GB2355982A

GB2355982A - Heterocyclic amino acids

Info

Publication number: GB2355982A
Application number: GB9926057A
Authority: GB
Inventors: Stephen Richard Baker; Timothy Colin Hancox
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1999-11-03
Filing date: 1999-11-03
Publication date: 2001-05-09
Also published as: WO2001032644A3; AU1433901A; WO2001032644A2; GB9926057D0

Abstract

Compounds of formula I <EMI ID=1.1 HE=43 WI=55 LX=806 LY=701 TI=CF> <PC>in which:- Y represents O, NR<SP>a</SP>, S, SO or SO<SB>2</SB>; X<SP>1</SP> represents (CR<SP>1</SP>R<SP>2</SP>)<SB>m</SB>; X<SP>2</SP> represents (CR<SP>3</SP>R<SP>4</SP>)<SB>n</SB>; one of m and n is 1 and the other is 0 or 1; and R<SP>a</SP>, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> are each as defined in the specification; and non-toxic metabolically labile esters or amides thereof; and pharmaceutically acceptable salts thereof; are useful as modulators of metabotropic glutamate receptor function.

Description

1 2355982 EXCITATORY AMINO ACID DERIVATIVES In the mammalian central

nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway 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 Watkins & Evans, Ann. 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). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.

Excitatory amino acid receptors are classified into two general types. 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), (X-amino-3-hydroxy-5methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D 2 and or C, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).

The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.

The metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. Compounds which modulate the function of these receptors, in particular agonists and antagonists of glutamate, are useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant, and anti-emetic agents.

European patent applications publication numbers EP 0696577 Al, EP 0774454 Al, EP 0774455 Al and EP 0774461 Al, and International patent application publication number WO 98/51655 disclose certain aminobicyclo[3.1.0]hexane dicarboxylic acids which are modulators, in particular agonists or antagonists of glutamate at metabotropic 3 glutamate receptors. The compounds of EP 0774461 Al possess a heteroatom in the bicyclohexane ring. The priority documents for EP 0696577 Al also disclose higher aminobicycloalkanedicarboxylic acids, such as 2aminobicyclo[4.1.0]heptane-2,7-dicarboxylic acid, as modulators of glutamate at metabotropic glutamate receptors.

The present invention provides a compound of the formula H2N COOH COOH x H y_X2 10)(2 in which:- Y represents 0, NW, S, SO or S02; X1 represents (CR"R 2 X2 represents (CR 3 R 4 one of m and n is 1 and the other is 0 or 1; R I and R 2 each independently represents a hydrogen atom, a (1-4C) alkyl group or a fluorine atom; or R' represents a hydrogen atom and R 2 represents Xa ORb, XbNRcRd, SO 3 H, tetrazol e f h 5-yl, CN, NO 21 PO 3 R 21 N 31 (CH 2) COOR, (CH') PPO 3 Rg 2, NHCONHR or NHSO 2 R i; or R1 and R 2 together represent =0, =NORj, =CR k R2, =CHCOOR', =CHPO 3 W 2 or =CHCN; or R1 represents amino and R 2 represents carboxyl; R 3 and R4 each independently represents a hydrogen atom, a (1-4C) alkyl group or a fluorine atom; or R 3 represents a hydrogen atom and R 4 represents Xa ORb, XbNRcR d' so 3 H, tetrazol- e f h 5-yl, CN, NO 21 PO 3 R 21 NI I (CH 2) COOR, (CH 2) PP03 Rg 2. NHCONHR or i 3 4 k NHSO 2 R; or R and R together represent =0, =NORj, =CR R =CHCOORm, =CHPO,Rn2 or =CHCN; or R 3 represents amino and R" represents carboxyl; and 4 R' represents a hydrogen atom, a (1-4C)alkyl group, a (1-4C)alkanoyl group or a (1-4C)alkylsulfonyl group, provided that when n is 0, Y does not represent NR a in which R' represents hydrogen or (1-4C)alkyl; R b represents a hydrogen atom; a (1-6C) alkyl group; a (3-6C)alkenyl group; a (3-6C)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 non-aromatic monocyclic heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; or a (1-6C) alkyl, (3-6C)alkenyl or (3-6C)alkynyl group which is substituted by one, two or three groups selected independently from an optionally substituted aromatic group, an optionally substituted heteroaromatic group, a nonaromatic carbocyclic group, a non-aromatic heterocyclic group, a nonaromatic monocyclic carbocyclic group 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; f h i m b R, R, R and R are as def ined for R Xa and Xb each represents a bond, CH2 or CO; z and p each represents an integer of from 1 to 3; b Rc represents CORO or is as defined for R d k z 0 b , R R, R and R are as def ined for R e represents hydrogen or a (1-6C)alkyl group; and R' and R' are as defined for R e; or a non-toxic metabolically labile ester or amide thereof; or a pharmaceutically acceptable salt thereof.

Compounds of formula I have been found to modulate glutamate function at metabotropic glutamate receptors.

The present invention therefore also provides a compound of formula I, or a non-toxic metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof for use in therapy.

According to another aspect, the present invention provides a method of modulating one or more metabotropic glutamate receptor functions in a mammal (including a human) which comprises administering an effective amount of a compound of formula I, or a non-toxic metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof.

According to yet another aspect, the present invention provides the use of a compound of formula I, or a non-toxic metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a condition indicating administration of a metabotropic glutamate receptor modulator It will be appreciated that the compounds of formula I contain at least four asymmetric carbon atoms; three being in the cyclopropane ring and one or more being in the other ring. The present invention includes all stereoisomeric forms of the compounds of formula I, including each of the individual diastereoisomers, enantiomers and mixtures thereof.

Preferably the compounds of formula I have the configuration shown below H N COOH 2 HH COOH X\ -2 H Y_X 6 For consistency, the following numbering convention is used throughout this specification:

4S C02 H H2N/.,,,4s C02H H2N,,,,, 5S H 5S H 3 6R CO 2H 3 6S CO 2H H S 7R H 1 H2Ni,,,3R C02H H 4 2 C02H 0 5S H 7 6R H Unless specified otherwise, the term "alkyl" as used herein means a straight chain or branched alkyl group.

Examples of values for a (1-6C)alkyl group include (1 4C)alkyl such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

The term (3-6C)alkenyl includes (3-4C)alkenyl such as allyl.

The term (3-6C)alkynyl includes (3-4C)alkynyl such as propynyl.

The term heteroaromatic group includes an aromatic 5-6 membered ring containing from one to four heteroatoms 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 with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups are furyl, thiophenyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, imidazolyl, pyrimidyl, benzofuryl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzo- thiazolyl and indolyl.

7 The term aromatic group includes phenyl and a polycyclic aromatic carbocyclic ring such as 1-naphthyl or 2-naphthyl.

The term "optionally substituted", as used in the term "optionally substituted heteroaromatic or aromatic group", herein signifies that one, two or more substituents may be present, said substituents being 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 metabotropic glutamate receptor function.

Examples of atoms and groups which may be present in an optionally substituted heteroaromatic or aromatic group are amino, hydroxy, nitro, halogeno, (1-6C) alkyl, (1-6C) alkoxy, (1-6C)alkylthio, carboxy, (1-6C) alkoxycarbonyl, carbamoyl, (1-6C) alkanoylamino, (1-6C)alkylsulphonyl, (16C) alkylsulphonylamino, (1-6C)alkanoyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, phenylsulphonylamino, toluenesulphonylamino, and (16C)fluoroalkyl. Examples of particular values are amino, hydroxy, nitro, fluoro, chloro, bromo, iodo, methyl, methoxy, methylthio, carboxy, acetylamino, methanesulphonyl, methanesulphonylamino, acetyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, 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, 3 fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4 difluorophenyl, pentafluorophenyl, 2-chlorophenyl, 3 chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4 dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3 bromophenyl, 4-bromophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4 methoxyphenyl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 8 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-3- trifluoromethylphenyl, 3-trifluoromethyl4-fluorophenyl, 3-trifluoromethyl- 5-fluorophenyl, 2-fluoro5 5-trifluoromethylphenyl, 2-phenoxyphenyl, 3- phenoxyphenyl, 3-carboxyphenyl, and 4-carboxyphenyl.

The term "non-aromatic carbocyclic group" includes a monocyclic group, for example a (3-10C)cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, and a fused polycyclic group such as 1-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, 01non-1-yl, -2-yl, -3-yl or -7yl, bicyclo[5,3,01dec-1-yl, -2-yl, -3-yl, - 4-yl, -8-yl or 15 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 or two heteroatoms selected from oxygen, sulphur and nitrogen, for example azetidin-1-yl or -2-yl, pyrrolidin-1-yl, -2-yl or - 3-yl, 20 piperidin-1-yl, -2-yl, -3-yl or -4-yl, hexahydroazepin-1-yl, -2- yl, -3-yl or -4-yl, oxetan-2-yl or -3-yl, tetrahydrofuran-2-yl or -3-yl, tetrahydropyran-2-yl, -3-yl or -4-yl, hexahydrooxepin-2-yl, -3-yl or -4yl, thietan-2-yl or -3-yl, tetrahydrothiophen-2-yl or -3-yl, tetrahydrothiopyran-2-yl, 25 -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-lyl, -2-yl, -4-yl or -5-yl, imidazolin-1-yl, -2-yl or -4-yl, imidazolidin-1-yl, -2-yl or -4yl, oxazolin-2-yl, -3-yl, -430 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-yl, -3yl, -4-yl or -5-yl. The term "a non-aromatic monocyclic carbocyclic group fused with one or two monocyclic aromatic or heteroaromatic 9 groups" includes a (3-10C)cycloalkyl group fused with a benzene ring or a an aromatic 5-6 membered ring containing from one to four heteroatoms 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-tetrahydrobenzothiophen-4-yl, -5-yl, -6-yl or - 7-yl, dibenzo[2,3,6,7]cycloheptan-1-yl or -4-yl, dibenzo [2,3,6,71cyclohept-4-en-1-yl or -4-yl, or 9-fluorenyl.

The term "a non-aromatic monocyclic heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups" includes a 4 to 7 membered ring containing one or two heteroatoms selected from oxygen, sulphur and nitrogen, fused with a benzene ring or a an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, such as 2,3-dihydrobenzopyran2-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-9yl or -10-yl, 2,3-dihydrobenzothiopyran-2-yl, -3-yl or -4- yl, or dibenzothiopyran-4-yl.

An example of a value for R a is hydrogen.

Examples of values for R b when it represents a (1-6C) alkyl group are methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

An example of a value for R b when it represents a (3- 6C) alkenyl group is allyl.

An example of a value for R b when it represents a (3- 6C) alkynyl group is propynyl.

When R b represents an optionally substituted aromatic group, it preferably represents a 2-naphthyl group, a pentafluorophenyl group or a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen, (1-4C) alkyl, fluoro(14C)alkyl and (1-4C) alkoxy.

Examples of values for R b when it represents an optionally substituted aromatic group are 2-naphthyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4difluorophenyl, pentafluorophenyl, 2-chlorophenyl, 3chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2,5dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4- bromophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3trifluoromethylphenyl and 4-trifluoromethylphenyl.

Examples of values for R b when it represents a substituted (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl group are phenyl (1-4C)alkyl and diphenyl (1-4C)alkyl groups which are unsubstituted or substituted on phenyl by one or two of halogen, (1-4C)alkyl and (1-4C)alkoxy, for example benzyl, 2phenylethyl, 2-phenylpropyl, and 2-thiophenylmethyl. other examples are (3-6C)cycloalkyl(1-4C)alkyl groups, such as cyclopropy1methyl. 20 An example of a value for R b when it represents an optionally substituted heteroaromatic group is 2-pyrimidyl. Examples of particular values for Rf are hydrogen and (1-6C)alkyl, such as methyl or ethyl. Examples of particular values for R h and Rm are hydrogen and (1-6C)alkyl, such as methyl or ethyl.

Examples of particular values for R i are (1-6C)alkyl such as methyl.

Examples of more particular values for Rc are hydrogen, (1-6C)alkanoyl such as acetyl and (1-6C)alkyl such as methyl.

Examples of more particular values for R d are hydrogen and (1-6C)alkyl such as methyl.

11 Examples of particular values for Re are hydrogen, methyl and ethyl.

Examples of particular values for R9 and R' are hydrogen, methyl and ethyl.

k z Examples of more particular values for R R, R and Ro are hydrogen, (1-6C)alkyl such as methyl and optionally substituted aromatic such as phenyl.

Y preferably represents 0, S, SO or S02.

Pref erably R1 and R 2 each independently represents a hydrogen atom or a fluorine atom; or R' represents a hydrogen atom and R 2 represents hydroxyl, CN, NO 21 PO 3 H 21 methoxy, amino, N 3. acetylamino, benzoylamino, methanesulfonylamino, methylaminocarbonylamino, N,N dicyclopropy1methylamino, carboxy or carboxamido; or R1 and R 2 together represent =O, =NOH, =CH 21 =CHCOOH, =CHPO 3 (C2 H 5) 2 or =CHCN. More preferably, R 1 and R 2 each independently represents a hydrogen atom.

R 3 and R4 preferably each independently represents a hydrogen atom or a fluorine atom; or R 3 represents a hydrogen atom and R4 represents hydroxyl, CN, NO 2 1 PO 3 H 21 methoxy, amino, N 3. acetylamino, benzoylamino, methanesulfonylamino, methylaminocarbonylamino, N,N dicyclopropy1methylamino, carboxy or carboxamido; or R 3 and R" together represent =O, =NOH, =CH 21 =CHCOOH, =CHPO 3 (C2 H5) 2 or =CHCN. More preferably R 3 and R" each independently represents a hydrogen atom.

Examples of particular values for m and n are m is 1 and n is 0; m is 1 and n is 1; and m is 0 and n is 1. Preferably one of m and n is 1 and the other is 0. More preferably m is I and n is 0.

Examples of particular values for the group Xl_y_X2 are CH 2 0, OCH 21 CH 2 S, SCH 21 SOCH 21 CH2SO' S02 CH 2' CH 2SOI' OCO' Cool CHFO, CF 2 0, OCHF, OCF 21 CH(CN)O and OCH(CN).

12 Particularly preferred compounds are (4S, 5S, 6S, 7R)-4-amino-i-thia[4.1.0]bicyclo-heptane-4,6-dicarboxylic acid; (lR, 4S, 5S, 6S, 7R)-4-amino-l sulfinyl[4.1.0]bicycloheptane-4,6-dicarboxylic acid; and (4S, 5S, 6S, 7R)-4-amino-l-sulfonyl[4.1.0]bicycloheptane-4,7-dicarboxylic acid. These compounds have been found to be agonists at cAMP-linked metabotropic glutamate receptors. Accordingly, these compounds, non-toxic metabolically labile esters or amides thereof; and pharmaceutically acceptable salts thereof are particularly preferred.

The present invention includes pharmaceutically acceptable salts of the formula I compounds. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. 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 employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para- bromophenylsulfonic, carbonic, succinic, citric, benzoic, and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, ammonium, monohydrogenphosphate, dihydrogenphosphate, meta-phosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, 13 heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, hippurate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, 5 phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, (Xhydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, mandelate, magnesium, tetramethylammonium, potassium, trimethylammonium, sodium, methylammonium, calcium, and the like salts.

Non-toxic metabolically labile ester and amide of compounds of formula I are ester or amide derivatives of compounds of formula I that are hydrolyzed in vivo to afford said 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 moiety may be optionally substituted by a (1-8C) alkox-y group, for example methanol, ethanol, propanol and methoxyethanol. Examples of metabolically labile amides include amides formed with amines such as methylamine. It will be appreciated that the compounds according to the invention may also form solvates. The present invention includes any such solvates. 25 According to another aspect, the present invention provides a process for the preparation of a compound of formula I which comprises (a) hydrolyzing a compound of formula 30 14 R 5 HN CN R 6 x H Cx Y-)(1 III in which R5 represents a hydrogen atom or an acyl group and R6 represents a carboxyl group, an esterified carboxyl group or a cyano group, or a salt thereof; (b) hydrolyzing a compound of formula 0 R 8 N 47 NR 0 R 9 x H Y-X 2 IV in which R9 represents a carboxyl group, an esterified carboxyl group or a cyano group, R7 represents a hydrogen atom, a (2-6C) alkanoyl group, a (1-6C)alkoxycarbonyl group or a benzyloxycarbonyl group, and R8 represents a hydrogen atom, a (2-6C) alkanoyl group, a (1-6C)alkoxycarbonyl group, a benzyloxycarbonyl group, a (1-4C) alkyl group, or a phenyl (1-4C) alkyl group in which the phenyl is unsubstituted or substituted by halogen, (1-4C) alkyl or (1-4C) alkoxy, or a 20 salt thereof; or (c) deprotecting a compound of formula R 10 HN COOR 11 COOR 12 X H Y_X 2 V in which R10 represents a hydrogen atom or a nitrogen protecting group and each of R11 and R12 independently represent a hydrogen atom or a carboxyl protecting group, or a salt thereof; whereafter, if necessary and/or desired (i) resolving the compound of formula I; (ii) converting the compound of formula I into a nontoxic metabolically labile ester thereof; and/or; (iii) converting the compound of formula I or a non- toxic metabolically labile ester or amide thereof into a pharmaceutically acceptable salt thereof.

The protection of 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 tamyl; aralkyl groups such as benzyl, 4-nitrobenzyl, 4- methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6- trimethoxybenzyl, 2,4,6-trimethylbenzyl, benzhydryl and trityl; silyl groups such as trimethylsilyl and tbutyldimethylsilyl; and allyl groups such as allyl and 1(trimethylsilylmethyl)prop-l-en-3-yl. Examples of amine protecting groups include acyl groups, such as groups of 16 formula R13CO in which R13 represents (1-6C) alkyl, (3-10C) cycloalkyl, phenyl(I-6C) alkyl, phenyl, (1-6C) alkoxy, phenyl(1-6C)alkoxy, or a (3- 10C) cycloalkoxy, wherein a phenyl group may optionally be substituted by one or two substituents independently selected from amino, hydroxy, nitro, halogeno, (1-6C) alkyl, (1-6C) alkoxy, carboxy, (16C) alkoxycarbonyl, carbamoyl, (1- 6C) alkanoylamino, (1-6C) alkylsulphonylamino, phenylsulphonylamino, toluenesulphonylamino, and (1-6C)fluoroalkyl.

The compounds of formula III 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 performed in an aqueous solvent such as water and at a temperature in the range of from 50 to 2002C.

Preferred values for R5 are hydrogen and (2-6C)alkanoyl groups, such as acetyl.

Preferred values for R6 when it represents an esterified carboxyl group are (1-6C)alkoxycarbonyl groups such as ethoxycarbonyl.

The compounds of formula IV 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 of from 50 to 1500C.

Preferred values for R 7 and R" are independently hydrogen or benzyl.

Preferred values for R9 are alkoxycarbonyl groups such as ethoxycarbonyl.

The compounds of formula V may be deprotected by a conventional method. Thus, an alkyl carboxyl protecting group may be removed by hydrolysis. The hydrolysis may conveniently be performed by heating the compound of formula 17 V in the presence of either a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkaline metal hydroxide, such as barium hydroxide, or an acid such as hydrochloric acid. The hydrolysis is conveniently performed at a temperature in the range of from 10 to 300 OC. An aralkyl carboxyl protecting group may conveniently be removed by hydrogenation. The hydrogenation may conveniently be effected by reacting the compound of formula V with hydrogen in the presence of a Group VIII metal catalyst, for example a palladium catalyst such as palladium on charcoal. Suitable solvents for the reaction include alcohols such as ethanol. The reaction is conveniently performed at a temperature in the range of from 0 to 1000C. An acyl, amine protecting group is also conveniently removed by hydrolysis, for example as described for the removal of an alkyl carboxyl protecting group.

A preferred value for R10 is t-butoxycarbonyl.

Preferred values for R" and R 12 are methyl and ethyl.

The compounds of formula I may, if required, be resolved by a conventional method, for example by formation of a crystalline salt with a chiral acid or base, or by chiral chromatography. Instead of resolving a compound of formula I, it may be convenient to resolve an intermediate during the synthesis of the compound of formula I. 25 Non-toxic metabolically labile esters and amides of the compounds of formula I, and pharmaceutically acceptable salts, may be prepared by conventional methods. The starting materials used in the process according to the invention may be prepared by methods analogous to those known in the art, for example as described in European patent applications publication numbers EP 0696577 Al, EP 0774454 Al, EP 0774455 Al and EP 0774461 Al, and International patent application publication number WO 98/51655.

18 The compounds of formula III may be prepared by reacting a compound of formula VI 0 H R 6 X H \\, -2 Y-X H VI 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 alumina and ultrasound. Thus, the alkali metal cyanide and the ammonium halide are mixed with chromatography grade alumina in the presence of a suitable diluent such as acetonitrile. The mixture is then irradiated with ultrasound, whereafter the compound of formula VI is added, and the mixture is again irradiated.

The resultant mixture of diastereoisomeric aminonitriles is then conveniently reacted with an acylating agent, such as acetyl chloride in the presence of a suitable base, for example an amine such as ethyl diisopropylamine or Hunigs base and in the presence of a suitable solvent, such as dichloromethane, to afford a mixture of diastereomeric acylamino nitriles. The desired diastereoisomer is conveniently separated from this mixture, for example by chromatography.

The compounds of formula IV may be prepared by reacting a compound of formula V (where R9 is represented by R6) with an alkali metal cyanide,such as lithium, sodium or potassium cyanide, and ammonium carbonate or ammonium carbamate. Convenient solvents include alcohols, such as methanol, aqueous methanol and aqueous ethanol.

Conveniently the reaction is performed at a temperature in 19 the range of from 10 to 1500C. If desired, the compounds of formula IV may then be alkylated, for example using an 8 9 appropriate compound of formula RCl and/or RC1.

The compounds of formula V may be prepared by conventional methods, for example as 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.

The compounds of formula VI may be prepared by reacting a compound of formula 0 X 2 VII with a carboxyl-protected (dimethylsulfuranylidene)acetate, such as ethyl (dimethylsulfuranylidene)acetate. The reaction is conveniently performed at a temperature in the range of from 0 to 1202C. The carboxyl-protected (dimethylsulfuranylidene)acetate may conveniently be generated as described in European patent application, publication number EP 0696577 Al), by reacting a carboxy protected methyl dimethylsulfonium bromide with a base, for example an amine such as 1,8-diazabicyclo[5.4.0]undec-7-ene.

Convenient solvents include acetonitrile, dichloromethane and toluene.

Compounds of formula III, IV and VI in which Y represents SO or SO 2 may conveniently be prepared from the corresponding compound in which Y represents S or SO by reaction with an appropriate oxidizing agent. Thus a compound of formula III, IV and VI in which Y represents S may conveniently be reacted with a peracid, such as m- chloroperbenzoic acid, to afford a corresponding compound in which Y represents SO. Convenient solvents include halogenated hydrocarbons, such as dichloromethane. The oxidation is conveniently performed at a temperature in the range of from -78 to 02C. The resultant compound of formula III, IV or V may be further oxidized, for example by reaction with oxone@ (oxoneg is produced by Du Pont and is 2KHS05.KHS04.K2SO4). Convenient solvents include aqueous alcohols, such as aqueous ethanol. The reaction is conveniently performed at a temperature of from 0 to 1002C.

The compounds of formula VII are known or may be prepared by methods known in the art. Examples of procedures for their preparation are shown in Scheme I below.

21 0 0 NCS Py CH2C12 S S 0 0 OH MCPBA TFA, EtSiH 0 0) 0 H 0 Ho-"OH 0 0 Py HBr,, 0 0 Br DMSO 0 0 0 PTSA KOtBu 0 ni 0 H+ H20 0 0 Scheme I In Scheme I the following abbreviations are used: NCS, N-chlorosuccinimide; Py, pyridine; MCPA, m-chloroperbenzoic acid; TFA, trifluoroacetic acid; PTSA, p-toluenesulfonic acid and DMSO, dimethylsulfoxide.

Many of the intermediates described herein, for example the compounds of formula III, IV and V are believed to be novel, and are provided as further aspects of the invention.

The particular dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the 22 compound administered, the route of administration, the particular condition being treated, and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may 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, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.

A variety of physiological functions have been shown to be subject to influence by excessive or inappropriate stimulation of excitatory amino acid transmission. The formula I compounds of the present invention are believed to have the ability to treat a variety of neurological disorders in mammals associated with this condition, including acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. The formula I compounds are believed to have the ability to treat a variety of chronic neurological disorders, such as Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, and idopathic and drug-induced Parkinson's. The present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof.

23 The formula I compounds of the present invention are also believed to have the ability to treat a variety of other neurological disorders in mammals that are associated with glutamate dysfunction, including muscular spasms, convulsions, migraine headaches, urinary incontinence, nicotine withdrawal, psychosis, (such as schizophrenia), drug tolerance, withdrawal and cessation (i.e. opiates, benzodiazepines, nicotine, cocaine or ethanol), smoking cessation, anxiety and related disorders (e. g. panic attack and stress-related disorders), emesis, brain edema, chronic pain, sleep disorder, Toeurettes syndrome, attention deficit disorder, and tardive dyskinesia. The formula I compounds 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.

The ability of compounds to modulate metabotropic glutamate receptor function may be demonstrated by examining their ability to influence either cAMP production (mGluR 2, 3, 4, 6, 7 or 8) or phosphoinositide hydrolysis (mGluR 1 or 5) in cells expressing these individual human metabotropic glutamate receptor (mGluR) subtypes. (D. D. Schoepp, et al., Neuropharmacol., 1996, 35, 1661-1672 and 1997, 36, 111).

The compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I and a pharmaceutically-acceptable carrier, diluent, or excipient. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available 24 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 enclosed 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 may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, 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, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.

Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.

26 Formulation 1 Hard gelatin capsules are prepared using the following ingredients: 5 Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. 20 27 Formulation 2 A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg. 20 Formulation 3 An aerosol solution is prepared containing the following components: 25 Weight % Active Ingredient 0.25 Ethanol 29.75 Propellant 22 70.00 (Chlorodifluoromethane) 28 Total 100.00 The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to 300C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.

Formulation 4 Tablets each containing 60 mg of active ingredient are made as follows:

Active Ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 500C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, 29 previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Formulation 5 Capsules each containing 80 mg medicament are made as follows: 5 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 blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.

Formulation 6 Suppositories each containing 225 mg of active ingredient may be made as follows:

Active Ingredient 225 mg Saturated fatty acid glycerides 2,000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

32 Formulation 7 Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows:

Active Ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v.

Color q.v.

Purified water to total 5 ml The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

Formulation 8 An intravenous formulation may be prepared as follows:

Active Ingredient 100 mg Mannitol 100 mg N Sodium hydroxide 200 ml Purified water to total 5 ml 33 Example 1 (4R, SS, 6S, 7R)-4-Amino-l-thia[4.1.0]bicycloheptane-4,6- dicarboxylic acid.

i) To 2, 3 -dihydrothian-4 -one (500 mg, 4.38 mmol) at 80'C was added the preformed ylide (8.76 mmol, 1.51 g) of ethyldimethylsulfuranilydene acetate (preparation described in European patent application, publication no. EP 0696577 Al) in portions every 2 h for 7 h with stirring and then the orange mixture stirred for a further 17 h. The mixture was allowed to cool and purified by column chromatography (20% ethyl acetate-hexane) to give (5S, 6S, 7R)-l-thia-4-oxo6-ethoxycarbonyl[4.1.0]bicycloheptane as a pale yellow oil. 1H NMR (CDC13) 6: 4.20 (2H, d, J 7.2), 3.05 (2H, m), 2.75 (1H, m, CH), 2.60 (2H, t, J 4.3), 2.50 (1H, dd, J 8.6, 4.0), 2.45 (1H, t, J 4.0), 1.30 (3H, t, J 7.2).

ii) A mixture of potassium cyanide (6.62 mmol, 431 mg), ammonium chloride (7.28 mmol, 390 mg) and alumina (3.4 g) in acetonitrile (7.5 ml) sonicated for 1 h. (5S, 6S, 7R)-l-thia-4-oxo-6- ethoxycarbonyl[4.1.0]bicycloheptane (221 mg, 1.10 mmol) was added as a solution in acetonitrile (7.5 ml) and the mixture was sonicated for 17 h. The mixture was filtered and the alumina washed thoroughly with acetonitrile. The crude mixture was purified by chromatography eluting with 50% ethyl acetate-hexane + ammonia to give (4R, 5S, 6S, 7R)4-amino-4-cyano-6-ethoxycarbonyl-l-thia[4. 1.0]bicycloheptane and (4S, 5S, 6S, 7R)-4-amino-4-cyano-6-ethoxycarbonyll- thia[4.1.0]bicycloheptane as gums which solidified upon standing. (4R, 5S, 6S, 7R)-4-Amino-4-cyano-6-ethoxycarbonyl-lthia[4.1.0]bicycloheptane, 1H NMR (CDC13) 8 (300 MHz, CDC13) 34 4.15 (2H, q, J 7.1), 3.05 (1H, dt J 12.9, 0.8), 2.65 (1H, dd, J 10.3, 5.1), 2.25-1.95 (5H, M), 1.90 (2H, s, br), 1.30 (3H, t, 1 7.1).

(4S-, 5S-, 6S, 7R)-4-amino-4-cyano-6-ethoxycarbonyl-lthia[4.1.0]bicycloheptane, 1H NMR (CDC13) 5 4.15 (2H, q, J 8.6), 2.95 (1H, dt, J 12.9, 2.5), 2.7 (1H, dd, J 11.1, 1.7), 2.50-2.25 OH, m), 1.95 (3H, m), 1.60 (1H, dt, J 12.9, 2.5), 1. 2 5 (3H, t, 1 8. 6).

iii) To a solution of (4R, 5S, 6S, 7R)-4-amino-4-cyano6-ethoxycarbonyl-lthia[4.1.0]bicycloheptane (330 mg, 1.46 mmol) in dichloromethane (8 ml) was added Hunigs base (2.19 mmol, 0.38 ml) and acetyl chloride (2.19 mmol, 156 ml) and the mixture stirred at room temperature for 5 h. The reaction mixture was diluted with dichloromethane (30 ml) and poured into water (30 ml). The aqueous layer was separated and extracted with dichloromethane (30 ml). The combined organic layers were dried (MgS04) and the solvent removed in vacuo. The crude material was purified by column chromatography eluting with 75% ethyl acetate-hexane to give (4R, 5S, 6S, 7R)-4-acetamido-4-cyano-6-ethoxycarbonyl-l- thia[4.1.0]bicycloheptane as a viscous gum which solidified upon standing. 1H NMR (CDC13) 6 (300 MHz, CDC13) 5.75 (1H, s, br), 4.20 (2H, q, 1 7.1), 2.95 (1H, m), 2.75 (1H, m), 2.60 (1H, dd, J 8.6, 4.2), 2.35-2.25 (2H, m), 2.10 (3H, s), 1.95 (1H, m), 1.30 OH, t, 1 7.1); 13 C(75 MHz, CDC13) 170.6, 169.8, 118.9, 61.7, 47.1, 30.9, 30.2, 28.4, 23.3, 22.3, 19.0, 14.1.

iv) A solution of (4R, 5S, 6S, 7R)-4-acetamido-4-cyano 6-ethoxycarbonyl-l-thia[4.1.0]bicycloheptane (77 mg, 0.29 mmol) in 2 M sodium hydroxide (1.72 mmol, 0.86 ml) was heated at 90 'C in a reactor vial for 16 h. The resultant brown solution was allowed to cool and the crude material purified by ion exchange chromatography on DOWEX 50WX8-100 resin to give (4R, 5S, 6S, 7R)-4-amino-l-thia[4.1.0] bicycloheptane-4,6-dicarboxylic acid as a white solid.

IH NMR (CDC13) 8 (300 MHz, D20, NaOD) 2.80 (1H, dt, J 12.9, 4.2), 2.25 (1H, dd, J 10.3, 2.6), 2.20 (1H, m), 1.90 (2H, m), 1.55-1.70 (2H, m).

Example 2 (4S, 5S, 6S, 7R)-4-amino-l-thia[4.1.0]bicycloheptane4,6-dicarboxylic acid i) To a solution of (4S, 5S, 6S, 7R)-4-amino-4-cyano-6 ethoxycarbonyl-l-thia[4.1.0]bicycloheptane (82 mg, 0.36 mmol) in dichloromethane (2 ml) was added Hunigs base (0.54 mmol, 95 ml) and acetyl chloride (0.54 mmol, 39 ml) and the solution stirred at room temperature for 5.5 h. The mixture was poured into water (20 ml) and extracted with dichloromethane (2 x 20 ml). The combined organic layers were dried (MgS04) and the solvent removed in vacuo. The crude material was purified by column chromatography eluting with 75% ethyl acetate-hexane to give (4S, 5S, 6S, 7R) 4-acetamido-4-cyano-6-ethoxycarbonyl-l-thia[4.1.0]bicyclo- heptane as a viscous oil which gives a white solid upon standing. 1H NMR (CDC13) 8 (300 MHz, CDC13) 5.60 (1H, s, br) 4.15 (2H, q, 1 7.1), 3.10 (1H, t, J 12.9), 2.95 (IH, m), 2.80 (2H, m), 2.40 (1H, m) 2.05 (3H, s), 1.90 (1H, t, i 5.6), 1.55 (1H, t, 1 12.9), 1.30 (3H, t, J 7.1).

ii) A solution of (4S, 5S, 6S, 7R)-4-Acetamido-4-cyano 6-ethoxycarbonyl-l-thia[4.1.0]bicycloheptane (306 mg, 1.14 mmol) in 2M sodium hydroxide (6.84 mmol, 3.42 ml) was heated at 900C in a reactor vial for 16 h. The resultant brown solution was allowed to cool and the residue purified by ion 36 exchange chromatography on DOWEX 50WX8-100 resin to give (4S-, SS-, 6S, 7R)-4-amino-l-thia[4.1.0]bicycloheptane4,6-dicarboxylic acid as a white solid. 1H NMR (CDC13) 8 (300 MHz, D20, NaOD) 3.10 (1H, dt J 12.9, 1.3), 3.00 (1H, dd, J 10.3, 3.4), 2.35-2.55 (3H, m), 2.20 (1H, t, J 6.4), 1.90 (1H, dt, J 13.7, 1.3).

Example 3 (lR, 4S, SS, 6S, 7R)-4-Amino-1 sulfinyl[4.1.0]bicycloheptane-4,6-dicarboxylic acid.

i) m-Chloroperbenzoic (mCPBA) acid (3 g, 9.9 mmol minimum, 57-86% with benzoic acid) was dissolved in dichloromethane (30 ml) and washed with brine (30 ml). The organic layer was separated and made up to 40 ml. To a solution of (4S, 5S, 6S, 7R)-4-Acetamido-4-cyano-6-ethoxycarbonyl-lthia[4.1.0]bicycloheptane (389 mg, 1.45 mmol) in dichloromethane (10 ml) at -50 'C was added this solution of mCPBA (3.9 ml, 0.96 mmol) dropwise with stirring. After 2.5 h the reaction was quenched by the addition of aqueous sodium sulfite (20 ml) and the mixture allowed to warm to room temperature. The organic layer was separated and the aqueous layer extracted with dichloromethane (2 x 25 ml). The combined organic layers were washed with aqueous sodium hydrogen carbonate (30 ml), separated and dried (MgSO,). The solvent was removed in vacuo to give (IR, 4S, 5S, 6S, 7R)-4-acetamido-4-cyano-6- ethoxycarbonyl-lsulfinyl[4.1.0]bicycloheptane as a white solid. 1H NMR (CDC13) 8 (3 0 0 MHz, CDC13) 5. 8 5 (1H, s, br), 4. 15 (2H, q, i 7.1), 3.30 (IH, dd, J 8.6, 5.1), 2.90 (IH, m), 2.80 (1H, m), 2.70 (1H, dt, J 13.7, 1.7), 2.75 (1H, t, 1 6.4), 2.00 (3H, s), 1.95 (1H, m,), 1.25 OH, t, 1 7.1). The stereochemistry of this compound was confirmed by single crystal X-ray diffraction.

37 ii) A solution of (lR, 4S, 5S, 6S, 7R)-4-acetamido-4 cyano-6-ethoxycarbonyl-l-sulfinyl[4.1.0]bicycloheptane (103 mg, 0.36 mmol) in 5M hydrochloric acid (4 ml) was heated at 700C in a reactor vial for 47 h. The solution was allowed to cool, the water evaporated and the residue purified by ion exchange chromatography on DOWEX 50WX8-100 resin to give (lR, 4S, SS, 6S, 7R)-4-amino-l-sulfinyl[4.1.0]bicycloheptane-4,6-dicarboxylic acid as a white solid. 1H NMR (CDC13) 8 (300 MHz, D20, NaOD) 3.40 (1H, dd, J 8.6, 6.9), 3.85 (2H, m), 2.35-2.25 (2H, m), 2.00 (1H, m), 2.70 (IH, m) Example 4 (4S, 5S, 6S, 7R)-4-Amino-l sulfonyl[4.1.0]bicycloheptane-4,6-dicarboxylic acid.

i) To a solution of (lR, 4S, 5S, 6S, 7R)-4-acetamido-4 cyano-6-ethoxycarbonyl-l-sulfinyl[4.1.0]bicycloheptane (37 mg, 0.13 mmol) in ethanol: water (1:1; 1.2 ml) was added oxone(g) (0.19 mmol, 120 mg) (oxone@ is produced by Du Pont and is 2KHS05.KHS04.K2SO4) as a solution in water (2 ml) and the solution stirred at OQC for 2.5 h. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (4 x 15 ml). The organic layers were combined, dried (MgS04) and the solvent removed in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate to give (4S, 5S, 6S, 7R)-4-acetamido-4 cyano-6-ethoxycarbonyl-l-sulfonyl[4.1.0]bicycloheptane as a white solid. 'H NMR (CDC13) 5 (300 MHz, CDC13) 5.8 (1H, s, br), 4.25 (2H, q, J 7.1), 3.40-3.30 (2H, m), 3.15-2.95 (3H, m), 2.55 (1H, dd, J 8.6, 6.9), 2.10 (3H, s), 2.00 (1H, m), 1.30 (3H, t, 1 7.1) 38 ii) A solution of (4S, 5S, 6S, 7R)-4-acetamido-4-cyano6-ethoxycarbonyl-l- sulfonyl[4.1.0]bicycloheptane (31 mg, 0.1 mmol) in 5M hydrochloric acid (2 ml) was heated at 70 'C in a reactor vial for 40 h. The solution was allowed to cool, the water evaporated and residue purified by ion exchange chromatography on DOWEX 50WX8-100 resin and then further purified using a Zorbax 300 SCX column eluted with water and 0.1% trifluoroacetic acid to give (4S, 5S, 6S, 7R)-4 amino-l-sulfonyl[4.1.0]bicycloheptane-4,6-dicarboxylic acid as a white solid. 1H NMR 8 (300 MHz, D20, NaOD), 3.20-3.05 (3H, m), 2.45 (1H, t, J 6.4), 2.35-2.15 (3H, m), 1.85 (1H, dt, 1 12.9, 4.3).

1 H NMR 8 (300 MHz, D20 0.1% TFA) 4.47-3.42 (2H, m), 3.20 3.17 (1H, d), 2.67-2.61 (2H, m), 2.45-2.24 (IH, d), 2.15 2.09 (1H, t).

Example 5 (4S, 5S, 6R, 7R)-4-Amino-l-oxa[4.1.0]bicyclo-heptane4,6dicarboxylic acid.

The title compound was prepared by a method similar to that described in Example 1, by hydrolysis of (4S, 5S, 6R, 7R)-4-acetamido-4-cyano-6-ethoxycarbonyl-l-oxa [4.1.0]bicycloheptane m.p. 128-130'C 'H NMR (CDC13)8 6.26 (1H, s), 4.1 (2H, m), 3.8-3.7 (2H, m), 2.65 (1H, d), 2.60 (1H, t), 2.05 (3H, s), 1.81 (lH,dd), 1.6 (2H, m), 1.25 OH, t)using 2M sodium hydroxide for 48hrs at 90'C.

1H NMR (D20) 8: 4.37 (IH, dd 4.05 (IH, t), 3.55 (IH, dt), 2.34 (1H, t), 2.24 (2H, m), 1.92 (1H, m) Example 6 (4R, 5S, 6R, 7R)-4-Amino-l-oxa[4.1.0]bicyclo-heptane- 4,6-dicarboxylic acid.

39 The title compound was prepared by a method similar to that described in Example 1, by hydrolysis of (4R, SS, 6R, 7R)-4-acetamido-4-cyano-6-ethoxycarbonyl-l-oxa [ 4. 1. 01 bicycloheptane oil 1H NMR (CDC13) 8 6. 65 (1H, s), 4. 18 (2H, q), 3.98 (1H, dd), 3.58 (2H, m) 2.5 (1H, d)2.20 (IH, t), 2.1 OH, s), 1.9 (2H,m), 1.45 OH, t)using 2M sodium hydroxide hydrolysis 2.5 days 95'C. 1 H NMR (D20) 8:4.24 (1H, dd), 3.79 (1H, m), 3.72 (1H, td), 2.30 (2H, m), 1.96 (2H, m) Example 7 (3R, 4S, 5S, 6R)-3-Amino-l-oxa[4.1.0]bicyclo-heptane- 3,5-dicarboxylic acid The title compound was prepared by a method similar to that described in Example 1, by hydrolysis of (3R, 4S, 5S, 6R)-3-acetamido-3-cyano-5-ethoxycarbonyl-l-oxa [4. 1. 01 bicycloheptane mp 140-20C 1H NMR (CDC13),S 6.15 (1H, s) 4.18 (2H, q),4.0 (1H, dd), 3.9 (IH, m), 3.8 (1H, m), 3.6 (1H, d), 2.21 (1H, m), 2.1 (3H, s), 2.05 (1H, m), 1.9 (1H, m), 1.23 (3H, t) using 2M HC1 overnight at 100'C.

mp >2600C 1H NMR (D20) 8:4.23 (1H, d), 3.94 (2H, m), 3.61 (1H, d), 2.34 (1H, dd), 2.05 (2H, m).

Example 8 (3S, 4S, 5S, 6R)-3-Amino-l-oxa[4.1.0]bicyclo-heptane3,5-dicarboxylic acid The title compound was prepared by a method similar to that described in Example 3, by hydrolysis of (3S, 4S, 5S, 6R)-3-acetamido-3- cyano-5-ethoxycarbonyl-l-oxa (4.1.0]bicycloheptane oil 1H NMR (CDC13)8 5. 95 (1H, S),4.16 (2H, q),4.0 (1H, d)3.9 (1H, m),3.85 (1H, m), 3.65 (1H, d), 2. 6 (IH, m) 2.1 (3H, S) 1. 9 (1H, m) 1. 85 (1H, t), 1. 23 (3H, t) using 2M HC1 overnight at 100'C. 1H NMR (D20) 8:4.51 (1H, dd), 3.94 (2H, m), 3. 62 (IH, d), 2.26 (IH, t), 2.04 (2H, m) 5 41

Claims

Claims:

1. A compound of the formula H 2 N COOH COOH x H y_X2 in which:- Y represents 0, NR3, S, SO or S02; x 1 represents (CR"R 2).; x 2 represents (CR 3 R4).; one of m and n is 1 and the other is 0 or 1; R I and R2 each independently represents a hydrogen atom, a (1-4C) alkyl group or a fluorine atom; or R1 represents a hydrogen atom and R2 represents XaORI, XNRcR d' So 3 H, tetrazol f h 5-yl, CN, NO 21 PO 3 Re 21 N 3 1 (CH,,) COOR, (CH 2) PP03 R9 2. NHCONHR or i 2 k NHSO 2 R; or R1 and R together represent =O, =NORj, =CR R pn 2 =CHCOORm, =CHPO 3, 2 or =CHCN; or R1 represents amino and R represents carboxyl; R 3 and R 4 each independently represents a hydrogen atom, a (1-4C) alkyl group or a fluorine atom; or R 3 represents a hydrogen atom and R 4 represents XaORb, XbNRcRd, S03 H, tetrazol- e f -yl, CN, N021 PO 3 R 21 N 3. (CH,).COOR, (CH 2) PP03 W' 21 NHCONIfRh or i 3 4 k NHSO 2 R; or R and R together represent =O, =NORj, =CR R =CHCOOW, =CHPO 3 R n 2 or =CHCN; or R 3 represents amino and R 4 represents carboxyl; and R' represents a hydrogen atom, a (1-4C)alkyl group, a (1-4C)alkanoyl group or a (1-4C)alkylsulfonyl group, provided that when n is 0, Y does not represent NR' in which R' represents hydrogen or (1-4C)alkyl; 42 R b represents a hydrogen atom; a (1-6C) alkyl group; a (3-6C)alkenyl group; a (3-6C)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 non-aromatic monocyclic heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; or a (1-6C) alkyl, (3- 6C)alkenyl or (3-6C)alkynyl group which is substituted by one, two or three groups selected independently from 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 and a non-aromatic monocyclic heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; f h i m b R, R, R and R are as defined for R X' and Xb each represents a bond, CH 2 or CO; z and p each represents an integer of from 1 to 3; Rc represents CORO or is as def ined for R b; d k z 0 b_ , R R, R and R are as def ined f or R e represents hydrogen or a (1-6C)alkyl group; and e R' and Rn are as defined for R or a non-toxic metabolically labile ester or amide thereof; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in Claim 1, in which Y represents 0, S, SO or S02.

43

3. A compound as claimed in Claims I or Claim 2, in which R 1 and R 2 each independently represents hydrogen atom or a fluorine atom; or R' represents a hydrogen atom and R 2 represents hydroxyl, CN, N021 PO,H,, methoxy, amino, N,, 5 acetylamino, benzoylamino, methanesulfonylamino, methylaminocarbonylamino, N,N-dicyclopropylmethylamino, carboxy or carboxamido; or R' and R 2 together represent =0, =NOH, =CH 2. =CHCOOH, =CHPO 3 (C2 H,) 2 or =CHCN.

4. A compound as claimed in Claim 3, in which R' and R 2 each independently represents a hydrogen atom.

5. A compound as claimed in any one of Claims 1 to 4, in which R 3 and R4 each independently represents hydrogen atom or a fluorine atom; or R 3 represents a hydrogen atom and R" represents hydroxyl, CN, N02' P03 H 2' methoxy, amino, N 3' acetylamino, benzoylamino, methanesulfonylamino, methylaminocarbonylamino, N,N- dicyclopropylmethylamino, carboxy or carboxamido; or R 3 and R4 together represent =0, =NOH, =CH 2. =CHCOOH, =CHPO 3 (C2 H,) 2 or =CHCN.

6. A compound as claimed in Claim 5, in which R 3 and R4 each independently represents a hydrogen atom.

7. A compound as claimed in any one of Claims 1 to 6, in which one of m and n is 1 and the other is 0.

8. A compound as claimed in Claim 7, in which m is I and n is 0.

9. A compound as claimed in any one of Claims 1 to 8, which has the stereochemistry shown below.

44 H N COOH 2 HH COOH X H 2 -2 Y_X H II

10. A compound as claimed in Claim 1, which is selected 5 from:(4S-, 5S-, 6S-, 7R-)-4-amino-l-thia[4.1.0]bicycloheptane4,6-dicarboxylic acid; (lR, 4S, 5S, 6S, 7R)-4-amino-l-sulfinyl[4.1.0]bicycloheptane-4,6-dicarboxylic acid; and (4S, 5S, 6S, 7R)-4-amino-l-sulfonyl[4.1.0]bicycloheptane-4,7-dicarboxylic acid; and non-toxic metabolically labile esters and amides thereof; and pharmaceutically acceptable salts thereof.

11. A process for the preparation of a compound as claimed in any one of Claims 1 to 10, which comprises (a) hydrolyzing a compound of formula R'HN CN Y R 6 X 1 H Y_X 2 III in which R5 represents a hydrogen atom or an acyl group and R6 represents a carboxyl group, an esterified carboxyl group or a cyano group, or a salt thereof; 25 (b) hydrolyzing a compound of formula 0 R 8 N 47 NR 7 NR 0 R 9 x H Y-X 2 IV in which R9 represents a carboxyl group, an esterified carboxyl group or a cyano group, R7 represents a hydrogen atom, a (2-6C) alkanoyl group, a (1-6C)alkoxycarbonyl group or a benzyloxycarbonyl group, and R8 represents a hydrogen atom, a (2-6C) alkanoyl group, a (1-6C)alkoxycarbonyl group, a benzyloxycarbonyl group, a (1-4C) alkyl group, or a phenyl (1-4C) alkyl group in which the phenyl is unsubstituted or substituted by halogen, (1- 4C) alkyl or (1-4C) alkoxy, or a salt thereof; or (c) deprotecting a compound of formula R 10 HN COOR 11 COOR 12 x H Y V in which RIO represents a hydrogen atom or a nitrogen protecting group and each of R11 and R12 independently represent a hydrogen atom or a carboxyl protecting group, or a salt thereof; 46 whereafter, if necessary and/or desired (i) resolving the compound of formula I; (ii) converting the compound of formula I into a non toxic metabolically labile ester thereof; and/or; (iii) converting the compound of formula I or a nontoxic metabolically labile ester or amide thereof into a pharmaceutically acceptable salt thereof.

11. A pharmaceutical formulation, which comprises a compound as claimed in any one of Claims I to 10 and a pharmaceutically acceptable carrier, diluent or excipient.

12. A compound as claims in any one of Claims 1 to 10, for use in therapy.

13. Use of a compound as claimed in any one of Claims 1 to 10 for the manufacture of a medicament for the prevention or treatment of a condition indicating administration of a metabotropic glutamate receptor modulator.

14. A compound as claimed in any one of Claims 1 to 10, for use as a modulator of metabotropic glutamate receptor function.

15. A method of modulating metabotropic glutamate receptor function in a mammal requiring such treatment, which comprises administering an effective amount of a compound as claimed in any one of Claims 1 to 10.