MXPA98003835A - Amino acid derivatives excited - Google Patents

Abstract

Compounds for formula (I) are described, in which X represents O, NRa, S, SO or SO2, and R is defined in the specification, and metabolically labile, non-toxic esters and amides thereof, and pharmaceutically acceptable salts thereof. which are useful as modulators of the metabotropic glutamate receptor function

Description

DERIVATIVES OF? MOX? CTDOS EXCITER --- DESCRIPTION OF IA O-JVING In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, which is released by the transmitting neuron, and a surface receptor in a receiving neuron, which causes the excitation of this receiving neuron. L-glutamate, which is the most abundant neurotransmitter in the CNS, mediates most of the excitatory pathways in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See atkins & Evans, Aun. Rev. Pharmacol. Toxicol , 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol , 29, 365, (1989): Watkins, Krogsgaard-Larsen and Honore, Trans. Pharm. Sci. , 11, 25 (1990). Excitatory amino acids are of great physiological importance, play a role in various physiological processes such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation and sensory perception. REF: 27189 > - 2 - Excitatory amino acid receptors are classified into two general types. The receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed "ionotropic". This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole- 4-propionic (AMPA), and cainic acid (KA). He The second general type of receptor is the G protein or the excitatory amino acid (metabotropic) receptor bound to the second messenger. This second type is coupled to multiple second messenger systems that lead to increased hydrolysis of phosphoinositide, activation of phospholipase D, increases or decreases in cAMP formation and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci. , 14, 13 (1993). Both types of receptors seem to not only mediate normal synaptic transmission along excitatory pathways, but also also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert and Sladeczek, Trends in Pharmacol. Sci. , ll, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).

Excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss through a mechanism known as excitotoxicity. It has been suggested that this process mediates neuronal degeneration in various conditions. The medical consequences of such a neuronal degeneration makes the abatement of these neurogenic degenerative processes an important therapeutic goal. Metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple pathways of the second messenger. These receptors function to modulate the presynaptic release of glutamate and the postsynaptic sensitivity of the neuronal cell to excitation by glutamate. The compounds which modulate the function of these receptors, in particular glutamate agonists and antagonists, are useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant and antiemetic agents. The present invention provides a compound of formula > - 4 - in which X represents O, NRa, S, SO or S02; R represents a hydrogen atom, an alkyl group of 1-6C; a 2-6C alkenyl group; a 2-6C alkynyl group; an optionally substituted aromatic group; an optionally substituted heteroaromatic group; a non-aromatic carbocyclic group; - a non-aromatic heterocyclic group; a non-aromatic monocyclic carbocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; a monocyclic heterocyclic group does not Aromatic fused with one or two monocyclic aromatic or heteroaromatic groups; or an alkyl group of 1-6C, 2-6C alkenyl or 2-6C alkynyl which is substituted by one, two or three groups which are independently selected from an aromatic group optionally replaced; an optionally substituted heteroaromatic group; a non-aromatic carbocyclic group, a non-aromatic heterocyclic group, a non-aromatic monocyclic carbocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups and a group A non-aromatic monocyclic heterocyclic fused with one or two monocyclic aromatic or heteroaromatic groups; Rd represents hydrogen or a group of formula (CO) nRb; n is 0 or 1; and Rb is as defined by par .. R; or an ester or amide thereof metabolically labile, non-toxic thereof; or a salt Pharmaceutically acceptable thereof.

It will be appreciated that the compounds of formula I contain at least four asymmetric carbon atoms; three are in the cyclopropane ring and one or two are in the cyclopentane ring. The present invention includes all stereoisomeric forms of the compounds of formula I, including each of ICL "individual enantiomers and mixtures thereof. Preferably, the compounds of formula I have the configuration shown below.

As used herein, the term "1-6C alkyl" means a straight or branched chain group.

Examples of values for an alkyl group of 1-6C include alkyl of 1-4C such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl. The term "2-6C alkenyl" includes 2-4C alkenyl, such as allyl. The term 2-6C alkynyl includes 2-4C alkynyl such as propynyl.

The term heteroaromatic group includes a 5-6 membered aromatic ring containing from 1 to 4 heteroatoms which are selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused to a benzene ring or a 5-6 membered ring containing one to four heteroatoms that are selected from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups are furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrimidyl, benzofuryl, benzotophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and indolyl. The term aromatic group includes phenyl and a polycyclic aromatic carbocyclic ring such as naphthyl. The term "optionally substituted" as used in the term "an optionally substituted heteroaromatic or aromatic group" herein means that one or more substituents may be present, the substituents are selected from atoms and groups which, when present in the compound of formula I, do not prevent the compound of formula I from functioning as a modulator of the metabotropic glutamate receptor functions.

Examples of atoms and groups which may be present in an optionally substituted heteroaromatic or aromatic group are amino, hydroxy, nitro, halogen, alkyl of 1-6C, alkoxy of 1-6C, alkylthio of 1-6C, carboxy, alkoxycarbonyl of 1-6C, carbamoyl, 1-6C-alkanoylamino, 1-6C-alkylsulfonyl, 1-6C-alkylsulfonylamino, optionally substituted phenylthio, phenoxy, phenyl, phenylsulfonyl, phenylsulfonylamino, toluenesulfonylamino, fluoroalkyl of 1-6C and fluoroalkoxy of 1- 6C. Examples of particular values are amino, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, methylthio, carboxy, acetylamino, methanesulfonyl, nitro, acetyl, phenoxy, phenylthio, phenylsulfonyl, methanesulphonylamino and trifluoromethyl. Examples of values for an optionally substituted aromatic group are 1-naphthyl, 2-naphthyl, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-fluorophenyl, -fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pentafluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3-chloro-4 -fluorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl , 2,5- dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl, 3-trifluoromethyl-1,4-fluoro-phenyl, 3-trifluoromethyl-5-fluorophenyl , 2-fluoro-5-trifluoromethylphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 3-carboxyphenyl and 4-carboxyphenyl. The term "non-aromatic carbocyclic group" includes a monocyclic group, for example, a cycloalkyl group of 3-10C, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, and a fused polycyclic group such as - adamantyl or 2-adamantyl, 1-decalyl, 2-decalyl, 4a-decalyl, bicyclo [3, 3, 0] oct-1-yl, -2-yl or 3-yl, bicyclo [4.3, 0] non-1-yl, -2-yl, -3-yl or -7-yl, bicyclo [5, 3, 0] dec-1-yl, -2-yl, -3-yl, -4-yl, -8-ilo or -9-yl and bicyclo [3.3.1] non-1-yl, -2-yl, -3-yl or 9-yl. The term "non-aromatic heterocyclic group" includes a 4- to 7-membered ring containing one to two heteroatoms which are selected from oxygen, sulfur and nitrogen, for example azetidin-1-yl or 2-yl, pyrrolidin-1-yl or -2-yl or -3-yl, piperidin-l-yl or -2-yl, -3-yl, or -4-yl, hexahydroazepin-1-yl, -2-yl or -3-yl or -4 -yl, oxetan-2-yl or -3-yl, tetrah-drofuran-2-yl or -3-yl, tetrahydropyran-2-yl, -3-yl or -4-yl, hexahydrooxepin-2- ilo, -3-yl or -4-yl, thyetan-2-yl or -3-yl, tetrahydrothiophen-2-yl or-3-yl, tetrahydrothiopyran-2-yl, -3-yl or -4-yl, hexahydrothiepin-2-yl, -3-yl or -4-yl, piperazin-1-yl or -2-yl, morpholin-1-yl, -2-yl or -3-yl, thiomorpholin-1-yl, - 2-yl or -3-yl, tetrahydropyrimidin-1-yl, -2-yl, -4-yl or -5-yl-; imidazolin-1-yl, -2-yl or -4-yl, imidazolidin-1-yl, -2-yl or -4-yl, oxazolin-2-yl, -3-yl, -4-yl or -5 -yl, oxazolidin-2-yl, -3-yl, -4-yl or -5-yl, thiazolin-2-yl, -3-yl, -4-yl or -5-yl, or thiazolidin-2- ilo, -3-yl, -4-yl or -5-yl. The term "a non-aromatic monocyclic carbocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups" includes a 3-10C cycloalkyl group fused to a benzene ring or a 5-6 aromatic member ring containing one to four heteroatoms that they are selected from oxygen, sulfur and nitrogen, such as indanyl, 1, 2, 3, 4-tetrahydronaphth-1-yl or -2-yl, 5, 6, 7, 8-tetrahydroquinolin-5-yl, -6-yl , -7-yl or -8-yl, 5, 6, 7, 8-tetrahydroisoquinolin-5-yl, -6-yl, -7-yl, or -8-yl, 4, 5, 6, 7-tetrahydrobenzothiophene 4-yl, -5-yl, -6-yl or -7-yl, dibenzo [2, 3, 6, 7] cycloheptan-1-yl, or -4-yl, dibenzo [2, 3, 6, 7] cyclohep-4-en-l-yl or -4-yl or 9-fluorenyl. The term "a non-aromatic monocyclic heterocyclic group fused with one or more aromatic groups or monocyclic heteroaromatics "includes a 4- to 7-membered ring" containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, fused with a benzene ring or a 5-6 membered aromatic ring containing from one to four heteroatoms that are selected of oxygen, sulfur and nitrogen, such as-2, 3-dihydrobenzopyran-2-yl, -3-yl or -4-yl, xanthen-9-yl, 1, 2, 3, 4-tetrahydroquinolin-1-yl, -2-yl, -3-yl or -4-yl, 9,10-dihydroacridin-9-yl or -10-yl, 2,3-dihydro-benzothiopyran-2-yl, -3-yl or -4-yl or dibenzothiopyran-4-yl An example of a value for R when it represents an optionally substituted heteroaromatic group is 2-pyrimidyl When R represents an optionally substituted aromatic group, preferably represents a 2-naphthyl group or a phenyl group which is unsubstituted or substituted by one or two substituents which are independently selected from halogen, 1-4C alkyl and 1-4C alkoxy. for R when it represents an optionally substituted aromatic group are 2 -naphthyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, pentafluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, , 4-dichlorophenyl, 2,5-dichlorophenyl, 2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl. Examples of values for R when it represents an alkyl group of 1-6C, 2-6C alkenyl or alkynyl of 2-6C substituted are phenylalkyl groups of 1-4C and diphenylalkyl of 1-4C which are unsubstituted or substituted on the phenyl by one or two substituents which are independently selected from halogen, 1-4C-alkoxy alkyl of 1-4C and phenyl. More particularly R can represent a benzyl group in which the phenyl ring is unsubstituted or substituted by one or two substituents which are independently selected from fluoro, chloro, methyl, isopropyl, methoxy and phenyl; such as 3-chloro-4-fluorobenzyl, 4-fluorobenzyl, 3-methylbenzyl, 4-fluoro-3-methylbenzyl, 2,3-difluorobenzyl, 3,4-difluorobenzyl and 3-chlorobenzyl. A preferred value for R is hydrogen A preferred value for Ra is hydrogen. Preferably X represents O or S. Particularly preferred compounds are 1SR, 4SR, 5RS, 6SR- -amino-2-oxabicyclo [3.1.0] hexan-4,6-dicarboxylic acid and 1SR, 4SR, 5RS, 6SR acid -4-amino-2-thiabicyclo [3.1.0] -hexan-4,6-dicarboxylic acid. (1-) 1R, 4R, 5S, 6R-4-amino-2-oxabicyclo [3.1.0] hexan-4,6-dicarboxylic acid they are especially preferred. These compounds have been found to be potent glutamate agonists of metabotropic glutamate receptors linked to cAMP. Another preferred compound is 1SR, 3RS, 4SR, 5RS, 6SR-3 - (3-chloro-4-fluoro) benzyl-4-amino-2-oxabicyclo [3.1.0] hexan-4,6-dicarboxylic acid. * The present invention includes pharmaceutically acceptable salts of the compounds of formula I. These salts may exist together with the acid or basic portion of the molecule and may exist as acid addition salts, primary, secondary, tertiary or quaternary ammonium salts, salts of alkali metal or alkaline earth metal. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula I. The alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula I. Acids commonly used to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic acid. citric, benzoic, and acetic and inorganic and organic acids related Such pharmaceutically acceptable salts therefore include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, ammonium, monoacid phosphate, diacid phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, capr ^ -to, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, hipurate, butyn-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylenbenzoate, dinitrobenzoate, hydrobenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, a-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, magnesium, tetramethylammonium, potassium, trimethylammonium, sodium, methylammonium, calcium and similar salts. The metabolically labile, non-toxic ester and amide of compounds of formula I which are hydrolyzed in vivo to provide the compound of formula I and a pharmaceutically acceptable alcohol or amine. Examples of metabolically labile esters include esters formed with 1-6C alkanols in which the alkanol portion may be optionally substituted by an alkoxy group of 1-8C, for example methanol, ethanol, propanol and methoxyethanol. The Examples of metabolically labile amides include amides formed with amines such as methylamine. According to another aspect, the present invention provides a process for the preparation of a compound of formula I, which comprises: (a) hydrolyzing a formula compound of formula wherein R 1 represents a hydrogen atom or an acyl group and R 2 represents a carboxyl group or an esterified carboxyl group, or a salt thereof; hydrolyze a compound of formula III wherein R3 represents a carboxyl group or an esterified carboxyl group and R4 and R5 each independently represent a hydrogen atom, an alkanoyl group of 2-6C, an alkyl group of 1-4C, an alkenyl group of 3-4C or a phenylalkyl group of 1-4C in which the phenyl is unsubstituted or substituted by halogen, alkyl of 1-4C or alkoxy of 1-4C, or a salt thereof; or (c) deprotecting a compound of the formula wherein R6 represents a hydrogen atom or a nitrogen protecting group, and each of R7 and R3 independently represents a hydrogen atom or a carboxyl protecting group, or a salt thereof; subsequently, if necessary and / or desired (i) to separate the compound of formula I; (ii) converting the compound of formula I to a metabolically labile, non-toxic ester or amide thereof; I (iii) converting the compound of formula I or a metabolically labile, non-toxic ester or amide thereof into a pharmaceutically acceptable salt thereof. Protection of the carboxylic acid and amine groups is generally described in McOmie, Protecting Groups in Organic Chemistry, »Plenum Press, NY, 1973, and Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd. Ed., John Wiley & Sons, NY, 1991. Examples of carboxy protecting groups include alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aralkyl groups such as benzyl, 4-nitrobenzyl, -methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, benzhydryl and trityl; silyl groups such as trimethylsilyl and t-butyldimethylsilyl; and allyl groups such as allyl and 1- (trimethylsilylmethyl) prop-1-en-3-yl. Examples of amine protecting groups include acyl groups, such as groups of formula R1XC0 in which R'L represents alkyl of 1-6C, cycloalkyl of 3-10C, phenylalkyl of 1-6C, phenyl, alkoxy of 1-6C, phenylalkoxy of 1-6C or a cycloalkoxy of 3 -10C, wherein the phenyl group may be optionally substituted by one or two its components selected independently from amino, hydroxy, nitro, halogen, alkyl of 1-6C, alkoxy of 1-6C, carboxy, alkoxycarbonyl of 1-6C, carbamoyl, aral.oylamino of 1-6C, 1-6C alkylsulfonylamino, phenylsulfonylamino, toluenesulfonylamino and fluoroalkyl of 1-6C. The compounds of formula II are conveniently hydrolyzed in the presence of an acid such as hydrochloric acid or sulfuric acid, or a base, such as an alkali metal hydroxide, for example sodium hydroxide. The hydrolysis is conveniently carried out in an aqueous solvent such as water at a temperature in the range from 50 to 200 ° C. The compounds of formula III are conveniently hydrolyzed in the presence of a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide such as barium hydroxide. Suitable reaction media include water. The temperature is conveniently in the range from 50 to 150 ° C. Preferred values for R1 are hydrogen and 2-6C alkanoyl groups, such as acetyl. Preferred values for R2 when representing an esterified carboxyl group are 1-6C alkoxycarbonyl groups such as ethoxycarbonyl. The compounds of formula IV can be deprotected by a conventional method. Therefore, an alkylcarboxyl protecting group can be removed by hydrolysis. The hydrolysis can be carried out conveniently by heating the compound of formula V in the presence of either a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkali metal hydroxide such as barium hydroxide, or an acid such as acid hydrochloric. The hydrolysis is conveniently carried out at a temperature in the range from 10 to 300 ° C. A protective aralkylcarboxyl group can be conveniently removed by hydrogenation. The hydrogenation can be conveniently carried out by reacting a compound of formula V with hydrogen in the presence of a group VIII metal catalyst., for example a palladium catalyst such as palladium on activated carbon. Suitable solvents for the reaction include alcohols such as ethanol. The reaction is conveniently carried out at a temperature in the range from 0 to 100 ° C. An amine protecting group, acyl, is also conveniently removed by hydrolysis, for example, as described for the removal of an alkylcarboxyl protecting group. The compounds of formula II can be prepared by reacting a compound of formula V V with an alkali metal cyanide such as lithium, sodium or potassium cyanide, and an ammonium halide, such as ammonium chloride, conveniently in the presence of ultrasound. Therefore, the ammonium halide is mixed with chromatographic grade alumina in the presence of a suitable diluent such as acetonitrile. Subsequently the mixture is irradiated with ultrasound, after which the compound of formula V is added and the mixture is again irradiated. Subsequently, the alkali metal cyanide is added, followed by additional irradiation with ultrasound. The resulting mixture of diastereomeric aminonitriles can then be reacted with an acylating agent, such as acetyl chloride in the presence of a suitable base, for example, an amine such as ethyl diisopropylamine and in the presence of a suitable solvent such as dichloromethane, provide a mixture of diastereomeric acylaminonitriles. The desired diastereomer can be conveniently separated from this mixture, for example, by chromatography. The compounds of formula III can be prepared by reacting a compound of formula V with an alkali metal cyanide such as lithium, sodium or potassium cyanide, an ammonium carbonate or an ammonium carbamate. Suitable solvents include alcohols such as methanol, aqueous methanol and aqueous ethanol. Conveniently, the reaction is carried out at a temperature in the range from 10 to 150 ° C. If desired, the compounds of formula III can be subsequently alkylated, for example, using an appropriate compound of formula R4C1 and / or RSC1. The compounds of formula III can subsequently be separated before hydrolysis. Thus, for example, a compound of formula III in which R 2 represents a carboxyl group can be removed by treatment with an optically active amine, such as (R) -2-phenylglycinol. The compounds of formula V in which X represents 0 can be prepared by cyclizing a compound of formula wherein Z represents an atom or leaving group, for example, an iodine atom. The reaction is conveniently carried out in the presence of a base such as 1,8-diazabicyclo [5.4..0] undec-7-ene. Suitable solvents include ethers, such as tetrahydrofuran. The temperature is conveniently in the range from 0 to 100 ° C.

Compounds of formula VI can be prepared by oxidizing a compound of formula The oxidation is conveniently carried out using an appropriate conventional oxidation method, for example, using oxalyl chloride in dimethyl sulfoxide or (when X is O, NRa or S02 only), chromium trioxide in sulfuric acid (Jones reagent) . The compounds of formula Via can be prepared by the method described in J. Amer. Che. Soc. , 110 (14), 1988, pages 4533-4540. The compound of formula V can also be prepared by oxidizing a compound of formula VII Oxidation can be conveniently carried out by reacting the compounds of formula VII with dimethyl sulfoxide in the presence of the activating agent, such as oxalyl chloride followed by treatment with a base, such as triethylamine. The reaction is conveniently carried out at a temperature in the range of -80 to -20 ° C. The compounds of formula VII can be prepared by reacting a compound of formula with a hydroborating agent such as borane or texilborane, followed by an oxidizing agent such as hydrogen peroxide in the presence of a base such as sodium hydroxide or an aqueous buffer in a pH range of 5 to 14. Conveniently, the temperature is in the range from -20 to 25 ° C. Generally the reaction can be carried out with the methods described in J. Am. Chem. Soc. 1986, 108, 2049 and J. Am. Chem. Soc. , 1991, 113, 4037. The compounds of formula IX can be prepared by reacting a compound of formula with a compound of formula R2CN2 in the presence of a transition metal catalyst, such as a rhodium or copper catalyst. The reaction can generally be carried out according to the methods described in J. Chem. Soc. Perkin Tran I, 1979, 2624; Tetrahedron, 1971, 27, 2957. Justus Liebigs Ann. Chem. 1963, 668, 19; and Tet. Let. 1964, 2185. Compounds of formula V in which R represents an alkyl group of 1-6C or substituted alkyl of 1-6C can also be prepared from the corresponding compounds of formula V in which R represents a hydrogen atom by reaction with the appropriate aldehyde, in the presence of pyrrolidine, followed by hydrogenation of the resulting alkylidene adduct, for example using Raney nickel or palladium on carbon as a catalyst. Many of the intermediates described herein, for example the compounds of formula II, III and IV are considered to be novel and are provided as further aspects of the invention.

The particular dose of the compound administered according to this invention will of course be determined by the particular circumstances of each case, which include the compound administered, the route of administration, the particular condition to be treated and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal. Alternatively, the compound can be administered by continuous infusion. A typical daily dose will contain from about 0.01 mg / kg to about 100 mg / kg of the active compound of this invention. Preferably, the daily doses will be from about 0.05 mg / kg to about 50 mg / kg, more preferably from about 0.1 mg / kg to about 25 mg / kg. It has been shown that several physiological functions are subject to influence by excessive or inappropriate stimulation of the transmission of excitatory amino acids. The compounds of formula I of the present invention are considered to have the ability to treat various neurogenic disorders in mammals associated with this condition, including acute neuroimagic disorders such as brain deficits subsequent to cardiac bypass and graft surgery, seizures, cerebral ischemia, trauma in the spinal cord, cephalic crauma, epoxy perinatal, heart attack and hypoglycemic neuronal damage. The compounds of formula I are considered to have the ability to treat various chronic neurogenic disorders such as Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, eye damage and retinopathy, cognitive disorders and Parkinson's disease. idiopathic and drug-induced * The present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of a compound of formula I or a metabolically labile, pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof. The compounds of formula I of the present invention are also considered to have the ability to treat various different neurogenic disorders in mammals, which are associated with glutamate dysfunction, including muscle spasms, seizures, migraine headaches, urinary incontinence, nicotine suppression, psychosis (such as schizophrenia) tolerance suppression and elimination of medications (ie, opiates, benzodiazepine, nicotine, ***e or ethanol), smoking cessation, anxiety and related disorders (eg panic attack and disorders related to 'stress', emesis, cerebral edema, chronic pain, sleep disorders, Tourettes syndrome, efficient attention disorder and tardive dyskinesia. The compounds of formula I are also useful as antidepressant and analgesic agents. Therefore, the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of formula I or a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof. Experiments were performed to demonstrate the ability of the compounds of formula I to alter the excitatory amino acid receptors. The affinity for metabotropic glutamate receptors was demonstrated by the selective displacement of [3 H] glutamate binding responsive to L >.-3i? -ACPD in membranes of rat brain cells. Binding of [3 H] glutamate was carried out with untreated membranes of rat forebrain as described by Schoepp and True. Neuroscience Lett. , 145, 100-104 (1992) and Wright et al., J. Nuerochemistry 63: 938-945 (1994). For example, the compound of Example 1 is found to have an IC50 of 0.055 μM in this test.

Based on the studies of changes mediated by receptor in intracellular second messengers, the metabotropic glutamate receptor is coupled to improved phosphoinositide hydrolysis or decreases the formation of cAMP stimulated by forskolin. The compounds can also be determined to determine their ability to prevent the inhibition of cAMP formation stimulated by forskolin (30 μM) by a mGluR agonist (1S, 3R-ACPD, 20 μM) using rat hippocampal slices, as described by DD Schoepp and B.G. Johnson, Mierochemistry International 22: 277-283 (1993) and non-neuronal cells expressing human mGluR2 (D.D. Schoepp et al., Nueropharmacology, 34: 843-850, 1995). According to another aspect, the present invention provides a method for modulating one or more metabotropic glutamate receptor functions in homeothermic mammals which comprises administering an effective amount of a compound of formula I or a metabolically labile, non-toxic ester or amide, thereof, or a pharmaceutically acceptable salt thereof. The compounds of the present invention are preferably formulated before administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I and a carrier, diluent or excipient pharmaceutically acceptable. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or included within a carrier, and may be in the form of a capsule, sachet, paper or other container . When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. The compositions may be in the form of tablets, pills, powders, dragees, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, sprays, ointments containing, for example, up to 10% by weight of the active compound, gelatin capsules soft and hard, suppositories, sterile injectable solutions and sterile packaged powders. Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, I cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate and mineral oil. Additionally, the formulations may include lubricating agents, wetting agents, emulsifying agents and improving the suspension, preservatives, sweetening agents or flavoring agents. The compositions of the invention can be formulated so as to provide a rapid, sustained or delayed release of the active ingredient after administration to the patient by using procedures well known in the art. The compositions are preferably formulated in unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably, from about 25 mg to about 300 mg of the active ingredient. The term "unit dosage form" refers to a physically separate unit, suitable as a unit dosage for human subjects and other mammals, each containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a carrier, pharmaceutically suitable diluent or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention of sea.

Formulation 1 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg / capsule) Active ingredient 250 Starch, dry 200 Magnesium stearate 10 Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in amounts of 460 mg.

Formulation 2 A tablet is prepared using the following ingredients: Amount 'mg / tablet) Active ingredient 250 Microcrystalline cellulose 400 Silicon dioxide, smoked 10 Stearic acid 5 Total 665 mg The components are mixed and compressed to form tablets, each weighing 665 mg.

Formulation 3 An aerosol solution is prepared containing the following components: % in weigh Active ingredient 0.25 Ethanol 29.75 Propellant 22 70.0Q (Chlorodifluoromethane) Total 100.0 The active compound is mixed with ethanol and the mixture is added to a portion of propellant 22, cooled to -30 ° C and transferred to a refilling device.

The required quantity is then supplied to a stainless steel container and diluted with the rest of the propellant. Subsequently, valve units are placed in the container.

Formulation 4 They are made as follows tablets, each containing 60 mg of the active ingredient: Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinyl pyrrolidone 4 mg Sodium starch 4.5 mg Magnesium stearate 0.5 mg Talc X mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh American sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders and then passed through a North American mesh No. 14 screen. The granules produced in this way are they are dried at 50 ° C and passed through an American No. 18 mesh screen. Sodium carboxymethylstarch, magnesium stearate and talcum, which have previously been passed through an American sieve No. of mesh 60, then they are added to the granules which, after mixing, are compressed in a tableting machine to provide tablets, each weighing 150 mg.

Formulation 5 They are made as follows capsules, each containing 80 mg of the drug: Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a No. 45 sieve and filled into hard gelatin capsules in amounts of 200 mg.

Formulation 6 As suppositories can be prepared as follows, each with 225 mg of the active ingredient: Active ingredient - 225 mg Glycerides of saturated fatty acids 2,000 mg Total 2,225 mg The active ingredient is passed through a North American No. 60 sieve and suspended in the saturated and previously melted fatty acid glycerides using the minimum necessary heat. The mixture is then poured into a suppository mold with a nominal capacity of 2 g and allowed to cool.

Formulation 7 Suspensions are prepared as follows, each containing 50 mg of the drug per 5 ml dose: Active ingredient 50 mg Sodium carboxymethylcellulose. 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Taste c.v. Color c.v. Purified water up to a total of 5 ml The medicament is passed through a No. 45 mesh North American sieve and mixed with the sodium carboxymethyl cellulose and the syrup to form a regular paste. The benzoic acid solution, flavor and color are diluted with one part of water and added, with stirring. Subsequently, enough water is added to produce the required volume.

Formulation 8 The intravenous formulation can be prepared as follows: Active ingredient 100 mg Mannitol 100 mg Sodium hydroxide 5 N 200 ml Purified water up to a total of • 5 ml The following examples illustrate the invention. The following abbreviations are used in the following: EtOAc, ethyl acetate; THF, tetrahydrofuran; EtOH, ethanol; TLC, thin layer chromatography; GC, gas chromatography; CLAP high pressure liquid chromatography; m-CPBA, m-chloroperbenzoic acid; Et20, diethyl ether; DMSO, dimethyl sulfoxide; DBU, 1,8-diazabicyclo [5.4.0] undec-7-en, MTBE, methyl t-butyl ether and FDMS, field desorption mass spectrometry.

Example 1 1SR, 4SR, 5RS, 6SR-2-amino-2-oxabicyclo [3.1.0] hexan-4,6-d-carboxylic acid (a) 2SR-1, 2-O-isopropylidene-butan-1,2,4-triol. A solution of 1,2,4-butanetriol (53 g, 500 mmol) in acetone (11) is treated in one portion with p-toluenesulfonic acid monohydrate (4.75 g, 25 mmol) and stirred at room temperature overnight. Triethylamine (2.5 g, 25 mmol) is added in one portion and the resulting reaction mixture is concentrated in vacuo to provide the untreated product. Purification via CLAP (EtOAc to % / hexanes to 50% EtOAc / hexanes) provides the title compound (53.1 g, 363 mmol), 73%. FDMS: M * + 1 = 147. Analysis calculated for CH.4O¡.0.5 H20; C, 54.18; H, 9.74. Found: C, 54.50; H, 9.56. (b) 5SR, E-5, 6-0-isopropylidene-5,6-dihydroxy-2-hexanoate ethyl. DMSO (56.65 g, 725 mmol) is added dropwise to a solution at -78 ° C of oxalyl chloride (48.32 g, 380.7 mmol) in CH2C12 (11) and stirred for 15 minutes. Subsequently, a solution of the product of step (a) (53 c, 362.6 mmoles) in CH2C12 (400 ml) is added dropwise at a rate to maintain the reaction temperature < . -60 ° C. Add NN-diisopropylethylamine depletes (140.6 g, 1087 mmol) and the resulting suspension allowed to warm to room temperature as it is stirred for 2 hours to give O-isopropylidene-4-oxo- (SR) butan-1,2-diol without treating. The reaction mixture is cooled to 0 ° C, added in one portion (carbethoxymethylene) -triphenylphosphorane (252.5 g, 725 mmol) and allowed to warm to room temperature as it is stirred overnight. The reaction mixture is diluted with diethyl ether, washed consecutively with H20, aqueous NaHSO4 and brine, dried over MgSO4 and concentrated in vacuo to provide the untreated product. The product is triturated with Et20, Ph3P = 0 is removed, via filtration, and the filtrate is concentrated in vacuo to provide the untreated product. Purification via CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) provides the Z isomer (1.52 g, 7.1 mmol), 2% and the title isomer (56.55 g, 264 mmol), 73%. Isomer Z: FDMS: M * + 1 = 215. Analysis calculated for C11H1804.0.2 H20; C, 60.39; H, 8.52. Found: C, 60.49; H, 8.28. Isomer E: FDMS M + + 1 = 215. Analysis calculated for C H1804: C, 61.66; H, 8.47. Found: C, 61.44; H, 8.24. (c) 5SR-E (SR, E) -5,6-dihydroxy-2-hexenoate ethyl. A solution of the product from step (b) (46.4 g, 216.6 mmol) in THF (700 ml) is treated in one portion with IN HCl (500 ml) and stirred at room temperature overnight. EtOAc and NaCl are added, and the resulting suspension is stirred vigorously for two hours. The reaction mixture is partitioned in a separatory funnel and the product is extracted with EtOAc. All organic fractions are combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude diol. Purification via CLAP (25% EtOAc / hexanes to 95% EtOAc / hexanes) gives the title compound (30.52 g, 175 mmol) 81%. FDMS: M + + 1 = 175. Analysis calculated for C8H14O4.0.25 H20; C, 53.77; H, 8.18. Found: C, 53.88; h, 7.95. (d) 2SR, ethyl 4RS-2- [(4-hydroxy tetrahydrofuran-2-yl)] -2-iodoacetate. A solution of the product of the stage (c) (30.41 g, 174.6 mmol) in diethyl ether (1.5 1) at room temperature is treated consecutively with NaHCO, (44.0 g, 524 mmol) and then with I2 (100.8 g, 788 mmol), and the resulting reaction mixture is stirred until complete as determined by TLC. Aqueous Na2S203 is added to the reaction mixture and the product is extracted with Et20. All organic fractions are combined, washed with Na2S203, then with brine, dried over Na2SO4 and concentrated in vacuo to provide the untreated product. Purification by CLAP (5% EtOAc / hexanes to 50% EtOAc / hexanes) gives the title compound (29.05 g, 97 mmol) 55%. FDMS: M + + 1 = 301. Analysis calculated for C8H13IO41.0 H20; C, 30.21; H, 4.75. Found: C, 30.23; H, 4.43. (e) ethyl 2SR-2- [(4-oxo-tetrahydrofuran-2-yl)] -iodoacetate. A solution of the product from step (d) (28.5 g, 95 mmoles) in CH2C12 (500 ml) with 3A sieves are treated in one portion with pyridinium chlorochromate (91.5 g, 425 mmoles) and stirred at room temperature overnight. The reaction mixture is diluted with Et20 and filtered through celite "11. The filtrate is partitioned with 1N HCl and the product is extracted with Et20.All organic fractions are combined, washed with IN HCl and brine, dried on MgSO4, and concentrated in v uo to provide the crude product. Purification via CLAP (10% EtOAc / hexanes to 5% EtOAc / hexanes) provides the compound of the title (17.9 g, 60.1 mmol) 63%. FDMS: M + = 298. Analysis calculated for C8HxlIO4.0.5 H20; C, 31.29; H, 3.94. Found: C, 31.16; H, 3.75. (f) 1SR, 5SR, 6SR-2-oxabicyclo [3.1.0] hexan-4-ene-6-ethylcarboxylate. A solution of the product of step (e) (5.25 g, 17.6 mmol) in THF (50 ml) is treated by dropwise addition of a solution of DBU (2.82 g, 18.5 mmol) in THF (10 ml) and the mixture The resulting reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is reduced in vacuo, partitioned between Et20 and IN HCl and the product extracted with Et20. All organic fractions are combined, washed with brine, dried over MgSO4, and concentrated in vacuo to provide the untreated product. Purification via CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) gives the title compound (1.47 g, 8.63 mmol) 49%. FDMS: M + = 170. Analysis calculated for C8H10O4.0.1 H20; C, 55.88; H, 5-98. Found: C, 55.73; H, 5.81. (g) 1SR, 4SR, 5RS, 6SR-diethyl-4-aminobenzyloxycarbonyl) -2-oxabicyclo [3.1.0] -hexan-4,6 -dicarboxylate. A solution of the product from step (f) (3.0 g, 17.6 mmol) in a 1: 1 mixture of EtOH: H20 (50 ml total volume) is treated consecutively with NH2CO; -NH4 '4.13 g, 52.9 mmol), after with KCN (1.72 g, 26.4 mmol) and heated at 55 ° C for 40 hours. NaOH (4.0 g, 100 mmol) is added in one portion to the reaction and heated under reflux for 48 hours. The reaction mixture is concentrated in vacuo and the untreated amino acid is reconstituted in H20. The aqueous component is washed with »Et20 (3X), cooled to 0 ° C and acidified to pH = 1 with concentrated HCl. The aqueous component is washed with Et20 (3X), made basic until pH = 10 with NaHCO3, and concentrated to dryness in vacuo. The solids are reconstituted in a 1: 1 mixture of THF: H20 (100 ml total volume), stirred at 0 ° C as benzyl chloroformate (4.50 g, 26.4 mmol) is added dropwise and allowed to warm to room temperature and stirred for 48 hours. The reaction mixture is diluted and washed with Et20. The aqueous layer is acidified to pH = 1, with concentrated HCl and partitioned with NaCl and EtOAc. The product is extracted with EtOAc, dried over MgSO4 and concentrated to provide the untreated N-CBZ diacid. This intermediate is reconstituted in CH3CN and treated consecutively with triethylamine (5.6 g, 56 mol) and then with iodoethane (6.5 g, 42 mmol) and heated at 50 ° C for 48 hours. The reaction mixture is diluted with Et20 and partitioned with IN HCl. The product is extracted with Et O, washed with brine, dried over MgSO4 and concentrated. vacuum to provide the untreated product, which is purified by CLAP (EtOAc % / hexanes to 50% EtOAc / hexanes) gives the title compound (1.18 g, 3.13 mmol) 18%. FDMS: M + = 377. Analysis calculated for C19H23N07: C, 60.47; H, 6.14; N, 3.71. Found: C, 60.61; H, 6.44; N, 3.75. (h) A solution of the product of step (g) (0.71 g, 1.86 mmol) in 2N NaOH (20 ml) is heated under reflux for 3 days. The reaction mixture is partitioned and washed with EtOAc. The resulting aqueous component is subsequently acidified with 6N HCl and washed with EtOAc. All organic fractions are discarded. The aqueous phase is concentrated to dryness, reconstituted in H20 and adjusted to pH 14 with IN NaOH. The resulting solids are removed by filtration and the filtrate is reduced in vacuo. The pH is adjusted to 2 with IN HCl, applied to a Dowex ™ 50X8-100 cation exchange resin and eluted with 10% pyridine / H 2 O to provide the title compound (0.25 g, 1.34 mmol), 72%. p.f. = decomposition >200 ° C. FDMS: M + + 1 = 188. Analysis calculated for C, H9N05: C, 44.92; H, 4.85; N, 7.48. Found: C, 44.69; H, 4.73; N, 7.25.

Example 2 Enantiónaero 1S, 4S, 5R, 6S and Enantióanero 1R, 4R, 5S, 6R of 4-amino-2-oxabicyclo [3 .1.0] hexan-2,6 -dicarboxílico (a) ethyl 2SR-2- [(4-oxo-tetrahydrofuran-2-yl)] -iodoacetate. A solution at 0 ° C of the product of example 1, step (d) (34.0 g, 113 mmol) in acetone (500 ml) is treated by dropwise addition of the Jones reagent (225 ml, 450 mmol) at a rate for maintain the reaction temperature < . 15 ° C. Upon completion of the addition, the reaction is allowed to warm to room temperature and is stirred for 3 hours. 2-Propanol (30 ml) is added dropwise to suspend the reaction. The reaction volume is reduced in vacuo and the product is extracted with Et20. All organic fractions, washed with brine, dried (MgSO4) and purified by preparative CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) to provide 24.6 g (82.5 mmol, 73% of the title compound. FDMS: M * = 298. Analysis calculated for C, 32.24; H, 3.72; N, 3.82. Found: C, 32.37; H, 3.82. (b) 1SR, 5SR, 6SR-ethyl-2-oxabicyclo [3.1.0] hexan-4-one-6-carboxylate. A solution at 10 ° C of the product from step (a) (39.6 g, 133 mmol) in EtOAc (1.5 1) is treated by dropwise addition of a solution of DBU (25.28 g, 166 mmol) in EtOAc (100 ml. ) and the resulting reaction mixture is stirred at 10-15 ° C until the reaction is considered complete by TLC and GC. The resulting reaction mixture is acidified with IN HCl and the product is extracted with EtOAc. All The organic fractions are combined, washed with Na2S203 and then with brine, dried over MgSO4 and concentrated in vacuo to give an untreated product. Purification via CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) gives the title compound (14.7 g, 86.3 mmol) 52%. FDMS: M + = .-- 170. Analysis calculated for C8H10O4.0.25 H20: C, 55.01; H, 6.06. Found: C, 55.32; H, 5.76. (c) 1SR, 4SR, 5RS, 6SR-ethyl- (4-spiro-5'-hydantoin) -2-oxabicyclo- [3.1.0] -hexan-6-carboxylate. A solution of the product from step (b) (14.0 g, 82 mmol) in 100% EtOH (100 ml) and H20 (40 ml) at room temperature, treated consecutively with (NH4) 2C03 (16.0 g, 205 mmol) and KCN (6.70 g, 103 mmol) and heated at 35 ° C for 1 hour. The reaction mixture is cooled to 0 ° C and the product is precipitated from a solution at pH = 4 by dropwise addition of 5N HCl. The solids are collected via vacuum filtration by washing with 2-propanol and dried at 80 ° C under vacuum to provide 12.24 g (51 mmol, 62%) of the title compound, m.p. = 161-163 ° C. FDMS: M "= 240. Analysis calculated for C10H12N2O50.60 H20: C, 47.85; H, 5.30; N, 11.16. Found: C, 47.53; H, 4.89; / -I, 10.91. (d) 1SR, 4SR, 5RS, 6SR-4- (spiro-5'-hydantoin) -2-oxabicyclo- [3.1.0] -hexan-6-carboxylic acid. A solution of the product from step (c) (8.5 g, 35.4 mmoles) in 2N NaOH (70 ml) is stirred at room temperature for 3 hours. The reaction mixture is cooled to 0 ° C and 5.0 g (23.6 mmol, 67%) of the product is precipitated from the solution at pH = 1 by dropwise addition of concentrated HCL. The aqueous filtrate is saturated with NaCl and extracted with EtOAc to provide an additional 2.3 g (10.8 mmol, 16%) of the desired product. The combined total yield of the title compound is 7.3 g (34.4 mmol, 97%). p.f. = 258-261 ° C. FDMS: M + + 1 = 213. Analysis calculated for C8H8N205: C, 45.29; H, 3.80; N, 13.20. Found: C, 45.00; H, 3.65; N, 12.99. (e) 1R, 4R, 5S, 6R- (-) -4-spiro-5'-hydantoin) -2 -oxabicyclo- [3.1.0] -hexan-6-carboxylate. A solution at 65 ° C of the racemic mixture of the compounds prepared as described in step (d) (6.67 g, 31.4 mmoles) in EtOH (2 1) is treated with a solution of R- (-) -2- phenylglycinol (4.74 g, 34.5 mmol) in EtOH (500 mL) and the resulting reaction mixture is heated under reflux until dissolution occurs. The reaction mixture is allowed to cool to room temperature as it is stirred overnight. 4.20 g (12 mmoles) of the product are collected in .95% ee via vacuum filtration. Further recrystallization from EtOH provides 3.83 g (11 mmol, 35%) of the chiral salt in > 99.5% us aD = -111 ° (c = 0.1, H20). p.f. = 198-201 ° C. Analysis calculated for C 16 H 19 N 3 O 6-0.5 H20: C, 53.63; H, 5.63; N, 11.73. Found: C, 53.67; H, 5.60; N, 11.65. The chiral salt (3.8 g, 10.9 mmoles) converts the free acid by division between IN HCl, NaCl and EtOAc. The organic phase is separated, dried over MgSO4 and concentrated in vacuo to provide 2.15 g (10.1 mmol, 93%) of the title compound in > 99.5% us aD = -134 ° (c = 0.01, MeOH). p.f. = 260,262 ° C. FDMS: M + + 1 = 213. Analysis calculated for C8H8N205: C, 45.29; H, 3.80; N, 13.20. Found: C, 45.48; H, 4.04; N, 13.13. (f) IS, S, 5R, 6S- (+) -4- (spiro-5'-hydantoin) -2-oxabicyclo- [3.1.0] hexan-6-carboxylate. The mother liquors of stage (e) are combined and concentrated in vacuo. The base addition salt is converted to the free acid by dividing it between IN HCl, NaCl and EtOAc. The organic phase is separated, dried over MgSO4 and concentrated in vacuo to provide 2.2 g (10.4 mmol) of a solid. This solid is dissolved in hot EtOH (100 ml) and treated with a solution of S- (+) -2-phenylglycinol (1.56 g, 11.4 mmol) in EtOH (50 ml). After the initial precipitation of the salt, additional EtOH (50 ml) is added and refluxed. The chiral salt crystallized as the solution is allowed to cool to room temperature overnight to provide 2.4 g (6.9 mmole, 66%) in > 99.5%. "D = + 103 ° (c = 0.1, H20). p.f. = 217-220 ° C. Analysis calculated for ClsH19N3Os-0.5 H20: C, 53.63; H, 5.63; N, 11.73. Found: C, 53.87; H, 6.07; N, 10.69. The chiral salt (2.3 g, 6.6 mmol) is converted to the free acid by division between IN HCl, NaCl and EtOAc. The organic phase is separated, dried over MgSO4 and concentrated in vacuo to provide 1.30 g (6.1 mmol, 93%) of the title compound in > 99.5% us aD = + 128 ° (c = 0.01, MeOH). p.f. = 267-269 ° C. FDMS: M + + 1 = 213. Analysis calculated for C8H8N205.0.4 AcOH: C, 44.75; H, 4.10; N, 11.86. Found: C, 44.50; H, 4.06; N, 12.11. (g) IR, 4R, 5S, 6R (-) - 4-amino-2-oxabicyclo [3.1.0] hexan-4,6-dicarboxylic acid. A solution of the product from step (d) (2.10 g, 10 mmol) in 2N NaOH (35 ml) is heated at reflux overnight.

Subsequently the reaction mixture is cooled to 0 ° C, acidified with 6N HCl to pH = 1, and concentrated to dryness. The solid is reconstituted in H20 at pH = 12, applied to an anion exchange resin Bio-Rad "11 AG1- X8, and eluted with 3N AcOH to provide 1.51 g (8.07 mmol, 81%) of the title compound in > 99.5% us p.f. > 275 ° C (decomposition) a- = -63 ° (c = 0.1, H20).

FDMS: M + + 1 = 188. Analysis calculated for C7H9NOs: C, 44.93; H, 4.85; N, 7.48. Found: C, 44.66; H, 4.82; N, 7.36. (h) SSc, 4S, 5R, 6S (+) - 4-amino-2-oxabicyclo- [3.1.0] hexan-4,6-dicarboxylic acid. A solution of the product from step (f) (1.20 g, 5.6 mmol) in 2N NaOH (15 ml) is heated at reflux overnight. Subsequently the reaction mixture is cooled to 0 ° C, acidified with 6N HCl to pH = 1, and concentrated to dryness. The solid is reconstituted in H20 at pH = 12, applied to an anion exchange resin Bio-Rad "11 AG1-X8, and eluted with 3N AcOH to give 0.83 g (4.40 mmol, 79%) of the title compound in >99.5% ee pf> 275 ° C (decomposition) aD = + 62 ° (c = 0.1, H20) FDMS: M * + 1 = 188. Analysis calculated for C7H9NOS-0.3 H20: C, 43.66; H, 5.03; N, 7.27, Found: C, 43.37; H, 4.68; N, 7.06.

Example 3 1R, 4R, 5S, 6R-4-amino-2-oxabicyclo [3.1.0] hexan-4,6-dicarboxylic acid (a) 2S-1, 2-O-isopropyl? den-butan-l, 2,4-triol. A solution of (S) - (-) -1, 2, -butanotr? Ol (25 g, 236 mmol) in Acetone (500 ml) is treated in one portion with p-toluenesulfonic acid monohydrate (1.80 g, 9.4 mmol) and stirred at room temperature overnight. Triethylamine (0.95 g, 9.4 mmol) is added in one portion and the resulting reaction mixture is concentrated 222 vacuo to provide the untreated product. Purification via CLAP (10% EtOAc / hexanes to 90% EtOAc / hexanes) gives the title compound (29.88 g, 204 mmol), 87%. aD = + 2 ° (c = 0.01, CH2C12). FDMS: M + + 1 = 147. Analysis calculated for C7H1403.0.25 H20; C, 55.79; H, 9.70. Found: C, 55.80; H, 9.32. (b) 5SR, ethyl E-5,6-O-isopropylidene-5,6-dihydroxy-2-hexanoate. Oxalyl chloride (38.71 g, 305 mmol) is added dropwise to a solution at -78 ° C of DMSO (31.75 g, 406 mmoles) in CH2C12 (11) at a rate to maintain a reaction temperature. -65 ° C and subsequently stirred for an additional 30 minutes. To this reaction mixture is added a solution of the product from step (a) (29.7 g, 203 mmol) in CH2Cl (100 ml) at a rate to maintain the reaction temperature =. -60 ° C. Upon completion of the addition of the reaction mixture, stir at -78 ° C for 2 6 hours. Triethylamine (101 g, 1000 mmol) is added dropwise and the resulting suspension allowed to warm to room temperature Conforming environment is stirred during the night. The reaction mixture is washed consecutively with H20, aqueous NaHS04 and brine, dried over MgSO4 and concentrated in vacuo to provide the untreated product. The product is triturated in Et20 (500 ml), and Ph3P = 0 is removed, via filtration, and the filtrate is concentrated in vacuo-to provide the crude product. Purification via CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) gives the title compound (35.55 g, 166 mmol) 82%. aD = -9 ° (c = 0.01, CH2Cl2). aD = -11 ° (c, 0.01, MeOH), FDMS: M + = 214. Analysis calculated for C11H1804: C, 61.66; H, 8.47. Found: C, 61.53; H, 8.17. (c) Ethyl 5S-ethyl-5,6-dihydroxy-2 -hexenoate. A solution of the product of step (b) (35.4 g, 165 mmol) in THF (330 ml) is treated in one portion with IN HCl (330 ml) and stirred at room temperature overnight. The pH of the reaction is adjusted to 7 with NaHCO 3, then EtOAC and NaCl are added, and the resulting suspension is stirred vigorously for one hour. The reaction mixture is partitioned in a separatory funnel and the product is extracted with EtOAc. All organic fractions are combined, washed with brine, dried over MgSO4 and concentrated m vacuo to give the untreated diol. Purification via CLAP (10% EtOAc / hexanes to 90% EtOAc / hexanes) gives the title compound (24.6 g, 141 mmol) 86%. aD = -6o (c = 0.01, CH2C12), aD - -22 ° (c-0.01, MeOH). FDMS: M + + 1 = 175. Analysis calculated for C8HX4O4.0.25 H20: C, 53.77; H, 8.18. Found: C, 53.50; H, 8.48. (d) 2R, 4S-2- [(4-hydrO-tetrahydrofuran-2-yl)] -2-ethyl iodoacetate. A solution of the product of the stage (c) (24.6 g, 141 mmol) in diethyl ether (11) at room temperature is treated consecutively with NaHCO3 (35.6 g, 4.24 mmol) and then with I2 (80.7 g, 635 mmol), and the resulting reaction mixture it is stirred until it is complete determined by CCF. Solid Na2S203 is added to the reaction mixture and stirred vigorously until a change in coloration occurs. The reaction mixture is partitioned with water and the product is extracted with Et20. All organic fractions are combined, washed with Na2S203, H20, then with brine, dried over Na2SO4 and concentrated in vacuo to provide the untreated product. Purification by CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) gives the title compound (23.51 g, 78.3 mmol) 55%. a- = + 64 ° (c = 0.01, CHC13). FDMS: M + = 300. Analysis calculated for C8H13IO4.0.5 H20: C, 31.09; H, 4.57. Found: C, 30.89; H, 4.48. (e) ethyl 2R-2- [(4-oxo-tetrahydrofuran-2-yl)] -iodoacetate. A solution at 0 ° C of the product from step (d) (23.3 g, 77.6 mmol) in acetone (500 ml) is treated by dropwise addition of Jones reagent (225 ml, 450 mmol) at a rate to maintain the reaction temperature < 10 ° C. Upon completion of the addition, the reaction is allowed to warm to room temperature as it is stirred for 6 hours. 2-Propanol (25 ml) is added dropwise to suspend the reaction. The reaction volume is reduced in vacuo and the product is extracted with Et20. Combine all organic fractions, wash with 10% NaHCO3, H20 and brine, dry (MgSO4), and purify by preparative CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) to provide 18.6 g. (62.3 mmol, 80%) of the title compound aD = + 65 ° (c = 0.01, CHC13). FDMS: M + = 298. Analysis calculated for C8H I04: C, 32.24; H, 3.72. Found: C, 32.48; H, 3.62. (f) 1 R, 5R, 6R-2-oxabicyclo [3.1.0] he an-4-one-6-carboxylic acid ethyl ester. A solution at 10 ° C of the product from step (e) (18.45 g, 61.9 mmol) in EtOAc (750 mL) is treated by dropwise addition of a solution of DBU (11.78 g, 77.4 mmol) in EtOAc (75 mL). ) and the resulting reaction mixture is stirred at 11 ° C for 1 hour. The reaction mixture is acidified with IN HCl and the product is extracted with Et20. Combine all organic fractions, wash with Na2S203 then with brine, dry (MgSO4), and concentrate in vacuo to provide the untreated product. Purification via CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) gives the title compound (6.62 g 38.9 mmoles) 63% p. f. ^ 88-89 ° C. aD = + 164 ° (c = 0.01, CHC13). FDMS: M + +1 = 171. Analysis calculated for C8H10O4: C, 56.47; H, 5.92. Found: C, 56.18; H, 5.65. (g) IR, 4R, 5S, 6R- (4-spiro-5'-hydantoin) -2 -oxabicyclo- [3.1.0] -hexan-6-ethyl carboxylate. At room temperature, a solution of the product from step (f) (3.0 g, 17.6 mmol) in EtOH (25 ml) and H20 (10 ml) is treated consecutively with (NH4) 2C03 (3.44 g, 44.1 mmol) and KCN (1.43 g, 22 mmol) and heated at 35 ° C for 1 hour. The pH of the reaction mixture is decreased to 1 with 5N HCl and concentrated to dryness. The product is recrystallized from 2-propanol / H20 (10: 1), filtered and dried under vacuum at 80 ° C to provide 1.15 g (4.8 mmol, 27%) of the title compound, m.p. 195-197 ° C. aD = -128 ° (c = 0.01, MeOH). FDMS: M + + 1 = 241. Analysis calculated for C10H12N2O5: C, 50.00; H, 5.04; N, 11.66. Encentered: C, 49.99; H, 4.89; N, 11.44. (h) 1R, 4R, 5S, 6R (4-spiro-5 * -hydantoin) -2-oxabicyclo- [3.1.0] hexan-6-carboxylate. A solution of the product of Example g (1.10 g, 4.58 mmol) in IN NaOH (15 mL) is stirred at room temperature for 3 hours. The reaction mixture is acidified to pH = 1 with 5N HCl and the product is extracted with EtOAc. All organic fractions are combined, washed with brine, dried (MgSO4) and concentrated to give 0.94 (4.4 mmol, 97%) of the title compound ccD = -139 ° (c = 0.01, MeOH). p.f. = 268-270 ° C. FDMS: M + + 1 = 213. Analysis calculated for C8H8N2Os-0.1 H20: C, 44.91; H, 3.86; N, 13.09. Found: C, 44. 80; H, 3.85; N, 12.92. (i) 1R, 4R, 5S, 6R- (-) 4-amino-2-oxabicyclo [3.1.0] -hexan-4,6-dicarboxylic acid. Using 0.90 g (4.2 grams) of the product from step h, the title compound is obtained identical to the compound of example 2g.

Example 4 1SR, 4RS, 5RS, 6RS-4-amino-2-thiabicyclo [3.1.0] hexan-4, ß-dicaxy? (a) (1SR, 5RS, 6RS) - [2-thiabicyclo [3.1.0j hex-3-en] -ethylcarboxylate. A solution of ethyl diazoacetate (11.4 g, 100 mmol) in thiophene (20 ml) is added dropwise to a 70% solution of [Rh (0Ac) 2] 2 in thiophene (100 ml). Upon completion of the addition, the reaction mixture is heated under reflux for 3 hours, concentrated to an orange oil and purified by preparative CLAP (10% EtOAc / hexanes) to provide 6.51 g (38%, 38.2 mmol) of the composed of the title. FDMS: M + = 170. Analysis calculated for C8H10O2S: C, 56.45; H, 5.92; S, 18.84. Found: C, 56.72; H, 6.21; S, 19.11. (b) (1SR, 4RS, 5RS, 6RS) -4-hydroxy- [2-thiabicyclo [3.1.0] -hexan] ethyl carboxylate. A solution of BH3THF (1M, 5.3 mmol) is added dropwise to a 0 ° C solution of the product from step (a) (0.90 g, 5.29 mmol) in THF (25 ml) and subsequently stirred at 0 ° C. for 6 hours. 3N NaOH (5 ml) followed by 30% H202 (1 ml) is added dropwise. The resulting reaction mixture is allowed to warm to room temperature as it is stirred overnight. The reaction is partitioned with saturated NaHCO 3 and the product is extracted with Et * 0. All organic fractions are combined, washed with brine, dried (MgSO4) and purified by TLC-PC ((10% EtOAc / hexanes to 50% EtOAc / hexanes) to provide 0.48 g (48%, 2.5 mmol. ) of the title compound FDMS: M * = 188.

Analysis calculated for C8H1203S .0.4 H20: C, 49.16; H, 6.60; S, 16 O Found: C, 49.03; H, 6.28; S, 17.80. (c) (1SR, 5RS, 6RS) -4-oxo- [2-thiabicyclo [3.1.0] hexan] -carboxylic acid ethyl ester. Oxalyl chloride (4.35 g, 34.3 mmol) is added dropwise to one. solution at -78 ° C DMSO (3.56 g, 45.6 mmol) in CH2C12 (400 mL) at a rate to maintain a reaction temperature < . -65 ° C. Upon completion of the action, the reaction is allowed to equilibrate for 30 minutes, followed by dropwise addition to a solution of the product from step (b) (4.31 g, 22.8 mmol) in CH2C12. (20 ml) maintaining the reaction temperature < . -65 ° C. The reaction is allowed to slowly warm to -40 ° C, after which the reaction is cooled once more to -78 ° C, and suspended by the addition of triethylamine drops. (11.54 g, 114 mmol). The reaction is divided with IN HCl and NaCl and the product is extracted with Et20. All the organic phases are combined, washed with H20 and brine, dried (MgSO4) and purified by preparative CLAP (10% EtOAc / hexanes to 50% EtOAc / hexanes) to provide 3.20 g (17.2 mmol), 75% of the title compound m.p. 55-57 ° C. FDMS: M + = 186. Analysis calculated for CgH10O3S: C, 51.60; H, 5.41, S, 17.23. Found: C, 51.59; H, 5.32; S, 17.63. (d) (1SR, 4RS, 5RS, 6RS) -4- (spiro-5'-hydantoin) - [2-thiabicyclo [3.1.0] -hexan] -ethylcarboxylate. A solution of the product from step (c) (3.22 g, 17.3 mmol) in EtOH (25 ml) and H20 (10 ml) at room temperature, treated consecutively with (NH4) 2C03 (3.37 g, 43.3 mmol) and KCN (1.41 g, 21.6 mmol) and is encouraged at 35 ° C until the reaction is considered complete by TLC. The reaction mixture is acidified with 6N HCl, partitioned with NaCl and the product extracted with EtOAc. All organic fractions are combined, dried (MgSO 4), and recrystallized from 2-propanol to provide 2.25 g (8.8 mmol, 51%) of the title compound, m.p. 197-200 ° C. FDMS: M + = 256. Analysis calculated for C10H12N2O4S .0.75 IPA: C, 48.83; H, 6.02; N, 9.30. Found: C, 48.75; H, 6.07; N, 8.94. (e) (1SR, 4RS, 5RS, 6RS-4-amino [2-thiabicyclo [3.1.0] -hexan] -4,6 -dicarboxylate.A solution of the product of step (d) (0.85 g, 3.30 mmol. ) in 2N NaOH (20 ml) is heated under reflux for 4 days, then the reaction mixture is acidified with 6N HCl and concentrated to dryness The solid is reconstituted in H20 at pH = 11, applied to an anion exchange resin Bio-RadMR AG1X8 is eluted with 3N AcOH and concentrated to dryness.The product is triturated in a hot mixture of H- and O-2-propanol and filtered to provide 0.31 g (46%, 1.5 mmol) of the composed of the title, p.f. > 250 ° C. FDMS: M + = 203. Analysis calculated for C7H9N04S .0.5 H20: C, 39.62; H, 4.75; N, 6.60; s, 15.11. Found: C, 39.81; H, 4.48; N, 6.69; S, 14.27.

Example 5 IR acid, 4R, 5S, 6R-4-amino-2-oxabicyclo [3.1.0] hexan-, 6-dicarboxylic acid (a) (1SR, 5SR, 6SR) - [2 -oxabicyclo [3.1.0] hex-3-ene-carboxylic acid ethyl ester. A solution of ethyl diazoacetate (100 g) in furan (250 ml) is added dropwise to a solution of [Rh (OAc) 2] 2 in furan (250 ml) with stirring at 10 ° C for a period of about 2 hours. to 2.5 hours. An additional 0.1 g of [Rh (OAc) 2] 2 is added approximately two-thirds of the process in the addition. After the CLAP analysis shows complete consumption of the ethyl diazoacetate, a solution of NaHS03 (200 g) in water (400 ml) is added, and the resulting mixture in two phases is allowed to warm to room temperature with stirring during 1 to 2 hours. Subsequently the reaction mixture is extracted with MTBG (500 ml), and the organic phase is washed with water (400 ml) and saturated NaCl (300 ml), then dried over Na2SO4. The solvent is then removed by evaporation and the resulting oil is distilled in vacuo (45 ° C. at 0.2 mmHg) to provide the title compound (47-54 g), as an oil. (b) (1SR, 4RS 5SR, 6SR) - Hydroxy [2-oxabicyclo [3.1.0] hexan] ethyl carboxylate. A solution of hexyl borane is prepared by adding a solution of 2,3-dimethyl-2-butene (4M, 53.0 ml) in THF via syringe, to a complex of borane and dimethyl sulfide (10 M, 21.2 ml) in a dry flask under nitrogen at less than 0 ° C. The solution is stirred for 2 hours at <0 ° C before use. The product of (a) (32.73 g, 212.30 mmol) is dissolved in 150 ml of THF under N2. The resulting solution is cooled with stirring at -0.5 ° C. While the agitated solution cools, the system is evacuated and purged with N2 twice. The totality of the previously prepared texilborane solution is added via a cannula for 40 minutes, maintaining the temperature < 4.4 ° C. After stirring 2 hours at 0 ° C, 87 ml of 30% H202 are added slowly, over 70 minutes, to maintain the temperature at < 30 ° C. Following the addition of peroxide, add 15 ml of pH = 7 phosphate buffer (KH, P0 1M and in 1M K2HP04) and allow the mixture to stir overnight (14 hours) while heating up to 1. tempe : ambient ratio. The mixture is cooled < 5 ° C and 25 ml of saturated aqueous Na2S203 are added slowly. Subsequently, 75 ml of EtOAc, followed slowly by 75 ml of saturated aqueous Na2S203. Then another 40 ml of saturated aqueous Na2S203 is slowly added. The mixture is stirred for 15 minutes, then divided between 75 ml of EtOAc and 30 ml of saturated aqueous Na2S203. The aqueous layer is back-extracted three times with 50 ml of EtOAc. The combined organic layers are washed with 30 ml of brine and dried over Na2SO4. The solvent is removed to provide 54.44 g of an oil. The oil is purified by flash chromatography (370 g of silica gel, wet packed with 3: 2 hexanes: EtOAc) eluting with 3: 2 hexanes: EtOAc, to provide 31.72 g of the title compound as an oil. (c) (1SR, 5SR, 6SR) -4-oxo- [2 -oxabic io [3.1.0] -hexan] ethyl carboxylate. To a solution of DMSO (28.74 g, 367.8 mmol), oxalyl chloride (25.70 g, 202.44 mmol) in CH2C12 is added dropwise over 35 minutes. (300 ml) under N2, while maintaining the temperature at less than < -65 ° C. The solution is stirred for 10 minutes and cooled again to -70 ° C. A solution of 31.68 g of the product of step (b) (26.29 g, 152.71 mmol, corrected for 83% strength) dissolved in 100 ml of CH2C12, is added dropwise, during 40 minutes while maintaining the temperature at -67 °. C. The mixture is stirred for 5 minutes, and then 62 ml are added dropwise for 15 minutes. (45.01 g, 444.83 mmoles) of triethylamine, keeping the temperature below -50 ° C. After stirring for 15 minutes, the TLC indicates complete reaction and the mixture is allowed to warm to about -40 ° C. The mixture is filtered and washed through 300 ml of CH2C12. The filtrate is extracted twice with 150 ml of IN HCl. The aqueous layer is back-extracted with 50 ml of CH2C12. The combined organic layers are washed with 75 ml of brine and dried over MgSO4. The majority of the solvent is removed by rotary evaporation to provide 44.36 g of liquid. Some seed crystals are added and the flask is coated with N2 and stirred at room temperature for 30 minutes while forming a light suspension. At room temperature, the suspension is slowly added to 20 ml of hexanes. The suspension is stirred for 90 minutes at room temperature and then 3 hours in an ice / NaCl / water bath. The solids are filtered, washed with 25 ml of 5: 1 hexanes: EtOAc, and dried under vacuum to provide the title compound (19.48 g) as white crystals. A second crop of crystals (2.28 g) of the filtrate is obtained. (d) (1SR, 4SR, 5RS, 6SR) -4 - > spiro-5'-hydantoin) -2 -oxabicyclo [3.1.0] ethyl hexan carboxylate. To a suspension of ammonium carbonate (5.65 g, 58.8 mmol), Potassium cyanide (2.01 g, 30.9 mmol) in 25 ml of methanol, at room temperature, add a solution of the product from step (c) (5.0 g, 29.4 mmol) in 25 ml of methanol. The mixture is stirred at room temperature and monitored by CLAP. After 23 hours, the reaction ends. The mixture was diluted 100 ml of water, cooled and seeded. The pH is adjusted from 9.6 to 7.0 with 6N hydrochloric acid which gives a white solid. The suspension is stirred at 0-5 ° C for 1.5 hours, filtered and washed with 75 ml of cold water-methanol (2: 1). The white solid is dried in vacuo at 40 ° C, which gives the title compound (5.55 g, 78.6%). The product is identified by XH NMR. (e) Acid (1SR, 4SR, 5RS, 6SR) -4- (spiro-5'-hydantoin) -2-oxabicyclo [3.1.0] hexancarboxylic acid. A solution of the product from step (d) (7.59 g, 31.6 mmol) in 2N NaOH (63.2 ml) is stirred for 30 minutes at room temperature. Subsequently, the hydrolysis is suspended by the addition of 12N HCl (5.27 ml, 63.2 mmol). The reaction mixture is then stirred for three hours at 0 ° C and then filtered under vacuum. The collected solid is dried under vacuum at 50 ° C overnight, which gives the title compound (6.12 g, 91.3%). XH NMR (DMSO-d 6 2.24 (s, ÍH), 2.26 (s, ÍH), 3.35 (d, ÍH, J = 11Hz), 4.05 (d, ÍH, J = 11Hz), 4.39 -. - 63 - (d, ÍH, J = 5 Hz), 13C NMR (DMSO-d6) d 22.14, 30.75, 65.74, 68.32, 70.61, 156.32, 171.11, 175.63. Analysis calculated for C8H8N2Os: C, 45.29; H, 3.80; N, 13.2. Found: C, 45.02; H, 3.75; N, 12.92. 5 (f) Salt of (R) - (-) - 3-phenylglycinol, of IR acid, 4R, 5S, 6R- (-) -4-spiro-5'-hydantoin-2-oxabicyclo [3.1.0] - hexancarboxylic To the product of step (e), (0.80 g, 3.8 mmol) is added (R) - (-) - phenylglycinol (0.52 g, 3.8 mmol) in ethanol (20 ml) and water (4 ml). The mixture is heated to reflux, and an additional 1 ml of water is added, which produces a homogeneous solution. After about 30 minutes at reflux, the mixture is allowed to cool to room temperature. After After stirring at room temperature overnight, the reaction mixture is filtered, washed with 1 ml of a cold 25: 5 mixture of ethanol and water, and dried under vacuum at 50 ° C overnight, which provides the compound of the title (0.57 g, 43.3%) as a white solid. ? NMR (DMS0-ds) d 2.05 (t, ÍH, J = 3.3 Hz), 2.20 (d, ÍH, J = 3Hz), 3.30 (d, ÍH, J = 11Hz, 3.50 (m, ÍH), 3.55: m, ÍH), 4.0 ( d, HH, J = 11Hz), 4.1 (m, HH), 4.18 (d, HH, J = 6Hz), 7.25 (m, HH), 7.30 (m, 2H), 7.35 (m, 2H). It is determined that the enantiomeric excess is 98.8%, by CLAP. 25 (g) IR, 4R, 5S, 6R- (-) 4-amino-2-oxabicyclo- [3.1.0] hexan-4,6-dicarboxylic acid. To the product of stage (f) (1.0 g, 2.86 mmol) are added 15 ml (30 mmol, 10 equivalents) of 2M aqueous sodium hydroxide. The solution is refluxed for 43 hours. The resulting mixture is allowed to cool to & at room temperature, and then extracted with CH2C12 (5 x 30 ml). The aqueous layer is diluted with 10 ml of H20 and acidified to pH 2 with HCl 3M. The turbid mixture is filtered, and the pH is adjusted to 8 using 2M NaOH, after which the solution is allowed to rest during the weekend. This results in the formation of a gel from the remaining silicic acid. The gel is removed by filtration through a glass medium frit for 1 hour and moistened with 50 ml of H20. An ion exchange column is prepared from 25 g of a resin, in the form of acetate, Bio-Rad AG 1-X8, 100-200 mesh. The resin is transferred to a gravity flow column using deionized H20 and washed sequentially with 1M NaOH (2 x 50 ml) and H20 (2 x 50 ml or up to a neutral eluent). The solution of the aqueous product is poured onto the resin in 50 ml portions. The column is washed sequentially with H20 until the eluent is neutral (approximately 100 ml), 70 ml of 1: 1 THF / H20, and 100 ml of H20. The product is eluted with 120 ml of a 1: 3 mixture of acetic acid and H20. The whole eluent is collected in a flask and evaporated to 0.48 g of a white solid. The solid is suspended in 5 ml of H20 and collected in a thick glass frit. The flask is moistened with additional H20 (2 x 5 ml) and these rinses are used to wash the collected solid. After drying under vacuum at 70 ° C for 18 hours, the title compound (0.33 g, 62%) is obtained as a white solid. The structure is confirmed by XH NMR and analysis.

Example 6 LSR, 4RS, 5RS, 6RS-4-amino- (2-sulfonyl-bicyclo [3.1.0] hexan) -4,6-dicarboxylic acid (a) (1SR, 4RS, 5RS, 6RS) - (4-spiro-5'-hydantoin) - [2-sulfonylbicyclo [3.1.0] hexan] -6-carboxylic acid ethyl ester. M-CPBA (1.56 g, 5.0 mmol) is added in one portion to a room temperature solution of the product of Example 4 (d) (0.51 g, 2.0 mmol) in EtOAc (50 mL) and stirred at room temperature until The reaction is considered complete by CCF. The reaction is diluted with 10% NaHCO 3 and the product is extracted with EtOAc. All organic fractions are combined, washed with brine, dried over Na2SO4 and purified by preparative CLAP (EtOAc % / hexanes to 50% EtOAc / hexanes) to provide 0.21 g (0.73 mmol, 36%) of the title compound, m.p. > 275 ° C. FMDS: M * = 288. Analysis calculated for C10H12N2O6S .0.4 of m-chlorobenzoic acid: C, 43.81; H, 4.02; N, 7.98; S, 9.14. Found: C, 43.87; H, 4.04; N, 7.96; S, 9.44. (b) (1SR, 4RS, 5RS, 6RS) -4 -amino- (2-sulphonylbicyclo- [3.1.0] -hexan) -6-carboxylate. A solution of the product of (a) (0.14 g, 0.49 mmol) in 2N NaOH (10 mL) is heated under reflux overnight. The reaction mixture is acidified to pH = 1 with 5N HCl and concentrated to dryness.

The product is reconstituted in H20 at pH = 12, applied to an anion exchange resin BioRad "1 * AG1-X8, and eluted with 3N AcOH to provide 0.10 g (87%, 0.43 mmol) of the title compound, mp > 250 ° C. FMDS: M * + 1 = 236.

Analysis calculated for C7H9N06S .0.5 H20: C, 34.43; H, 4.13; N, 5.74. Found: C, 34.29; H, 3.98; N, 5.45.

Example 7 LSR, 3RS, 4SR, 5RS, 6SR-3- ((3-chloro-4-fluoro) benzyl) -4-amino-2-oxabicyclo [3.1.0] hexan-4,6-dicarboxylic acid (a) (1SR, 5SR, 6SR-ethyl-3- ((3-chloro-4-fluoro) benzylidene) -2-oxabicyclo [3.1.0] hexan-4-on-6-carboxylate. Example product 1 (f) (4.3 g, 25.2 mmol), 3-chloro-4-fluorobenzaldehyde (8.0 g, 50.4 mmol) and pyrrolidine (0.9 g, 12.6 mmol) in EtOH (100 mL) is stirred at room temperature for 18 hours The reaction mixture is concentrated to dryness and the residue is purified by CLAP (5% EtOAc / hexane to 50% EtOAc / hexane) which gives 4.2 g (53%) of the title compound, mp 110- 112 ° C. FMDS: M + = 310. Analysis calculated for C15H12C1F04: C, 57.99; H, 3.89, Found: C, 57.92; H, 3.75. (b) lSR, 3SR, 5SR, 6SR-ethyl-3- ((3-chloro-4-fluoro) benzyl) -2-oxabicyclo [3.1.0] hexan-4-on-6-carboxylate and 1SR, 3RS, 5SR, -6SR-ethyl-3- ((3-chloro-4-fluoro) benzyl) -2-oxabicyclo [3.1.0] -hexan-4-on-6-carboxylate. The compounds of the title mixture are prepared using the product from step (a) (8.8 g, 28.3 mmol), Raney Ni (0.2 g), EtOAc and hydrogen at 2.9 kg / cm2 (40 psi) for 15 minutes. Due to the above reduction of the ketone, the untreated product is oxidized using pyridinium chlorochromate and pulverized sieves, which provides 6.8 g of the untreated ketone. The residue is purified by CLAP (5% EtOAc / hexane to 50% EtOAc / hexanes) which provides 5.2 g (58%) of the title mixture of the compounds. FMDS: M '= 312. Calculated analysis for C15H14C1F04: C, 57.61; H, 4.51. Found: C, 56.98; H, 4.70. (c) lSR, 3RS, 4SR, 5RS, 6SR-ethyl-3- ((3-chloro-4-fluoro) -benzyl) - (4-spiro-5'-hydantoin) -2-oxabicyclo [3.1.0] hexan-6-carboxylate. Prepare the title compound using the product of step (b) (1.0 g, 3.2 mmol), ammonium carbonate (0.75 g, 9.6 mmol) and KCN (0.25 g, 3.8 mmol) in a 1: 1 mixture of EtOH /Water. The reaction mixture is heated at 35-40 ° C for 48 hours. The reaction mixture is partitioned between water and EtOAc. After extraction with EtOAc, the organic layer is dried with MgSO 4, concentrated and purified using radial chromatography (EtOAc / hexane) to provide 0.18 g (14%) of the product hydantoin. Crystallization of the product from chloroform gives white solids, m.p. = 224-226 ° C. FMDS: M * -382. Analysis calculated for C, -, H, 6C1FN205. -0.5 CHC13: C, 47.51; H, 3.75; N, 6.33. Found: C, 47.87; H, 3.69; N, 6.22. (d) 1SR, 3RS, 4SR, 5RS, 6SR-3- ((3-Chloro-4-fluoro) -benzyl) -4-amino-2-oxabicyclo [3.1.0] hexan-4,6-dicarboxylic acid. The title compound is prepared using the product from step (c) (0.1 g, 0.26 mmol) and IN NaOH (10 mL) at reflux for 48 hours. The reaction mixture is adjusted at pH = 10 with IN HCl and anion exchange is performed on the untreated product. The product is recrystallized from H20 and dried in a vacuum oven at 70 ° C to provide 8 mg (9%) of the title compound, m.p. = 250-251 ° C. FDMS: M + = 330. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it refers. Having described the invention as above, property is claimed as contained in the following:

Claims (10)

- 70 - REVIVALS
1. A compound of formula wherein X represents O, NRa, S, SO or S02; R 10 represents a hydrogen atom, an alkyl group of 1-6C; a 2-6C alkenyl group; a 2-6C alkynyl group; an optionally substituted aromatic group; an optionally substituted heteroaromatic group; a non-aromatic carbocyclic group; a heterocyclic group does not 15 aromatic; a non-aromatic monocyclic carbocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; a non-aromatic monocyclic heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; or an alkyl group of 1-6C, 20 2-6C alkenyl or 2-6C alkynyl which is substituted by one, two or three groups which are independently selected from an optionally substituted aromatic group; an optionally substituted heteroaromatic group; a non-aromatic carbocyclic group, a group 25 non-aromatic heterocyclic, a carbocyclic group non-aromatic monocyclic fused with one or two monocyclic aromatic or heteroaromatic groups and a non-aromatic monocyclic heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; Ra represents hydrogen or a group of formula (CO) nRb; n is 0 or 1; and Rb is as defined for R; or an ester or amide thereof metabolically labile, non-toxic thereof; or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1, characterized in that Ra represents hydrogen.
3. 3. The compound according to claim 1, characterized in that X represents O or S.
4. 4. The compound according to any one of claims 1 to 3, characterized in that R represents a hydrogen atom or a phenylalkyl group of 1-4C or diphenylalkyl of 1-4C which is unsubstituted or substituted on the phenyl by one or two substituents which are independently selected from halogen, 1-4C alkyl, 1-4C alkoxy and phenyl.
5. 5. The compound according to any of claims 1 to 4, characterized in that it has the stereochemistry shown below.
6. 6. The compound according to any of claims 1 to 5, characterized in that R represents a hydrogen atom.
7. 7. The compound according to claim 1, characterized in that it is selected from 1SR, 4SR, 5RS, 6SR-4-amino-2 -oxabicyclo [3.1.0] hexan-4, or -dicarboxylic acid; 1SR, 4SR, 5RS, 6SR-4-amino-2-thiabicyclo [3.1.0] hexan-4,6-d-carboxylic acid; 1SR, 4RS, 5? -4-amino- (2-sulfonylbicyclo [3.1.0] exan-4,6-dicarboxylic acid; and 1SR, 3RS, SR, 5RS, 6SR-3 - '3-chloro-4-flucrobenzyl: -4-amino acid -2-oxabicyclo [3.1.0] hexan-4, 5 -dicarboxylic acid.
8. 8. The compound according to claim 1, characterized in that it is the acide IR, 4R, 5S, 6R-4-amino-2-oxabicyclo [3.1. O] hexan-4,6-dicarboxylic acid.
9. 9. A process for the preparation of a compound of formula I, characterized in that it comprises (a) hydrolyzing a compound of formula in the sual R1 represents a hydrogen atom or an acyl group and R2 represents a carboxyl group or an esterified carboxyl group, or a salt thereof; (b) hydrolyzing a compound of formula wherein R3 represents a carboxyl group or an esterified carboxyl group and R4 and R5 each independently represent a hydrogen atom, an alkanoyl group of 2-6C, an alkyl group of 1-4C, an alkanoyl group of 3-4C or a phenylalkyl group of 1-4C in which the phenyl is unsubstituted or substituted by halogen, alkyl of 1-4C or alkoxy of 1-4C, or a salt thereof; or (c) deprotecting a compound of the formula wherein Rs represents a hydrogen atom or a nitrogen protecting group, and each of R7 and R8 independently represents a hydrogen atom or a carboxyl protecting group, or a salt thereof; subsequently, if necessary and / or desired (i) to separate the compound of formula I; (ii) converting the compound of formula I to a metabolically labile ester, r .. toxic thereof; I (iii) converting the compound of formula I or a metabolically labile, non-toxic ester or amide thereof into a pharmaceutically acceptable salt thereof.
10. 10. A pharmaceutical formulation, characterized in that it comprises a compound according to claim 1, and a pharmaceutically acceptable carrier, diluent or excipient. -XÓH Compounds for formula (I) are described, in which X represents 0, NR *, S, SO or S02; and R is defined in the specification; and metabolically labile, non-toxic esters and amides thereof and pharmaceutically acceptable salts thereof which are useful as modulators of metabotropic glutamate receptor function.