a temperature of 0 ° C to 150 ° C; or • to ethyl chloroformate or isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine in tetrahydrofuran or acetone or diethyl ether at a temperature of -40 ° C to 78 ° C followed by the addition of sodium azide in water and tetrahydrofuran or acetone followed by the addition of toluene or benzene and brought to reflux. (g) The simultaneous hydrolysis of the isocyanate and the ester groups of the compound (63), for example, by means of aqueous hydrochloric acid at a concentration of 0.01 M to 12 M in the presence or absence of a solvent such as 1, 4- dioxane, acetic acid or water provides the amino acid (64). Method E: (a) The cyanoester (47) is reacted with allyl magnesium chloride or bromide or 2-butenylmagnesium chloride or a dialkyl zinc such as dimethyl-zinc or a copper (I) salt as copper iodide (I) or copper (I) cyanide in a dry organic solvent, for example, tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl ether or tert-butyl methyl ether at a temperature of -100. ° C at 110 ° C to provide an unsaturated addition product of formula (65). (b) The cyano group of the addition product (65) is separated by reaction with a base, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or cesium hydroxide in an organic solvent selected from ethylene glycol, 2-methoxyethyl ether, 1,4-dioxane or diethylene glycol. The reaction mixture is stirred at a temperature of 25 ° C to 250 ° C to provide a carboxylic acid of formula (66). (c) The carboxylic acid group of the acid (66) is converted to an ester group by addition to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene or 1,4-dioxane to which a base is added as 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), triethylamine or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and is stirred at a temperature of -40 ° C at 110 ° C to produce the ester of formula (67); or • to a mixture of methanol and a concentrated acid such as sulfuric acid or hydrochloric acid at a temperature ranging from 0 ° C to 100 ° C; or to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature of -40 ° C to 100 ° C or to diazomethane in a solvent such as benzene, toluene or dichloromethane at a temperature of -40 ° C to 40 ° C. (d) The unsaturated group in the ester (67) is oxidized by means of sodium periodate and ruthenium chloride (III) in a mixture of carbon tetrachloride or ethyl acetate and acetonitrile to which water is added. The mixture is stirred at a temperature of -40 ° C to 80 ° C to provide a carboxylic acid of formula (68). (e) The carboxylic acid (68) is converted to an amino acid (69) as in Method C. The above ketones can also be transformed into amino acids using one of the following general methods F to G, as illustrated below for the type ketone (9). Method F (70) (71) (72) (a) The ketone is converted to the nitro-ester (70) according to the methods described above. (b) The nitro-ester (70) is hydrolyzed with a suitable base, such as aqueous sodium hydroxide, to produce the nitro-acid (71) which is reduced by suitable hydrogenation, for example, H2 on a palladium catalyst / carbon in a suitable solvent such as ethanol, to provide the amino acid (72). Method G (73) (74) (75) (a) The unsaturated ester (73) in which R is benzyl or diphenylmethyl, can be prepared from the ketone according to any of the general methods described above, (b) The nitro-ester (74) is converted into the amino acid (75) by reduction by catalytic hydrogenation in a suitable solvent. The compounds of the invention can alternatively be prepared from the known unsaturated version of a ketone of type (8) as follows in methods H and I: Method H (76) (77) (78) (79) (80) (a) The ketone (76) is converted to the unsaturated nitro ester (78) according to the general methods described above. (b) The nitro-ester (78) is hydrolyzed with a suitable base, such as aqueous sodium hydroxide, to provide the nitro-acid (79) which is reduced by hydrogenation, for example, H2 on a pala-dio catalyst / carbon in a suitable solvent such as ethanol, to provide the amino acid (80). Method I (a) The unsaturated nitro ester (82) can be prepared from the ketone (76) according to the methods generally described above. (b) The nitro ester (82) is converted to the amino acid (83) by reduction by catalytic hydrogenation in a suitable solvent. A pharmaceutically acceptable salt of a compound of the invention can be easily prepared by mixing together solutions of a compound of the invention and the desired acid or base, to the appropriate extent. The salt can precipitate in the solution and be collected by filtration or it can be recovered by evaporation of the solvent. Referring to the above general methods, it will be readily understood by one skilled in the art that when protecting groups are present, they will generally be interchangeable with other protecting groups of a similar nature, for example, when an acidic group is described as being protected with an ethyl group, this can easily be exchanged with any suitable alkyl group, suitably a Ci-6 alkyl group. It will be readily understood by the person skilled in the art that particular steps in the general methods presented hereinabove may be suitably combined in any other manner not shown to provide a compound according to the present invention. Therefore, in summary, the invention provides: (i) the use of a compound of formula I-XXV or a salt, solvate, polymorph, prodrug or composition thereof, for the manufacture of a medicament for the treatment of flbromyalgia; (ii) a method for the treatment of fibromyalgia in a mammal, which includes treating said mammal with an effective amount of a compound of formula I-XXV or with a pharmaceutically acceptable salt, solvate, polymorph, prodrug or composition thereof; and (ii) a pharmaceutical composition for the treatment of fibromyalgia, which comprises a compound of formula I-XXV or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof and a suitable vehicle. The present invention is illustrated by the following examples and non-limiting intermediates. EXAMPLE 1 Hydrochloride of r (1R, 5R.6S) -6- (aminomethanoyl [3.2.Qlhept-6-yl-a1acetic acid) Isocyanate of preparation 9 (about 9.33mmol) and hydrochloric acid 6 N (30 mL) were refluxed for 18 h.The mixture was allowed to cool, diluted with water (60 mL) and extracted with dichloromethane (2 x 50 mL) .The aqueous phase was concentrated under reduced pressure to leave the mixture. Provide a yellow solid which was washed with ethyl acetate and acetonitrile to give 0.92 g of the title compound as a white solid H1-RN (400 MHz, d6-DMSO): d = 7.94 (3H, s wide), 3.15 (1H, d), 3.07 (1H, d), 2.72 (1H, quin), 2.46 (1H, m), 2.42 (H, d) , 2.33 (H, d), 1, 98 (1 H, m), 1, 80-1, 64 (2H, m), 1.59 (1 H, m), 1, 48-1, 28 (3H, m), 1, 23 (1 H, dd). LRMS (APCI): m / z [(MH-HCI) *] 184. LCMS (Prodigy ODS3 column (3 μ) 150 mm x 4.6 mm di, 20-100% acetonitrile + 0.1% formic acid) Retention time = 4.34 minutes, 100% purity. [<; X] D (c = 0.127 in methanol) = -12.4 °. Microanalysis: Found: C, 54.64; H, 8.19; N, 6.42. C 10 H 17 NO 2, HCl requires C, 54.67; H, 8.26; N, 6.38%. Melting point (Perkin Elmer DSC7): 198 Alternatively: EXAMPLE 1A [(1 R.5R, 6S) -6- (aminomethylD-bicyclo | 3.2.01hept-6-yl-acetic acid hydrochloride The nitro-acid of preparation 32 (2.0 g, 9.4 mmol) in (1: 1 1PA: H20 or) 1: 1 MeCN: H20 (40 mL, 20 mL / g) was hydrogenated using 10% Pd / C (0.2 g; 0.1 g / g) at 50 ° C and 414 kPa for 18 hours The reaction mixture was filtered through Celite and the filter cartridge was washed with 1: 1 IPA: H20 or 1: 1 eCN: H20 (20 mL) The combined filtrate and wash liquid were concentrated under vacuum and subjected to dry azeotropic distillation with additional IPA or MeCN to yield the title compound as a white crystalline solid (1.52 g) EXAMPLE 1 B Hydrochloride acid f (1R.5R, 6S) -6- (aminomethyl) bicyclo r3.2.01hept-6-nacinate The lactam of Preparation 33 (4.70 g, 28.44 mmol) and hydrochloric acid (57 ml of a 6 N solution) were refluxed together for 6 h. cooled and then diluted with water (60 ml). The aqueous layer was washed with dichloromethane (2 x 100 mL), filtered and then evaporated under reduced pressure. The resulting off white solid was triturated with ethyl acetate and recrystallized using acetonitrile: water 1: 1 to give the title compound (4.51 g). EXAMPLE 1 C Acid f (1 R.5R.6S) -6- (amnnomethyndicichlor3.2.01hept-6-il1acetic (Hybrid ion) The amino acid hydrochloride of Example 1 (2.2 g) was dissolved in 7.25 ml of H2O (3.3 ml / g). The solution was adjusted to pH 7.5, initially with approximately 1.6 ml of aqueous NaOH, but finally with a few drops of 0.1 N aqueous NaOH. The precipitated hybrid ion was stirred for 8 hours at 8 ° C and the suspension it was filtered and the residues were washed with ice-cold water (6 ml). The filter cake moistened with water was suspended in IPA (5 ml) and refluxed for 10 minutes. After cooling to room temperature the suspension was filtered and the residues were washed with IPA (5 ml). The filter cake was resuspended in IPA (15 mL), refluxed and cooled to room temperature. The suspension was filtered and the residues were washed with IPA (5 ml) and dried under vacuum at 40 ° C to a constant weight to yield the title compound as a crystalline solid. (1.4 g). Melting point (Perkin Elmer DSC7): 208 ° C. EXAMPLE 2 Acid hydrochloride [nS.5S, 6R) -6- (aminometiO-biciclor3.2.01heDt-6-il1acetic acid The isocyanate of Preparation 12 (approximately 1.0 mmol) and 6 N hydrochloric acid (30 mL) were refluxed for 16 h. The mixture was allowed to cool, diluted with water (100 ml) and extracted with dichloromethane (2 x 50 ml). The aqueous phase was concentrated under reduced pressure to give a yellow solid and washed with ethyl acetate and acetonitrile to give 0.94 g of the title compound as a white solid. H1-NMR (400 Hz, d6-DMSO): d = 7.94 (3H, broad s), 3.15 (1H, d), 3.07 (1 H, d), 2.72 (1 H, quin), 2.46 (1 H, m), 2.42 (H, d), 2.33 (1 H, d), 1.98. (1 H, m), 1, 80-1, 64 (2H, m), 1, 59 (1H, m), 1, 48-1, 28 (3H, m), 1, 23 (1H, dd ), LRMS (APCI): m / z [(MH-HCI) +] 184. LCMS (Prodigy ODS3 column (3 μ) 150 mm x 4.6 mm dL, 20-100% Acetonitrile + 0.1% formic acid ). Retention time = 4.34 min, 00% purity. [] D (c = 0.35 in methanol) = + 13.0 °. EXAMPLE 3 nRS.5RS.6RSV6- (aminomethyl-biciclor3.2.0] hept-6-yl-aethac acid hydrochloride The isocyanate of Preparation 17 (approximately 2.79 mmol) and 6 N hydrochloric acid (15 mL) were refluxed for 18 h. The mixture was allowed to cool, was diluted with water (60 ml) and extracted with dichloromethane (3 x 50 ml). The aqueous phase was concentrated under reduced pressure to provide a yellow solid which was washed with ethyl acetate and acetonitrile to give 0.45 g of the title compound as a white solid. H1-NMR (400 MHz, d6-D SO): 8 = 7.84 (3H, broad s), 2.92 (1 H, d), 2.85 (1H, d), 2.75 (1H, t), 2.69 (1H, d), 2.59 (1 H, d), 2.39 (1H, t), 1, 81-1, 62 (4H, m), 1, 41-1, 30 (4H, m). LRMS (APCI): m / z [(MH-HCI) +] 184. LCMS (Prodigy ODS3 column (3μ) 150 mm x 4.6 mm d.i., 20-100% Acetonitrile + 0.1% formic acid). Retention time = 4.27 min, 99.8% purity. EXAMPLE 4 Hydrochloride of acid f (1 RS.6RS.7SRV7-faminometin-biciclor4.2.01oct-7-il] acetic acid The lactam of Preparation 22 (3.20 g, 17.9 mmol) was heated to reflux in 1.4 dioxane (15 mL) and 6 N HCl (50 mL). After 4 h the mixture was cooled to room temperature and washed with dichloromethane (2 x 30 mL). The aqueous phase was collected and the solvent was removed in vacuo. The residue was triturated with ethyl acetate and the resulting solid was collected by filtration and dried under vacuum to provide 2.74 of the title compound as a white solid. H-NMR (400 MHz, D20): 3.24 (2H, m), 2.58 (2H, s), 2.39 (1 H, m), 2.03 (1 H, m), 1, 76 (2H, m), 1, 59-1, 10 (7H, m), 0.96 (1H, m). LRMS (APCl): m / z [(MH-HCl) +] 198. EXAMPLE 5 [(1 RS.6RS.7RSV7- (aminomethyl-4-cyclo [4.2.01oct-7-yl-acetic acid] hydrochloride] Diphenylphosphoryl azide (0.43 ml, 1.98 mmol) was added to a stirring solution of triethylamine (0.28 ml, 2.03 mmol) and the acid of Preparation 29 (0.47 g, 1%). 96 mmol approximately) in toluene (15 ml) at room temperature under nitrogen. The mixture was stirred for 16 h and then heated at 35 ° C for 1 h. The mixture was allowed to cool, was diluted with ethyl acetate (60 mL), washed with saturated aqueous sodium hydrogen carbonate (2 x 100 mL), brine and dried (MgSO4). The solvent was removed under reduced pressure and the resulting yellow oil was heated to reflux in 6 N HCl (20 mL). After 18 hours the mixture was cooled to room temperature and washed with dichloromethane (2 x 60 mL) and diethyl ether (60 mL). The aqueous phase was collected and the solvent was removed in vacuo. The residue was triturated with ethyl acetate and the resulting solid was collected by filtration and dried under vacuum to provide 0.304 g of the title compound as a white solid. H-NMR (400 MHz, d6-DMSO): 3.04 (1 H, d), 2.99 (1 H, d), 2.68 (1 H, d), 62 (1 H, d), 1.98 (1 H, m), 1.83 (1H, t), 1, 69-1, 28 (9H, m), 1.00 (1H, m). LRMS (APCI): m / z [MH-HCI) +] 198. PREPARATION 1 (1RS, 5RSVbiciclof3.2.01heptan-6-one Palladium (1 g, 10% w / w over carbon) was added to a solution of bicyclo [3.2.0] hept-2-en-6-one (12 mL, 111.3 mmol) in ethyl acetate ( 100 ml) and the mixture was hydrogenated for 6 hours at 30 ° C and 483 kPa. The reaction mixture was filtered and the solvent was evaporated under reduced pressure to provide 12.1 g of the title compound as a colorless oil. vmax (film) / cm_1 1777. H1-NMR (400 MHz, CDCl3): d = 3.54 (1H, m), 3.19 (1H, ddd), 2.88 (1H, m), 2 , 49 (1H, ddd), 2.04 (1 H, m), 1, 91-1, 49 (5H, m). PREPARATION 1A (1R.5R) -biciclor3.2.0lheptan-6-one A solution of (1S, 5R) -bicyclo [3.2.0] hept-2-en-6-one1 (50.0 g; 462 mmol) in EtOAc (375 ml) was hydrogenated using 50% wet Pd / C (5.0 g) at 414 kPa for 8 hours at room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to yield 41.3 g of the title compound as a colorless oil. H1-NMR (400 MHz, CDCl 3): d = 3.55 (1 H, m), 3.20 (1 H, m), 2.90 (1 H, m), 2.50 (1 H, m) , 2.0-1, 5 (6H, m). 1 Ref: EP 0074856. PREPARATION 2 (2E / Z) - (1RS.5RS: Vbiciclor3.2.01heDt-6-ylidene (ethyl cyano-ethanoate The ketone of Preparation 1 (22.4 g, 204.1 mmol), ethyl cyanoacetate (21.7 mL, 204.1 mmol), ammonium acetate (15.7 g, 204.1 mmol) and Glacial acetic acid (11.7 mL, 204.1 mmol) was refluxed in toluene (220 mL) using a Dean Stark separator. After 8 h, the mixture was allowed to cool and was diluted with ethyl acetate (30 mL), washed with water (3 x 50 mL), brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed (S1O2, heptane / ethyl acetate, 95: 5 to 7: 3) to provide 30 g of a 6: 4 mixture of isomers of the title compound as a yellow solid. max (film) / cm "1 2225, 1725, 1640. H1-NMR (400 MHz, CDCl 3): d (major isomer) = 4.26 (2H, m), 3.64 (1H, m), 3, 36 (1 H, ddd), 2.96 (1 H, m), 2.70 (1 H, dt), 2.11 (1 H, m), (1, 92-1, 58, 5H, m ), 1, 32 (3H, m), 8 (minor isomer) = 4.26 (2H, m), 3.85 (1H, m), 3.15 (1H, ddd), 2.96 ( 1 H, m), 2.52 (1 H, dt, J 20, 0.4, 4), 2.02 (1 H, m), (1, 92-1, 58, 5H, m), 1 , 32 (3H, m) .LR S (APCI): m / z [MH] 204. PREPARATION 3 rnRS.5RS.6RS 6-Benzylbichloride3.2.01hept-6-n (cyano ethyl acetate The cyanoester from Preparation 2 (10.0 g, 48.7 mmol) in THF (60 mL) was added over 1 h to a stirred solution of benzyl magnesium chloride (78 mL of a 1 M solution in ether, 78 mmol) in THF (100 ml) at -78 ° C under argon. After stirring for 2 h at this temperature, the mixture was quenched by the addition of saturated ammonium chloride solution (40 ml). The mixture was allowed to warm to room temperature and dilute hydrochloric acid (150 ml) was added. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure to provide the title compound as a mixture of diastereoisomers and a yellow oil form which was used in the crude in the next step, max (film) / cm_ 12247, 1741. LRMS (APCI): m / z [MH] 296. PREPARATION 4 Acid G (1 RS.5RS.6SR) -6-benzylbicycloi3.2.01heDt-6-ill- acetic The mixture of the diastereomeric cyano-esters of Preparation 3 (20.3 g, 68.4 mmol) and potassium hydroxide (23.0 g, 410.4 mmol) was heated to 160 ° C in ethylene glycol (350 mi) for 38 h. After this period of time, the mixture was allowed to cool and dilute hydrochloric acid (300 ml) was carefully added. The mixture was extracted with ethyl acetate (3 x 200 mL) and the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane / ethyl acetate, 8: 2) to provide 14.6 g of the racemic diastereomer title compound as a white solid. vmax (film) / cm "1 3344, 1704. H1-NMR (400 Hz, CDCl 3): d = 7.31-7, 22 (5H, m), 3.02 (1H, d), 2.97 ( 1 H, d), 2.64 (2 H, m), 2.34 (1 H, d), 2.24 (1 H, d), 2.13 (1 H, m), 1.84-1, 59 (3H, m), 1, 50- 1.32 (4H, m).

LRMS (APCI): m / z [M-H] 243. PREPARATION 5 U 1 Acid R.5R.6R) -6-benzylbicyclo3.2.01heDt-6-ill-acetic (R) - (+) - -Methylbenzylamine (6.67 g, 55 mmol) was added to a stirred solution of the racemic acid of Preparation 4 (24 g, 98.2 mmol) dissolved in ethyl acetate. The acid salt was separated by precipitation from the solution as a white solid. This was recrystallized three times from ethyl acetate to provide 8.5 g of the acid salt. Further recrystallization of the residue gave an additional batch of 8.5 g of the acid salt. The first batch of the salt was taken up in dichloromethane, washed with dilute hydrochloric acid, brine and dried (MgSO4). The solvent was evaporated under reduced pressure to provide 5.0 g of the title compound as a white solid. HPLC (Chiralcel OD 250 x 4.6 mm column (mobile phase: 90% hexane, 10% IPA cont 0.5% TFA)]: retention time = 5.1 minutes (94% ee). a] D (c = 1.13 in methanol) = -20.2 ° The second batch of the salt was taken up in dichloromethane, washed with dilute hydrochloric acid, brine and dried (MgSO4) to give an additional 5 g of acid 86% ee Analogously prepared: PREPARATION 6 Acid r (1S, 5S.6R) -6-benzylbicyclo3.2.0lhept-6-ill-acetic by recrystallization of the salt generated by the addition of (S) - (-) - α-methylbenzylamine. HPLC [Chiralcel OD 250 x 4.6 mm column (Mobile phase: 90% hexane, 0% IPA containing 0.5% TFA)]: Retention time = 4.2 min (95% ee).

ND (C = 1.0 in methanol) = + 17.3 ° PREPARATION 7 r (1R.5R.6S) -6-benzylbicyclof3.2.0] hept-6-inacetate dd methyl Trimethylsilyldiazomethane (17.7 ml of a 2M solution in hexane, 35.4 mmol) was added dropwise to a stirred solution of the acid of Preparation 5 (7.85 g, 32.1 mmol) in a mixture of toluene (90 ml) and methanol (22.5 ml) at 0 ° C under argon. The mixture was allowed to warm to room temperature and was stirred for 4 h. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (150 ml), washed with saturated sodium hydrogen carbonate (150 ml), dilute hydrochloric acid (100 ml), brine and dried (MgSO 4).; 4). The solvent was evaporated under reduced pressure. The residue was chromatographed (SIO2, heptane / ethyl acetate, 9: 1) to afford 7.0 g of the title compound as a colorless oil. Vmax (film) / cm "1 1736. H1-NMR (400 MHz, CDCl 3): d = 7.28-7.21 (5H, m), 3.67 (3H, s), 2.97 (1 H , d), 2.92 (1 H, d,), 2.65-2, 60 (2H, m), 2.26 (1H, d), 2.18 (1 H, d), 2.08 (1 H, m), 1, 82-1, 52 (3H, m), 1, 48-1, 22 (4H, m) LRMS (APCI): m / z [MEt] 259. [a]? (c = 0.11 in methanol) = -24, 1 PREPARATION 8 Acid f (1 R.5R.6S) -6- (2-methoxy-2-oxoethyl) bicyclo-f3.2.01hept-6- l] acetic The ester of Preparation 7 (7.0 g, 27.1 mmol) and sodium periodate (81.1 g, 379.3 mmol) were stirred together in ethyl acetate (100 mL), acetonitrile (100 mL) and water (150 mi) for 5 minutes. The mixture was cooled to 0 ° C and ruthenium chloride hydrate (III) (0.11 g, 0.54 mmol) was added to the reaction mixture. The reaction was allowed to warm to room temperature and was stirred for 24 h. Diethyl ether (150 ml) was added and the mixture was stirred for 40 minutes. Dilute hydrochloric acid (200 ml) was added to the mixture which was then extracted with ethyl acetate (3 x 100 mmI). The combined organic fractions were washed with saturated sodium thiosulfate solution, brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure to provide the title compound as a yellow oil. vmax (film) / cm "1 1733, 1715. H1-NMR (400 MHz, CDCl 3): d = 3.65 (3H, s), 2.82-2.76 (3H, m), 2.55- 2.49 (3H, m), 2.05 (1H, m), 1.81 (1 H, m), 1, 73-1, 69 (2H, m), 1, 49-1, 28 (4H , m). LRMS (APCl): m / z [MH] 225. PREPARATION 9 [nR.5R.6S) -6-nsocianatometnibiCichlor3.2.01hept-6-yl1 methyl acetate Diphenylphosphoryl azide (8.45 ml, 39.2 mmol) was added to a stirring solution of triethylamine (5%)., 6 mL, 40.4 mmol) and the acid of Preparation 8 (8.78 g, 38.8 mmol) in toluene (80 mL) at room temperature under nitrogen. The mixture was stirred for 3 hours and then heated at 35 ° C for 1.5 hours. The mixture was allowed to cool, diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium hydrogen carbonate (150 mL), brine and dried (MgSC). The solvent was removed under reduced pressure to provide 8.7 g of the title compound as a yellow oil. vmax (film) / cnT1 2265, 2171, 1733.

PREPARATION 10 (1S.5S.6RV6-benzylbicyclo [3.2.01hept-6-methyl inacetate] ph C02Me Trimethylsilyldiazomethane (5.7 ml of a 2 M solution in hexane, 11.4 mmol) was added dropwise to a stirred solution of the acid of Preparation 6 (2.77 g, 11.3 mmol) in a mixture of toluene (30 ml) and methanol (7.5 ml) at 0 ° C under argon. The mixture was allowed to warm to room temperature and was stirred for 4 h. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (100 ml), washed with saturated sodium hydrogen carbonate (100 ml), dilute hydrochloric acid (100 ml), brine and dried (MgSO 4). . The solvent was evaporated under reduced pressure. The residue was chromatographed (S1O2, heptane / ethyl acetate, 9: 1) to give 2.84 g of the title compound as a colorless oil.

H1-NMR (400 MHz, CDCl 3): d = 7, 28-7, 21 (5H, m), 3.67 (3H, s), 2.97 (1H, d), 2.92 (1H, d,), 2.65-2, 60 (2H, m), 2.26 (1H, d), 2.18 (1H, d), 2.08 (1H, m), 1.82-1, 52 (3H, m), 1, 48-1, 22 (4H, m). [a] D (c = 0.11 in methanol) = +23, 1. PREPARATION 11 Acid r (1S.5S.6RV6- (2-methoxy-2-oxoetih-bicyclo-r3.2.01hept-6-il) acetic CO "H C02 e The ester of Preparation 10 (7.0 g, 27.1 mmol) and sodium periodate (81.1 g, 379.3 mmol) were stirred together in ethyl acetate (100 mL), acetonitrile (100 mL) and water (150 mi) for 5 minutes. The mixture was cooled to 0 ° C and ruthenium chloride (III) hydrate (0.11 g, 0.54 mmol) was added to the reaction mixture. The reaction was allowed to warm to room temperature and was stirred for 24 h. Diethyl ether (150 ml) was added and the mixture was stirred for 40 minutes. Dilute hydrochloric acid (220 ml) was added to the mixture which was then extracted with ethyl acetate (3 x 100 ml). The combined organic fractions were washed with saturated sodium thiosulfate solution, brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure to provide the title compound as a yellow oil. H1-R N (400 Hz, CDCl 3): d = 3.65 (3H, s), 2.82-2.76 (3H, m), 2.55-2, 49 (3H, m), 2.05 (1H, m), 1.81 (1H, m), 1, 73-1, 69 (2H, m), 1, 49-1, 28 (4H, m) . PREPARATION 12 rf1S.5S.6R) -6-fisocianatometinbiciclor3.2.01hept-6-methyl methyl acetate Diphenylphosphoryl azide (2.4 ml, 11.1 mmol) was added to a stirred solution of triethylamine (1.6 ml, 11.4 mmol) and the acid of Preparation 1 (1.0 mmol about) in toluene. (30 ml) at room temperature under nitrogen. The mixture was refluxed for 2 hours. The mixture was allowed to cool, diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium hydrogen carbonate (2 x 150 mL), brine and dried (MgSO4). The solvent was removed under reduced pressure to provide the title compound as a yellow oil, max (film) / cm "1 2265, 2151, 1734. PREPARATION 13 r (1 RS.5RS.6SR) -6-benzylbicyclo3. 2.01hept-6-tere-butyl inacetate Oxalyl chloride (0.92 ml, 10.5 mmol) was added dropwise to a stirred solution of the acid of Preparation 4 (2.34 g, 9.58 mmol) in dichloromethane (30 ml) under argon a 0 ° C. Dimethyl formamide (0.3 ml) was added carefully and the mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The solvent was removed in vacuo and the residue was diluted with dichloromethane (20 ml). 2-Methyl-propan-1-ol (10 mL) in dichloromethane (20 mL) was carefully added to the reaction mixture under argon followed by isopropylethylamine (2.5 mL, 14.4 mmol). The mixture was stirred for 17 hours and then taken up in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate (2 x 200 ml) and dried (MgSO 4). The solvent was removed under reduced pressure and the residue was chromatographed (SiO 2, heptane / ethyl acetate 95: 5) to give the title compound (2.40 g) as a yellow oil. max (film) / cm "1 1727. H1-NMR (400 MHz, CDCl 3): d = 7.28-7, 21 (5H, m, Ph), 2.98 (1 H, d), 2.92. (1H, d), 2.64-2.56 (2H, m), 2.16 (1H, m), 2.09 (1 H, d), 2.04 (1 H, m), 1, 80-1, 50 (3 H, m), 1, 48 (9H, s), 1, 47-1, 20 (4H, m) PREPARATION 14 Acid í (1 RS.5RS.6SR) -6- ( 2-tert-butoxy-2-oxoetin-biciclof3.2.0 lhept-6-iljacetic The ester of Preparation 13 (2.4 g, 7.99 mmol) and sodium periodate (23.93 g, 111.8 mmol) were stirred together in ethyl acetate (24 mL), acetonitrile (24 mL) and water (36 mi) for 5 minutes. The mixture was cooled to 0 ° C and ruthenium chloride hydrate (III) (0.033 g, 0.16 mmol) was added to the reaction mixture. The reaction was allowed to warm to room temperature and was stirred for 24 h. Diethyl ether (60 ml) was added and the mixture was stirred for 40 minutes. Dilute hydrochloric acid (150 ml) was added to the mixture which was then extracted with ethyl acetate (3 x 100 ml). The combined organic fractions were washed with brine, dried (MgSC) and the solvent was evaporated under reduced pressure to give the title compound (1.78 g, 83%) as a yellow oil, vmax (film) / cm "1 1728, 714. H NMR (400 MHz, CDCl 3): d = 2.78 (1 H, d), 2.71 (1 H, d), 2.43 (1 H, d), 2, 38 (1 H, d), 2.01 (1 H, m), 1, 86-1, 64 (3H, m), 1, 52-1, 36 (6H, m), 1.45 (9H, s). LRMS (APCI): m / z [MH] 267. PREPARATION 15 Methyl ester of acid rMRS.5RS.6SR) -6- (2-tert-butoxy-2-oxoethyl) biciclof3.2.01hept-6-il1acetic Tritymethyldiazomethane (4.3 ml of a 2M solution in hexane, 8.6 mmol) was added dropwise to a stirred solution of the acid of Preparation 14 (1.78 g, 6.63 mmol) in a mixture of toluene (24 ml) and meta-nol (6 ml) at 0 ° C under argon. The mixture was allowed to warm to room temperature and was stirred for 24 h. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (100 ml), washed with saturated sodium hydrogencarbonate (100 ml), dilute hydrochloric acid (100 ml), brine and dried (gS04). . The solvent was evaporated under reduced pressure to provide the title compound as a yellow oil, vmax (film) / cm "1 1732. LRMS (APCI): m / z [M-OtBu] 209. PREPARATION 16 Acid f ( 1RS.5RS.6RSV6-f2-methoxy-2-oxoetin-bicyclo-r3.2.01hept-6-yl] acetic Trifluoroacetic acid (5 ml) was added dropwise to a stirred solution of the ester of Preparation 15 (about 6.63 mmol) in dichloromethane (15 ml) at 0 ° C. The mixture was allowed to warm to room temperature and was stirred for an additional 17 hours. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution until it reached a neutral pH and extracted with dichloromethane (50 ml). It was then re-acidified to pH 4 with dilute hydrochloric acid. The mixture was then extracted further with dichloromethane (2 x 50 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was removed under reduced pressure. The residue was purified by chromatography (S¡C> 2, 8: 2 to 6: 4 heptane / ethyl acetate) to give 0.63 g of the title compound as a colorless oil. vmax (film) / cm "1 3200, 1738, 1705. H1 NMR (400 MHz, CDCl 3): d = 3.68 (3H, s), 2.84-2.73 (3H, m), 2.61 -2.48 (3H, m), 2.03 (1 H, m), 1.80 (1 H, m), 1, 79-1, 32 (6H, m) LRMS (APCI): m / z [MH] 225. PREPARATION 17 r (1 RS.5RS.6RS) -6- (isocanatomethylbichloride3.2.01hept-6-methyl acetate) Diphenylphosphoryl azide (0.61 ml, 2.82 mmol), triethylamine (0.40 ml, 2.90 mmol) and the acid from Preparation 16 (0.63 g, 2.79 mmol) were brought to reflux. toluene (15 ml) for 6 h. The mixture was allowed to cool and was diluted with ethyl acetate (60 ml). The resulting solution was washed with saturated aqueous sodium hydrogen carbonate (150 ml), brine and dried (g S04). The solvent was removed under reduced pressure to provide the title compound as a yellow oil. Rf (heptane-ethyl acetate, 9: 1) 0.36. Vmax (film) / cm "1 2259, 2171, 1736. PREPARATION 18 (1RS.6SR 8.8-dichlorobicicofof.2.2.0] octan-7-one Copper (II) sulfate (2.0 g, 8.0 mmol) was dissolved in water (75 ml) and added to zinc powder (30 g) The mixture was stirred for 2 hours.The mixture was filtered and the solid was collected, washed twice with acetone and dried under vacuum at 100 °. C for 24 hours, a part of activated zinc (8, 0 g) was added to a solution of cyclohexene (10 mL, 98.9 mmol) in diethyl ether (180 mL). Trichloroacetyl chloride (10.48 ml, 93.96 mmol) in diethyl ether (20 ml) was added at such a rate that the mixture was kept under reflux. After the addition was complete, the mixture was refluxed for 4 hours. The mixture was cooled to room temperature, diluted with diethyl ether (50 ml) and carefully poured into a saturated aqueous solution of sodium bicarbonate. The mixture was acidified with 2 N HCl and the organic phase was separated. The ex-ether tract was washed with water and then with saturated aqueous sodium bicarbonate. The organic phase was collected, dried (MgSO 4) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica, EtOAc-heptane 1: 9) to provide 8.62 g of the title compound as a clear oil. H1 NMR (400 MHz, CDCl3): d = 3.94 (1H, m), 2.95 (1H, m), 2.18-1.82 (2H, m), 1.80-1.20 (6H, m). PREPARATION 19 (1 RS.6RS) -biciclor4.2.01octan-7-one It was heated to reflux (1RS, 6SR) -8,8-dichlorohydclo- [4.2.0] octan-7-one (Preparation 18) (8.60 g, 44.6 mmol) in acetic acid (100 ml) with powder zinc (29.0 g, 446 mmol). After 4 hours the mixture was cooled to room temperature, diluted with diethyl ether (200 ml) and washed with 2N NaOH (2 x 100 ml) and then with NaHCC > 3 aqueous saturated (4 x 100 ml). The ether phase was collected, dried (MgSC) and the solvent was removed under reduced pressure to provide 4.79 g of the title compound as a clear oil. H1 RN (400 MHz, CDCl 3): d = = 3.27 (1 H, m), 3.12 (1H, m), 2.42 (2H, m), 2.20-1, 02 (8H, m). PREPARATION 20 Í2Z / EH1 RS.6RSVbiciclor4.2.01oct-7-ylideneethenoate ethyl Sodium hydride (60% dispersion in oil, 1.46 g, 36.6 mmol) in dry tetrahydrofuran (150 ml) was placed in suspension and cooled to 0 ° C. Trityl phosphonoacetate (7.65 ml, 38.5 mmol) was added and the mixture was stirred at 0 ° C for 15 minutes. Then a solution of (1 RS, 6RS) -bicyclo [4.2.0] octan-7-one (Preparation 19) (4.78 g, 38.5 mmol) in THF (20 mL) was added and the mixture was stirred at 0 ° C. After 1 hour the mixture was allowed to warm to room temperature, diluted with ethyl acetate (200 ml) and washed with 2 N HCl (2 x 150 ml). The organic phase was collected, dried (MgSO 4) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica, EtOAc: heptane 3:20) to provide 5.49 g of the title compound as a clear oil, max (film) / cm "1 2929, 1715, 1 86. H NMR (400 MHz, CDCl 3): d = 5.63 and 5.58 (1 H in total - E / Z isomers, 2 xm), 4.15 (2H, m), 3.38-2.98 (2H , m), 2.79-2.35 (2H, m), 2.13-1, 05 (11H, m). LRMS (APCI): m / z [MHt] 195. PREPARATION 21 G (1 RS. 6SR.7SRV7- (nitrometinbicichlor4.2.0] oct-7-ethyl inacetate Heated (2Z / E) - (1 RS, 6RS) -bicyclo [4.2.0] oct-7-ylidene-ethoate ethyl (Preparation 20) (5.47 g, 28.2 mmol) at 60 ° C in tetrahydrofuran ( 50 ml) with nitromethane (3.05 ml, 56.4 mmol) and tetrabutylammonium fluoride (1 M in THF, 42 ml, 42.0 mmol). After 18 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with 2 N HCl (2 x 100 ml) and then brine. The organic phase was collected, dried (g S04) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, EtOAC: heptane 1: 9) to provide 4.73 g of the title compound as a clear oil. vmax (film) / cm "1 1182, 1547.1731, 2936. H1 NMR (400 MHz, CDCl3): d = 4.83 (2H, m), 4.12 (2H, q), 2.66 (2H , m), 2.57 (1H, m), 2.22 (1H, m), 2.05 (1H, m), 1.86 (1H, m), 1, 76-1, 31 (7H , m), 1, 26 (3H, t), 1, 10 (1H, m) .LR S (APCI): m / z [H +] 256. PREPARATION 22 f1S.6S.7R) -spiroíb¡cicloí4.2.0 loctane-7.3'-pyrrolidin-5'-one [(1RS, 6RS, 7SR) -7- (Nitromethyl) bicyclo- [4.2.0] oct-7-yl-ethyl acetate (Preparation 21) (4.70 g, 18.4 mmol) in methanol (50 mL) was stirred. ) at 30 ° C on a Raney nickel catalyst under an atmosphere of hydrogen gas at 483 kPa. After 4 hours the catalyst was removed by filtration through Celite and the solvent was removed under reduced pressure to provide 3.23 g of the title compound as a clear oil which solidified on standing. vmax (film) / cm "1 2919, 1712, 1677. H1 NMR (400 MHz, CDCl3): d = 5.61 (1 H, broad s), 3.46 (2H, m), 2.42 (2H , m), 2.18-1.01 (12H, m). LRMS (APCI): m / z [MHF] 180.

PREPARATION 23 r2E / Z) -n RS.6R8Vbic¡chlor4.2.0] oct-7-ylidene (ethyl cyano-ethoate The ketone of Preparation 19 (2.85 g, 23.0 mmol), ethyl cyanoacetate (2.45 mL, 23.0 mmol), ammonium acetate (1.77 g, 23.0 mmol) and Glacial acetic acid (1.32 ml) were refluxed in toluene (40 ml) using a Dean-Stark trap. After 6 h, the mixture was allowed to cool and was diluted with ethyl acetate (150 ml), washed with water (50 ml), brine and dried (MgSO 4). The solvent was removed under reduced pressure. The residue was chromatographed (Si02, heptane / ethyl acetate, 4: 1) to give 2.76 g of a mixture of cyano-esters as a yellow solid. H1 NMR (400 MHz, CDCl3): d = (major isomer); 4.26 (2H, q), 3.36 (1 H, m), 3.02 (2H, m), 2.58 (1 H, m), 1, 30-2.18 (8H, m), 1.33 (3H, t). d (minor isomer) = 4.25 (2H, q), 3.48 (1 H, m), 3.23 (2H, m), 2.58 (1 H, m), 1, 30-2, 18 (8H, m), 1, 32 (3H, t). PREPARATION 24 r (1 RS.6RS.7RS) -7-benzylbicyclo4.2.0loct-7-in (cyano) ethyl acetate (+/-) The cyanoester of Preparation 23 (2.75 g, 12.5 mmol) in THF (60 mL) was added over 1 h to a stirred solution of benzylmagnesium chloride (20 mL of a 1 M solution in ether, mmol) in THF (20 ml) at -78 ° C under argon. After stirring for 2 h at this temperature, the mixture was quenched by the addition of saturated ammonium chloride solution (10 ml). The mixture was allowed to warm to room temperature and dilute hydrochloric acid (30 ml) was added. The aqueous layer was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure to provide a mixture of diastereomeric cyano-esters. The residue was chromatographed (S1O2, heptane / ethyl acetate, 4: 1) to provide 3.53 g of a mixture of diastereomeric cyano-esters in the form of a clear oil. Rf (heptane-ethyl acetate, 4: 1) = 0.30. vmax (film) / cm "1 2247, 740. PREPARATION 25 f (1 RS.6RS.7SRV7-benzylbicyclo4.2.01oct-7-naeacetic acid The mixture of diastereomeric cyano-esters of Preparation 24 (3.52 g, , 3 mmol) and potassium hydroxide (3.8 g, 67.9 mmol) was heated at 160 ° C in ethylene glycol (75 ml) for 72 h After this period, the mixture was allowed to cool and acid was carefully added. hydrochloric diluted until the solution was acidic by means of a pH paper The mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure The residue was chromatographed (S1O2, ethyl acetate: heptane 1: 4) to give 2.11 g of the racemic diastereomeric acid as a yellow oil, HRN (400 Hz, CDCl 3): d = = 7, 31-7.22 (SH, m), 3.08 (1H, d), 3.00 (1H, d), 2.56 (1H, m), 2.44 (1H, d), 2.38 (1 H, d), 2.25 (1 H, m), 1.98 (1 H, m), 1.75 (1 H, t), 1, 71-1, 30 (7H, m), 1, 10 (1 H, m). LRMS (ES-): m / z [M-H] 257. PREPARATION 26 ff 1 RS.6RS.7SR 7-benzylbicylurea4.2.01oct-7-yl-tert-butyl acetate Oxalyl chloride (0.67 mL, 7.62 mmol) was added dropwise to a stirred solution of the acid of Preparation 25 (1.79 g, 6.93 mmol) in dichloromethane (25 mL) under nitrogen 0 ° C. Dimethylformamide (0.25 ml) was added carefully and the mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The solvent was removed in vacuo and the residue was diluted with dichloromethane (20 ml). 2-Methyl-propan-1-ol (9 ml) in dichloromethane (20 ml) was carefully added to the reaction mixture under argon followed by isopropylethylamine (1.8 ml, 10.4 mmol). The mixture was stirred for 18 hours and then saturated aqueous sodium hydrogen carbonate (30 ml) was added. The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic fractions were washed with brine and dried (gSC). The solvent was removed under reduced pressure and the residue was chromatographed (SIO2, heptane / ethyl acetate 98: 2) to give the ester (2.42 9) -H1 NMR (400 MHz, CDCl3): d = 7, 33-7.19 (5H, m), 3.05 (1H, d), 2.96 (1H, d), 2.53 (1H, m), 2.30-2.18 (3H, m ), 1, 90 (1 H, m), 1, 72 (1H, t), 1, 65-1.55 (2H, m), 1, 48 (9H, s), 1, 47-1, 00 (6H, m). PREPARATION 27 Acid r (1 RS.6RS.7SR 7- (2-tert-butoxy-2-oxoetin-biciclof4.2.0] oct-7-yl-acetic acid The ester of Preparation 26 (6.93 mmol) and sodium periodate (20.75 g, 97.02 mmol) were stirred together in ethyl acetate (20 mL), acetonitrile (20 mL) and water (30 mL). for 5 minutes. The mixture was cooled to 0 ° C and ruthenium chloride hydrate (III) (0.03 g, 0.14 mmol) was added to the reaction mixture. The reaction was allowed to warm to room temperature and was stirred for 24 h. Diethyl ether (100 ml) was added and the mixture was stirred for 40 minutes. Dilute hydrochloric acid (150 ml) was added to the mixture which was then extracted with ethyl acetate (3 x 100 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure to provide 0.64 g of acid. H1 NMR (400 MHz, CDCl3): d = 2.84 (1H, d), 2.75 (1 H, d), 2.61-2.48 (3H, m), 2.17 (1 H, m), 1, 95-1.80 (3H, m), 1, 78-1, 30 (7H, m), 1.44 (9H, s) . PREPARATION 28 Methyl ester of acid (1RS.6RS.7SRV6- (2-tert-butoxy-2-oxoetiPbic¡clof4.2.Q] oct-7-il1acetic acid Trimethylsilyldiazomethane (1.2 ml of a 2M solution in hexane, 2.4 mmol) was added dropwise to a stirred solution of the acid of Preparation 27 (0.64 g, 2.28 mmol) in a mixture of toluene (10 ml) and meta-nol (2.5 ml) at 0 ° C under argon. The mixture was allowed to warm to room temperature and was stirred for 16 h. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (150 ml), washed with saturated sodium hydrogencarbonate (100 ml), dilute hydrochloric acid (100 ml), brine and dried (gS04). . The solvent was evaporated under reduced pressure to provide 0.65 g of ester in the form of a yellow oil. H1 NMR (400 MHz, CDCl3): d = 3.66 (3H, s), 2.83 (1 H, d), 2.74 (H, d), 2.57 (1 H, d), 2 , 49 (1 H, d), 2.15 (1H, m), 1, 94-1, 78 (3H, m), 1, 72-1.06 (8H, m), 1.43 (9H, s). PREPARATION 29 Acid fn RS.6RS.7SR) -7- (2-methoxy-2-oxoetinbicyclo-r4.2.01oct-7-yl-acetic) Trifluoroacetic acid (3 ml) was added dropwise to a stirring solution of the ester of Preparation 28 (0.65 g, 2.19 mmol) in diclothromethane (9 ml) at 0 ° C. The mixture was allowed to warm to room temperature and was stirred for an additional 16 hours. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate (50 ml). The aqueous layer was acidified to pH 4 with dilute hydrochloric acid and then extracted with ethyl acetate (2 x 50 mL). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was removed under reduced pressure. The residue was purified by chromatography (SiO, 6: 4 heptane / ethyl acetate) to give 0.47 g of acid as a yellow oil.

H1 NMR (400 MHz, CDCl3): d = 3.67 (3H, s), 2.84 (1 H, d), 2.78 (1 H, d), 2.74 (1 H, d), 2.66 (1 H, d), 2.49 (1 H, m), 2.14 (1 H, m), 1, 95-1, 81 (2H, m), 1.70 (1 H, m ), 1, 63 (H, m), 1, 55-1, 30 (5H, m), 1, 07 (1 H, m). PREPARATION 30 (2EH1 R.5R bicyclo [3.2.01hept-6-ylidene-ethyl acetate / f2ZV (1 R.5RVbiciclor3.2.01hept-6-ylidene-ethyl acetate C02Et A solution of triethyl phosphonoacetate (53.4 g, 238.3 mmol) in THF (25 mL) was added to a 60% dispersion suspension of sodium hydride (9.53 g, 238.3 mmol). ) in THF (75 ml) maintaining the temperature between 5-15 ° C. A solution of (1T, 5R) -bicyclo [3.2.0] heptan-6-one (Preparation 1A) (25 g, 226.9 mmol) in THF (150 mL) was added maintaining the temperature between 5-15 ° C . The reaction mixture was stirred at room temperature for 30 minutes and then water (100 ml) was added. The phases were separated and the organic layer containing the title compound was used directly in the next step. H1 NMR (400 MHz, CDCl3): d = 5.55 (1 H, d), 4.15 (2 H, q), 3.40 (1 H, m), 3.20 (1 H, m), 2.90 (H, m), 2.55 (1 H, m), 1, 8-1, 5 (5H, m), 1, 30 (3H, t). PREPARATION 31 1 R 5 R 6 S) -r 6 -methrometinbicyclic 3-2.0lheDt-6-H-ethyl acetate The THF solution of the compound of Preparation 30 (assuming 40.9 g of compound in a total volume of 225 ml) diluted with THF (270 ml). TBAF: 3 H20 (93.1 g, 295.0 mmol) and MeN02 (453.9 mmol) were added and the solution was heated to reflux for 4 hours. The reaction mixture was cooled and concentrated under reduced pressure. Toluene (330 ml) was added and the biphasic mixture was washed with water (165 ml), 2 M aqueous HCl (165 ml + 100 ml) and then again with water (165 ml). The toluene layer containing the product was dried over gS04 and concentrated under reduced pressure to provide the title compound as a red / brown oil (90% (over two steps)). H NMR (400 MHz, CDCl 3): d = 4.80 (2H, m), 4.15 (2H, m), 2.85 (1H, m), 2.65 (1H, m), 2.55. (2H, m), 2.20 (1H, m), 1, 9-1, 4 (7H, m), 1.25 (3H, t). PREPARATION 32 Acid (1R.5R.6SV [6- (Nitrometinbicyclo [3.2.01hept-6-yl] acetic acid A solution of the nitro-ester of Preparation 31 (200 g, 828.9 mmol) in THF (1.0 1) was combined with 2 M aqueous NaOH (1.041, 2.08 mol) and stirred at room temperature for 18 hours. The biphasic mixture was diluted with toluene (500 ml) and the layers were separated. The aqueous was adjusted to pH 1-3 with concentrated aqueous HCl and extracted with CH2CI2 (1.0 I + 600 mL). The combined layers of CH2Cl2 containing the product were concentrated under reduced pressure to yield the title compound as an orange oil, which was separated by decantation to a solid (163.4 g). H1 NMR (400 MHz, CDCl3): d = 4.80 (2H, m), 2.85 (1H, m), 2.60 (3H, m), 2.20 (1H, m), 1 , 85 (1H, m), 1.70 (2H, m), 1, 6-1, 4 (4H, m). PREPARATION 33 (1RS.5RS.6SR) -esDolbicbiclor3.2.0lheptane-6.3'-pyrrolidinV5'-one The nitroester of Preparation 31 (13.0 g, 53.9 mmol) was stirred in methanol (125 ml) at 25 ° C on a nickel sponge catalyst under an atmosphere of hydrogen gas at 345 kPa. After 24 hours the catalyst was removed by filtration through Arbocel and the solvent was evaporated under reduced pressure. The residue was then chromatographed (S1O2, ethyl acetate) to give the lactam (4.76 g). H1 NMR (400 MHz, CDCl3): d = 5.86 (1 H, broad s), 3.40 (2H, s), 2.79- 2.70 (1 H, m), 2.54-2 , 47 (1 H, m), 2.32 (1 H, d), 2.12 (1 H, t), 2.03 (1 H, d), 1, 86-1, 60 (31-1 , m), 1.57-1, 38 (4H, m). Microanalysis: Found: C, 72.48; H, 9.15; N, 8.43. C10H15NO requires C, 72.69; H, 9.15; N, 8.48%. [< x] D = -28.4 ° (25 ° C). Examples of pharmaceutical compositions In the following Examples, the active compound can be any compound of formula I-XXV and / or a physiologically functional and pharmaceutically acceptable salt, solvate or derivative thereof. (i) Compositions for 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 magnesium stearate. and compression. Composition A mq / comp. mg / comp (a) Active ingredient 250 250 (b) Lactose B.P. 210 26 (c) Sodium starch glycolate 20 12 (d) Povidone B.P. 15 9 (e) Magnesium stearate _5 _3 500 30 - Composition B mq / comp. mg / comp (a) Active ingredient 250 250 (b) Lactose 150 150 (c) Avicel PH 101 26 (d) Sodium starch glycolate 12 (e) Povidone B.P. 9 (f) Magnesium stearate _3 300 Composition C Active ingredient Lactose Starch Povidone Magnesium Stearate The following compositions D and E can be prepared by direct compression of the mixed ingredients. The lactose in formulation E is of the direct compression type. Composition D mg / tablet Active ingredient 250 Magnesium stearate 4 Pregelatinised starch NF15 146 400 Composition E mg / tablet Active ingredient 250 Magnesium stearate 5 Lactose 145 Avicel 100 500 Composition F (Controlled release composition) mg / tablet (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose 112 (Methocel K4 Premium) (c) Lactose BP 53 (d) Povidone B.P.C. 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, hydroxypropylmethyl phthalate. -cellulose or ammonium polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers must also include 10% (by weight of 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 polymerizer such as cellulose acetate phthalate, poly (vinyl acetate phthalate) , hydroxypropylmethyl cellulose phthalate or anionic polymers of methacrylic acid and methyl methacrylic acid ester (Eudragit L). Except for Eudragit L, these polymers must also include 10% (by weight of 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. (ii) Compositions for capsules Composition A Capsules can be prepared by mixing the ingredients of Composition D above and filling two-part hard gelatin capsules with the resulting mixture. The following Composition B can be prepared in a similar manner. Composition B mg / capsule (a) Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium starch glycolate 25 (d) Magnesium stearate 2 420 Composition C mg / capsule (a) Active ingredient 250 (b) Macrobol 4000 BP 350 600 Capsules can be prepared by melting Macrobol 4000 BP, dispersing the ingredient active in the molten material and filling with the same two-part hard gelatin capsules. Composition D mg / capsule Active ingredient Lecithin Peanut oil Capsules can be prepared by dispersing the active ingredient in lecithin and peanut oil and filling soft elastic gelatin capsules with the dispersion.

Composition E (Controlled release capsule mg / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose BP 125 (d) Ethyl cellulose _13 513 Formulation for controlled release capsules can be prepared by extruding ingredients (a) ) a (c) mixed using an extruder and then spheronizing and drying the extruded material The dried granules are coated with a release control membrane (d) and filled into two part hard gelatin capsules. (Enteric capsule) mg / capsule (a) Active ingredient (b) Microcrystalline cellulose (c) Lactose BP (d) Cellulose acetate-phthalate (e) Diethyl phthalate The composition for enteric capsules can be prepared by extruding the mixed ingredients (a) to (c) using an extruder and then spreading and drying the extruded material. The dried granules are coated with an enteric membrane (d) containing a plasticizer (e) and filled into two-part 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, poly (vinyl acetate phthalate), phthalate dehydroxypropylmethylcellulose or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these po-limeros must also include 0% (by weight of the amount of polymer used) of a plasticizer to avoid membrane cracking during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. (iii) Composition for intravenous injection Active ingredient 0.200 g Phosphate buffer free of pyrogens and sterilized (pH 9.0) up to 0 ml The active ingredient is dissolved in most of the phosphate buffer at 35-40 ° C, then fill the volume and filter through a sterile micropore filter in 10 ml sterilized glass vials (Type 1) that are sealed with sterile closures and overlapping seals. (iv) Composition for intramuscular injection Active ingredient 0.20 g Benzyl alcohol 0.10 g Glycofurol 75 1.45 g Water for injection is. up to 3.00 ml The active ingredient dissolves in glycofurol. Then the benzyl alcohol is added and dissolved and water is added to 3 ml. The mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (Type 1). (v) Composition for syrup Active ingredient 0.25 g Sorbitol solution 1.50 g Glycerol 1.00 g Sodium benzoate 0.005 g Taste 0.0125 ml Purified water is. up to 5.0 ml The sodium benzoate is dissolved in a part 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 then completed to the required volume with the purified water, (vi) Suppository composition mq / suppository Active ingredient 250 Hard fat, BP (Witepsoi H15-Dynamit NoBel) 1770 2020 A fifth is melted part of Witepsol H15 in a tray with water vapor jacketed at 45 ° C maximum. The active ingredient is sieved through a 2001 m sieve and added to the molten base with hard-mix, using a Silverson device equipped with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45 ° C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogenous mixture. The complete solution is then passed through a 2051 m stainless steel screen, with continuous stirring, and allow to cool to 40 ° C. At a temperature of 38-40 ° C, aliquots of 2.02 g of the mixture are filled into suitable plastic molds and the suppositories are allowed to cool to room temperature, (vi i) Composition for pessaries mg / pessary Ingredient active (631 m) 250 Dextrose anhydrous 380 Potato starch 363 Magnesium stearate 7 1000 The above ingredients are mixed directly and pessaries prepared by compression of the resulting mixture, (viii) Transdermal composition Active ingredient 200 mg Alcohol USP 0.1 ml Hydroxyethyl cellulose The active ingredient and alcohol USP are gelled with hydroxyethyl cellulose and filled into a transdermal device with a surface area of 10 cm2. Biological Data The compounds of Examples 1 and 4 were tested in the radioligand binding assay described in the present specification and found to have binding affinities of 46.8 and 600 nM, respectively.

Claims

CLAIMS 1.- Use of a compound of any of the formulas (l) - (XXV): H02C ÍJIM, (I) (II) (III) (IV) (V) (VI) (VII) (VIII) (IX) (X) (XI) (XII) XXII XXIII XXIV XXV in which R1 and R2 are each independently selected from hydrogen, linear or branched alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl and benzyl, with the proviso that , except in the case of a tricyclooctane compound of formula (XVII), R1 and R2 are not simultaneously hydrogen, or a pharmaceutically acceptable salt or solvate thereof, or a prodrug thereof, in the manufacture of a medicament for the treatment of fibromyalgia. 2. Use according to claim 1, wherein R1 and R2 are both hydrogen or methyl. 3. Use according to claim 1 or 2, wherein the compound is selected from: Acid ((1 R, 5S) -3-aminometl-1, 5-dimethyl-bicyclo- [3.2.0] hept- 3-yl) -acetic; ((1 S, 5R) -3-aminomethyl-, 5-dimethyl-bicyclo- [3.2.0] hept-3-yl) -acetic acid; ((1 R, 5S) -3-aminomethyl-6,6-dimethyl-bicyclo- [3.1.0] hex-3-yl) acetic acid; Acid ((S.SRJ-S-aminomethyl-ee-dimethyl-bicyclic-O-hexhex-Si-acetic acid ((1S, 2S, 5R) -2-aminomethyl-6,6-dimethyl-bicyclo- [3.1. 0] hex-2-yl) -acetic acid: ((1 R, 2S, 5S) -2-aminomethyl-6,6-dimethyl-bicyclo- [3. 0] hex-2-y () -acetic acid; ((1S, 2R, 5R) -2-aminomethyl-6,6-dimethyl-bicyclo- [3.1.0] hex-2-yl) -acetic acid; ((1R, 2R, 5S) -2-aminomethyl- 6,6-dimethyl-bicyclo- [3.

1.0] hex-2-yl) -acetic acid ((1R, 5R, 6S) -6-aminomethyl-bicyclo [3.2.0] hept-6-yl) -acetic acid; ((1S, 5S, 6S) -6-aminomethyl-bicyclo [3.2.0] hept-6-yl) -acetic acid; ((1R, 5R, 6R) -6-aminomethyl-bicyclo [3.2.0] hept-6-yl) -acetic acid ((1S, 5S, 6R) -6-arTiinomethyl-bicyclo [3.2.0] hept-6-yl) -acetic acid; cis ((1S, 2R, 4S, 5R) -3-aminomethyl-2,4-dimethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid; trans - ((1S, 2R, 4S, 5R) -3-aminomethyl-2,4-dimethyl- bicyclo [3.2.0] hept-3-yl-acetic acid ((IS.SR.eSJRJ-S-aminomethyl-ej-dimethyl-bicyclo-IS ^ .Olhept-Si-acetic acid ((1S, 5R, 6RJS ) -3-aminomethyl-6,7-dimethyl-bicyclo- [3.

2.0] hept-3-yl) - acetic acid ((1R, 2S, 5S) -7-aminomethyl-3,3-dimethyl-tricyclo- [3.

3.0.0] oct-7-yl) -acetic acid; ((1 R, 6R, 7S) -7-aminomethyl-bicyclo [4.2.0] oct-7-yl) -acetic acid; ((1S, 6S, 7S) -7-aminomethyl-bicyclo [4.2.0] oct-7-yl) -acetic acid; ((1R, 6R, 7R) -7-aminomethyl-bicyclo [4.2.0] oct-7-yl) -acetic acid; ((1S, 6S, 7R) -7-aminomethyl-bicyclo [4.2.0] oct-7-yl) -ac0tico acid; ((1R, 7R, 8S) -8-aminomethyl-bicyclo [5.2.0] non-8-yl) -acetic acid; ((1S, 7S, 8S) -8-aminomethyl-bicyclo [5.2.0] non-8-yl) -acetic acid; Acid ((1 R, 7R, 8R) -8-aminomethyl-bicyclo [5.2.0] non-8-yl) -acetic; and ((1S, 7S, 8R) -8-aminomethyl-bicyclo [5.2.0] non-8-yl) -acetic acid.

4. Use according to any one of claims 1-3, wherein the compound is selected from: Acid [(1 R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6 -yl] acetic; [(1S, 5S, 6R) -6- (aminometii) bicyclo [3.2.0] hept-6-yl] acetic acid; [(1 RS, 5RS, 6RS) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid; Acid [(1 RS, 6RS, 7SR) -7- (aminomethyl) bicyclo [4.2.0] oct-7-yl] acetic acid; and Acid [(1 RS, 6RS, 7RS) -7- (aminomethyl) bicyclo [4.2.0] oct-7-yl] acetic acid.

5. Use according to any one of claims 1-4, wherein the compound is [(1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid.

6. A method for treating fibromyalgia, comprising administering a therapeutically effective amount of a compound of formula (I) - (XXV) according to claim 1, to a mammal in need of said treatment.

7. A pharmaceutical composition for the treatment of fibromyalgia, comprising a therapeutically effective amount of a compound of formula (I) - (XXV) according to claim 1 and a pharmaceutically acceptable carrier.