WO2004113280A1

WO2004113280A1 - Glyt1 transporter inhibitors and uses thereof in treatment of neurological and neuropsychiatric disorders

Info

Publication number: WO2004113280A1
Application number: PCT/EP2004/006595
Authority: WO
Inventors: Clive Leslie Branch; David John Nash; Roderick Alan Porter
Original assignee: Glaxo Group Limited
Priority date: 2003-06-20
Filing date: 2004-06-17
Publication date: 2004-12-29
Also published as: GB0314476D0

Abstract

Use of a compound of formula (I): or a salt, solvate or a physiologically functional derivative thereof, for the manufacture of a medicament for treating a disorder mediated by GlyT1, such as foe example schizophrenia, is disclosed, wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in the specification.

Description

GlyT1 Transporter inhibitors And Uses Thereof In Treatment Of Neurological And Neuropsychiatric Disorders

The present invention relates to glycine transporter inhibiting compounds, their use in the manufacture of medicaments for treating neurological and neuropsychiatric disorders, in particular psychosis, dementia or attention deficit disorder. The invention further comprises processes to make these compounds and pharmaceutical formulations thereof.

Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialised structures in both the pre-and post-synaptic terminal and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1987:1032). Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighbouring synapses, transporters maintain the fidelity of synaptic transmission. Last, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilisation.

Neurotransmitter transport is dependent upon extracellular sodium and the voltage difference across the membrane; under conditions of intense neuronal firing, as, for example, during seizure, transporters can function in reverse, releasing neurotransmitter in a calcium-independent non-exocytotic manner (Atwell et al., Neuron, 11 , 1993: 401-407). Pharmacologic modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of neurological and psychiatric disturbances.

The amino acid glycine is a major neurotransmitter in the mammalian central nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are thus referred to as "strychnine-sensitive".

Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions. Glycine also functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the central nervous system. See Johnson and Ascher, Nature, 325, 1987: 529-531 ; Fletcher et al., Glycine Transmission, Otterson and Storm-Mathisen, eds., 1990: 193-219. Specifically, glycine is an obligatory co-agonist at the class of glutamate receptor termed N- methyl-D-aspartate (NMDA) receptor. Activation of NMDA receptors increases sodium and calcium conductance, which depolarises the neuron, thereby increasing the likelihood that it will fire an action potential. NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.

Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT1 and GlyT2. GlyT1 is found predominantly in the forebrain and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992: 927-935). Molecular cloning has further revealed the existence of three variants of GlyT1 , termed GlyT-la,- GlyT-1 b and GlyT-1c (Kim et al., Molecular Pharmacology, 45, 1994: 608-617), each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by differential splicing and exon usage, and differ in their N-terminal regions. GlyT2, in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033). Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT1. These data are consistent with the view that, by regulating the synaptic levels of glycine, GlyT1 and GlyT2 selectively influence the activity of NMDA receptors and strychnine-sensitive glycine receptors, respectively.

NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev.. 19 533-552 (1995); Danysz et al, Behavioral Pharmacol..

6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996).

Thus, agents that inhibit GlyT1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes. Conversely, over-activation of NMDA receptors has been implicated in a number of disease states, in particular the neuronal death associated with stroke and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma. Coyle & Puttfarcken, Science. 262, 689-695 (1993); Lipton and Rosenberg, New Enαl. J. of Medicine. 330, 613-622 (1993); Choi, Neuron, 1, 623-634 (1988). Thus, pharmacological agents that increase the activity of GlyTI will result in decreased glycine-activation of NMDA receptors, which activity can be used to treat these and related disease states. Similarly, drugs that directly block the glycine site of the NMDA receptors can be used to treat these and related disease states.

Glycine transport inhibitors are already known in the art, for example as disclosed in published International Applications WO97/45423 (Trophix Pharmaceuticals, Inc.), and WO97/45115 (Trophix Pharmaceuticals Inc.). The classes of compounds disclosed in these applications inhibit glycine transport via the GlyTI or GlyT2 transporters.

In published International Application WO99/34790 (Allelix Neuroscience, Inc.), there is disclosed a class of compounds which also inhibits glycine transport via the GlyTI or GlyT2 transporters, with preferred compounds showing selectivity for the inhibition of glycine transport via GlyT2 versus GlyTI .

There still remains the need to identify further compounds that can inhibit GlyTI transporters, including those that inhibit GlyTI transporters selectively over GlyT2 transporters. Such compounds would thus be suitable for the treatment of certain neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes. Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and ***e) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.

WO95/24385 (Vertex Pharmaceuticals Incorporated) discloses certain compounds which are claimed to be aspartyl protease inhibitors useful for inhibiting HIV-1 and HIV-2 protease activity.

Hori and Janda (J. Organic Chem. 1998, 63(3), 889-894) disclose the compounds of the following structure:

wherein NR¹R² is

It has now surprisingly been found that a class of compounds, including certain of the known compounds referred to above, inhibit GlyTI transporters and are thus useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.

Thus, in the first aspect, there is provided the use of a compound of formula (I):

or a salt, solvate or a physiologically functional derivative thereof, for the manufacture of a medicament for treating a disorder mediated by GlyTI , wherein:

R¹ and R² is independently selected from hydrogen, substituted Chalky!, substituted C3_6cycloalkyl, optionally substituted aryl, optionally substituted arylC-]. 4alkyl and optionally substituted arylC3_6cycloalkyl, wherein R¹ and R² are not both hydrogen, and wherein the substituent in each case is one or more groups independently selected from:

halogen, hydroxy, oxo, cyano, nitro, C^.galkyl, C-^alkoxy, haloci-4alkyl, haloC-|_4alkoxy, arylC-^alkoxy, C^alkylthio, hydroxyC^alkyl, C-μ 4alkoxyCι _4alkyl, C3_6cycloalkyl, C3_6cycloalkylC-|_4alkoxy, C-^alkanoyl, C-ι_4alkoxycarbonyl, C<| _4alkylsulfonyl, C-^alkylsulfonyloxy, C1_ 4alkylsulfonylC-|_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-|_4alkyl, C-|_4alkylsulfonamido, C<|_4alkylamido, C-|_4alkylsulfonamidoC-|_4alkyl, C-j. 4alkylamidoC-|_4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoCι_ 4alkyl, arylcarboxamidoC-^alkyl, aroyl, aroylC-^alkyl, arylC^alkanoyl, C-|_ 4acyl, aryl, arylC-i^alkyl, C^alkylaminoC^alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-j_4alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_6(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO-

(wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C-^alkyl group or with the nitrogen to which it is attached, may form a second Cs.ρazacycloalkane fused to the first C3_ gazacycloalkane;

or R¹ and R², together with the nitrogen atom to which they are attached, are linked to form a 4-, 5-, 6- or 7-membered saturated ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said saturated ring being substituted by one or more groups independently selected from:

halogen, hydroxy, oxo, cyano, nitro, C-^alkoxy, halo i^alkyl, haloC<_|_ 4alkoxy, arylC-_|_4alkoxy, C-_|_4alkylthio, hydroxyC-ι_4alkyl, Cι_4alkoxyC-|.

4alkyl, C3_6cycloalkylCι_4alkoxy, C-|_4alkanoyl, C^alkoxycarbonyl, C-_j. 4alkylsulfonyl, C-|_4alky[sulfonyloxy, C1_4alkylsulfonylC-ι_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-|.4alkyl, C^alkylsulfonamido, C<|_4alkylamido, C^ _4alkylsulfonamidoC-ι _4alkyl, C-| _4alkylamidoC-_| _4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-^alkyl, arylcarboxamidoC-|.4alkyl, aroyl, aroylC-_|_4alkyl, arylC^alkanoyl, C^acyl, C-i^alkylaminoCi^alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r,

R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a Ci^alkyl group or where appropriate R³⁰R³¹ forms part of a C3_6azacyloalkane or C3_β(2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_6azacycloalkane and R³¹ may represent hydrogen, a C-_j_

4alkyl group or with the nitrogen to which it is attached, may form a second C3_6azacycloalkane fused to the first C3_6azacycloalkane; wherein when the only substituent in the saturated ring formed by R¹ and R² is oxo, then the carbon to which the oxo group is attached is not adjacent to the nitrogen to which R¹ and R² are attached;

R³ is wherein

Y is Ci-Ca alkylene, C₂ alkenylene or C₂ alkynylene, and n is 0 or 1, and

Z is a 5- to 8-membered monocyclic or 6- to 10-membered bicyclic aromatic ring system wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, and said ring system being optionally substituted by one or more groups independently selected from -hal, -R¹⁰, -CF3, -C-i-βalkylsulphonyl, -OR¹¹, -COOR¹², -CN, -NO₂, -NR¹³R¹⁴, -C(O)NR¹⁵R¹⁶, -NR¹⁷C(O)R¹⁸, -C(O)R¹⁹, -C(NR²⁰)NR²¹R²², -C(NOR²³)R²⁸, wherein hal is F, Cl, Br or l, R¹⁰ is Ci-Ce alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylC₁-C₄ alkyl, aryl, aryloxy or aryl Cι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, C-Ce alkyl, -OR¹¹, -COOR¹² -CN, -NO₂ and -NR¹³R¹⁴, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R ⁶, R¹⁷, R¹⁸, R²⁰, R²¹, R²², R²³ and R²⁸ are independently selected from hydrogen and C|-C₆ alkyl; R⁴ and R¹⁹ are independently selected from hydrogen, C-i-Ce alkyl, C₃-C₆ cycloalkyl, aryl or arylC-i-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl, -OR²⁴, -COOR²⁵ -CN, -NO₂ and -NR²⁶R²⁷; R⁶, R⁷, R⁸ and R⁹ are independently selected from hydrogen, C-|-C₆ alkyl or aryld- C₄ alkyl, or R⁶ and R⁷ together form a C₃-C₆ cycloalkyl group, or R⁸ and R⁹ together form a C₃-C₆ cycloalkyl group; wherein the Ci-Ce alkyl, aryld-C alkyl group, the C₃-C₆ cycloalkyl group formed by R⁶ and R⁷, and the C₃-C₆ cycloalkyl group formed by R⁸ and R⁹, are optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl, -OR²⁴, -COOR²⁵, -CN, -NO₂ and -NR²⁶R²⁷, wherein R²⁴, R²⁵, R²⁶ and R²⁷ are independently selected from hydrogen and d-C₆ alkyl; and

R⁵ is independently selected from hydrogen, d-C₆ alkyl, C₃-C₆ cycloalkyl, aryl and arylCι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl, -OR²⁴, -COOR²⁵ -CN, -NO₂ and -NR²⁶R²⁷, wherein R²⁴, R²⁵, R²⁶ and R²⁷ are as hereinbefore defined.

As used herein, the term "disorders mediated by GlyTI" refers to disorders that may be treated by the administration of a medicament that alters the activity of the GlyTI transporter. As hereinbefore described, the action of GlyTI transporters affects the local concentration of glycine around NMDA receptors. As a certain amount of glycine is needed for the efficient functioning of NMDA receptors, any change to that local concentration can affect NMDA-mediated neurotransmission. As hereinbefore described, changes in NMDA-mediated neurotransmission have been implicated in certain neuropsychiatric disorders such as dementia, depression and psychoses, for example schizophrenia, and learning and memory disorders, for example attention deficit disorders and autism. Thus, alterations in the activity of the GlyTI transporter are expected to influence such disorders.

As used herein, the terms "Cx-y" and "Cx-Cy" are equivalent. Thus, "C1-6alkyl" is the same as "C1-C6 alkyl".

As used herein, the term "d.Ce alkyl" refers to a straight or branched chain hydrocarbon which contains at least 1 , and at most 6, carbon atoms. Examples of "Ci.Ce alkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl.

In a like manner, the term "C-|.C₄ alkyl" refers to a straight or branched chain hydrocarbon which contains at least 1 , and at most 4, carbon atoms. Examples of "d-C₄ alkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-propyl and t-butyl.

As used herein, the term "C_3-C₆ cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to six carbon atoms. Exemplary "C₃-C₆ cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "C₃-C₆ cycloalkylC₁-C₄ alkyl" refers to a C_3-C₆ cycloalkyl group, as hereinbefore defined, attached through a C C₄ alkylene linker, wherein d- C₄ alkylene is as defined herein. Examples of "C₃-C₆ cycloalkylC₁-C₄ alkyl" include, but are not limited to, cyclohexylmethyl.

As used herein, the term "aryl" refers to a 5- to 7-membered aromatic or heteroaromatic ring system wherein the heteroaromatic ring contains at least one heteroatom selected from N, O and S. Examples of "aryl" groups include, but are not limited to, thienyl, furanyl, phenyl and pyridyl.

As used herein, the term "aryl C C₄ alkyl" refers to an aryl group, as hereinbefore defined, attached through a C C₄ alkylene linker, wherein C C₄ alkylene is as defined herein. Examples of "aryl d-C₄ alkyl" include, but are not limited to, benzyl, phenethyl, pyridylmethyl and phenylpropyl.

As used herein, the terms "Cι_C₂ alkylene", "d.C₃ alkylene" and "Cι.C₄ alkylene" refer to a straight or branched chain divalent hydrocarbon radical, which contains at least

1 , and at most 2, 3 or 4, carbon atoms respectively. Examples of "d-C₂ alkylene", "d.C₃ alkylene" and "d.C₄ alkylene" groups useful in the present invention include methylene, ethylene, n-propylene and n-butylene.

As used herein, the term "C₂ alkenylene" refers to a divalent hydrocarbon radical with a double bond, which contains 2 carbon atoms.

As used herein, the term "C₂ alkynylene" refers to a divalent hydrocarbon radical with a triple bond, which contains 2 carbon atoms.

As used herein, the term "hal" is an abbreviation for "halogen" and refers to fluorine, chlorine, bromine, or iodine.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur, and event(s) that do not occur.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution by independently chosen substituents being allowed unless otherwise stated. Where there is more than one substituent, the substituents may be different or the same.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation. Suitably physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p- toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N- methylglucamine), lysine and procaine; and internally formed salts. Salts having a non-physiologically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or formula (la), or a salt or physiologically functional derivative thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term "physiologically functional derivative" refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5^th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.

R¹ and R² may be independently selected from the group defined in the first aspect of the invention. When R¹ and/or R² are independently substituted C<ι_galkyl, substituted C3_6cycloalkyl, substituted aryl, substituted arylC^alkyl or substituted arylC3_gcycloalkyl, the substituent(s) in each case is/are independently selected from the group defined in the first aspect of the invention. Preferably the number of substituents is 1 , 2, 3 or 4.

Alternatively, R¹ and R², together with the nitrogen atom to which they are attached, may be linked to form a 4-, 5-, 6- or 7-membered saturated ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said saturated ring being substituted by one or more groups independently selected from the group defined in the first aspect of the invention.

Preferably the number of substituents is 1 , 2, 3 or 4.

Suitably, the 5- to 8-membered aromatic monocyclic moiety of Z is selected from: furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.

Suitably, the 6- to 10-membered aromatic bicyclic moiety of Z is selected from: thienofuranyl, indolizinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, chromanyl, chromenyl, isochromanyl, indenyl, imidazoleisothiazolyl benzothiadiazolyl, naphthyl or azulenyl.

Preferably, the compound of formula (I) as hereinbefore described has the following stereochemical configuration:

It will be understood by the skilled artisan that the stereochemical configuration at the chiral centre marked with a * will be assigned the Cahn-lngold-Prelog notation of (R).

In one embodiment, R¹ and R² together with the nitrogen atom to which they are attached are linked to form a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein the sole heteroatom in the heterocyclic ring is the nitrogen atom to which R¹ and R² are attached, said ring being substituted as hereinbefore described.

In another embodiment, R¹ and R² together with the nitrogen atom to which they are attached are linked to form a 5- or 6-membered ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said ring being substituted as hereinbefore described .

In another embodiment, R¹ and R² together with the nitrogen atom to which they are attached are linked to form a 5- or 6-membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R¹ and R² are attached, said ring being substituted as hereinbefore described.

Suitably, the 4-, 5-, 6- or 7-membered saturated ring formed by R¹ and R² together with the nitrogen atom to which they are linked is selected from the group comprising: azetidine, azepine, pyrrolidine, imidazolidine, piperidine, morpholine, thiomorpholine, and piperazine.

When the only substituent in the saturated ring formed by R¹ and R² is oxo, then the carbon to which the oxo group is attached is not adjacent to the nitrogen to which R¹ and R² are attached. Thus, R¹ or R², together with the nitrogen atom to which they are attached, may not form any of the following structures:

In another embodiment, n is 0.

In another embodiment, Z is a 5- to 8-membered monocyclic ring system as hereinbefore described. Preferably, Z is a 5- or 6-membered monocyclic ring system as hereinbefore described. More preferably, Z is phenyl optionally substituted as hereinbefore described, preferably by one or more groups independently selected from -hal, -R¹⁰, -CF3, -Ci-Cβalkylsulphonyl, -OR¹¹, -COOR¹², -CN, -NO₂, -NR¹³R¹⁴ as hereinbefore defined, more preferably by one or more groups independently selected from -hal, d-C₆ alkyl, d-C₆ alkoxy, CF3, -CN and C₃-C₆ cycloalkyl.

In another embodiment, Z is a 6- to 10-membered bicyclic ring system as hereinbefore described. Preferably, Z is naphthyl, naphthyridinyl, quinolyl, isoquinolyl, benzothienyl, chromanyl, chromenyl, imidazoleisothiazolyl, benzothiadiazolyl, benzofuryl, optionally substituted as hereinbefore described. More preferably, Z is quinolinyl (preferably 5-quinolinyl), optionally substituted as hereinbefore described, preferably by one or more groups independently selected from -hal, -R¹⁰, -OR¹¹, -COOR¹², -CF3, -C^<|-C6alkylsulphonyl, -CN, -NO₂, and - NR¹³R¹⁴, wherein hal, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are as hereinbefore defined, preferably hal, Ci-Ce alkyl, Cι-C₆ alkoxy, CF3, -CN and C₃-C₆ cycloalkyl. Most preferably, Z is 5-quinolinyl optionally substituted by one or more groups independently selected from -hal, Cι-C₆ alkyl, Ci-Ce alkoxy, -CF3, -CN and C₃-C₆ cycloalkyl.

Preferably, R³ is phenyl or 5-quinolinyl.

In another embodiment, R⁴ is hydrogen or d-C₆ alkyl, preferably hydrogen.

In another embodiment, R⁵ is selected from hydrogen, Cι-C₆ alkyl, aryl and benzyl, optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl and OR²⁴. Preferably, R⁵ is hydrogen.

In another embodiment, R⁶, R⁷, R⁸ and R⁹are independently selected from hydrogen and Ci-Ce alkyl, preferably hydrogen. In a second aspect of the present invention, there is provided the use of a compound of formula (la) for the manufacture of a medicament for treating disorders mediated by GlyTI , said compound having the formula (la):

R²

or a salt or solvate or a physiologically functional derivative thereof, wherein: R¹ and R² is independently selected from hydrogen, substituted C-μgalkyl, substituted C3_gcycloalkyl, optionally substituted aryl, optionally substituted arylC-μ 4alkyl and optionally substituted arylC3_gcycloalkyl, wherein R¹ and R² are not both hydrogen, and wherein the substituent in each case is one or more groups independently selected from:

halogen, hydroxy, oxo, cyano, nitro, C-]_galkyl, C^alkoxy, haloci-4alkyl, haloC<|_4alkoxy, arylC-| ^alkoxy, C-|_4alkylthio, hydroxyC^alkyl, Cι_ 4alkoxyC^_4alkyl, C3_gcycloalkyl, C3_gcycloalkylC-ι_4alkoxy, C-^alkanoyl,

C-]_4alkoxycarbonyl, C-|_4alkylsulfonyl, C-^alkylsulfonyloxy, C1_ 4alkylsulfonylC-_|_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-^alkyl, C^alkylsulfonamido, C-_|_4alkylamido, C-ι_4alkylsulfonamidoCι_4alkyl, C-|_ 4alkylamidoC'i.4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-]. 4alkyl, arylcarboxamidoC-^alkyl, aroyl, aroylC-|_4alkyl, arylC-i^alkanoyl, C-|_

4acyl, aryl, arylC-|_4alkyl, C-i^alkylaminoC-i^alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CI-l₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-^alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C^alkyl group or with the nitrogen to which it is attached, may form a second C3_gazacycloalkane fused to the first C3_ gazacycloalkane;

halogen, hydroxy, oxo, cyano, nitro,

haloci-4alkyl, haloC-μ 4alkoxy, arylC-j ^alkoxy, C-ι_4alkylthio, hydroxyC-_|_4alkyl, C-_|_4alkoxyC-]_

4alkyl, C3_gcycloalkylC-j_4alkoxy, C-^alkanoyl, C<|_4alkoxycarbonyl, C-j. 4alkylsulfonyl, C-^alkylsulfonyloxy, C1_4alkylsulfonylC-|_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-^alkyl, C-]_4alkylsulfonamido, C-|_4alkylamido, C-j _4alkylsulfonamidoC-| _4alkyl, C-] ^alkylamidoC-i _4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-i^alkyl, arylcarboxamidoC^alkyl, aroyl, aroylC-^alkyl, arylC-|.4alkanoyl, C-^acyl, C^alkylaminoC-^alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r,

R³⁰R³¹NSO₂(CH₂)r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C^alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C-|_

4alkyl group or with the nitrogen to which it is attached, may form a second C3_gazacycloalkane fused to the first C3_gazacycloalkane; wherein when the only substituent in the saturated ring formed by R¹ and R² is oxo, then the carbon to which the oxo group is attached is not adjacent to the nitrogen to which R¹ and R² are attached;

R³ is

"C=C _{l n} H H ^{J n} wherein n is O oM . and

Z is a 5- or 6-membered monocyclic or 8- to 10-membered bicyclic aromatic ring system wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, and said ring system being optionally substituted by one or more groups independently selected from -hal, -R¹⁰, -OR¹¹, -

COOR¹², -CN, -NO₂, -NR¹³R¹⁴, -CF3, and -Ci-Cgalkylsulphonyl, wherein hal is F, Cl, Br or l,

R¹⁰ is Cι-C₄ alkyl or phenyl, optionally substituted by one or more hal groups, and R¹¹, R¹², R¹³and R¹ are independently selected from hydrogen and methyl. Suitably, when n is 1 , the C₂ alkenylene group may be in the cis or trans configuration, preferably the trans configuration.

In another embodiment, the compound of formula (la) as hereinbefore described has the following stereochemical configuration:

It will be understood by the skilled artisan that the stereochemical configuration at the chiral centre marked with a ^* will be assigned the Cahn-lngold-Prelog notation of (R).

All the embodiments and preferred features of formula (I) apply to formula (la).

Examples of compounds of the invention include:

• 3,5-Dichloro-Λ/-{(2R)-2-hydroxy-3-[2-(trifluoromethyl)-1- pyrrolidinyl]propyl}benzenesulfonamide

• 3,5-Dichloro-Λ/-[(2R)-2-hydroxy-3-(4-hydroxy-2,6-dimethyl-1 - piperidinyl)propyl]benzenesulfonamide • 3,5-Dichloro-Λ/-{(2R)-2-hydroxy-3-[(1- methylethyl)(phenylmethyl)amino]propyl}benzenesulfonamide and salts, solvates and physiologically functional derivatives thereof.

The compounds of formulae (I) and (la) have the ability to crystallise in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of formulae (I) and (la).

Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process.

Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.

Certain of the compounds described herein may exist in stereoisomeric forms (i.e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formulae (I) and (la) may exist in tautomeric forms other than that shown in the formulae and these are also included within the scope of the present invention. As referred to above, individual enantiomers of compounds of formulae (I) and (la) may be prepared and an indication of the preferred stereochemistry for such enantiomers has been given. In a preferred embodiment, an optically pure enantiomer is desired. The term "optically pure enantiomer" means that the compound contains greater than about 90 % of the desired isomer by weight, preferably greater than about 95 % of the desired isomer by weight, and most preferably greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.

It is to be understood that the following embodiments refer to compounds within the scope of both formula (I) and formula (la) as defined above unless specifically limited by the definition of each formula or specifically limited otherwise. It is also understood that the embodiments of the present invention described herein, including uses and compositions, are applicable to both formula (I) and formula (la).

The affinities of the compounds of this invention for the GlyTI transporter can be determined by the following assay:

HEK293 cells expressing the Glycine (Type 1) transporter were grown in cell medium (DMEM/NUT mix F12) containing 2 mM L-Glutamine, 0.8 mg/mL G418 and 10% heat inactivated fetal calf serum (Gibco BRL) at 37°C in 5% CO2. Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 1.6x10^ cells/ml in assay buffer [NaCI (140 mM), KCI (5.4 mM), CaCI₂ (1.8 mM), MgSO₄ (0.8 mM), HEPES (20 mM), glucose (5 mM) and alanine (5 mM), pH 7.4]. An equal volume of LeadseekerTM SPA beads (12.5mg/ml suspended in assay buffer) was added to the cells and 25μL of the cell/bead suspension transferred to each well of a 384-well white solid bottom plate (20,000 cells/well) that contained 14μL of assay buffer. Compounds were prepared as 10mM stocks in DMSO. Two-fold serial dilutions of the compounds were made in DMSO from a top concentration of 5mM. 1μL of compound at each concentration was added to the assay plate using 384-well parallel dispensing. Substrate (10μL) was added to each well [1 :40 dilution of [^H]- glycine in assay buffer containing 5μM glycine). Final DMSO concentration = 2%. Data was collected using a PerkinElmer Viewlux as 5 minute exposures. IC50 values were determined using Grafit.

The example compounds shown below were found to have an affinity of greater than or equal to PIC50 of 5.

In another aspect of the invention, there is provided a method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GlyTI which comprises administering an effective amount of a GlyTI inhibiting compound of formula (I) or (la) as hereinbefore defined or a salt, solvate or a physiologically functional derivative thereof.

The disorders mediated by GlyTI referred to herein include neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes. Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and ***e) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.

Preferably, the disorders mediated by GlyTI to be treated by the use or method as hereinbefore described are psychoses, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.

It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.

Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide. Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.

Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine. Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.

Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.

It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.

As indicated above, certain of the compounds of formulae (I) and (la) are known compounds, e.g. within synthetic organic chemistry publications.

Accordingly, in a third aspect of the invention, there is provided a compound of formula (I) as hereinbefore described and salts, solvates and physiologically functional derivatives thereof, but not including the following compounds:

and salts thereof.

In a further aspect of the present invention, there is provided a compound of formula (I) or formula (la) as hereinbefore described and salts, solvates and physiologically functional derivatives thereof for use in therapy, but not including the compounds excluded from the third aspect of the present invention.

Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.

Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt, solvate or a physiologically functional derivative thereof, but not including the compounds excluded from the third aspect of the present invention, and at least one pharmaceutically acceptable carrier, diluent or excipient.

In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (la) as hereinbefore described or a salt, solvate or a physiologically functional derivative thereof, but not including the compounds excluded from the third aspect of the present invention, and at least one pharmaceutically acceptable carrier, diluent or excipient.

These pharmaceutical compositions may be used in the treatment of clinical conditions for which a GlyTI inhibitor is indicated such as, for example, schizophrenia. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or (la) as hereinbefore described as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.

Possible formulations include those suitable for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose). The most suitable means of administration for a particular patient will depend on the nature and severity of the conditions being treated and on the nature of the active compound, but, where possible, oral administration is preferred.

Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.

Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.

Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intraveneously, they may also be administered by subcutaneous or intramuscular injection.

Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.

Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.

The formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.

For example, a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent. Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.

It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.

It will be appreciated that the precise dose administered will depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician. The compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.

A proposed dose of the active ingredient for use according to the invention for oral, sub-lingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GlyTI inhibitor, including schizophrenia, may be about 1 to about 1000 mg, preferably about 5 to about 500 mg, more preferably about 10 to about 100 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.

As indicated above, certain of the compounds of formulae (I) and (la) are known compounds. However, the present invention also relates to novel compounds encompassed within the definitions of formulae (I) and (la).

Accordingly, in a further aspect of the invention, there is provided a compound of formula (I) as hereinbefore described and salts, solvates and physiologically functionally derivatives thereof, but not including the compounds excluded from the third aspect of the present invention. In a further aspect of the invention, there is provided a compound of formula (la) as hereinbefore described and salts, solvates and physiologically functionally derivatives thereof but not including the compounds excluded from the third aspect of the present invention. The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.

Compounds of general formula (I) or formula (la) may be prepared by methods disclosed in the documents hereinbefore referred to and by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. Generally, the following schemes are illustrated using compounds of formula (la), but it is recognised that such schemes are easily adaptable by the skilled artisan to prepare compounds of formula (I). It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I) or (la). Those skilled in the art will recognise if a stereocentre exists in compounds of formula (I) or (la). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Where the stereochemistry is indicated as being variable at certain positions, a mixture of stereoisomers may be obtained, this mixture having been separated where indicated. Stereoisomers may be separated by high- performance liquid chromatography or other appropriate means. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

Typical reaction routes for the preparation of a compound of formula (I) as hereinbefore defined, wherein R⁵, R⁶, R⁷, R⁸ and R⁹ are hydrogen, are shown in Schemes 1 , 2 and 3.

Scheme 1 Scheme 2

R³-S0₂CI DCM

(I)

Alternatively, compounds of formula (I) may be prepared as follows: Scheme 3

NH, BoC O

R³SO,Cl R³S0₂NH₂ R³S0₂NHC0₂'Bu

R¹R²N

(I)

In Scheme 1 , the compounds of formula (I) may be prepared using methodology similar to that described by Gutcait A. et al., Tetrahedron Asymmetry, 1996, 7(6), 1641-1648.

In Scheme 2, the reduction of the azide may be carried out using all methods known to those skilled in the art, for example, hydrogenation in the presence of catalyst such as palladium on carbon, Pd(OH)₂ and those known in the art, see for example March, Advanced Organic Chemistry, 4^th edition, Wiley Interscience. The reduction of the azide is preferably carried out by hydrogenation in the presence of a catalyst such as palladium on carbon.

As indicated above, Schemes 1 , 2 and 3 can be adapted to prepare compounds wherein R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are other than hydrogen.

Thus, in a further aspect of the invention, there is provided a process for the preparation of the compound of formula (I) as hereinbefore defined by

(a) reacting a compound of formula (II)

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as hereinbefore defined, with a compound of formula (III): R^JSO₂L (III)

wherein R³ is as hereinbefore defined and L is a suitable leaving group, such as, for example, a halogen, preferably chlorine; or

(b) for compound wherein R^ is hydrogen, reacting a compound of formula (IV):

(IV)

wherein R³, R⁵, R⁶ and R⁷ are as defined for formula (!), with a compound of formula R¹R²N wherein R¹ and R²are as defined for formula (I),

and thereafter optionally:

• removing any protecting groups and/or • converting a compound of formula (I) into another compound of formula (I) and/or

• forming a pharmaceutically acceptable salt.

Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques. For example, and by way of illustration rather than limitation, possible conversion reactions include acylation with an appropriate acylating agent such as acetyl chloride, alkylation using an appropriate alkylating reagent such as methyl iodide, and sulfonylation using a sulfonylating agent such as methanesulfonic anhydride.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

The invention is further illustrated by the following non-limiting examples.

Description

Description 1: 3,5-DichIorobenzenesulfonamide

To a solution of 3,5-dichlorobenzenesulfonyl chloride (25g, 0.1 mol) in tetrahydrofuran (100ml) was added 0.88 ammonia (200ml) and the mixture stirred at ambient temperature for 18h. before evaporation under reduced pressure to ca. 100ml. The resulting suspension was filtered and the solid washed with water. After air-drying the white solid was dissolved in ethyl acetate, dried with sodium sulphate and the organic evaporated to afford the title product as a cream solid (23.2g, 100%). ¹H NMR δ: (d⁶-DMSO) 7.62 (2H, s), 7.80 (2H, d, J = 1.6Hz), 7.92 (1 H,d, J = 1.6Hz).

Description 2: 1,1-Dimethylethyl [(3,5-dichlorophenyl)sulfonyl]carbamate

To the product of D1 (23.2g, 0.1 mol) suspended in dichloromethane (500ml) containing triethylamine (16ml, 0.12mol) and 4-dimethylaminopyridine (1.26g, 0.01 mol) was added a solution of di-tetif-butyl dicarbonate (25g, 0.12mol) in dichloromethane (200ml) dropwise at ambient temperature. After 18h. the reaction mixture was evaporated and the residue partitioned between ethyl acetate and 1 M hydrochloric acid. The organic phase was dried and evaporated. The resulting green gum was refluxed with hexane to afford a suspension which was cooled in ice and filtered. The solid was washed with cold hexane and dried in vacuo to afford the title product (28.3g, 84%) as a colourless solid. ¹H NMR δ: (d⁶-DMSO) 1.33 (9H, s), 7.82 (2H, d, 1.6Hz), 8.07(1 H, t, 1.6Hz), 12.00 (1 H, br s).

Description 3: 1,1-Dimethylethyl [(3,5-dichlorophenyl)sulfonyl][(2S)-2- oxiranylmethyl]carbamate

To a stirred solution of the product of D2 (8.81 g, 27mmol) in dry tetrahydrofuran

(110ml) under argon at 0°C was added sequentially triphenylphosphine (7.1g, 27mmol), (S)-glycidol (2g, 27mmol) and diisopropyl azodicarboxylate (5.32ml,

27mmol). The reaction was allowed to reach ambient temperature and after 18h. was poured into water and extracted with ethyl acetate (x3). The combined extracts were dried, evaporated and the residue chromatogaphed on silica gel, eluting with pentane-ethyl acetate mixtures to afford the title product (8.4g, 81%) as a colourless solid. ¹H NMR δ: (CDCI₃) 1.42 (9H, s), 2.71 (1H, m), 2.87 (1H, m), 3.26 (1H, m), 4.01 (2H, m), 7.60 (1 H, m), 7.90 (2H, m).

Example 1 : 3,5-Dichloro-W-{(2R)-2-hydroxy-3-[2-(trifluoromethyl)-1- pyrrolidinyl]propyl}benze e

A mixture of the product from D3 (0.2g, 0.52mmol) and 2-trifluoromethyl pyrrolidine (0.08g, 0.57mmol) was heated under argon at 90°C for 24h. The resultant was then cooled and stirred with dichloromethane (4ml) and trifluoroacetic acid (1 ml) for 2 days at ambient temperature. The reaction mixture was evaporated in vacuo and partitioned between dichloromethane and 1 M sodium hydroxide. The organic phase was separated, dried and evaporated and the residue chromatographed on silica gel eluting with ethyl acetate-pentane mixtures. The compound containing fractions were combined and evaporated, dissolved in dichloromethane and following the addition of ethereal hydrogen chloride evaporated to afford the title product (0.105g, 47%). Mass Spectrum (Electrospray LC/MS): Found 421 (MH⁺). Cι₄Hι₇ ³⁵Cl₂F₃N₂O₃S requires 420.

Examples 2-3, shown below, were prepared using methods similar to that described in Example 1.

Claims

1. Use of a compound of formula (I):

R¹ and R² is independently selected from hydrogen, substituted C-]_galkyl, substituted C3_gcycloalkyl, optionally substituted aryl, optionally substituted arylCι_ 4alkyl and optionally substituted arylC3_gcycloalkyl, wherein R¹ and R² are not both hydrogen, and wherein the substituent in each case is one or more groups independently selected from:

halogen, hydroxy, oxo, cyano, nitro, C^galkyl, C<|_4alkoxy, haloci-4alkyl, haloC-_|_4alkoxy, arylC-^alkoxy, C^alkylthio, hydroxyC-^alkyl, C-]_ 4alkoxyCι_4alkyl, C3_gcycloalkyl, C3_gcycloalkylCι ^alkoxy, C-^alkanoyl, C-_j_4alkoxycarbonyl, C-|_4alkylsulfonyl, C^alkylsulfonyloxy, C1_

4alkylsulfonylC'i.4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC^alkyl, C^alkylsulfonamido, C-i^alkylamido, Ci^alkylsulfonamidoC-i^alkyl, C-μ 4alkylamidoC-|_4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-j_ 4alkyl, arylcarboxamidoC<|_4alkyl, aroyl, aroylC^alkyl, arylC<|_4alkanoyl, C-_|. 4acyl, aryl, arylC-_|_4alkyl, C-_|.4alkylaminoC-|.4alkyl, a group R³⁰R³¹N-,

R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-|_4alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO-

(wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C^alkyl group or with the nitrogen to which it is attached, may form a second C3_gazacycloalkane fused to the first C3_ gazacycloalkane; or R¹ and R², together with the nitrogen atom to which they are attached, are linked to form a 4-, 5-, 6- or 7-membered saturated ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said saturated ring being substituted by one or more groups independently selected from:

halogen, hydroxy, oxo, cyano, nitro, C^alkoxy, haloci-4alkyl, haloC-j. 4alkoxy, arylC^alkoxy, C^alkylthio, hydroxyC-^alkyl, C-_|_4alkoxyC-]_ 4alkyl, C3_gcycloalkylC-| ^alkoxy, C-|_4alkanoyl, C-^alkoxycarbonyl, C-|. 4alkylsulfonyl, Ci^alkylsulfonyloxy, C1_4alkylsulfonylC-|_4alkyl, arylsulfonyl, arylsulfonyloxy,

R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C^alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_ (2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂) O, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C- 4alkyl group or with the nitrogen to which it is attached, may form a second C3_gazacycloalkane fused to the first C3_gazacycloalkane; wherein when the only substituent in the saturated ring formed by R¹ and R² is oxo, then the carbon to which the oxo group is attached is not adjacent to the nitrogen to which R¹ and R² are attached;

R³ is

^■ (Y)„

wherein Y is Cι-C₂ alkylene, C₂ alkenylene or C₂ alkynylene, and n is 0 or 1 , and

Z is a 5- to 8-membered monocyclic or 6- to 10-membered bicyclic aromatic ring system wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, and said ring system being optionally substituted by one or more groups independently selected from -hal, -R¹⁰, -CF3, -C-i-βalkylsulphonyl, -OR¹¹, -COOR¹², -CN, -NO₂, -NR¹³R¹⁴, -C(O)NR¹⁵R¹⁶, -NR¹⁷C(O)R¹⁸, -C(O)R¹⁹, -C(NR²⁰)NR²¹R²², -C(NOR²³)R²⁸, wherein hal is F, Cl, Br or I, R¹⁰ is Cι-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylCι-C₄ alkyl, aryl, aryloxy or aryl Cι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl, -OR¹¹, -COOR¹² -CN, -NO₂ and -NR¹³R¹⁴, R ¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²⁰, R²¹, R²², R²³ and R²⁸ are independently selected from hydrogen and d-C₆ alkyl; R⁴ and R¹⁹ are independently selected from hydrogen, Ci-Ce alkyl, C₃-C₆ cycloalkyl, aryl or arylCι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, Cι-C₆ alkyl, -OR²⁴, -COOR²⁵ -CN, -NO₂ and -NR²⁶R²⁷; R⁶, R⁷, R⁸ and R⁹ are independently selected from hydrogen, Ci-Ce alkyl or arylCi- C₄ alkyl, or R⁶ and R⁷ together form a C₃-C₆ cycloalkyl group, or R⁸ and R⁹ together form a C₃-C₆ cycloalkyl group; wherein the Cι-C₆ alkyl, arylC₁-C₄ alkyl group, the C₃-C₆ cycloalkyl group formed by R⁶ and R⁷, and the C₃-C₆ cycloalkyl group formed by R⁸ and R⁹, are optionally substituted by one or more groups independently selected from hal, Cι-C₆ alkyl, -OR²⁴, -COOR²⁵, -CN, -NO₂ and -NR²⁶R²⁷, wherein R²⁴, R²⁵, R²⁶ and R²⁷ are independently selected from hydrogen and Cι-C₆ alkyl; and

R⁵ is independently selected from hydrogen, Ci-Ce alkyl, C₃-C₆ cycloalkyl, aryl and arylCι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, Ci-Ce alkyl, -OR²⁴, -COOR²⁵ -CN, -NO₂ and -NR²⁶R²⁷, wherein R²⁴, R²⁵, R²⁶ and R²⁷ are as hereinbefore defined.

2. The use as claimed in claim 1 , wherein the 5- to 8-membered aromatic monocyclic moiety of Z is selected from: furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyridazinyl, pyhmidinyl, pyrazinyl or triazinyl.

3. The use as claimed in claim 1, wherein the 6- to 10-membered aromatic bicyclic moiety of Z is selected from: thienofuranyl, indolizinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, chromanyl, chromenyl, isochromanyl, indenyl, imidazoleisothiazolyl benzothiadiazolyl, naphthyl or azulenyl.

4. The use as claimed in claim 1 , 2 or 3, wherein, the compound of formula (I) has the following stereochemical configuration:

5. The use as claimed in any of claims 1-4, wherein when R¹ and/or R² are independently substituted C-ι_galkyl, substituted C3_gcycloalkyl, substituted aryl, substituted arylC<|_4alkyl or substituted arylC3_gcycloalkyl, the number of substituent(s) in each case is 1 , 2, 3 or 4 and is/are independently selected from the group consisting of:

halogen, hydroxy, oxo, cyano, nitro, C-_|.galkyl, C-] ^alkoxy, haloci-4alkyl, haloC^alkoxy, arylC-|_4alkoxy, C-i^alkylthio, hydroxyC<|_4alkyl, C-|_ 4alkoxyC-|_4alkyl, C3_gcycloalkyl, C3_gcycloalkylCι_4alkoxy, C-^alkanoyl, C-|_4alkoxycarbonyl, C-|_4alkylsulfonyl, C^alkylsulfonyloxy, C1_ 4alkylsulfonylCι_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-i^alkyl, C^alkylsulfonamido, C<_|_4alkylamido, C^alkylsulfonamidoC-^alkyl, C-|. 4alkylamidoC-ι.4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-i. 4alkyl, arylcarboxamidoC-_|.4alkyl, aroyl, aroylC-].4alkyl, arylC-|.4alkanoyl, C-i_ 4acyl, aryl, arylCι_4alkyl, C-ι_4alkylaminoC-|_4alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-_|_4alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C-|_4alkyl group or with the nitrogen to which it is attached, may form a second C3_gazacycloalkane fused to the first C3_ gazacycloalkane.

5. The use as claimed in any of claims 1-4, wherein R¹ and R² together with the nitrogen atom to which they are attached are linked to form a 4-, 5-, 6- or 7- membered substituted heterocyclic ring, wherein the sole heteroatom in the heterocyclic ring is the nitrogen atom to which R¹ and R² are attached.

6. The use as claimed in any of claims 1-4, wherein R¹ and R² together with the nitrogen atom to which they are attached are linked to form a substituted 5- or 6- membered ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S.

7. The use as claimed in any of claims 1-4, wherein R¹ and R² together with the nitrogen atom to which they are attached are linked to form a substituted 5- or 6- membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R¹ and R² are attached.

8. The use as claimed in any of claims 1-4, wherein the substituted 4-, 5-, 6- or 7-membered saturated ring formed by R¹ and R² together with the nitrogen atom to which they are linked is selected from the group comprising: azetidine, azepine, pyrrolidine, imidazolidine, piperidine, morpholine, thiomorpholine, and piperazine.

9. The use as claimed in any of claims 5-8, wherein the saturated ring formed by R¹ and R² is substituted by 1 , 2, 3 or 4 substituents independently selected from the group consisting of:

halogen, hydroxy, oxo, cyano, nitro, C^alkoxy, haloci-4alkyl, haloC-|_ 4alkoxy, arylC-_|_4alkoxy, C-j_4alkylthio, hydroxyC-j_4alkyl, Cι_4alkoxyCι_ 4alkyl, C3_gcycloalkylC-ι ^alkoxy, C^alkanoyl, C-_j^alkoxycarbonyl, C- .

4alkylsulfonyl, C-|.4alkylsulfonyloxy, C1_4alkylsulfonylC-ι_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC^alkyl, C^alkylsulfonamido, C^alkylamido, Cι_4alkylsulfonamidoC-ι_4alkyl, C^alkylamidoC-^alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-|_4alkyl, arylcarboxamidoC^alkyl, aroyl, aroylC<_|_4alkyl, arylCι_4alkanoyl, C^acyl, C^alkylaminoC^alkyl, a group

R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r,

R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-^alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C-μ 4alkyl group or with the nitrogen to which it is attached, may form a second

C3_gazacycloalkane fused to the first C3_gazacycloalkane, wherein when the only substituent in the saturated ring formed by R¹ and R² is oxo, then the carbon to which the oxo group is attached is not adjacent to the nitrogen to which R¹ and R² are attached.

10. The use as claimed in any of claims 1-9, wherein n is 0.

11. The use as claimed in any of claims 1-10, wherein Z is a 5- to 8-membered monocyclic ring system.

12. The use as claimed in claim 11, wherein Z is a 5- or 6-membered monocyclic ring system.

13. The use as claimed in claim 12, wherein Z is phenyl optionally substituted by one or more groups independently selected from -hal, -R¹⁰, -CF3, -Cι- Cgalkylsulphonyl, -OR¹¹, -COOR¹², -CN, -NO₂, -NR¹³R¹⁴.

14. The use as claimed in any of claims 1-10, wherein Z is a 6- to 10-membered bicyclic ring system.

15. The use as claimed in claim 14, wherein Z is naphthyl, naphthyridine, quinolyl, isoquinolyl, benzothienyl, chromanyl, chromenyl, imidazoleisothiazolyl, benzothiadiazolyl or benzofuryl, optionally substituted by one or more groups independently selected from -hal, -R¹⁰, -OR¹¹, -COOR¹², -CF3, -C1- Cgalkylsulphonyl, -CN, -NO₂, and -NR¹³R¹⁴.

16. The use as claimed in claim 15, wherein Z is 5-quinolinyl optionally substituted by one or more groups independently selected from -hal, Cι-C₆ alkyl, Ci-Ce alkoxy, -CF3, -CN and C₃-C₆ cycloalkyl.

17. The use as claimed in any of claims 1-16, wherein R³ is 5-quinolinyl.

18. The use as claimed in any of claims 1-17, wherein R⁴ is hydrogen or Cι-C₆ alkyl, preferably hydrogen.

19. The use as claimed in any of claims 1-18, wherein R⁵ is selected from hydrogen, Cι-C₆ alkyl, aryl and benzyl, optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl and OR²⁴.

20. The use as claimed in any of claims 1-19 wherein R⁶, R⁷, R⁸ and R⁹ are independently selected from hydrogen and Ci-Ce alkyl, preferably hydrogen.

21. The use of a compound of formula (la) for the manufacture of a medicament for treating disorders mediated by GlyTI , said compound having the formula (la):

or a salt or solvate or a physiologically functional derivative thereof, wherein: R¹ and R² is independently selected from hydrogen, substituted C-μgalkyl, substituted C3_gcycloalkyl, optionally substituted aryl, optionally substituted arylC-|_ 4alkyl and optionally substituted arylC3_gcycloalkyl, wherein R¹ and R² are not both hydrogen, and wherein the substituent in each case is one or more groups independently selected from: halogen, hydroxy, oxo, cyano, nitro, C^.galkyl, C-|_4alkoxy, haloci-4alkyl, haloC-j_4alkoxy, arylC-] ^alkoxy, Cι_4alkylthio, hydroxyC-i^alkyl, C-]_

4alkoxyCι_4alkyl, C3_gcycloalkyl, C3_gcycloalkylC-|_4alkoxy, C-_|.4alkanoyl, C^alkoxycarbonyl, C-|_4alkylsulfonyl, C-|_4alkylsulfonyloxy, C1_ 4alkylsulfonylC-|_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-_j^alkyl, C-ι_4alkylsulfonamido, Ci^alkylamido, C^alkylsulfonamidoC^alkyl, C-|_ 4alkylamidoCι_4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-].

4alkyl, arylcarboxamidoC-^alkyl, aroyl, aroylC<|_4alkyl, arylC-^alkanoyl, Cι_ 4acyl, aryl, arylC-i^alkyl, C^alkylaminoC-^alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-^alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C<|_4alkyl group or with the nitrogen to which it is attached, may form a second C3_gazacycloalkane fused to the first C3.. gazacycloalkane;

halogen, hydroxy, oxo, cyano, nitro, C^alkoxy, halocι_4alkyl, haloC-|_ 4alkoxy, arylC-|_4alkoxy, C-j_4alkylthio, hydroxyC<|_4alkyl, C-|_4alkoxyC-|_ 4alkyl, C3_gcycloalkylCι_4alkoxy, C-^alkanoyl, C-|_4alkoxycarbonyl, C-|_ 4alkylsulfonyl, C-_|_4alkylsulfonyloxy, C1_4alkylsulfonylC-|_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-|_4alkyl, C<|_4alkylsulfonamido, C-^alkylamido, C-_| _4alkylsulfonamidoC-] _4alkyl, C-_| _4alkylamidoC-| _4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-]_4alkyl, arylcarboxamidoC<|_4alkyl, aroyl, aroylC-_|_4alkyl, arylC-|.4alkanoyl, C-|_4acyl, C^alkylaminoC^alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-|_4alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³ N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C- .

R³ is

-C=C-

^L H H wherein n is 0 or 1 , and

COOR¹², -CN, -NO₂, -NR¹³R¹⁴, -CF3, and -Ci-Cgalkylsulphonyl, wherein hal is F, Cl, Br or i,

R¹⁰ is Cι-C₄ alkyl or phenyl, optionally substituted by one or more hal groups, and R¹¹, R¹², R¹³and R¹⁴are independently selected from hydrogen and methyl.

22. The use as claimed in claim 21, wherein when n is 1 , the C₂ alkenylene group is in the trans configuration.

23. The use as claimed in claim 21 or 22, wherein the compound of formula (la) as hereinbefore described has the following stereochemical configuration:

24. The use of compound as defined in claim 1 , wherein the compound is:

• 3,5-Dichloro-Λ/-{(2f?)-2-hydroxy-3-[2-(trifluoromethyl)-1 - pyrrolidinyl]propyl}benzenesulfonamide

• 3,5-Dichloro-Λ/-[(2f?)-2-hydroxy-3-(4-hydroxy-2,6-dimethyl-1 - piperidinyl)propyl]benzenesulfonamide

• 3,5-Dichloro-Λ/-{(2ft)-2-hydroxy-3-[(1 - methylethyl)(phenylmethyl)amino]propyl}benzenesulfonamide or a salt, a solvate or a physiologically functional derivative thereof.

25. The use as claimed in any of claims 1-24, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.

26. A method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GlyTI which comprises administering an effective amount of a GlyTI inhibiting compound of formula (I):

or a salt, solvate or a physiologically functional derivative thereof, wherein:

R¹ and R² is independently selected from hydrogen, substituted Cι_galkyl, substituted C3_gcycloalkyl, optionally substituted aryl, optionally substituted arylCι_ 4alkyl and optionally substituted arylC3_gcycloalkyl, wherein R¹ and R² are not both hydrogen, and wherein the substituent in each case is one or more groups independently selected from:

halogen, hydroxy, oxo, cyano, nitro, C-|_galkyl, C<|_4alkoxy, haloci-4alkyl, haloC-ι_4alkoxy, arylC^alkoxy, C<|_4alkylthio, hydroxyC^alkyl, C-]. 4alkoxyC-|_4alkyl, C3_gcycloalkyl, C3_gcycloalkylC-|_4alkoxy, C-ι.4alkanoyl, C^alkoxycarbonyl, C^alkylsulfonyl, C^alkylsulfonyloxy, C1_ 4alkylsulfonylC-]_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-|_4alkyl, C-ι_4alkylsulfonamido, C-^alkylamido, Cι_4alkylsulfonamidoC<_|_4alkyl, C-μ 4alkylamidoCι_4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-].

4alkyl, arylcarboxamidoC-|.4alkyl, aroyl, aroylC^alkyl, arylC-^alkanoyl, C-\. 4acyl, aryl, arylC-|_4alkyl, C-_|_4alkylaminoC-|_4alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-|_4alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C-^alkyl group or with the nitrogen to which it is attached, may form a second C3_gazacycloalkane fused to the first C3_ gazacycloalkane;

halogen, hydroxy, oxo, cyano, nitro, C-|_4alkoxy, haloci-4alkyl, haloC-j_ 4alkoxy, arylC-|_4alkoxy, C-^alkylthio, hydroxyC^alkyl, C-|_4alkoxyC-|_ 4alkyl, C3_gcycloalkylC-| ^alkoxy, C<|_4alkanoyl, C<μ4alkoxycarbonyl, C-j. 4alkylsulfonyl, C-^alkylsulfonyloxy, Cl^alkylsulfonylC^^alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-i^alkyl, C-^alkylsulfonamido, C-j_4alkylamido,

C-| _4alkylsulfonamidoCι _4alkyl, C-_| _4alkylamidoC-j _4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-^alkyl, arylcarboxamidoC-j_4alkyl, aroyl, aroylC^alkyl, arylC-ι_4alkanoyl, C^acyl, C-ι_4alkylaminoC-ι_4alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C^alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³ N(CH₂)n- or

R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C<_|_ 4alkyl group or with the nitrogen to which it is attached, may form a second C3-gazacycloalkane fused to the first C3_gazacycloalkane; wherein when the only substituent in the saturated ring formed by R¹ and R² is oxo, then the carbon to which the oxo group is attached is not adjacent to the nitrogen to which R¹ and R² are attached;

R³ is

wherein

Y is Cι-C₂ alkylene, C₂ alkenylene or C₂ alkynylene, and n is 0 or 1 , and

Z is a 5- to 8-membered monocyclic or 6- to 10-membered bicyclic aromatic ring system wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, and said ring system being optionally substituted by one or more groups independently selected from -hal, -R¹⁰, -CF3, -Ci-galkylsulphonyl, -OR¹¹, -COOR¹², -CN, -NO₂, -NR¹³R¹⁴, -C(O)NR¹⁵R¹⁶, -NR¹⁷C(O)R¹⁸, -C(O)R¹⁹, -C(NR²⁰)NR²¹R²², -C(NOR²³)R²⁸, wherein hal is F, Cl, Br or l,

R¹⁰ is C -Ce alkyl, C₃-C₆ cycloalkyl, C₃-C_e cycloalkylC -C₄ alkyl, aryl, aryloxy or aryl Cι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl, -OR¹¹, -COOR¹² -CN, -NO₂ and -NR¹³R¹⁴, R¹\ R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²⁰, R²¹, R²², R²³ and R²⁸ are independently selected from hydrogen and d-C₆ alkyl;

R⁴ and R¹⁹ are independently selected from hydrogen, Cι-C₆ alkyl, C₃-C₆ cycloalkyl, aryl or arylCι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl, -OR²⁴, -COOR²⁵ -CN, -NO₂ and -NR²⁶R²⁷; R⁶, R⁷, R⁸ and R⁹ are independently selected from hydrogen, d-C₆ alkyl or arylCi- C₄ alkyl, or R⁶ and R⁷ together form a C₃-C₆ cycloalkyl group, or R⁸ and R⁹ together form a C₃-C₆ cycloalkyl group; wherein the Ci-Ce alkyl, arylC₁-C₄ alkyl group, the C₃-C₆ cycloalkyl group formed by R⁶ and R⁷, and the C₃-C₆ cycloalkyl group formed by R⁸ and R⁹, are optionally substituted by one or more groups independently selected from hal, Cι-C_β alkyl, -OR²⁴, -COOR²⁵, -CN, -NO₂ and -NR²⁶R²⁷, wherein R²⁴, R²⁵, R²⁶ and R²⁷ are independently selected from hydrogen and Ci-Ce alkyl; and

R⁵ is independently selected from hydrogen, Cι-C₆ alkyl, C₃-C₆ cycloalkyl, aryl and arylCι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, d-Cβ alkyl, -OR²⁴, -COOR²⁵ -CN, -NO₂ and -NR²⁶R²⁷, wherein R²⁴, R²⁵, R²⁶ and R²⁷ are as hereinbefore defined.

27. The method as claimed in claim 26, wherein the disorder mediated by GlyTI is psychosis, including schizophrenia, dementia or attention deficit disorder.

28. A compound of formula (I):

or a salt, solvate or a physiologically functional derivative thereof, wherein:

R¹ and R² is independently selected from hydrogen, substituted C<_|_galkyl, substituted C3_gcycloalkyl, optionally substituted aryl, optionally substituted arylC-]. 4alkyl and optionally substituted arylC3_gcycloalkyl, wherein R¹ and R² are not both hydrogen, and wherein the substituent in each case is one or more groups independently selected from:

halogen, hydroxy, oxo, cyano, nitro, C-|.galkyl, C-|_4alkoxy, haloci-4alkyl, haloC^alkoxy, arylC^alkoxy, C^alkylthio, hydroxyC-^alkyl, C<|_ 4alkoxyC-|_4alkyl, C3_gcycloalkyl, C3_gcycloalkylC-ι ^alkoxy, C-_j^alkanoyl, C-]_4alkoxycarbonyl, C-|.4alkylsulfonyl, C^alkylsulfonyloxy, C1_ 4alkylsulfonylCι.4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-_|.4alkyl, C^alkylsulfonamido, C-j^alkylamido, C-^alkylsulfonamidoC^alkyl, C-_|. 4alkylamidoC-ι_4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-j. 4alkyl, arylcarboxamidoC-i^alkyl, aroyl, aroylC<_|_4alkyl, arylCi^alkanoyl, C<|_ 4acyl, aryl, arylC-^alkyl, C<j_4alkylaminoC<|_4alkyl, a group R³⁰R³¹N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)_r, R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C-|_4alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_g(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C^^alkyl group or with the nitrogen to which it is attached, may form a second C3_gazacycloalkane fused to the first C3. gazacycloalkane; or R¹ and R², together with the nitrogen atom to which they are attached, are linked to form a 4-, 5-, 6- or 7-membered saturated ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said saturated ring being substituted by one or more groups independently selected from:

halogen, hydroxy, oxo, cyano, nitro,

4alkoxy, arylC-^alkoxy, C-i^alkylthio, hydroxyC^alkyl, C^alkoxyCi. 4alkyl, C3_gcycloalkylCι_4alkoxy, C-|_4alkanoyl, C-]_4alkoxycarbonyl, C< _

4alkylsulfonyl, C^alkylsulfonyloxy, C1_4alkylsulfonylC-|_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC-|_4alkyl, C-|_4alkylsulfonamido, C^alkylamido, C^ _4alkylsulfonamidoC-] _4alkyl, C^ .4alkylamidoC-| _4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-i^alkyl, arylcarboxamidoC<|_4alkyl, aroyl, aroylC-|_4alkyl, arylC-|.4alkanoyl, C^acyl, Cι_4alkylaminoC-|_4alkyl, a group

R³⁰R³ N-, R³⁰OCO(CH₂)_r, R³⁰CON(R³¹)(CH₂)_r, R³⁰R³¹NCO(CH₂)r,

R³⁰R³¹NSO₂(CH₂)_r or R³⁰SO₂NR³¹(CH₂)_r (where each of R³⁰ and R³¹ independently represents a hydrogen atom or a C^alkyl group or where appropriate R³⁰R³¹ forms part of a C3_gazacyloalkane or C3_ (2- oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO- (wherein n represents an integer from 1 to 4); wherein when the substituent is R³⁰R³¹N(CH₂)n- or R³⁰R³¹N(CH₂)nO, R³⁰ with at least one CH₂ of the (CH₂)n portion of the group may also form a C3_gazacycloalkane and R³¹ may represent hydrogen, a C-|_ 4alkyl group or with the nitrogen to which it is attached, may form a second

C3_gazacycloalkane fused to the first C3_gazacycloalkane; wherein when the only substituent in the saturated ring formed by R¹ and R² is oxo, then the carbon to which the oxo group is attached is not adjacent to the nitrogen to which R¹ and R² are attached;

R³ is

wherein Y is Cι-C₂ alkylene, C₂ alkenylene or C₂ alkynylene, and n is 0 or 1, and

Z is a 5- to 8-membered monocyclic or 6- to 10-membered bicyclic aromatic ring system wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, and said ring system being optionally substituted by one or more groups independently selected from -hal, -R¹⁰, -CF3, -Ci-galkylsulphonyl, -OR¹¹, -COOR¹², -CN, -NO₂, -NR¹³R¹⁴, -C(O)NR¹⁵R¹⁶, -NR¹⁷C(O)R¹⁸, -C(O)R¹⁹, -C(NR²⁰)NR²¹R²², -C(NOR²³)R²⁸, wherein hal is F, Cl, Br or I, R¹⁰ is C-i-Ce alkyl, C₃-C_e cycloalkyl, C₃-C₆ cycloalkylCι-C₄ alkyl, aryl, aryloxy or aryl Cι-C alkyl, optionally substituted by one or more groups independently selected from hal, Ci-Ce alkyl, -OR¹¹, -COOR¹² -CN, -NO₂ and -NR¹³R¹⁴, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²⁰, R²¹, R²², R²³ and R²⁸ are independently selected from hydrogen and Cι-C₆ alkyl; R⁴ and R¹⁹ are independently selected from hydrogen, Ci-Ce alkyl, C₃-C₆ cycloalkyl, aryl or arylCι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, Ci-Ce alkyl, -OR²⁴, -COOR²⁵ -CN, -NO₂ and -NR²⁶R²⁷; R⁶, R⁷, R⁸ and R⁹ are independently selected from hydrogen, Ci-Ce alkyl or arylCi- C₄ alkyl, or R⁶ and R⁷ together form a C₃-C₆ cycloalkyl group, or R⁸ and R⁹ together form a C₃-C₆ cycloalkyl group; wherein the Ci-Ce alkyl, arylCι-C₄ alkyl group, the C₃-C₆ cycloalkyl group formed by R⁶ and R⁷, and the C₃-C₆ cycloalkyl group formed by R⁸ and R⁹, are optionally substituted by one or more groups independently selected from hal, Ci-Ce alkyl, -OR²⁴, -COOR²⁵, -CN, -NO₂ and -NR²⁶R²⁷, wherein R²⁴, R²⁵, R²⁶ and R²⁷ are independently selected from hydrogen and d-C₆ alkyl; and

R⁵ is independently selected from hydrogen, Cι-C₆ alkyl, C₃-C₆ cycloalkyl, aryl and arylCι-C₄ alkyl, optionally substituted by one or more groups independently selected from hal, d-C₆ alkyl, -OR²⁴, -COOR²⁵ -CN, -NO₂ and -NR²⁶R²⁷, wherein R²⁴, R²⁵, R²⁶ and R²⁷ are as hereinbefore defined;

but not including the following compounds:

and salts thereof.

29. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 28, but not including the following compounds:

and salts thereof; and at least one pharmaceutically acceptable carrier, diluent or excipient.

30. A compound of formula (I) as defined in claim 28, but not including the following compounds:

and salts thereof, for use in therapy.