CHEMICAL COMPOUNDS AND THEIR USE TO ELEVATE PYRUVATE DEHYDROGENASE ACTIVITY

Abstract: The use of a compound of formula (I) wherein: ring C is phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; and wherein said phenyl or heteroaryl is substituted as defined herein; A-B is selected from NHCO, OCH2, SCH2, NHCH2, trans-vinylene, and ethynylene; R<1> is linked to ring C at a carbon ortho to the position of A-B attachment and is defined herein; n is 1 or 2; R<2> and R<3> are alkyl, haloalkyl or together from cycloalkyl or halocycloakyl as defined herein; in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans is described. Salts and esters of compounds of formula (I) are also described.

Description: CHEMICAL COMPOUNDS AND THE IR USE TO ELEVATE PYRUVATE DEHYDROGENASE ACTIVITY The present invention relates to compounds which elevate pyruvate dehydrogenase (PDH) activity, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with reduced PDH activity, to their use as medicaments and to their use in the manufacture of medicaments for use in the elevation of PDH activity in warm-blooded animals such as humans. Within tissues adenosine triphosphate (ATP) provides the energy for synthesis of complex molecules and, in muscle, for contraction. ATP is generated from the breakdown of energy-rich substrates such as glucose or long chain free fatty acids. In oxidative tissues such as muscle the majority of the ATP is generated from acetyl CoA which enters the citric acid cycle, thus the supply of acetyl CoA is a critical determinant of ATP production in oxidative tissues. Acetyl CoA is produced either by β-oxidation of fatty acids or as a result of glucose metabolism by the glycolytic pathway. The key regulatory enzyme in controlling the rate of acetyl CoA formation from glucose is PDH which catalyses the oxidation of pyruvate to acetyl CoA and carbon dioxide with concomitant reduction of nicotinamide adenine dinucleotide (NAD) to NADH. In disease states such as both non-insulin dependent (NIDDM) and insulin-dependent diabetes mellitus (IDDM), oxidation of lipids is increased with a concomitant reduction in utilisation of glucose, which contributes to the hyperglycaemia. Reduced glucose utilisation in both IDDM and NIDDM is associated with a reduction in PDH activity. In addition, a further consequence of reduced PDH activity may be that an increase in pyruvate concentration results in increased availability of lactate as a substrate for hepatic gluconeogenesis. It is reasonable to expect that increasing the activity of PDH could increase the rate of glucose oxidation and hence overall glucose utilisation, in addition to reducing hepatic glucose output. .Another factor contributing to diabetes mellitus is impaired insulin secretion, which has been shown to be associated with reduced PDH activity in pancreatic β-cells (in a rodent genetic model of diabetes mellitus Zhou et al. (1996) Diabetes 45: 580-586). Oxidation of glucose is capable of yielding more molecules of ATP per mole of oxygen than is oxidation of fatty acids. In conditions where energy demand may exceed energy supply, such as myocardial ischaemia, intermittent claudication, cerebral ischaemia and reperfusion, (Zaidan et al., 1998; J. Neurochem. 70: 233-241), shifting the balance of - 2 - substrate utilisation in favour of glucose metabolism by elevating PDH activity may be expected to improve the ability to maintain ATP levels and hence function. An agent which is capable of elevating PDH activity may also be expected to be of benefit in treating conditions where an excess of circulating lactic acid is manifest such as in certain cases of sepsis. The agent dichloroacetic acid (DCA) which increases the activity of PDH after acute administration in animals, (Nary et al., 1988; Circ. Shock, 24: 3-18), has been shown to have the predicted effects in reducing glycaemia, (Stacpoole et al, 1978; Ν. Engl. J. Med. 298: 526-530), and as a therapy for myocardial ischaemia (Bersin and Stacpoole 1997; American Heart Journal, 134: 841-855) and lactic acidaemia, (Stacpoole et al., 1983; Ν. Engl. J. Med. 309: 390-396). PDH is an intramitochondrial multienzyme complex consisting of multiple copies of several subunits including three enzyme activities El, E2 and E3, required for the completion of the conversion of pyruvate to acetyl CoA (Patel and Roche 1990; FASEB J., 4: 3224-3233). El catalyses the non-reversible removal of CO 2 from pyruvate; E2 forms acetyl CoA and E3 reduces NAD to NADH. Two additional enzyme activities are associated with the complex: a specific kinase which is capable of phosphorylating El at three serine residues and a loosely-associated specific phosphatase which reverses the phosphorylation. Phosphoiylation of a single one of the three serine residues renders the El inactive. The proportion of the PDH in its active (dephosphorylated) state is determined by a balance between the activity of the kinase and phosphatase. The activity of the kinase may be regulated in vivo by the relative concentrations of metabolic substrates such as NAD/NADH, CoA/acetylCoA and adenine diphosphate (,ADP)/ATP as well as by the availability of pyruvate itself. European Patent Publication No. 617010 describes compounds which are capable of relaxing bladder smooth muscle and which may be used in the treatment of urge incontinence. Whilst the compounds of the present invention fall within the general structural disclosure of EP 0617010, we have found, surprisingly, that the compounds of the present invention are very good at elevating PDH activity, a property nowhere disclosed in EP 0617010. The present invention is based on the surprising discovery that certain compounds elevate PDH activity, a property of value in the treatment of disease states associated with disorders of glucose utilisation such as diabetes mellitus, obesity, (Curto et al., 1997; Int. J. Obes. 21 : 1137-1142), and lactic acidaemia. Additionally the compounds may be expected to - 3 - have utility in diseases where supply of energy-rich substrates to tissues is limiting such as peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, muscle weakness, hyperlipidaemias and atherosclerosis (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530). A compound that activates PDH may also be useful in treating Alzheimer disease (AD) (J Neural Transm (1998) 105: 855-870). According to one aspect of the present invention there is provided the use of a compound of the formula (I): ^ /( Rl )n R2 HO R (I) wherein: ring C is phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; wherein said phenyl or heteroaryl is substituted on carbon at one or both positions meta to the position of A-B attachment or on carbon at the position para to the position of A-B attachment by a group selected from cyano, trifluoromethyl, nitro, trifluoromethoxy, trifluoromethylthio and a group .ArY; and further, wherein said phenyl or heteroaryl is substituted on carbon at any remaining meta position(s) or para position by a group or groups independently selected from hydrogen, (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (l-4C)alkenyloxy, cyano, nitro, halo, hydroxy and trifluoromethylthio; in which Ar is selected from the group consisting of phenyl, a carbon-linked six-membered heteroaryl ring containing 1 -2 nitrogen atoms and a carbon-linked fϊve-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said phenyl or heteroaryl ring Ar is optionally substituted at carbon, with 1-4 substituents selected from (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo and trifluoromethylthio; Y is selected from carbonyl, sulphinyl and sulphonyl; A-B is selected from NHCO, OCH 2 , SCH 2 , NHCH 2 , trαrø-vinylene, and ethynylene; R 1 is linked to ring C at a carbon ortho to the position of A-B attachment and is selected from the group consisting of (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo, trifluoromethylthio and hydroxy; - 4 - n is 1 or 2; R 2 and R 3 are independently (l-3C)alkyl optionally substituted by from 1 to 2k+l atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said (l-3C)alkyl, provided that R 2 and R 3 are not both methyl; or R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring optionally substituted by from 1 to 2m-2 fluorine atoms wherein m is the number of carbon atoms in said ring; and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I); and a pharmaceutically acceptable salt of said compound or said ester; provided said compound is not N-(4-benzoyl-2,6-dimethylphenyl)-2-hydroxy-2-methyl-3 ,3 J -trifluoropropanamide, in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. Preferably ring C is phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted as defined hereinbefore. More preferably ring C is phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of A-B attachment by a group selected from cyano, trifluoromethyl, nitro, trifluoromethoxy, trifluoromethylthio and a group ArY (wherein A-B and ArY are as defined hereinbefore). Particularly ring C is phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of A-B attachment by a group selected from cyano, trifluoromethyl, nitro, trifluoromethoxy and a group ArY (wherein A-B and ArY are as defined hereinbefore). More particularly ring C is phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of A-B attachment by a group selected from cyano, trifluoromethyl, nitro and a group ArY (wherein A-B and ArY are as defined hereinbefore). Particularly prefeired ring C is phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of A-B attachment by a group ArY (wherein A-B and ArY are as defined hereinbefore). Especially ring C is phenyl and is substituted as defined hereinbefore. More especially ring C is phenyl wherein said phenyl is substituted on carbon at the - 5 - position para to the position of A-B attachment by a group selected from cyano, trifluoromethyl, nitro, trifluoromethoxy and a group ArY (wherein A-B and ArY are as defined hereinbefore). Particularly preferred ring C is phenyl wherein said phenyl is substituted on carbon at the position para to the position of A-B attachment by a group ArY (wherein A-B and ArY are as defined hereinbefore). More especially ring C is phenyl which is substituted on carbon at the position para to the position of A-B attachment by a group ArY (wherein A-B and ArY are as defined hereinbefore). In one embodiment of the present invention Ai is phenyl, 4-pyridyl, 2-thienyl, 2-pyrimidyl, 2-imidazolyl, 2-pyridyl, 3 -pyridyl, 2-thiazolyl or 3-furyl and is optionally substituted as defined hereinbefore. In a further embodiment of the present invention Ar is phenyl (optionally substituted with fluoro, methoxy, bromo, trifluoromethyl, nitro or methyl), or Ar is 4-pyridyl, 5-methylthien-2-yl, 2-pyrimidyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, 2-thiazolyl or 2-methylfur-3-yl. In another embodiment of the present invention Ar is phenyl or 4-pyridyl and is optionally substituted as defined hereinbefore. In an alternative embodiment of the present invention Ar is phenyl and is optionally substituted as defined hereinbefore. In an additional aspect of the invention Ar is selected from the group consisting of a carbon-linked six-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked five-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said heteroaryl ring (.Ar) is optionally substituted as defined hereinbefore. In one aspect of the invention, preferably Y is sulphinyl or sulphonyl. Preferably A-B is NHCO or ethynylene. More preferably A-B is NHCO. Preferably R 1 is selected from the group consisting of (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, cyano, nitro, halo and hydroxy. More preferably R 1 is selected from the group consisting of (l-2C)alkyl, (l-2C)alkoxy, cyano, nitro, halo and hydroxy. - 6 - Particularly R 1 is selected from methyl, methoxy, nitro, fluoro, chloro, bromo and hydroxy. More particularly R 1 is selected from methoxy, nitro, fluoro, chloro, bromo and hydroxy. Especially R 1 is fluoro, chloro or bromo. Preferably n is 1. Preferably R 2 and R 3 are independently (l-3C)alkyl optionally substituted by from 1 to 2k+l atoms selected from fluoro and chloro, wherein k is the number of carbon atoms in the said (l-3C)alkyl, provided that R 2 and R 3 are not both methyl; or R 2 and R 3 , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms. More preferably R 2 and R 3 are independently (l-2C)alkyl optionally substituted by from 1 to 2k+l fluorine atoms, wherein k is the number of carbon atoms in the said (l-2C)alkyl, provided that R 2 and R 3 are not both methyl; or R 2 and R 3 , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms. Particularly R 2 and R 3 are independently methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and perfluoroethyl provided that R 2 and R 3 are not both methyl; or R 2 and R 3 , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms. More particularly R 2 and R 3 are independently methyl, fluoromethyl, difluoromethyl and trifluoromethyl, provided that R 2 and R 3 are not both methyl; or R 2 and R 3 , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms. In another aspect of the invention preferably R 2 and R 3 are independently methyl, ethyl, difluoromethyl, trifluoromethyl provided that R 2 and R 3 are not both methyl; or R 2 and R 3 , together with the carbon atom to which they are attached, form a cyclopropane ring. In a further aspect of the invention preferably one of R 2 and R 3 is methyl and the other is trifluoromethyl. - 7 - Where applicable, the R-configuration at the carbinol centre generally represents a preferred stereochemistry for compounds of formula (I). According to another aspect of the present invention there is provided the use of a compound of the formula (la): ^ ,1aX R 2a ( ^-Aa-Ba-^ HO R (la) wherein: ring Ca is phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of Aa-Ba attachment by a group selected from cyano, trifluoromethyl, nitro, trifluoromethoxy, trifluoromethylthio and a group AraY a (wherein Ara is selected from the group consisting of phenyl, a carbon-linked six-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked five-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said phenyl or heteroaryl ring Ar is optionally substituted at carbon, with 1 -4 substituents selected from ( 1 -4C)alkyl, ( 1 -4C)haloalkyl, ( 1 -4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo and trifluoromethylthio, Y a is selected from carbonyl, sulphinyl and sulphonyl and Aa-Ba is selected from NHCO, OCH 2 , SCH 2 , NHCH 2 , trα«5-vinylene, and ethynylene); R la is linked to ring C at a carbon ortho to the position of Aa-Ba attachment and is selected from the group consisting of ( 1 -4C)alkyl, ( 1 -4C)haloalkyl, ( 1 -4C)alkoxy , (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo, trifluoromethylthio and hydroxy; na is 1 ; R 2a and R 3a are independently (l-3C)alkyl optionally substituted by from 1 to 2k+l atoms selected from fluoro and chloro, wherein k is the number of carbon atoms in the said (1 -3C)alkyl, provided that R 2a and R 3a are not both methyl; or R 2 and R 3a , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms; and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (la); and a pharmaceutically acceptable salt of said compound or said ester; - 8 - in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. Where applicable, the R-configuration generally represents a preferred stereochemistry for compounds of formula (la). According to another aspect of the present invention there is provided the use of a compound of the formula (lb): (lb) wherein: ring Cb is phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of NHCO attachment by a group selected from cyano, trifluoromethyl, nitro, trifluoromethoxy, trifluoromethylthio and a group ArbY b (wherein Arb is selected from the group consisting of phenyl, a carbon-linked six-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked five-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said phenyl or heteroaryl ring Arb is optionally substituted at carbon, with 1-4 substituents selected from (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo and trifluoromethylthio and Y b is selected from carbonyl, sulphinyl and sulphonyl); R lb is linked at a carbon ortho to the position of NHCO attachment and is selected from the group consisting of (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo, trifluoromethylthio and hydroxy; nb is 1 ; R 2b and R 3b are independently (l-2C)alkyl optionally substituted by from 1 to 2k+l fluorine atoms, wherein k is the number of carbon atoms in the said (1 -2C)alkyl, provided that R b and R 3b are not both methyl; or R 2b and R 3b , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms; and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (lb); - 9 - and a pharmaceutically acceptable salt of said compound or said ester; in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. Where applicable, the R-configuration generally represents a preferred stereochemistry for compounds of formula (lb). According to another aspect of the present invention there is provided the use of a compound of the formula (Ic): Arc — Y (Ic) wherein: ring Cc is phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of NHCO attachment by a group ArcY c (wherein Arc is selected from the group consisting of phenyl, a carbon-linked six-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked five-membered heteroaryl ring containing from 1 -2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said phenyl or heteroaryl ring Arc is optionally substituted at carbon, with 1-4 substituents selected from (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo and trifluoromethylthio, and Y c is selected from carbonyl, sulphinyl and sulphonyl); R lc is linked at a carbon ortho to the position of NHCO attachment and is selected from the group consisting of (l-2C)alkyl, (l-2C)alkoxy, cyano, nitro, halo and hydroxy; R 2c and R 3c are independently methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and perfluoroethyl, provided that R 2c and R 3c are not both methyl; or R 2c and R 3c , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms; and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (Ic); and a pharmaceutically acceptable salt of said compound or said ester; in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. - 10 - Where applicable, the R-configuration generally represents a preferred stereochemistry for compounds of formula (Ic). According to another aspect of the present invention there is provided the use of a compound of the formula (Id): Ard- (Id) wherein: Ard is selected from the group consisting of phenyl, a carbon-linked six-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked five-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said phenyl or heteroaryl ring Ard is optionally substituted at carbon, with 1-4 substituents selected from (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo and trifluoromethylthio and Y d is selected from carbonyl, sulphinyl and sulphonyl; R ld is linked at a carbon ortho to the position of NHCO attachment and is selected from the group consisting of methoxy, nitro, fluoro, chloro, bromo and hydroxy; R 2d and R d are independently methyl, fluoromethyl, difluoromethyl, trifluoromethyl, provided that R 2d and R 3d are not both methyl; or R 2d and R 3d , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (Id); and a pharmaceutically acceptable salt of said compound or said ester; in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. Where applicable, the R-configuration generally represents a preferred stereochemistry for compounds of formula (Id). Many of the compounds of the present invention are novel and as such are provided as a further feature of the present invention. - 11 - According to another aspect of the present invention there is provided a compound of the formula (I): HO κ (I) wherein ring C, R 1 , n, A-B, R 2 and R 3 are as defined hereinbefore, and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I); and a pharmaceutically acceptable salt of said compound or said ester; provided said compound is not selected from N-(4-benzoyl-2,6-dimethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-fluorophenyl)-2-hydJoxy-2-methyl-3,3,3-trifluoropropanamide, N-(6-chloro-3-phenylsulfonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-N-[2-methoxy-4-(4-pyridylsulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-2-methyl-N-[2-nitro-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoropropanamide, S-(-)-N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-bromophenyl)-3J-difluoro-2-(difluoromethyl)-2-hydroxypropanamide, N-(4-benzoyl-2-bromophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-cyanophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-methoxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-hydroxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-N-[2-hydroxy-4-(4-pyridylsulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2,6-dimethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(2-Fluoro-5-nitrophenyl)-2-hydroxy-2-trifluoromethylbutanamide, N-(2-Fluoro-5-nitrophenyl)-2-hydroxy-2-difluoromethyl-3 ,3-difluoropropanamide, and 3-Hydroxy-3-trifluoromethyl-l-(2-chloro-5-trifluoromethylphenyl)-4,4,4-trifluorobut-l-yne,a nd pharmaceutically acceptable in vivo cleavable esters of said compounds, and pharmaceutically acceptable salts of said compounds and said esters. According to another aspect of the present invention there is provided a compound of the formula (la): - 12 - )na R2a Aa-Ba- / 3a HO R (la) wherein: ring Ca, R la , na, Aa-Ba, R 2a and R 3a are as defined hereinbefore, and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (la); and a pharmaceutically acceptable salt of said compound or said ester; provided said compound is not selected from: N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-fluorophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, 2-hydroxy-N-[2-methoxy-4-(4-pyridyl-sulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-2-methyl-N-[2-nitro-4-(phenyl-sulfonyl)phenyl]-3J,3-trifluoropropanamide, S-(-)-N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3J,3-trifluoropropanamide, N-(4-benzoyl-2-chlorophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-bromophenyl)-3,3-difluoro-2-(difluoromethyl)-2-hydroxypropanamide, N-(4-benzoyl-2-bromophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-cyanophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-methoxyphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-hydroxyphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide and 2-hydroxy-N-[2-hydroxy-4-(4-pyridylsulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide and pharmaceutically acceptable in vivo cleavable esters of said compounds, and pharmaceutically acceptable salts of said compounds and said esters. According to another aspect of the present invention there is provided a compound of the formula (lb): wherein: - 13 - Cb, R lb , R 2b , R 3b and nb are as defined hereinbefore, and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (lb); and a pharmaceutically acceptable salt of said compound or said ester; provided said compound is not selected from: N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-fluorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-N-[2-methoxy-4-(4-pyridyl-sulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-2-methyl-N-[2-nitro-4-(phenyl-sulfonyl)phenyl]-3,3,3-trifluoropropanamide, S-(-)-N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-chlorophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-bromophenyl)-3J-difluoro-2-(difluoromethyl)-2-hydroxypropanamide, N-(4-benzoyl-2-bromophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-cyanophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-methoxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-hydroxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide and 2-hydroxy-N-[2-hydroxy-4-(4-pyridylsulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, and pharmaceutically acceptable in vivo cleavable esters of said compounds, and pharmaceutically acceptable salts of said compounds and said esters. According to another aspect of the present invention there is provided a compound of the formula (Ic): Arc — Y (Ic) wherein: Cc, R lc , R 2c , R 3c , Arc and Y c are as defined hereinbefore, and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (Ic); and a pharmaceutically acceptable salt of said compound or said ester; provided said compound is not selected from: N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-fluorophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, - 14 - 2-hydroxy-N-[2-methoxy-4-(4-pyridyl-sulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-2-methyl-N-[2-nitro-4-(phenyl-sulfonyl)phenyl]-3,3,3-trifluoropropanamide, S-(-)-N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-chlorophenyl)-2-hydroxy-2-methyl-3J,3-trifluoropropanamide, N-(4-benzoyl-2-bromophenyl)-3,3-difluoro-2-(difluoromethyl)-2-hydroxypropanamide, N-(4-benzoyl-2-bromophenyl)-2-hydroxy-2-methyl-3J,3-trifluoropropanamide, N-(4-benzoy 1-2-cy anophenyl)-2-hy droxy-2-methy 1-3 ,3,3 -trifluoropropanamide, N-(4-benzoyl-2-methoxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-hydroxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide and 2-hydroxy-N-[2-hydroxy-4-(4-pyridylsulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, and pharaiaceutically acceptable in vivo cleavable esters of said compounds, and pharaiaceutically acceptable salts of said compounds and said esters. According to another aspect of the present invention there is provided a compound of the formula (Id): Ard — HO (Id) wherein: R ld , R 2d , R 3d , Ard and Y d are as defined hereinbefore, and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (Id); and a pharmaceutically acceptable salt of said compound or said ester; provided said compound is not selected from: N-(4-benzoyl-2-fluorophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, 2-hydroxy-N-[2-methoxy-4-(4-pyridyl-sulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-2-methyl-N-[2-nitro-4-(phenyl-sulfonyl)phenyl]-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-chlorophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-bromophenyl)-3,3-difluoro-2-(difluoromethyl)-2-hydroxypropanamide, N-(4-benzoyl-2-bromophenyl)-2-hyάJoxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-methoxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, - 15 - N-(4-benzoyl-2-hydroxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide and 2-hydroxy-N-[2-hydroxy-4-(4-pyridylsulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, and pharmaceutically acceptable in vivo cleavable esters of said compounds, and pharmaceutically acceptable salts of said compounds and said esters. According to another aspect of the present invention there is provided a compound of the formula (le): Are- (le) wherein: R le is fluoro, chloro or bromo; m is 1 or 2; Are is selected from the group consisting of a carbon-linked six-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked five-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said heteroaryl ring is optionally substituted at carbon, with 1-4 substituents selected from (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo and trifluoromethylthio; and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (le), and a pharmaceutically acceptable salt of said compound or said ester. The compounds of the present invention which are of the R-configuration at the carbinol centre form a preferred group of compounds of the present invention. According to another aspect of the present invention there is provided the use of a compound selected from Examples 1, 2, 7, 8 and 10-15 and a pharmaceutically acceptable in vivo cleavable ester of said compound, and a pharmaceutically acceptable salt of said compound or said ester in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. According to a preferred aspect of the present invention there is provided the use of a compound selected from Examples 2 and 10-14 and a pharaiaceutically acceptable in vivo cleavable ester of said compound, and a pharmaceutically acceptable salt of said compound or - 16 - said ester, in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. According to another preferred aspect of the present invention there is provided the use of Example 1 and a pharmaceutically acceptable in vivo cleavable ester of said compound, and a pharmaceutically acceptable salt of said compound or said ester, in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. According to a more preferred aspect of the present invention there is provided the use of a compound selected from Examples 7, 8 and 15 and a pharmaceutically acceptable in vivo cleavable ester of said compound, and a pharmaceutically acceptable salt of said compound or said ester, in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. Compounds of the invention include: (S)-2-hydroxy-2-methyl-N-(2-mtro-4-phenylsulphonylphenyl)-3,3,3-trifluoropropanamide, (S)-N-(2-chloro-4-phenylsulphonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-cyano-2-methylphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-cyano-2-trifluoromethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, and Examples 3, 4, 9, 16 - 26, 34, 35, 40 - 44 and 48 - 52 and a pharmaceutically acceptable in vivo cleavable ester of said compound; and a pharmaceutically acceptable salt of said compound or said ester. Preferred compounds are: N-(4-cyano-2-methylphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-cyano-2-trifluoromethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, and Examples 3, 4, 26 and 49 - 52 and a pharmaceutically acceptable in vivo cleavable ester of said compound; and a pharmaceutically acceptable salt of said compound or said ester. More preferred compounds are Examples 22, 24 and 55 and a pharmaceutically acceptable in vivo cleavable ester of said compound; and a pharmaceutically acceptable salt of said compound or said ester. Particularly preferred compounds are Examples 34 and 35 and a pharmaceutically acceptable in vivo cleavable ester of said compound; and a pharmaceutically acceptable salt of said compound or said ester. More particularly preferred compounds are Examples 9, 16, 17, 19 - 21, 23, 40 - 44 - 17 - and 48 and a pharmaceutically acceptable in vivo cleavable ester of said compound; and a pharmaceutically acceptable salt of said compound or said ester. Another more particularly preferred compound of the invention is Example 18 and a pharmaceutically acceptable in vivo cleavable ester of said compound; and a pharmaceutically acceptable salt of said compound or said ester. Another more particularly preferred compound of the invention is Example 16 and a pharmaceutically acceptable in vivo cleavable ester of said compound; and a pharmaceutically acceptable salt of said compound or said ester. In another aspect of the invention preferred compounds of the invention include any one of Examples 3-6, 9, and 16-61 and pharmaceutically acceptable in vivo cleavable ester of said compounds and a pharmaceutically acceptable salt of said compounds or said esters. In a further aspect of the invention preferred compounds of formula (I) or (le) include Examples 28, 47 and 55 - 61 and a pharmaceutically acceptable in vivo cleavable ester of said compound; and a pharmaceutically acceptable salt of said compound or said ester. Preferred aspects of the invention are those which relate to the compound or a pharmaceutically acceptable salt thereof. For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined' or 'defined hereinbefore' the said group encompasses the first occurring and broadest definition as well as each and all of the preferred definitions for that group. In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. An analogous convention applies to other generic terms. Unless otherwise stated the term "alkyl" advantageously refers to chains with 1-6 carbon atoms, preferably 1-4 carbon atoms. In this specification the term "alkoxy" means an alkyl group as defined hereinbefore linked to an oxygen atom. In this specification the term "aryl" includes C 6 . I0 aromatic groups which may, if desired, carry one or more substituents selected from halogeno, alkyl, alkoxy, cyano, nitro or trifluoromethyl (wherein alkyl and alkoxy are as hereinbefore defined). The term "aryloxy" means an aryl group as defined hereinbefore linked to an oxygen atom. - 18 - Within the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which elevates PDH activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. It will be appreciated by those skilled in the art that certain compounds of formula (I) contain an asymmetrically substituted carbon and/or sulphur atom, and accordingly may exist in, and be isolated in, optically-active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the elevation of PDH activity, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, (for example WO 9738124), by biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the elevation of PDH activity by the standard tests described hereinafter. It is also to be understood that certain compounds of the foraiula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which elevate PDH activity. A compound of the formula (I), or salt thereof, and other compounds of the invention (as hereinafter defined) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes include, for example, those illustrated in European Patent Applications, Publication Nos. 0524781, 0617010, 0625516, and in GB 2278054, WO 9323358 and WO 9738124. Such processes, are provided as a further feature of the invention and are as described hereinafter, wherein, unless specified otherwise, Ar, Y, ring C, A-B, R 1 , R 2 , R 3 and n are as defined hereinbefore. Necessary starting materials may be obtained by standard procedures of - 19 - organic chemistry. The preparation of such starting materials is illustrated within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. Thus the following processes constitute further features of the present invention. Compounds of the formula (I) and salts thereof may be prepared: (a) by deprotecting a protected compound having formula (II): (i> A - B PNgO R (II) wherein "Pg" is a suitable alcohol protecting group such as for example a benzyl, acetate or silyl protecting group; examples of suitable reagents for deprotecting a compound of formula (II) when Pg is benzyl are (1) hydrogen in the presence of palladium-on-carbon catalyst, i.e. hydrogenolysis, or (2) hydrogen bromide or iodide; when Pg is acetate diluted inorganic base, for example aqueous lithium-, sodium- or potassium-hydroxide; and when Pg is a silyl protecting group are (1) tetrabutylammonium fluoride, or (2) aqueous hydrofluoric acid. The reaction can be conducted in a suitable solvent such as ethanol, methanol, acetonitrile, or dimethyl sulfoxide (DMSO) and may conveniently be performed at a temperature in the range of -40 to lOO°C; (b) when Y is carbonyl: by oxidizing a corresponding alcohol of formula (III): OH R κ ^ ^ ^ HO R (III) wherein ring D 1 has any of the values defined hereinbefore for ring C but in which the place of one of the possible substituents on ring C is taken by ArCH(OH). Oxidizing agents such as pyridinium dichromate and solvents such as methanol and dichloromethane, respectively, may be employed; (c) by deprotecting a corresponding compound of formula (I) wherein in place of Y is a ketal protected carbonyl, for example by deprotecting a compound of formula (IV): - 20 - A °r->^ F C^ A - B H^O R R (IV) wherein ring D 2 has any of the values defined hereinbefore for ring C but in which the place of one of the possible substituents on ring C is taken by Ar(-C-O-(CH 2 ) 3 -O-)-. A saturated aqueous acid such as oxalic or a mineral acid such as hydrochloric acid or sulphuric acid may conveniently be employed. The reaction may conveniently be performed at a temperature in the range of 0 to 100°C in a solvent such as a lower alcohol (e.g., methanol or ethanol), or mixtures of solvent pairs such as water/dichloromethane, water/tetrahydrofuran, and water/acetone; (d) by treating a compound of formula (V): -< Rl . " R . ' i - -A-B- γ C HO R3 (V) wherein ring D 3 has any of the values defined hereinbefore for ring C but in which the place of one of the possible substituents on ring C is taken by G 1 and G 1 is defined as a leaving group such as for example bromo, iodo or triflate, with a tin compound having the formula (R 6 ) pl Sn(Ar) p2 (wherein R 6 is (l-4C)alkyl such as methyl or butyl and pl+p2=4) and carbon monoxide to effect carbonylative coupling, in the presence of a suitable catalyst such as bis(triphenylphosphine)palladium dichloride. The reaction may conveniently be performed at a temperature in the range of 0 to 100°C and in a solvent such as tetrahydrofuran, l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, or DMSO; (e) by treating a compound of formula (V) wherein G 1 is a leaving group such as for example bromo, iodo or triflate, with an aluminium compound having the formula (R 6 ) p3 Al(Ar) p4 (wherein R 6 is (l-4C)alkyl such as methyl or butyl and p3+p4=3) and carbon monoxide to effect carbonylative coupling, in the presence of a suitable catalyst such as bis(triphenylphosphine)palladium dichloride. The reaction may conveniently be performed at a temperature in the range of 0 to 100°C and in a solvent such as diethyl ether, benzene, - 21 - toluene, or tetrahydrofuran; (f) when Y is sulfonyl: by treating a compound of formula (V), wherein G 1 is a leaving group such as for example bromo or iodo, especially iodo, with a compound of formula ArSO 2 " Na + in the presence of a Cu(I) catalyst such as cuprous iodide. The reaction may conveniently be performed at a temperature in the range of 30 to 200°C and in a solvent such as N,N-dimethylformamide, l,3-dimethyl-3,4,5,6-tetra-hydro-2(lH)-pyrimidinone, DMSO, or ethylene glycol; (g) when Y is sulfinyl or sulfonyl and A-B is any of the values defined above, except SCH 2 or ΝHCH 2 : by oxidizing a compound of formula (V) wherein G 1 is ArS. Suitable oxidizing agents include potassium permanganate, OXONE (trade mark of E.I. du Pont de Nemours & Co., Inc), sodium periodate, tert-butyl hydroperoxide (as solution in toluene), 3-chloroperoxybenzoic acid and hydrogen peroxide. The reaction may be conducted in a suitable solvent such as diethyl ether, dichloromethane, methanol, ethanol, water, acetic acid, or mixtures of two or more of the aforementioned. The reaction may conveniently be performed at a temperature in the range of -40 to 70°C; (h) when A-B is NHCO: by coupling a compound of formula (VI): ©-JH (VI) wherein J is NH 2 with an acid of formula (VII): ° ^ (VII) wherein G 2 is a hydroxy group. The reaction can be conducted in a suitable solvent and in the presence of a suitable coupling reagent. Suitable coupling reagents, for use in situ and generally known in the art as standard peptide coupling reagents, can be employed, for example thionyl chloride, oxalyl chloride, carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine. A suitable base for this process is for example triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as for example 2,6-lutidine or - 22 - 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of -40 to 40°C. The reaction may also be effected using an acid of formula (VII) wherein G 2 is protected hydroxy to give a compound of the formula (II) followed by deprotection, (which may be effected by a process as described in (a) above), to give a compound of formula (I); (i) by coupling a compound of formula (VI) wherein J is NH 2 with an activated acid derivative of an acid of formula (VII), wherein G 2 is a hydroxy group, such as for example stable acid chlorides, acid anhydrides, or phenylesters in the presence of a base such as for example triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as for example 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of -40 to 40°C. The reaction may also be effected using an activated acid derivative of formula (VII) wherein G 2 is protected hydroxy to give a compound of the formula (II) followed by deprotection, (which may be effected by a process as described in (a) above), to give a compound of formula (I); (j) by reacting an amide of formula (VIII): (VIII) with a base sufficiently basic (e.g., a lithium dialkylamide such as lithium diisopropyl amide) to yield an amide dianion, followed by treatment of the dianion with oxygen in the presence of a reducing agent (e.g., such as triphenylphosphine). The sequence of reactions may conveniently be performed at a temperature in the range of -100 to -20°C, preferably at a temperature in the range of -20 to 50°C, in a suitable solvent such as tetrahydrofuran or diethyl ether; (k) by reacting a corresponding compound of formula (IX): - 23 - y (Rl)n (cj-Ual (IX) wherein Hal indicates a halogen substituent (e.g., the corresponding chloride), with a corresponding alkali metal amide dianion having formula (X); M + - NH 3 o- R M + (X) wherein M is an alkali metal such as sodium or lithium. The reaction may conveniently be performed at a temperature in the range of -40 to 100°C and in a suitable solvent such as dimethylformamide, DMSO, or tetrahydrofuran; (1) when Y is sulfonyl and R 2 =R 3 : by reacting a corresponding compound of formula .(XI): / - (Rl) n ( C -r-A-B O (XI) wherein OR 4 is an alcohol residue such as for example methoxy or ethoxy, with a Grignard compound of formula R 2 MgBr or R 2 MgCl. The reaction may conveniently be perfoπned at a temperature in the range of -100 to 20°C, preferably at a temperature in the range of -20 to 20°C, in a suitable solvent such as tetrahydrofuran or diethyl ether; (m) when Y is sulfonyl: by treating a corresponding compound of formula (XII): I C 4- A-B ^^ -R» O (XII) with a compound of formula R 2 M wherein M is an alkali metal (such as lithium) or a Grignard - 24 - compound of formula R 2 MgBr or R 2 MgCl. The reaction may conveniently be performed at a temperature in the range of -100 to 0°C and in a solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane; (n) when A-B is ethynylene: by coupling a corresponding compound of formula (XIII): (XIII) wherein L is a leaving group such as bromo, iodo or triflate, with a corresponding acetylene of formula (XIV): R 2 H— -≡- PgO R3 (XIV) in the presence of a catalyst such as a combination of cuprous iodide and bis(triphenyl-phosphine)palladium dichloride or palladium(II) acetate to give a compound of formula (II). The reaction can be conducted in an inert solvent such as tetrahydrofuran, benzene, or toluene, or in a basic solvent such as diethylamine (DEA) or triethylamine (TEA), and at a temperature in the range of -20 to 110°C. The compound of formula (II) so formed can be deprotected as described in (a) hereinbefore; (o) by reacting a corresponding alkyne of formula (XV): /( Rl )n (XV) with a base such as lithium diisopropylamide (LDA), w-butyllithium or tert-butyllithium, followed by treatment with a ketone of formula R 3 -CO-R 2 . The reaction may conveniently be performed at a temperature in the range of -100 to -40°C preferably at a temperature in the range of -70 to -40°C and in a solvent such as tetrahydrofuran, diethyl ether, or 1 ,2-dimethoxyethane; (p) when A-B is ^αrø-vinylene: by reducing a corresponding acetylene of formula (XVI): - 25 - (R 1 ), t R>2 HO R3 (XVI) with a suitable reducing agent, for example lithium aluminum hydride. The reaction can be conducted in a suitable solvent such as tetrahydrofuran or diethyl ether, and at a temperature in the range of0 to 50°C; (q) by dehydration of a diol of formula (XVII): /( Rl )„ HO /V R HO 3 (XVII) in the presence of an acid catalyst (for example p-toluenesulfonic acid), neat or with a solvent such as toluene or dichloromethane, and at a temperature in the range of 0 to 200°C preferably a temperature in the range of 20 to 100°C; (r) by base catalysed opening of an epoxide of formula (XVIII): (XVIII). The opening may be carried out in a suitable organic solvent such as for example, ethers, alcohols, or toluene, of which ethers and toluene are preferred, especially ethers such as tetrahydrofuran. Suitable bases include for example potassium tert-butoxide or sodium hydride. A basic aqueous solution may conveniently be employed. A preferred base is aqueous sodium hydroxide. The opening may be carried out at a temperature in the range of -50°C to 100°C, preferably at a temperature in the range of 0 to 50°C, such as for example room temperature; (s) when A-B is NHCH 2 : by reducing a corresponding compound of formula (I) in which A-B is NHCO, with a suitable reducing agent such as lithium aluminum hydride or borane. The reaction can conveniently be carried out at a temperature in the range of 0°C to reflux, in - 26 - solvents such as for example diethyl ether, tetrahydrofuran, or 1,2-dimethoxyethane; (t) when A-B is OCH 2 , SCH 2 or NHCH 2 : by reacting an ethylene oxide of formula (XIX): R' (XIX) with a corresponding compound of formula (VI) (wherein J is, correspondingly, oxygen, sulphur or NH), in the presence of a base such as for example sodium hydride. The reaction can be conducted at reflux in a solvent such as dichloromethane; (u) by heating a corresponding compound of formula (XX): °^ R 3 R 2 (XX) wherein R 5 is correspondingly, OH, NH 2 or SH in the presence of a base such as for example an alkali metal hydride at a temperature in the range of 20°C to about reflux, in a solvent such as N,N-dimethylformamide; (v) when Y is sulfonyl, A-B is trαrø-vinylene or ethynylene, and R 2 =R 3 : for a compound of formula (I) which bears a hydroxy substituent on an aryl or heteroaryl group, by cleaving the alkyl ether or acyloxy ester of a corresponding compound of formula (I) which bears a lower alkoxy or lower acyloxy substituent on an aryl or heteroaryl group. Convenient methods include, for example, the cleavage of a methoxy group using boron tribromide and the cleavage of a tert-butoxy group using trifluoroacetic acid; (w) a compound of formula (I), wherein ring C is substituted by ArSO 2 , A-B is ΝHCO and R 1 is ortho-nitro may be made from a compound of formula (XXI): .0 ArSO^ (XXI) wherein ring D 4 has any of the values defined hereinbefore for ring C but in which the place of one of the possible substituents on ring C is taken by ArSO 2 , (1) on treatment with nitric acid, thereafter (2) treating the nitrated compound under mild alkaline conditions (i.e., - 27 - employing a base such as lithium hydroxide) to aid the cleavage of the acetate group to yield the desired amine, which can be converted to a compound of formula (II), wherein A-B is NHCO in a manner analogous to that described in procedure (h) or (i) hereinbefore for making an amide, that is, by coupling the amine formed with a corresponding acid or activated acid derivative of formula (VII). The resulting compound of formula (II) may then be deprotected by a process as described in (a) hereinbefore to give a compound of formula (I); and (x) a compound of formula (I), wherein ring C is substituted by ArC=O and A-B is NHCO, may be made by (1) acylation of a compound of formula (VI) wherein J is NH 2 . Acylating reagents such as benzoic acids, or derivatives thereof, may be employed in the presence of the appropriate activating reagent such as for example polyphosphoric acid. The reaction may conveniently be performed at a temperature in the range of 0 to 200°C employing a solvent such as N,N-dimethylformamide, l,3-dimethyl-3,4,5,6-tetra-hydro-2(lH)-pyrimidinone, DMSO, or ethylene glycol if required, followed by (2) the formation of an amide as described in (i) or (j) hereinbefore (Staskum, B., J. Org. Chem. (1964), 29, 2856-2860; Ohnmacht C, J. Med. Chem. (1996), 39, 4592-4601). The compound of formula (II) so formed may then be deprotected for example as described in (a) hereinbefore. If not commercially available, the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples. In the discussion which follows, "Ar" refers to an unsubstituted or substituted phenyl group or heteroaryl group as previously defined. In general, a compound of formula (II), wherein AB is OCH 2 , SCH 2 or ΝHCH 2 may be made by treating a corresponding compound of formula (VI) (wherein J is, correspondingly, oxygen, sulphur, or NH) with a coπesponding compound of formula (XXII): R 2 X^ R 3 PgO R (XXII) - 28 - wherein Pg is a protective group such as silyl and X is a suitable leaving group such as for example mesylate or triflate, in the presence of a base such as an alkali metal hydride (e.g., sodium hydride), in a solvent such as tetrahydrofuran, N,N-dimethylformamide, DMSO, or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, and at a temperature of about 20°C to about reflux. Compounds of formulae (II), (III), (VIII) and (XI), wherein A-B is ΝHCO, may be made in a manner analogous to that described in (h) or (i) above for making an amide of formula (II); that is, by coupling a corresponding amine with a corresponding acid. Thus, to make a protected amide of formula (II), a corresponding amine of formula (VI) may be coupled with an acid of formula (VII) wherein the group corresponding to G 2 is OPg. The protected acid may be made by a conventional procedure, for example by (1) esterifying an acid of formula (VII) wherein G 2 is hydroxy by means of a conventional esterification procedure such as reaction with a lower alcohol (e.g., methanol) in the presence of an acid catalyst (for example sulfuric acid) if carboxylate protection is required; (2) reaction of the ester thus formed with an agent which provides the protecting group Pg, such as benzyl chloride (to provide a benzyl protecting group) or any of the conventional silylating agents known and used for such purpose (such as 2-trimethylsilylethoxymethyl chloride, SEM, in the presence of a suitable base such as sodium hydroxide or triethylamine optionally in the presence of a catalyst such as 4-dimethylaminopyridine (DMAP)); and (3) cleavage of the ester group under mild alkaline conditions (i.e., employing a base such as potassium carbonate) to yield the desired protected acid. If the resolved acid is required it may be prepared by any of the known methods for preparation of optically-active forms (for example, by recrystallization of the chiral salt, by enzymatic resolution, (for example WO 9738124), by biotransformation, or by chromatographic separation using a chiral stationary phase). For example if an (R)-(+) resolved acid is required it may be prepared by the method of Scheme 2 in World Patent Application Publication No. WO 9738124 for preparation of the (S)-(-) acid, ie. using the classical resolution method described in European Patent Application Publication No. EP 0524781, also for preparation of the (S)-(-) acid, except that (lS,2R)-norephedrine may be used in place of (S)-(-)- 1 -pheny lethy lamine . A compound of formula (II) wherein A-B is OCH 2 , SCH 2 or NHCH 2 may be made by protecting a corresponding alcohol made in essentially any earlier stage of synthesis, for - 29 - example an alcohol of formula (V) or (XVI). The alcohol may be treated with a compound which reacts to form a trialkylsilyl (e.g. trimethylsilyl) group, such as trimethylsilyl chloride or trimethylsilyl triflate, in the presence of a base such as sodium hydride, diisopropylethylamine or triethylamine. A preferred base is diisopropylethylamine. Alternatively, if an ester protecting group is desired the alcohol may be reacted with an acid chloride of formula R 7 COCl or an acid anhydride of foπnula (R 7 CO) 2 O wherein R 7 is a lower alkyl or aryl group. The reaction may be conducted in a solvent such as dichloromethane, in the presence of a base such as TEA and DMAP, and at a temperature of -40 to about 25°C. A compound of formula (IV), wherein A-B is ethynylene, may be made by reacting a corresponding compound of formula (XXIII) : °><o ^ Rl) « ^ D^-A-B-H (XXIII) wherein ring D 5 has any of the values defined hereinbefore for ring C but in which the place of one of the possible substituents on ring C is taken by Ar(-C-O-(CH 2 ) 3 -O-)- with a base such as an alkyllithium (for example, butyllithium) followed by addition of a ketone having the formula R 2 -CO-R 3 . The reaction may be conducted at a temperature of from about -100 to about -40°C and in a solvent such as tetrahydrofuran, dimethyl ether, or 1 ,2-dimethoxyethane. A compound of formula (IV), wherein A-B is trαns-vinylene, may be made by reducing a corresponding compound of formula (IV), wherein A-B is ethynylene, with a suitable reducing agent such as lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminium, in a solvent such as tetrahydrofuran and at room temperature. A compound of formula (II), wherein A-B is tra s-vinylene, may be made by reacting a corresponding compound of formula (XXIV): R 2 M ^ ^ \ pg ° R3 (XXIV) wherein Pg is a protecting group such as for example benzyl or silyl and M is a metal such as - 30 - trialkyltin (for example tributyl or trimethyl tin) or bisalkyloxyborane (for example catecholborane), with a compound of formula (IX), wherein Hal may be for example iodide or bromide, in the presence of a catalyst such as bis(triphenylphosphine)palladium dichloride or tetrakistriphenylphosphinepalladium. The reaction may conveniently be conducted in a suitable inert solvent such as a tetrahydrofuran or dimethylformamide at a temperature of from 0 - 150°C. A compound of formula (XXIV) may be made by reacting a corresponding alcohol of formula (XXV): R 2 H- ^ HO R R J (XXV) with (1) an agent which provides the protecting group Pg, such as benzyl bromide (to provide a benzyl protecting group) or any of the conventional silylating agents known and used for such purpose (such as for example tert-butyl dimethylsilylchloride or triflate, in the presence of a suitable base such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylamine optionally in the presence of a catalyst such as DMAP); (2) reaction of the protected propargylic alcohol thus formed with an agent such as catecholborane, to form the vinylborane, or trialkyltin hydride in the presence of a catalytic amount of a radical chain initiator such as for example azo-bis-isobutyronitrile (AIBN), or a strong base such as alkyllithium and copper cyanide, or a transition metal catalyst such as for example tetrakistriphenylphosphinepalladium. The reaction may conveniently be conducted in a suitable inert solvent such as a tetrahydrofuran, toluene or xylene at a temperature of from 0 - 150°C. A compound of formula (XXIII) may be made by treating the coπesponding ketone with 1,3-propanediol in the presence of an acid catalyst such as p-toluenesulfonic acid (TsOH) and in a refluxing solvent such as toluene. A compound of formula (XV) may be made by (1) treating a corresponding compound of formula (XIII) wherein L is bromo with a protected acetylene such as trimethylsilylacetylene in the presence of a catalyst such as a combination of cuprous iodide and bis(triphenylphosphine)palladium dichloride in a solvent such as diethylamine, thereby making a corresponding compound of formula (XXVI): - 31 - ( CJ-A-B—?s (XXVI) wherein A-B is ethynylene and Ps is a silyl protecting group, followed by (2) removal of the silyl protecting group with a base such as an alkali metal (e.g. sodium hydroxide) in a solvent such as methanol. A compound of formula (V) wherein G 1 is halo, may be made by (1) treating a corresponding compound of formula (V), wherein G 1 is nitro, with a reducing agent such as tin(II)chloride, in the presence of an aqueous acid such as acetic acid to obtain the corresponding amine, followed by (2) treating the amine with a combination of nitric acid and sulfuric acid to effect diazotization, and thereafter (3) treating the diazotized compound with a corresponding copper(I)halide such as for example cuprous bromide. A compound of formula (V), wherein G 1 is SH and A-B is NHCO can be made by (1) coupling of a compound of formula (V) wherein G 1 is a leaving group such as halo or triflate with triisopropylsilanethiolate under palladium catalysis as described by Arnould et.al. in Tet. Let. (1996), 37 (26), p. 4523, followed by deprotection with tetrabutylammonium fluoride in a solvent such as tetrahydrofuran at a temperature of -78 to about 25°C; or (2) by Pummerer rearrangement as described in Tet. Let. (1984), 25 (17), p. 1753 of a compound of formula (V) wherein G 1 is CH 3 SO- and A-B is NHCO, which can be made from a compound of formula (V) wherein G 1 is a leaving group such as halo of triflate and A-B is NHCO, using a palladium catalysed coupling with methanethiol as described for example in Zheng et.al. in J. Org. Chem. (1998), 63, p. 9606 followed by an oxidation of the resulting sulphide to the corresponding sulphoxide using for example tert. -butyl hydroperoxide as oxidant; or (3) reduction of a compound of formula (V), wherein G 1 is SO 2 Cl and A-B is NHCO, by reducing the sulphonyl chloride using a small excess of for example triphenylphosphine in a solvent such as for example dichloromethane in the presence of a catalyst such as for example dimethylforamide, followed by an acidic workup. A compound of formula (V), wherein G 1 is SO 2 Cl and A-B is NHCO can be made by treatment with chlorosulphonic acid of a compound of formula (V), wherein G 1 is H and A-B is NHCO, under standard conditions. A compound of formula (XII), wherein A-B is ethynylene, may be made by treating a - 32 - corresponding compound of formula (XXVI) wherein Ps is trimethylsilyl, with a fluoride b-ase (for example, tetrabutylammonium fluoride (TBAF)) and an acid chloride of formula R 3 -CO-Cl, thereby making the desired compound. A compound of formula (XIII), wherein L is halo, may be made by treating a corresponding compound of formula (XIII), wherein L is nitro, with (1) iron dust and concentrated hydrochloric acid in 95% ethanol to reduce the nitro group and thereby form the coπesponding amine; (2) the amine may then be treated for example with a nitrite (such as tert-butyl nitrite or sodium nitrite in the presence of a mineral acid) to foπn the corresponding diazonium salt which may in turn be treated with a copper(I) salt (such as copper(I)bromide or copper(I)chloride). The diazotization and displacement reactions may be conducted in a solvent such as acetonitrile and at a temperature of from 0 to 25 °C. A compound of formula (XIV) may be made by reacting a corresponding ketone having the formula R 2 -CO-R 3 with an alkali metal acetylide (for example lithium acetylide) or alkaline earth metal acetylide (for example magnesium acetylide). The reaction may be conducted in a solvent such as tetrahydrofuran, diethyl ether, or 1 ,2-dimethoxyethane and at a temperature of about -100 to about 25°C. A compound of formula (XV) may be made by reacting a corresponding compound of formula (XIII), wherein L is halo, with trimethylsilylacetylene in the presence of a catalyst such as a combination of bis(triphenylphosphine)palladium dichloride and copper(I)iodide in diethylamine or triethylamine, followed by treatment with a base (for example, an alkali metal hydroxide such as sodium or lithium hydroxide) in a lower alcohol as solvent to effect removal of the trimethylsilyl group. A compound of formula (XIX) may be made by treating a corresponding ketone having the formula R 2 -CO-R 3 with the ylide derived from the reaction of a trimethylsulfonium salt (such as trimethylsulfonium iodide) with a base (such as an alkali metal hydroxide). The reaction may be conducted in a one-pot process employing a solvent such as dichloromethane. A compound of formula (VI), wherein J is oxy, may be made by diazotizing a corresponding amine of formula (XIII), wherein L is amino, as previously discussed, and heating in dilute sulfuric acid to form the corresponding phenol. The corresponding thiophenol may be formed by reacting an excess of methanethiol in the presence of sodium hydride with a corresponding compound of formula (XIII) wherein L is a leaving group such as for example chloro. - 33 - A compound of formula (XX) wherein R 5 is hydroxy, thiohydroxy or amino may be made by treating a corresponding compound of formula (XIII) wherein L is a halo group with a corresponding compound of formula (XXII), wherein X is hydroxy, thiohydroxy, or amino, and Pg is hydrogen. The reaction may conveniently be carried out in the presence of a catalyst such as copper bronze and a base such as an alkali metal hydride. The reaction may be conducted at reflux in a solvent such as tetrahydrofuran. A compound of formula (XXII), wherein X is for example triflate, may be made by (1) esterifying an acid of formula (VII) wherein G 2 is hydroxy; (2) protecting the alcohol G 2 , by treating with for example trimethylsilyl chloride in a solvent such as dichloromethane and at a temperature of from about -78 to about 25°C; (3) treating the protected compound thus obtained with a suitable reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran and at a temperature of about 0 to about 25°C, thereby reducing the carbonyl group to methylene; followed by (4) treating the reduced product with trifluoromethylsulfonic anhydride in the presence of a base such as triethylamine, in a solvent such as dichloromethane, and at a temperature in the range of about -78 °C to about 25°C. An epoxide of formula (XVIII) may be prepared from a diol of formula (XVII) using a suitable dehydrating agent, for example bis[α, -bis(trifluoromethyl)benzenemethanolato]diphenylsulphur. A diol of formula (XVII) may be prepared from a corresponding compound of formula (I), wherein A-B is CH 2 CO, by reduction. The reduction may be carried out using a suitable reducing agent, for example a hydride, such as sodium borohydride. A corresponding compound of formula (I), wherein A-B is CH 2 CO, may be prepared from a compound of formula (XIII), wherein L is methyl, by deprotonation and treatment with an amide of formula (XXVII): (XXVII) in which R 8 and R 9 are each independently lower alkyl, or in which R 8 and R 9 when taken together with the atoms to which they are attached form a 5-7 membered ring. The deprotonation of the toluene may be carried out with a suitable base, for example lithium - 34 - diisopropyl amide. The reaction may be carried out in a suitable organic solvent, for example, an ether such as tetrahydrofuran. The reaction may be carried out at a suitable temperature, for example a temperature in the range of -78°C to 100°C. An amide of formula (XXVII) may be prepared from an acid of formula (VII), wherein G 2 is hydroxy, or an activated derivative thereof, by reaction with the corresponding amine. A diol of formula (XVII) may be prepared by (1) treating a ketone of formula (XIII), wherein L is acetyl, with a base such as lithium diisopropylamide, lithium hexamethyldisilazide (LHMDS), or tetramethylpiperadide, in a solvent such as tetrahydrofuran, diethyl ether, or 1 ,2-dimethoxyethane, followed by addition of a ketone having the formula R 2 -CO-R 3 (aldol addition), and at a temperature of about -100 to about 25°C, followed by (2) reduction of the carbonyl group to alcohol with a reducing agent such as sodium borohydride or lithium aluminum hydride at a temperature of from about 0 to about 25°C. A corresponding compound of formula (I), wherein ring C is substituted by ArS, A-B is NHCO and R 1 is ortho-halo or ortho-hydroxy, may be made by treatment of a compound of formula (XXVIII): ArS- D -NO 2 (XXVIII) wherein ring D 6 has any of the values defined hereinbefore for ring C but in which the place of one of the possible substituents on ring C is taken by ArS and wherein the amino group is in a position ortho to the nitro group, with (1) a combination of nitric acid and sulphuric acid to effect diazotization, and thereafter (2) treating the diazotized compound with a corresponding copper (I) halide such as for example cuprous bromide or chloride, or heating in dilute sulphuric acid to form the coπesponding phenol, followed by (3) reduction of the nitro group with a reducing agent such as tin(II)chloride or iron dust in conjunction with concentrated acid followed by (4) amide formation as described in (h) or (i) hereinbefore. The diazotization and displacement reactions may be conducted in a solvent such as acetonitrile and at a temperature of from 0 - 25°C. A compound of formula (XXVIII) may be made for example according to procedures similar to those described in J. Med. Chem., 1975, 18, 1164. - 35 - A coπesponding compound of formula (I), wherein ring C is substituted by ArS and A-B is NHCO may be made by treatment of a compound of formula (V), wherein G 1 is a displaceable group such as halo or triflate, with a thiophenol in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium(0) or cuprous chloride. The reaction may conveniently be conducted in a suitable inert solvent such as a lower alcohol or dimethylformamide and in the presence of a base such as for example sodium methoxide if required. A coπesponding compound of formula (I), wherein ring C is substituted by ArS and A-B is NHCO may be made by treating a compound of formula (V), wherein G 1 is SH with an aromatic compound containing a displaceable group such as for example halo or triflate, in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium(0) or cuprous chloride. The reaction may conveniently be conducted in a suitable inert solvent such as a lower alcohol or dimethylformamide and in the presence of a base such as for example sodium methoxide if required at a temperature of 25 - 180°C. A coπesponding compound of formula (I), wherein ring C is substituted by ArS and A-B is not NHCO may be made by treating a compound of formula (V), wherein G 1 is an appropriate leaving group such as for example fluoro, with a compound of formula ArSH in the presence of a suitable base such as for example potassium carbonate. The reaction may conveniently be performed at a temperature in the range of 30 to 200°C and in a solvent such as N,N-dimethylformamide, l,3-dimethyl-3,4,5,6-tetra-hydro-2(lH)-pyrimidinone, DMSO, or ethylene glycol. According to a further feature of the invention, there is provided a process for preparing a compound of formula (le) using any one of processes a), f), g), h), i), j), k) or m); and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; or iii) forming a pharmaceutically acceptable salt or in vivo cleavable ester. It is noted that many of the starting materials for synthetic methods for intermediates as described above are commercially available and or widely reported in the scientific literature. If not commercially available, the necessary starting materials for the procedures such as that described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, - 36 - structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples. In cases where compounds of formula (I) are sufficiently basic or acidic to form stable acid or basic salts, administration of the compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following. Examples of suitable pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed such as sulfate, nitrate, and hydrochloride. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound of formula (I) (or its ester) with a suitable acid affording a physiologically acceptable anion. It is also possible with most compounds of the invention to make a coπesponding alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salt by treating a compound of formula (I) (and in some cases the ester) with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g. the ethoxide or methoxide in aqueous medium followed by conventional purification techniques. In vivo cleavable esters of compounds of the invention may be made by coupling with a pharmaceutically acceptable carboxylic acid or an activated derivative thereof. For example, the coupling may be carried out by treating a compound of formula (I) with an appropriate acid chloride (for example, acetyl chloride, propionyl chloride, or benzoyl chloride) or acid anhydride (for example, acetic anhydride, propionic anhydride, or benzoic anhydride) in the presence of a suitable base such as triethylamine. Those skilled in the art will appreciate that other suitable carboxylic acids (including their activated derivatives) for the formation of in vivo cleavable esters are known to the art and these are also intended to be included within the scope of the invention. Catalysts such as 4-dimethylaminopyridine may also be usefully employed. Many of the intermediates defined herein are novel and these are provided as a further feature of the invention. - 37 - The identification of compounds which elevate PDH activity is the subject of the present invention. These properties may be assessed, for example, using one or more of the procedures set out below: a In vitro elevation of PDH activity This assay determines the ability of a test compound to elevate PDH activity. cDNA encoding PDH kinase may be obtained by Polymerase Chain Reaction (PCR) and subsequent cloning. This may be expressed in a suitable expression system to obtain polypeptide with PDH kinase activity. For example rat PDHkinasell (rPDHKII) obtained by expression of recombinant protein in Escherichia coli (E. Coli), was found to display PDH kinase activity. In the case of the rPDHKII (Genbank accession number U10357) a 1.3kb fragment encoding the protein was isolated by PCR from rat liver cDNA and cloned into a vector (for example pQE32 - Quiagen Ltd.). The recombinant construct was transformed into E. coli (for example M15pRep4 - Quiagen Ltd.). Recombinant clones were identified, plasmid DNA was isolated and subjected to DNA sequence analysis. One clone which had the expected nucleic acid sequence was selected for the expression work. Details of the methods for the assembly of recombinant DNA molecules and the expression of recombinant proteins in bacterial systems can be found in standard texts for example Sambrook et al, 1989, Molecular Cloning - A Laboratory Manual , 2 nd edition, Cold Spring Harbour Laboratory Press. Other known PDH kinases for use in assays, may be cloned and expressed in a similar manner. For expression of rPDHKII activity, E. coli strain M15pRep4 cells were transformed with the pQE32 vector containing rPDHKII cDNA. This vector incorporates a 6-His tag onto the protein at its N-terminus. E. coli were grown to an optical density of 0.6 (600 nM) and protein expression was induced by the addition of 10 μM isopropylthio-β-galactosidase. Cells were grown for 18 hours at 18°C and harvested by centrifugation. The resuspended cell paste was lysed by homogenisation and insoluble material removed by centrifugation at 24000xg for 1 hour. The 6-His tagged protein was removed from the supernatant using a nickel chelating nitrilotriacetic acid resin (Ni-NTA: Quiagen Ltd.) matrix (Quiagen) which was washed with 20 mM tris(hydroxymethyl)aminomethane-hydrogen chloride, 20 mM imidazole, 0.5 M sodium chloride pH 8.0, prior to elution of bound protein using a buffer containing 20 mM tris(hydroxymethyl)aminomethane-hydrogen chloride, 200 mM imidazole, 0J5 M sodium chloride pH 8.0. Eluted fractions containing 6-His protein were pooled and stored in aliquots at -80°C in 10% glycerol. - 38 - Each new batch of stock enzyme was titrated in the assay to determine a concenfration giving approximately 90% inhibition of PDH in the conditions of the assay. For a typical batch, stock enzyme was diluted to 7.5μg/ml. For assay of the activity of novel compounds, compounds were diluted with 10% dimethylsulphoxide (DMSO) and lOμl transfeπed to individual wells of 96-well assay plates. Control wells contained 20μl 10% DMSO instead of compound. 40μl Buffer containing 50mM potassium phosphate buffer pH 7.0, lOmM ethylene glycol-bis(β-aminoethyl ether)- N,N,N,N-tetracetic acid (EGTA), lmM benzamidine, ImM phenylmethylsulphonyl fluoride (PMSF), 0.3mM tosyl-L-lysine chloromethyl ketone (TLCK), 2mM dithiothreitol (DTT), recombinant rPDHKII and compounds were incubated in the presence of PDH kinase at room temperature for 45 minutes. In order to determine the maximum rate of the PDH reaction a second series of control wells were included containing 10%) DMSO instead of compound and omitting rPDHKII. PDH kinase activity was then initiated by the addition of 5 μM ATP, 2 mM magnesium chloride and 0.04 U/ml PDH (porcine heart PDH Sigma P7032) in a total volume of 50 μl and plates incubated at ambient temperanire for a further 45 minutes. The residual activity of the PDH was then determined by the addition of substrates (2.5mM coenzyme A, 2.5mM thiamine pyrophosphate (cocarboxylase), 2.5mM sodium pyruvate, 6mM NAD in a total volume of 80μl and the plates incubated for 90 minutes at ambient temperature. The production of reduced NAD (NADH) was established by measured optical density at 340nm using a plate reading spectrophotometer. The ED 50 for a test compound was determined in the usual way using results from 12 concentrations of the compound. (b) In vitro elevation of PDH activity in isolated primary cells This assay determines the ability of compounds to stimulate pyruvate oxidation in primary rat hepatocytes. Hepatocytes were isolated by the two-step collagenase digestion procedure described by Seglen (Methods Cell Biol. (1976) 13, 29-33) and plated out in 6-well culture plates (Falcon Primaria) at 600000 viable cells per well in Dulbecco's Modified Eagles Medium (DMEM, Gibco BRL) containing 10% foetal calf serum (FCS), 10% penicillin/streptomycin (Gibco BRL) and 10% non-essential amino acids (NEAA, Gibco BRL). After 4 hours incubation at 37°C in 5% CO 2 , the medium was replaced with Minimum Essential Medium (MEM, Gibco BRL) containing NEAA and penicillin/streptomycin as above in addition to - 39 - 10nM dexamethasone and lOnM insulin. The following day cells were washed with phosphate buffered saline (PBS) and medium replaced with 1ml HEPES-buffered Krebs solution (25mM HEPES, 0J5M sodium chloride, 25 mM sodium hydrogen carbonate, 5mM potassium chloride, 2mM calcium chloride, ImM magnesium sulphate, 1 mM potassium dihydrogen phosphate) containing the compound to be tested at the required concentration in 0.1% DMSO. Control wells contained 0J%> DMSO only and a maximum response was determined using a 10 μM treatment of a known active compound. After a preincubation period of 40 minutes at 37°C in 5% CO 2 , cells were pulsed with sodium pyruvate to a final concentration of 0.5mM (containing 1- 1 C sodium pyruvate (Amersham product CFA85) 0J8Ci/mmole) for 12 minutes. The medium was then removed and transfeπed to a tube which was immediately sealed with a bung containing a suspended centre well. Absorbent within the centre well was saturated with 50% phenylethylamine, and CO 2 in the medium released by the addition of 0.2μl 60% (w/v) perchloric acid (PCA). Released 14 CO 2 trapped in the absorbent was determined by liquid scintillation counting. The ED 50 for a test compound was determined in the usual way using results from 7 concentrations of the compound. (c) In vivo elevation of PDH activity The capacity of compounds to increase the activity of PDH in relevant tissues of rats may be measured using the test described hereinafter. Typically an increase in the proportion of PDH in its active, nonphosphorylated form may be detected in muscle, heart, liver and adipose tissue after a single administration of an active compound. This may be expected to lead to a decrease in blood glucose after repeated administration of the compound. For example a single administration of DCA, a compound known to activate PDH by inhibition of PDH kinase (Whitehouse, Cooper and Randle (1974) Biochem. J. 141, 761-774) 150 mg/kg, intraperitoneally, increased the proportion of PDH in its active form (Nary et al. (1988) Circ. Shock 24, 3-18) and after repeated administration resulted in a significant decrease in plasma glucose (Evans and Stacpoole (1982) Biochem. Pharmacol.31, 1295-1300). Groups of rats (weight range 140-180g) are treated with a single dose or multiple doses of the compound of interest by oral gavage in an appropriate vehicle. A control group of rats is treated with vehicle only. At a fixed time after the final administration of compound, animals are terminally anaesthetised, tissues are removed and frozen in liquid nitrogen. For - 40 - determination of PDH activity, muscle samples are disrupted under liquid nitrogen prior to homogenisation by one thirty-second burst in a Polytron homogenizer in 4 volumes of a buffer containing 40 mM potassium phosphate pH 7.0, 5 mM EDTA, 2mM DTT, 1% Triton X-100, lOmM sodium pyruvate, lOμM phenylmethylsulphonyl chloride (PMSF) and2μg/ml each of leupeptin, pepstain A and aprotinin. Extracts are centrifuged before assay. A portion of the extract is treated with PDH phosphatase prepared from pig hearts by the method of Siess and Wieland (Eur. J. Biochem (1972) 26, 96): 20 μl extract, 40 μl phosphatase (1:20 dilution), in a final volume of 125 μl containing 25 mM magnesium chloride, 1 mM calcium chloride. The activity of the untreated sample is compared with the activity of the dephosphorylated extract thus prepared. PDH activity is assayed by the method of Stansbie et al., (Biochem. J. (1976) 154, 225). 50 μl Extract is incubated with 0.75 mM NAD, 0.2 mM CoA, 1.5 mM thiamine pyrophosphate (TPP) and 1.5mM sodium pyruvate in the presence of 20 μg/ml p-(p-amino-phenylazo) benzene sulphonic acid (AABS) and 50 mU/ml arylamine transferase (AAT) in a buffer containing 100 mM tris(hydroxymethyl)aminomethane, 0.5 mM EDTA, 50mM sodium fluoride, 5mM 2-mercaptoethanol and ImM magnesium chloride pH 7.8. AAT is prepared from pigeon livers by the method of Tabor et al. (J. Biol. Chem. (1953) 204, 127). The rate of acetyl CoA formation is determined by the rate of reduction of AABS which is indicated by a decrease in optical density at 460 nm. Liver samples are prepared by an essentially similar method, except that sodium pyruvate is excluded from the extraction buffer and added to the phosphatase incubation to a final concentration of 5mM. Treatment of an animal with an active compound results in an increase in the activity of PDH complex in tissues. This is indicated by an increase in the amount of active PDH (determined by the activity of untreated extract as a percentage of the total PDH activity in the same extract after treatment with phosphatase). According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) as defined hereinbefore or a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I) or a pharmaceutically acceptable salt of said compound or said ester, in association with a pharmaceutically acceptable excipient or carrier. According to an additional aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (le) as defined hereinbefore or a - 41 - pharmaceutically acceptable in vivo cleavable ester of said compound of formula (le) or a pharmaceutically acceptable salt of said compound or said ester, in association with a pharmaceutically acceptable excipient or carrier. According to an additional further aspect of the invention there is provided a pharmaceutical composition which comprises a compound selected from N-(4-benzoyl-2,6- dimethylphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide or 3 -hydroxy-3- trifluoromethyl- 1 -(2-chloro-5-trifluoromethylphenyl)-4,4,4-trifluorobut- 1 -yne or a pharmaceutically acceptable in vivo cleavable ester of said compound or a pharmaceutically acceptable salt of said compound or said ester, in association with a pharmaceutically acceptable excipient or carrier. The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream or for rectal administration for example as a suppository. In general the above compositions may be prepared in a conventional manner using conventional excipients. The compositions of the present invention are advantageously presented in unit dosage form. The compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000mg per square metre body area of the animal, i.e. approximately OJ-lOOmg/kg. A unit dose in the range, for example, l-lOOmg/kg, preferably l-50mg/kg is envisaged and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example l-250mg of active ingredient. According to a further aspect of the present invention there is provided a compound of the formula (I) or a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I) or a pharmaceutically acceptable salt of said compound or said ester as defined hereinbefore for use in a method of treatment of the human or animal body by therapy. We have found that compounds of the present invention elevate PDH activity and are therefore of interest for their blood glucose-lowering effects. A further feature of the present invention is a compound of formula (I) or a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I) or a pharmaceutically acceptable salt of said compound or said ester for use as a medicament, conveniently a compound of formula (I) or a pharmaceutically acceptable in vivo cleavable - 42 - ester of said compound of formula (I); or a pharmaceutically acceptable salt of said compound or said ester for use as a medicament for producing an elevation of PDH activity in a warm-blooded animal such as a human being. Thus according to a further aspect of the invention there is provided the use of a compound of the formula (I) or a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I) or a pharmaceutically acceptable salt of said compound or said ester in the manufacture of a medicament for use in the production of an elevation of PDH activity in a warm-blooded animal such as a human being. According to a further feature of the invention there is provided a method for producing an elevation of PDH activity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I) or a pharmaceutically acceptable salt of said compound or said ester as defined hereinbefore. As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of l-50mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient. The elevation of PDH activity described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. For example in the treatment of diabetes mellitus chemotherapy may include the following main categories of treatment: i) insulin; ii) insulin secretagogue agents designed to stimulate insulin secretion (for example glibenclamide, tolbutamide, other sulphonylureas); iii) oral hypoglycaemic agents such as metformin, thiazolidinediones; - 43 - iv) agents designed to reduce the absorption of glucose from the intestine (for example acarbose); v) agents designed to treat complications of prolonged hyperglycaemia; vi) other agents used to treat lactic acidaemia; vii) inhibitors of fatty acid oxidation; viii) lipid lowering agents; ix) agents used to treat coronary heart disease and peripheral vascular disease such as aspirin, pentoxifylline, cilostazol; and/or x) thiamine. As stated above the compounds defined in the present invention are of interest for their ability to elevate the activity of PDH. Such compounds of the invention may therefore be useful in a range of disease states including diabetes mellitus, peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, myocardial ischaemia, cerebral ischaemia and reperftision, muscle weakness, hyperlipidaemias, Alzheimers Disease and/or atherosclerosis. In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of elevators of PDH activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. It is to be understood that where the term "ether" is used anywhere in this specification it refers to diethyl ether. - 44 - Examples The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C and under an atmosphere of an inert gas such as argon; (ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was caπied out using a rotary evaporator under reduced pressure (600-4000 pascals; 4.5-30mmHg) with a bath temperature of up to 60°C; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a silica Mega Bond Elut column is refeπed to, this means a column containing lOg or 20g of silica of 40 micron particle size, the silica being contained in a 60ml disposable syringe and supported by a porous disc, obtained from Narian, Harbor City, California, USA under the name "Mega Bond Elut SI", "Mega Bond Elut" is a trademark;; (iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only; (v) melting points are uncoπected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations; (vi) final products had satisfactory proton nuclear magnetic resonance (ΝMR) spectra and/or mass spectral data; (vii) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (viii) when given, ΝMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO-d 6 ) as solvent unless otherwise indicated; coupling constants (J) are given in Hz; Ar designates an aromatic proton when such an assignment is made; (ix) chemical symbols have their usual meanings; SI units and symbols are used; (x) reduced pressures are given as absolute pressures in pascals (Pa); elevated - 45 - pressures are given as gauge pressures in bars; (xi) solvent ratios are given in volume:volume (v/v) terms; and (xii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (El), fast atom bombardment (F.AB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; (xiii) unless stated otherwise compounds containing an asymmetrically substituted carbon and/or sulphur atom have not been resolved; (xiv) where a synthesis is described as being analogous to that described in a previous example the amounts to be used are the millimolar equivalents to those used in the previous example; (xv) where a Chem Elut column is refeπed to, this means a "Hydromatrix" extraction cartridge for adsorption of aqueous material, i.e. a polypropylene tube containing a special grade of flux-calcined, high purity, inert diatomaceous earth, pre-buffered to pH 4.5 or 9.0, incorporating a phase-separation filtering material, used according to the manufacturers instructions, obtained from Narian, Harbor City, California, USA under the name of "Extube, Chem Elut", "Extube" is a trademark; (xvi) the following abbreviations have been used: DMF N,N-dimethylformamide; DMSO dimethylsulphoxide; DMA N,N-dimethylacetamide; THF tetrahydrofuran; and EA elemental analysis. Example 1 N-(4-Benzoyl-2-methylphenyl)-2-hvdroxy-2-methyl-3 ,3.3 -trifluoropropanamide (Example 1 of EP 0617010) To a solution of 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (l.Hg) in DMA (15ml) at -20°C was added thionyl chloride (0.84g) and the mixture was allowed to stir at -10 to -15°C for 1 hour. 4-Amino-3-methylbenzophenone (l.OOg), (J. Chem. Soc, 1952, 2205-2210), was added in one portion and the reaction mixture was stiπed at ambient temperature overnight. The mixture was poured into water and the resultant gummy solid was 46 collected by filtration. The solid was dissolved in dichloromethane, dried and evaporated to give a brown oil. Chromatography, with ether/dichloromethane (2/98) as the eluent, gave a white foam which was stiπed with hexane for 2 hours. The title compound was collected by filtration as a white solid (1.04g). M.p. 123-124°C; MS: 352 (M+H); NMR: 1.61 (s, 3H), 2.28 (s, 3H), 7.54-7.61 (m, 3H) 7.66-7.74 (m, 6H) 9.73 (s, 1H); EA: C 18 H 16 F 3 NO 3 requires: C, 61.54; H, 4.59; N, 3.99%; found: C, 61.53; H, 4.73; N, 4.01%. Example 2 N-(4-Benzoyl-2-fluorophenylV2-hvdroxy-2-methyl-3J.3-trifluoropropanamide (Example 2 of EP 0617010) To a solution of 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (4.5 lg) in DMA (60ml) at -20°C was added thionyl chloride (3.39g) and the mixture was allowed to stir at -10 to -15°C for 1 hour. 4-Amino-3-fluorobenzophenone (Method 1) (4.00g) was added in one portion and the reaction mixture was stiπed at ambient temperature overnight. The mixture was poured into water and the aqueous solution was decanted. The remaining oily precipitate was dissolved in dichloromethane, dried, and evaporated to yield a tan solid. Recrystallization from dichloromethane and hexanes yielded the title compound as a white solid (5.43g). M.p. 138-139°C; MS: 356(M+H); ΝMR: 1.62 (s, 3H), 7.56-7.64 (m, 4H), 7.70 (d, 1H, J=6.5), 7.75 (d, 2H, J=8.0), 7.82 (s, 1H), 8.01 (t, 1H, J=7.9), 9.39 (s, 1H); EA: C 17 H 13 F 4 ΝO 3 requires C, 57.47; H, 3.69; N, 3.94%; found: C, 57.51; H, 3.60; N, 3.93%. Examples 3-6 Following the procedure of Example 2 and using the appropriate starting material the following compound was prepared. EX COMPOUND EA M.p. 3 ' N-(2-Chloro-4-nitrophenyl)-2- C 10 H 8 C1F 3 Ν 2 O 4 requires C, 38.4; H, 124-12 hydroxy-2-methyl-3 ,3 ,3- 2.5; N, 9.0%; found: C, 38.9; H, 2.9; 5°C trifluoropropanamide N, 8.6%. 4 2 2-Hydroxy-2-methyl-N-(2- C π H π F 3 N 2 O 4 requires C, 45.2; H, 3.8; 123-12 methyl-4-nitrophenyl)-3 ,3 ,3- N, 9.6%; found: C, 45.0; H, 4.2; N, 5°C trifluoropropanamide 9.2% 47 - 5 3 N-(4-Cyano-2-methylphenyl)-2- C 12 H π F 3 Ν 2 O 2 requires C, 52.9; H, 4.0; 164-16 hydroxy-2-methy 1-3 ,3,3- N, 10.3%; found: C, 52.9; H, 4.1; N, 5°C trifluoropropanamide 10.4% N-(4-Cyano-2-trifluoromethyl- C 12 H 8 F 6 Ν 2 O 2 requires C, 44.2; H, 2.45; 121-12 phenyl)-2-hydroxy-2-methyl- N, 8.6%; found: C, 43.8; H, 2.4; N, 3°C 3,3,3 -trifluoropropanamide 8.7%. 1 Purification was by chromatography on Florisil, (Trade Mark of U.S. Silica Co.), eluting with 0-20% ethyl acetate/toluene then recrystallisation from toluene-hexanes 2 Purification was by recrystallisation from toluene-hexanes 3 Aniline ref: J. Med. Chem., 1991, 34, 3295-3301 and the reaction mixture was poured into ice-water and the resultant solid recrystallized from toluene. Example 7 2-Hvdroxy-N-[2-methoxy-4-(pyrid-4-ylsulphonyl phenyll-2-methyl-3.3.3- trifluoropropanamide (Example 4 of EP 0617010) To a stiπed, cooled (-20°C) solution of 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (1.35g) in DMA (20ml) was rapidly added thionyl chloride (l.Olg) and the mixture (a precipitate formed after a few minutes) was stiπed at -15 to -5°C for 1 hour. 2-Methoxy-4-(pyrid-4-ylsulphonyl)aniline (Method 2) (1.50g) was then added in one portion and the mixture allowed to stir at ambient temperature overnight. The solution was poured into ice water (200ml) and the resulting tan solid was collected and recrystallized from absolute ethanol to yield the title compound as a white solid (1.58g). M.p. 220-222°C; MS: 405 (M+H); ΝMR (250 MHz): 1.53 (s, 3H), 4.02 (s, 3H), 7.62 (d, IH, J=1.9), 7.68 (dd, IH, J=1.9, J=8.5), 7.92-7.95 (m, 2H), 8.02 (s, IH), 8.46 (d, IH, J=10) 8.80-8.89 (m, 2H), 9.90 (s, IH); EA: C 16 H 15 F 3 Ν 2 O 5 S requires C, 47.53; H, 3.74; N, 6.93%; found: C, 47.56; H, 3.77; N, 6.76%. 48 Example 8 2-Hvdroxy-2-methyl-N- 2-nitro-4-(phenylsulphonyl phenyl]-3J.3-trifluoropropanamide (Example 5 of EP 0617010) A mixture of 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (l.OOg), lJ'-carbonyldiimidazole (1.03g) and dry THF (25ml) was heated, under nitrogen, at 45°C in an ultrasound bath for 0.5 hour. 2-Νitro-4-(phenylsulphonyl)aniline (1.75g), (DE 2215733), was added, the mixture was heated at 45°C for 18 hours, poured onto water (350ml) and extracted with ether. The combined extracts were washed (brine), dried and evaporated to give an orange solid (3.01 g) that was purified by chromatography, with trichloromethane as the eluent, to yield the title compound as a pale yellow solid (0.46g). M.p. 191-192.5°C; MS: 419 (M+H); NMR: 1.58 (s, 3H), 7.63-7.76 (m, 3H), 8.02-8.07 (d, 3H), 8.34 (dd, IH, J=2.2, 8.6), 8.59 (s, IH), 8.61 (d, IH, j=2.3); EA: C 16 H 13 F 3 N 2 O 6 S requires C, 45.94; H, 3J3; N, 6.70%; Found: C, 45.95; H, 3J9; N, 6.53%. Example 9 Following the procedure of Example 8 and using (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid the following compound was prepared. EX COMPOUND ΝMR MS 9 l (R)-2-Hydroxy-2-methyl-N-[2- 1.55 (s, 3H), 7.63 (t, 2H), 7.72 (t, IH), 262 nitro-4-(phenylsulphonyl)-phenyl]- 8.0 (d, 3H), 8.3 (dd, IH), 8.58 (m, (M-H) " 3,3,3-trifluoropropanamide 2H), 11.53 (br s, IH) 1 The reaction was caπied out for 36 hours at 55°C and the product was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-40% ethyl acetate/hexane Example 10 N-(4-Benzoyl-2-chlorophenyl -2-hvdroxy-2-methyl-3JJ-trifluoropropanamide (Example 7 of EP 0617010) To a stiπed, cooled (-20°C) solution of 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (0.46g) in DMA (6ml) was rapidly added thionyl chloride (0.35g) and the mixture stiπed at -15 to -20°C for 1 hour. 4-Amino-3-chlorobenzophenone (0.45g), (J. Org. Chem., 1962, 27, - 49 - 1605-1608), was then added in one portion and the mixture allowed to stir at ambient temperature overnight. The solution was poured into ice water and filtered through diatomaceous earth. The diatomaceous earth was washed with dichloromethane, the organic solution dried and the solvent removed. Chromatography (eluent dichloromethane, then 5% 5 ethyl acetate in dichloromethane) gave the title compound (0.3 lg) as a white solid. M.p. 142-144°C; EA C 17 H 13 ClF 3 NO 3 requires C, 54.92; H, 3.53; N, 3.77%; Found: C, 54.89; H, 3.63; N, 3.68%. Example 11 10 N-(4-Benzoyl-2-bromophenyl)-2-hvdroxy-2-methyl-3.3 J -trifluoropropanamide (Example 9 of EP 0617010) To a stiπed, cooled (-20°C) solution of 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (0.75g) in DMA (10ml) was rapidly added thionyl chloride (0.56g) and the mixture stiπed at -15 to -20°C for 1 hour. 4-Amino-3-bromobenzophenone (0.75g), (j. Med. Chem., 15 1996, 39, 4592-4601 ), was then added in one portion and the mixture was allowed to stir at ambient temperature overnight. The solution was poured into ice water and the aqueous phase decanted from the resulting oily solid. Chromatography (eluent dichloromethane) gave the title compound (0.43g) as a white solid. M.p. 138-40°C; EA: C 17 H 13 BrF 3 ΝO 3 requires C, 49.06; H, 3.15; N, 3.37%; Found: C, 49.06; H, 3.10; N, 3.35%. 0 Example 12 N-(4-Benzoyl-2-cvanophenylV2-hvdroxy-2-methyl-3JJ-trifluoropropanamide (Example 10 of EP 0617010) To a stiπed, cooled solution of 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid 5 (0J 5g) in dichloromethane ( 10ml) was added thionyl chloride (0.12g) and the mixture was stiπed at reflux for 3 hours. The mixture was cooled to ambient temperature, triethylamine (0J lg) added and the mixture stiπed at reflux for 0.5 hour. The mixture was again cooled to ambient temperature, 4-amino-3-cyanobenzophenone (Method 5) (0J9g) in THF (2.5ml) was added and the mixture stiπed at reflux overnight. The solvent was evaporated and the residue 30 partitioned between ethyl acetate and 3M hydrochloric acid. The organic layer was washed with water, dried and evaporated to yield a pale yellow oil. Chromatography (eluent dichloromethane then 2% ether in dichloromethane) gave the title compound (0J lg) as a - 50 - white solid. M.p. 202-204°C; EA: C lg H 13 F 3 N 2 O 3 0.5H 2 O requires C, 58.22; H, 3.80; N, 7.54%; found: C, 58.03; H, 3.57; N, 7.26%. Example 13 5 N-(4-Benzoyl-2-methoxyphenyl)-2-hvdroxy-2-methyl-3JJ-trifluoropropanamide (Example 11 of EP 0617010) To a stiπed, cooled (-20°C) solution of 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (0.52g) in DMA (5ml) was rapidly added thionyl chloride (0.39g) and the mixture stiπed at -10 to -20°C for 1 hour. 4-Amino-3-methoxybenzophenone (0.50g), (J. Org. Chem., 1962, 10 27, 1605-1608) was then added in one portion and the mixture allowed to stir at ambient temperature overnight. The solution was poured into water and the aqueous phase decanted from the resulting oily solid. Chromatography (eluent dichloromethane then 2% ether in dichloromethane) gave the title compound (0.37g) as an off-white solid. M.p. 126-128°C; EA: C 18 H 16 F 3 ΝO 4 0.25H 2 O requires C, 58.14; H, 4.47; N, 3.77%; Found: C, 58.29; H, 4.48; N, 15 3.78%. Example 14 N-(4-Benzoyl-2-hvdroxyphenyl)-2-hvdroxy-2-methyl-3J.3 -trifluoropropanamide (Example 12 of EP 0617010) 20 To a stiπed, cooled (-20°C) solution of 2-hydroxy-2-methyl-3,3J-trifluoropropanoic acid (1.1 lg) in DMA (15ml) was rapidly added thionyl chloride (0.84g) and the mixture stiπed at -10 to -20°C for 1 hour. 4-Amino-3-hydroxybenzophenone (l.OOg), (Synthesis, 1990, 679-680), was then added in one portion and the mixture allowed to stir at ambient temperature overnight. The solution was poured into ice water and the aqueous phase 25 decanted from the resulting oily precipitate. Chromatography (eluent 2% to 5% methanol gradient in dichloromethane) yielded a white foam which was dissolved in a small amount of dichloromethane and added dropwise to stiπed hexane (100ml) to yield the title compound (0.86g) as a white solid. M.p. 119-121°C; EA: C 17 H 14 F 3 ΝO 4 requires C, 57.79; H, 3.99; N, 3.96%: Found: C, 57.85; H, 4.39; N, 3.72%. 30 - 51 - Example 15 2-Hydroxy-N-r2-hvdroxy-4-(pyrid-4-ylsulphonyl)phenyl]-2-methyl-3.3.3- trifluoropropanamide (Example 13 of EP 0617010) 5 To a stiπed suspension of 2-hydroxy-N-[2-methoxy-4-(pyrid-4-ylsulphonyl)phenyl]-2-methyl-3,3,3- trifluoropropanamide (Example 7) (1.30g) and molecular sieve dried dichloromethane (50ml) was added boron tribromide (1.6ml of a 1.0M solution in dichloromethane), and the mixture (a gummy ball of material and solvent) was stiπed at reflux for 2 hours and then stiπed 10 overnight at ambient temperature. The reaction mixture was poured into water, made basic with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (2x250ml; discarded) followed by ethyl acetate (100ml). The ethyl acetate solution was dried, filtered, evaporated to a brown oil and purified by chromatography twice (eluent ethyl acetate and eluent dichloromethane/ethyl acetate (1/4)) to yield the title compound (0J5g). M.p. 15 218-220°C; EA: C 15 H 13 F 3 Ν 2 O 5 S requires C, 46.16; H, 3.36; N, 7.18%: Found: C, 45.87; H, 3.47; N, 6.91%. Example 16 (R)-N-r2-Fluoro-4-(phenylsulphonyl)phenyl1-2-hvdroxy-2-methyl-3JJ-trifluoropropanamide 20 Hydrogen peroxide (0.2ml of a 30 wt. % solution in water) was added to a solution of (R)-N-[2-fluoro-4-(phenylthio)phenyl]-2-hydroxy-2-methyl-3JJ-trifluoropropanamide (Method 7) (0.212g) in glacial acetic acid (0.5ml) and the mixture was stiπed and heated at 100°C for 75 minutes then allowed to cool. Ethyl acetate (20ml) was added and the solution was washed with water (20ml), saturated sodium hydrogen carbonate solution (10ml) and 25 brine and then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 20-30% ethyl acetate/hexane to give the title compound (0J55g) as a solid. M.p. 121-122°C; ΝMR: 1.58 (s, 3H), 7.58-7.7 (m, 4H), 7.8 (d, IH), 7.9-8.05 (m, 4H), 9.8 (brs, IH); MS: 390 (M-H) " ; EA: C 16 H 13 F 4 ΝO 4 S 0.5H 2 0 requires C, 48.0; H, 3.5; N, 3.5%; found: C, 47.8; H, 3.5; N, 3.4%. 30 52 Examples 17 - 33 Following the procedure of Example 16 and using the appropriate starting materials the following compounds were prepared. "Meth" relates to the method used to make the starting materials (see below). EX COMPOUND ΝMR MS Meth 17 (R)-N-[2-Chloro-4-(2-methyl- 1.6 (s, 3H), 2.4 (s, 3H), 7.4 (d, 420 8a phenylsulphonyl)phenyl]-2- IH), 7.5 (t, IH), 7.62 (t, IH), (M-H) " hydroxy-2-methyl-3 ,3,3- 7.88 (dd, IH), 7.98 (d, IH), 8.1 trifluoropropanamide (d, IH), 8.3 (d, IH) 18 (R)-2-Hydroxy-2-methyl-N- 1.55 (s, 3H), 2.25 (s, 3H), 386 8b [2-methyl-4-(phenylsulphonyl) 7.55-7.67 (m, 4H), 7.72 (d, (M-H) " phenyl] -3 ,3 ,3 -trifluoroIH), 7.8 (dd, IH), 7.85 (brs, propanamide IH), 7.92 (m, 2H), 9.7 (brs, IH) 19 ' (R)-N-[2-Chloro-4-(phenyl- 1.6 (s, 3H), 7.6 (t, 2H), 7.68 406 10 sulphony l)phenyl] -2-hydroxy- (m, IH), 7.9-8.05 (m, 4H), 8J3 (M-H) " 2-methy 1-3 ,3,3 -trifluoro(d, IH), 8.27 (d, IH), 9.9 (br s, propanamide IH) 20 (R)-N-[2-Bromo-4-(phenyl- 1.6 (s, 3H), 7.58-7.78 (m, 3H), 452 16 sulphonyl)phenyl]-2-hydroxy- 8.0 (m, 4H), 8.2 (d, IH), 8.3 (d, (M-H)- 2-methyl-3,3,3-trifluoro- IH), 9.85 (s, IH) propanamide 21 (R)-N-[2-Chloro-4-(4-fluoro- 1.6 (s, 3H), 7.46 (t; 2H), 8.0 426 l ie phenylsulphonyl)phenyl]-2- (dd, IH), 8.08 (m, 2H), 8J5 (d, (M+H) hydroxy-2-methyl-3 ,3 ,3- IH), 8.3 (d, IH), 9.85 (br s, + trifluoropropanamide IH) 22 N-[2-Chloro-4-(phenyl- 0.87 (t, 3H), 1.8 (m, lH), 2J 420 10a sulphonyl)phenyl]-2-hydroxy- (m, IH), 7.62 (m, 3H), 7.9 (br (M-H)- 2-trifluoromethylbutanamide s, IH), 7.98 (m, 3H), 8.1 (s, IH), 8.25 (d, IH), 9.8 (br s, IH) 53 ' N-[2-Chloro-4-(phenyl- 1.4 (s, 3H), 6J (t, lH), 7.2 (s, 388 23 sulphonyl)phenyl]-3,3-difluoro IH), 7.62 (m, 3H), 7.98 (m, (M-H)- -2-hydroxy-2-methyl- 3H), 8.1 (d, IH), 8.4 (d, IH), propanamide 9.79 (s, IH) N-[2-Chloro-4-(phenyl- 1.02 (m, 2H), 1.2 (m, 2H), 7.02 350 24 sulphonyl)phenyl]-( 1 -hydroxy- (s, IH), 7.6,(m, 3H), 8.0 (m, (M-H)- 1 -cyclopropyl)carboxamide 3H), 8J2 (s, IH), 8.3 (dJH), 9.75 (s, IH) N-[2-Chloro-4-(phenyl- 0.8 (t, 3H), 1.3 (s, 3H), 1.57 366 25 sulphonyl)phenyl]-2-hydroxy- (m, IH), 1.72 (m, IH), 6.06 (s, (M-H)- 2-methylbutanamide IH), 7.6 (m, 3H), 7.95 (m, 3H), 8.08 (s, IH), 8.55 (d, IH), 9.8 (s, IH) N-[2-Chloro-4-(phenyl- 0.8 (t, 6H), 1.55 (m, 2H), 1.75 380 26 sulphonyl)phenyl]-2-ethyl- (m, 2H), 5.81 (s, lH), 7.62 (m, (M-H)- 2-hydroxybutanamide 3H), 7.95 (m, 3H), 8.08 (d, IH), 8.53 (d, IH), 9.75 (s, IH) (R)-N-[2-Fluoro-4-(2-fluoro- (CDC1 3 ): 1.75 (s, 3H), 4.27 (br 408 20e phenylsulphinyl)phenyl]-2- d, IH), 7.08 (t, IH), 7.35 (t, (M-H)- hydroxy-2-methyl-3,3,3- IH), 7.45 (m, IH), 7.6 (m, IH), trifluoropropanamide 7.75 (s, IH), 7.88 (t, IH), 8.54 (m, IH), 9.2 (s, IH) (R)-N-[2-Chloro-4-(thien-2-yl- (CDC1 3 ): 1.75 (s, 3H), 3.50 (s, 414 11a sulphonyl)phenyl] -2-hydroxy- IH), 7J0 (t, IH), 7.70 (m, 2H), (M+H) 2-methyl-3 ,3 ,3 -trifluoro7.90 (m, IH), 8.05 (s, IH), 8.60 propanamide (d, IH), 9.25 (br s, IH) (R)-N-[2-Chloro-4-(3 -methoxy (CDC1 3 ): 1.7 (s, 3H), 3.56 (s, 436 l ib phenylsulphonyl)phenyl]-2- IH), 3.82 (s, 3H), 7.07 (m, (M-H)- hydroxy 2-methyl-3,3,3- IH), 7.36-7.49 (m, 3H), 7.83 trifluoropropanamide (dd, IH), 7.79 (d, IH), 8.58 (d, IH), 9.23 (br s, IH) 54 30 (R)-N-[2-Chloro-4-(4-bromo- (CDClj): 1.68 (s, 3H), 3.9 and 468 l ld phenylsulphinyl)phenyl]-2- 3.98 (2 x s, IH), 7.4 (d, 3H), (M-H)- hy droxy-2-methyl-3 ,3,3- 7.57 (d, 2H), 7.63 (d, IH), 8.48 trifluoropropanamide (m, IH), 9.09 and 9.1 (2 x br s, IH) 31 3 (R)-N-[2-Chloro-4-(2-trifluoro- (CDC1 3 ): 1.75 (s, 3H), 3.95 (br 474 27e methylphenylsulphonyl) s, IH), 7.70 - 7.95 (m, 5H), (M-H)- phenyl]-2-hydroxy-2-methyl- 8.40 (d, IH), 8.60 (d, IH), 9.35 3,3,3 -trifluoropropanamide (br s, IH) 32 (R)-N- [2-Chloro-4-(4-trifluoro- (CDCI 3 ): 1.75 (s, 3H), 3.60 (br 474 27f methylphenylsulphonyl) s, IH), 7.75 (d, 2H), 7.85 (dd, (M-H)- phenyl]-2-hydroxy-2-methyl- IH), 8.00 (d, lH), 8.05 (d, 2H), 3 ,3 ,3-trifluoropropanamide 8.75 (d, IH), 9.35 (br s, IH) 33 (R)-N-[2-Chloro-4-(3-trifluoro- (CDClj): 1.75 (s, 3H), 3.55 (br 474 27g methylphenylsulphonyl) s, IH), 7.75 (t, IH), 7.85 (td, (M-H)- phenyl]-2-hydroxy-2-methyl- 2H), 8.05 (dd, IH), 8.15 (d, 3 ,3 ,3 -trifluoropropanamide IH), 8.20 (s, IH), 8.85 (d, IH), 9.30 (bs, IH) 1 Optical purity: 97.8%) ee by chiral HPLC (Chiralcel OJ column, 10% ethanol/hexane, flow rate: 1 ml/minute). 2 Product was purified by chromatography eluting with 10-20% ethyl acetate/Tiexane. 3 Product was purified by chromatography eluting with 20-66% ether/hexane. Example 34 (RVN-r2-Fluoro-4-(phenylsulphinvDphenyll-2-hvdroxy-2-methyl-3JJ-trifluoropropanamide m-Chloroperbenzoic acid (55%, 0J57g) was added to a solution of (R)-N-[2-fluoro-4-(phenylthio)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 7) (0.212g) in dichloromethane (5ml) and the mixture was stiπed at ambient temperature for 90 minutes. Ether (20ml) was added and the solution was washed with saturated aqueous sodium carbonate solution (2x10ml) and brine then dried. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 20-30% ethyl acetate/Tiexane to give the title compoimd 55 ' (0J38g) as a gum. NMR: 1.55 (s, 3H), 7.5-7.6 (m, 4H), 7.66 (d, IH), 7.74 (m, 2H), 7.87 (t, IH), 9.8 (br s, IH); MS: 374 (M-H) " . Examples 35 - 39 Following the procedure of Example 34 and using the appropriate starting material the following compound was prepared. "Meth" relates to the method used to make the starting materials (see below). EX COMPOUND ΝMR MS Meth 35 (R)-N-[2-Chloro-4-(phenyl- 1.6 (s, 3H), 7.5 (m, 3H), 7.7 (m, 390 10 sulphinyl)phenyl]-2-hydroxy- 3H), 7.8 (s, 2H), 8.1 (d, IH), 9.8 (M-H) 2-methyl-3 ,3 ,3 -trifluoro(s, IH) - propanamide 36 13 (R)-N-[2-Chloro-4-(2-nitro- 1.6 (s, 3H), 8.0 (m, 5H), 8.05 (s, 451 27 phenylsulphonyl)phenyl]-2- IH), 8.4 (m, 2H), 9.9 (s, IH) (M-H) hydroxy-2-methyl-3 ,3 ,3 - - trifluoropropanamide 37 (R)-N-[2-Chloro-4-(4-nitro- (CDC1 3 ): 1.65 (s, 3H), 7.8 (d, IH), 451 27a phenylsulphonyl)phenyl]-2- 7.9 (sJH), 8.0 (d, 2H), 8.3(d, (M-H) hydroxy-2-methyl-3 ,3 ,3 - 2H), 8.6 (d, 2H), 9.3 (s, IH) - trifluoropropanamide 38 w (R)-N-[2-Chloro-4-(3-nitro- (CDC1 3 ): 2.75 (s, 3H), 3.55 (s, 451 30 pheny lsulphony l)phenyl] -2- IH), 7.75 (t, IH), 7.90 (dd, IH), (M- hydroxy-2-methy 1-3 ,3,3- 8J0 (s, IH), 8.25 (d, IH), 8.45 (d, ΝH 4 )- trifluoropropanamide IH), 8.70 (d, IH), 8.75 (s, IH), 9.30 (br s, IH) 39 (R)-N-[2-Chloro-4-(4-fluoro- (CDC1 3 ): 1.74 (s, 3H), 4J6 and 408 20c phenylsulphinyl)phenyl]-2- 4.24 (2 x br s, IH), 7J9 (t, 2H), (M-H) hydroxy-2-methyl-3 ,3 ,3 - 7.49 (d, IH), 7.63 (dd, 2H), 7.7 - trifluoropropanamide (d, IH), 8.52 (m, IH), 9.2 (br s, IH) 1 Produ ct was purified by chromatograph y on a silica eel Mega Bond Elut col umn, elul ing with 5-60% ethyl acetate/hexane. 56 2 Product was purified by chromatography eluting with 50% dichloromethane/hexane to 5% methanol/dichloromethane. 3 Twice as much MCPBA was used. Example 40 (R)-N-[4-(4-Bromophenylsulphonyl)-2-chlorophenyll-2-hvdroxy-2-methyl-3.3J- trifluoropropanamide Oxalyl chloride (0.029ml) was added to a stiπed suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.047g) in dichloromethane (3ml) containing DMF (1 drop). The mixture was stiπed at ambient temperature for 30 minutes and was then added to a solution of 4-(4-bromophenylsulphonyl)- 2-chloroaniline (Method 12) (0J04g) in dichloromethane (3ml) and stiπed a further 1 hour. Water (10ml) was added and the mixture was extracted with dichloromethane (3x10ml). The organic extracts were combined, washed with brine then dried. Nolatile material was removed by evaporation and the residue was purified by flash chromatography on silica gel eluting with 1% methanol/dichloromethane to give the title compound (0.049g) as a foam. ΝMR (CDC1 3 ): 1.78 (s, 3H), 7.65 (d, 2H), 7.8 (m, 3H), 8.0 (s, IH), 8.6 (d, 2H), 9.3 (s, 1H);MS: 485 (M + ). Example 41 Following the procedure of Example 40 and using the appropriate starting material (p-thiocresole) the following compound was prepared. EX COMPOUND ΝMR (CDClj) MS 41 (R)-N-[2-Chloro-4-(4-methylphenyl- 1.75 (s, 3H), 2.4 (s, 3H), 1.3 (d, 2H), 420 sulphony l)phenyl] -2-hydroxy-2- 7.8 (m, 3H), 8.0 (s, IH), 8.6 (d, 2H), (M-H) " methyl-3 ,3 ,3 -trifluoropropanamide 9.25 (s, IH) Example 42 (R)-N-r2-Chloro-4-(2-methoxyphenylsulphonyl phenyll-2-hvdroxy-2-methyl-3JJ- trifluoropropanamide m-Chloroperbenzoic acid (55%, 0.424g) was added to a solution of (R)-N-[2-chloro-4-(2-methoxyphenylthio)phenyl]-2-hydroxy-2-rnethyl-3,3,3- 57 . trifluoropropanamide (Method 19) (0J66g) in dichloromethane (10ml) and the mixture was stiπed at ambient temperature for 18 hours. The mixture was then washed with saturated aqueous sodium hydrogen carbonate solution (3x70ml), water (50ml) and brine then dried. Nolatile material was removed by evaporation to give the title compound (0J37g) as a solid. M.p. 82-84°C; ΝMR (CDC1 3 ): 1.75 (s, 3H), 3.80 (s, 3H), 6.90 (d, IH), 7.10 (m, IH), 7.55 (m, IH), 7.90 (dd, IH), 8.05 (d, IH), 8.10 (dd, IH), 8.60 (d, IH), 9.35 (br s, IH); MS: 436 (M-H) " ; EA: C 17 H 15 C1F 3 ΝO 5 S OJ7 CH 2 C1 2 requires C, 46.1; H, 3.4; N, 3.1%; found: C, 46.0; H, 3.5; N, 3.1%. Examples 43-47 Following the procedure of Example 42 and using the appropriate starting material the following compounds were prepared. "Meth" relates to the method used to make the starting materials (see below). EX COMPOUND ΝMR (CDClj) MS Meth 43 R)-N-[2-Chloro-4-(4-methoxy- 1.75 (s, 3H), 3.85 (s, 3H), 7.00 436 20a phenylsulphonyl)phenyl]-2- (d, 2H), 7.85 (dd, IH), 7.90 (M-H)- hydroxy-2-methyl-3 ,3 ,3 -trifluoro(d, 2H), 7.95 (d, IH), 8.60 (d, propanamide IH), 9.20 (br s, IH) 44 (R)-N-[2-Chloro-4-(2-fluorophenyl 1.75 (s, 3H), 3.65 (br s, IH), 424 20b -sulphony l)pheny 1] -2-hydroxy-2- 7.15 (t, IH), 7.35 (t, IH), 7.60 (M-H)- methyl-3 , ,3 -trifluoropropanamide (m, IH), 7.95 (d, IH), 8.10 (m, 2H), 8.60 (d, IH), 9.30 (br s, lH) 45 (R)-N-[2-Chloro-4-(3-fluorophenyl 1.75 (s, 3H), 3.61 (s, IH), 1.3 424 20d -sulphony l)phenyl] -2-hydroxy-2- (m, IH), 7.5 (m, IH), 7.6 (d, (M-H)- methyl-3 ,3 ,3-trifluoropropanamide IH), 7.73 (d, IH), 7.86 (m, IH), 8.0 (d, IH), 8.62 (d, IH), 9.15 (br s, IH) 46 (R)-N-[2-Fluoro-4-(2-fluorophenyl- 1.59 (s, 3H), 7.38-7.55 (m, 408 20e sulphonyl)phenyl] -2-hydroxy-2- 2H), 7.7-7.9 (m, 4H), 8.05 (q, (M-H)- methy 1-3 ,3,3 -trifluoropropanamide 2H), 9.85 (br s, IH) - 58 47 (R)-N-[2-Chloro-4-((2-methylfuran 1.75 (s, 3H), 2.55 (s, 3H), 3.6 410 271 -3-yl)sulphonyl) phenyl]-2- (s, IH), 6.55 (dd, IH), 7.25 (M-H)- hydroxy-2-methyl-3 ,3 ,3 -trifluoro(dd, IH), 7.8 (dd, IH), 7.95 propanamide (d, IH), 8.6 (d, IH), 9.25 (br s, IH) Example 48 (R)-2-Hvdroxy-N-[2-methoxy-4-(phenylsulphonyl)phenyl1-2-methyl-3.3,3- trifluoropropanamide Oxalyl chloride (0.044ml) was added to a stiπed suspension of (R)-(+)-2-hydroxy-2- methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.08 lg) in dichloromethane (2ml) containing DMF (1 drop). The mixture was stiπed at ambient temperature for 2 hours and was then added to a solution of 2-methoxy-4-phenylsulphonylaniline (Method 21) (0J07g) and 2,6-di-tert-butylpyridine (0J2ml) in dichloromethane (2ml) and stiπed a further 5 hours. Hexane (1ml) was added and the solution was transfeπed to a silica gel Mega Bond Elut column and eluted with 30-40% ethyl acetate/hexane to give the title compound (0.070g) as a foam. ΝMR: 1.55 (s, 3H), 3.97 (s, 3H), 7.5-7.7 (m, 5H), 7.9-8.0 (m, 3H), 8.4 (d, IH), 9.62 (s, IH); MS: 402 (M-H) " . Examples 49-52 Following the procedure of Example 48 and using racemic 2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid and the appropriate aniline the following compounds were prepared. EX COMPOUND ΝMR MS 49 • N-(2-Bromo-4-trifluoromethoxy- 1.6 (s, 3H), 7.45 (d, IH), 7.8 (s, IH), 394, phenyl)-2-hydroxy-2-methyl-3 ,3,3- 7.81 (br s, IH), 8.03 (d, IH), 9.8 (br 396 trifluoropropanamide s, lH) (M-H)- 50 ' N-(2-Bromo-4-trifluoromethyl- 1.6 (s, 3H), 7.8 (dd, IH), 8.0 (br s, 378, phenyl)-2-hydroxy-2-methyl-3,3,3- IH), 8.1 (d, IH), 8.3 (d, IH), 9.9 (br 380 trifluoropropanamide s, IH) (M-H) " 59 51 l N-(2-Chloro-4-trifluoromethyl- 1.6 (s, 3H), 7.78 (d, IH), 7.96 (br s, 334 phenyl)-2-hydroxy-2-methyl-3 ,3 ,3 - IH), 7.98 (s, IH), 8.15 (d, IH), 9.85 (M-H)- trifluoropropanamide (br s, IH) 52 ' N-(2-Chloro-4-cyanophenyl)-2- 1.6 (s, 3H), 7.85 (dd, IH), 8.0 (s, 291, hydroxy-2-methyl-3,3,3-trifluoro- IH), 8.18 (d, IH), 8.25 (d, IH), 9.9 293 propanamide (br s, lH); (M-H) " 1 No 2,6-di-tert-butylpyridine was used and the reaction mixture was filtered before treating with hexane. Example 53 3-Hvdroxy-3-methyl-l-(4-phenylsulphonyl-2-fluorophenyl)-4,4,4-trifluorobut-l-yne ^-Butyllithium (0.24 ml of a 1.3M solution in hexanes) was added dropwise to a solution of 4-phenylsulphonyl-2-fluorophenylethyne (Method 28) (0.08g) in dry THF (3ml) at -50°C. After 25 minutes a solution of lJJ-trifluoroacetone (0.035g) in dry THF (0.5ml) was added and the mixture was allowed to warm to ambient temperature overnight. Water (10ml) was added and THF was evaporated off under reduced pressure. The residue was diluted with water (30ml) and extracted with ethyl acetate (30ml). The organic layer was washed with brine then dried. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-30% ethyl acetate/hexane then triturated with hexane to give the title compound (0.038g) as a solid. ΝMR (CDClj): 1.75 (s, 3H), 2.75 (s, IH), 7.5-7.75 (m, 6H), 7.93 (d, 2H); EA: C 17 H 12 F 4 O 3 S requires C, 54.8; H, 3.3%; found: C, 54.4; H, 3.4%. Examples 54 Following the procedure of Example 53 and using the appropriate starting material the following compound was prepared. EX COMPOUND NMR (CDClj) MS 54 l 3-Hydroxy- 1 -(4-phenylsulphonyl-2-fluorophenyl)- 4.0 (br s), 7.5-7.75 426 (M + ) 3-trifluoromethyl-4,4,4-trifluorobut- 1 -yne (m, 6H), 7.94 (d, 2H) 60 1 Anhydrous hexafluoroacetone (prepared by dropwise addition of hexafluoroacetone trihydrate to concentrated sulphuric acid and the anhydrous vapour was condensed onto a cold finger and dropped directly into reaction vessel) was used in place of lJJ-trifluoroacetone. Examples 55 - 60 Following the procedure of Method 3 (see below) and using the appropriate starting material to replace the 6-nitro-3-(4-pyridylthio)anisole the following compounds were prepared. "Meth" relates to the method used to make the starting materials (see below). EX COMPOUND ΝMR MS Meth 55 (R)-N-[2-Chloro-4-(pyrimid-2 1.64 (s, 3H), 7.82 (t, IH), 8.01 (dd, 408 27b -yl-sulphonyl) phenyl] -2- IH), 8J (br s, IH), 8J3 (d, IH), (M-H)- hydroxy-2-methyl-3,3,3- 8.4 (d, IH), 9.05 (d, 2H), 9.94 (br s, trifluoropropanamide IH) 56 (R)-N-[2-Chloro-4-(pyrid-4- (CDC1 3 + d 6 -DMSO): 1.59 (s, 3H), 407 8c ylsulphonyl)phenyl]-2- 7.5 (br s, IH), 7.7 (dd, 2H), 7.8 (dd, (M-H)- hydroxy-2-methyl-3 ,3 ,3- IH), 7.91 (d, IH), 8.6 (d, IH), 8.76 trifluoropropanamide (dd, 2H), 9.75 (br s, IH) 57 l (R)-N-[2-(5-Methyl-thien-2- (CDC1 3 ): 1.75 (s, 3H), 2.50 (s, 3H), 428 27h ylsulphonyl)phenyl]-2- 3.50 (br s, IH), 6.75 (m, IH), 7.50 (M+H) hydroxy-2-methyl-3 ,3 ,3 - (m, IH), 7.85 (dd, IH), 8.00 (d, + trifluoropropanamide IH), 8.60 (d, IH), 9.20 (br s, IH) 58 (R)-N-[2-Chloro-4-(imidazol- 1.62 (s, 3H), 7.35 (br s, 2H), 7.95 396 27i 2-ylsulphonyl)phenyl] -2- (dd, IH), 8.07 (d, IH), 8.32 (d, IH), (M-H)- hydroxy-2-methyl-3,3,3- 9.95 (br s, IH), 13.9 (br s, IH) trifluoropropanamide 59 (R)-N-[2-Chloro-4-(pyrid-2- 1.6 (s, 3H), 7.72 (m, IH), 8.0 (dd, 407 27j ylsulphonyl)phenyl]- 2- IH), 8.07 (br s, IH), 8J (d, IH), (M-H)- hydroxy-2-methyl-3 ,3,3- 8J7 (m, IH), 8.24 (d, IH), 8.33 (d, trifluoropropanamide IH), 8.7 (m, IH), 9.95 (br s, IH) - 61 60 (R)-N-[2-Chloro-4-(pyrid-3- 1.6 (s, 3H), 7.66 (m, IH), 8.05 (dd, 407 27k ylsulphonyl)phenyl]-2- 2H, including br s for OH), 8.26 (d, (M-H)- hydroxy-2-methyl-3 ,3 ,3 - IH), 8.34 (d, IH), 8.42 (m, IH), trifluoropropanamide 8.87 (m, IH), 9.2 (d, IH), 9.94 (br s, IH) ' Proc uct was purified by chromatography eluting with 10-100% ethyl acetate/hexane Example 61 (RVN-r2-Chloro-4-(thiazol-2-ylsulphonvnDhenvn-2-hvdroxy-2-methyl-3.3.3- trifluoropropanamide A solution of Oxone (Trademark of E.I. du Pont de Nemours & Co., Inc., potassium peroxymonosulphate) (0.317g) in a 1M solution of sodium acetate (2ml) was added to a stiπed solution of (R)-N-[2-chloro-4-(2-thiazolylthio)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide (Method 27c) (0J 31 g) in methanol (4ml). After 2 hours water (40ml) was added and the mixture was extracted with ethyl acetate (2 x 50ml). The reaction was repeated on the same scale and the organic extracts were combined and concentrated by evaporation to give a foam. This material was purified by chromatography on silica gel eluting with 7.5-10% ether/dichloromethane to give the title compound (0J 19g) as a solid. ΝMR: 1.6 (s, 3H), 8.05 (dd, IH), 8.1 (br s, IH), 8.12 (m, 2H), 8.3 (d, IH), 8.4 (d, IH), 9.9 (br s, IH); MS: 413 (M-H) " ; EA: C 13 H 10 C1F 3 Ν 2 O 4 S 2 requires C, 37.6; H, 2.4; N, 6.8%; found: C, 37.5; H, 2.2; N, 6.4%. Preparation of Starting Materials The starting materials for the Examples above are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions (Methods 1-32) are illustrations but not limitations of the preparation of some of the starting materials used in the above reactions. Method 1 4-.Amino-3 -fluorobenzophenone To stiπed polyphosphoric acid (125g) at 90°C was added benzoic acid (18.32g) and - 62 - 2-fluoroaniline (8.33g) and the bath temperature was raised to 200°C for 1 hour. The heating bath was removed and the stiπed mixture was treated cautiously with water (60ml). The mixture was stiπed at 140-160°C for 1 hour, the heating bath was removed, and 3M hydrochloric acid was added (50ml). The mixture was poured into water (750ml) and filtered through diatomaceous earth with a dichloromethane wash. The filtrate was made basic with 15% sodium hydroxide and the mixture was again filtered through diatomaceous earth with a dichloromethane wash. The combined dichloromethane extracts were washed (saturated aqueous sodium hydrogen carbonate), dried, filtered, and evaporated. Chromatography, with ether/hexanes (gradient, 10/90 to 50/50) as the eluent, followed by recrystallization from hexanes, yielded the title compound as a light yellow solid (7.48g). M.p. 83-85°C; MS: 216 (M+H); NMR (400 MHz): 6.27 (brs, 2H), 6.80 (t, IH, J=8.6), 7.36 (q, IH, J=8.4, 1.9), 7.41 (q, IH, J=12.4, 1.9), 7.49-7.51 (m, 2H) 7.60-7.63 (m, 3H); EA: C, 3 H 10 FNO requires C, 72.55; H, 4.68; N, 6.51%; found: C, 72.51; H, 4.82; N, 6.42%. Method 2 2-Methoxy-4-(pyrid-4-ylsulphonyl)aniline To a stiπed slurry of 6-nitro-3-(pyrid-4-yl)sulphonyl)anisole (Method 3) (3.40g) and absolute ethanol (30ml) was added stannous chloride dihydrate (13.0g) in one portion. The mixture was heated at reflux for 50 minutes, poured onto ice-water (200ml) and made basic with aqueous 15%> sodium hydroxide. The mixture was extracted with ethyl acetate and the organics were evaporated to yield a white solid which was recrystallized from boiling absolute ethanol. After cooling the solid was filtered to yield the title compound as a white solid (2.42g). M.p. 163-165°C; MS: 265(M+H); NMR: 3.85 (s, 3H), 6.01 (s, 2H), 6.73 (d, IH, J=8.4), 7.23 (d, IH, J=2.0), 7.34 (dd, IH, J=2.0, 8.4), 7.81-7.83 (m, 2H), 8.80-8.82 (m, 2H); EA: C 12 H I2 N 2 O 3 S requires C, 54.53; H, 4.58; N, 10.60%; Found: C, 54.45; H, 4.54; N, 10.58%. Method 3 6-Nitro-3-(pyrid-4-ylsulphonyl)anisole To a stiπed solution of 6-nitro-3-(pyrid-4-ylthio)anisole (Method 4) (6.49g) and acetic acid (200ml) was rapidly added a solution of potassium permanganate (4.69g) in water (100ml). After stiπing for 1 hour, the mixture was clarified by the addition of solid sodium - 63 - sulphite, diluted to a volume of 1 litre with water and the resulting solid was collected. Recrystallization from absolute ethanol (300ml) yielded the title compound (3.43g). M.p. 123-124°C; NMR: 4.07 (s, 3H), 7.75 (dd, IH, J=1.7, 8.4), 7.90 (d, IH, J=1.7), 8.02-8.04 (m, 2H), 8J2 (d, IH, J=8.4), 8.92-8.94 (m, 2H); EA: C 12 H 10 N 2 O 5 S requires C, 48.98; H, 3.42; N, 9.52%; found: C, 48.81; H, 3.45; N, 10.02%. Method 4 6-Nitro-3-(pyrid-4-ylthio)anisole 5-Chloro-2-nitroanisole (9.38g) was added to a solution of 4-mercaptopyridine potassium salt [prepared by adding 4-mercaptopyridine (6.67g) to a solution of potassium hydroxide (3.37g) in methanol (30ml) followed by evaporation of the methanol] and DMF (40ml). After stiπing for 1 hour, the mixture was heated at 110°C for 4 hours and allowed to stand overnight. The reaction mixture was poured into ice-water (1 litre), stiπed for 15 minutes, and the yellow solid was filtered off. The solid was stiπed with 3M hydrochloric acid (800ml) for 1 hour, filtered, and the filter cake was washed with 3M hydrochloric acid then water. The filtrate was cooled in an ice-bath and made basic with 28% aqueous ammonium hydroxide to yield approximately 2g of the title compound. The filter cake was suspended in water (100ml) with stirring and the mixture was made basic with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organics were combined, dried, filtered and evaporated to give a yellow solid that was triturated with hexane and filtered to give additional title compound (total yield 6.49g). M.p. 97-100°C; MS: 263 (M+H); NMR: 3.94 (s, 3H), 7J7 (dd, IH, j=1.8, 8.4), 7.27-7.7.29 (m, 2H), 7.51 (d, IH, J=1.8), 7.97 (d, IH, J=8.4), 8.48-8.50 (m, 2H). Method 5 4-.Amino-3 -cyanobenzophenone To a stiπed refluxing mixture of 3-cyano-4-nitrobenzophenone (Method 6) (1.50g) and iron powder (3.64g) in ethanol (50ml) was added dropwise over 0.5 hour a solution of concentrated hydrochloric acid (0.35ml) in ethanol (14ml) and reflux was maintained overnight. The hot mixture was filtered through diatomaceous earth and the reaction flask and diatomaceous earth pad was washed with three 50ml portions of ethanol. The combined filtrate was evaporated to yield a tan solid. Chromatography (eluent 10% to 40% ethyl acetate - 64 - gradient in dichloromethane) gave the title compound (0.21g) as a tan solid. M.p. 158-160°C; EA: C 14 H 10 N 2 O 0.25H 2 O requires C, 74.35; H, 4.33; N, 12.32%; found: C, 74.16; H, 4.66; N, 12.35%. Method 6 3 -C yano-4-nitrobenzophenone A stiπed mixture of 3-chloro-4-nitrobenzophenone (5.00g), (J. Org. Chem., 1962, 27, 1605-1608), and copper(I)cyanide (2.57g) in DMF (50ml) was heated at reflux for 16 hours. The hot reaction mixture was then poured into a stiπed solution of ferric chloride (15.30g) concentrated hydrochloric acid (5ml) and water (200ml). The mixture was heated at 65-70°C for 30 minutes, cooled to ambient temperature treated with ethyl acetate (250ml) and stiπed vigorously for 5 minutes. The organic phase was separated and the aqueous layer extracted with another 250ml portion of ethyl acetate. The combined organics were dried, filtered and evaporated to give a brown oil. Chromatography (eluent toluene) gave the title compound (2.77g) as a yellow solid. M.p. 117-119°C; EA C 14 H 8 N 2 O 3 requires C, 66.67; H, 3.20; N, 11.11%; found: C, 66.83; H, 2.99; N, 11.12%. Method 7 (R)-N-[2-Fluoro-4-(phenylthio phenyl1-2-hvdroxy-2-methyl-3JJ-trifluoropropanamide Oxalyl chloride (0.117ml) was added to a stiπed suspension of (R)-(+)-2-hydroxy-2-methyl-3,3J-rrifluoropropanoic acid (Method 9) (0.198g) in dichloromethane (3.5ml) containing DMF (1 drop). The mixture was stiπed at ambient temperature for 2 hours and was then added to a solution of 2-fluoro-4-phenylthioaniline (Method 8) (0.219g) in dichloromethane (5ml) and stiπed a further 2 hours. Ether (50ml) was added and the mixture was washed with water (2x50ml) and brine then dried. Nolatile material was removed by evaporation to give the title compound (0.423g) as a liquid that was used without further purification. ΝMR: 1.55 (s, 3H), 7.1 (d, IH), 7.2 (m, IH), 7.3-7.5 (m, 5H), 7.6 (s, IH), 7.7 (t, IH), 9.65 (s, IH); MS: 358 (M-H) " . 65 - Method 8 2-Fluoro-4-phenylthioaniline Tetrakis(triphenylphosphine)palladium(0) (0.578g) was added to a deoxygenated mixture of 2-fluoro-4-iodoaniline (2.37g), thiophenol (1.07ml) and sodium methoxide (lJ3g) in ethanol (80ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stirring under argon for 18 hours, cooled and filtered. The filter was washed with ether (3x20ml) and the filtrates were combined and volatile material was removed by evaporation. The residue was treated with dichloromethane (50ml), filtered and reconcentrated. This crude product was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50-70% dichloromethane/Tiexane to give the title compound (1.851g) as a solid. M.p. 48-49°C; NMR: 5.5 (s, 2H), 6.8 (t, IH), 7.0-7.15 (m, 5H), 7.25 (t, 2H). Methods 8a-8c Using the procedure of Method 8 followed by the procedure of Method 7 the following compounds were prepared: Method Replacement for Replacement for Compound Prepared thiophenol 2-fluoro-4-iodoaniline 8a o-thiocresol 2-chloro-4-iodoaniline (R)-N-[2-chloro-4-(2-methyl- phenylthio)phenyl]-2-hydroxy-2- methyl-3 ,3 ,3 -trifluoropropanamide 8b - 4-bromo-2- (R)-2-hydroxy-2-methyl-N-[2- methylaniline methyl-4-(phenylthio)phenyl]- 3,3,3-trifluoropropanamide 8c 1 4-mercapto- (R)-N-[2-chloro-4-iodo- (R)-N-[2-chloro-4-(pyrid-4-ylthio) pyridine phenyl]-2-hydroxy-2- phenyl]-2-hydroxy-2-methyl-3,3,3 methyl-3 ,3 ,3 -trifluoro-trifluoropropanamide propanamide 1 Method i only. - 66 - Method 9 (R)-(+)-2-Hvdroxy-2-methyl-3J.3-trifluoropropanoic acid This compound was prepared by the method of Scheme 2 in World Patent Application Publication No. WO 9738124 for preparation of the (S)-(-) acid, i.e. Using the classical resolution method described in European Patent Application Publication No. EP 0524781, also for preparation of the (S)-(-) acid, except that (1 S,2R)-norephedrine was used in place of (S)-(-)-l-phenylethylamine. The (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid thus obtained (in about 20% yield, of a maximum possible of 50%, after 3-5 recrystallizations of the diastereomeric salt followed by liberation of the free acid by treatment with hydrochloric acid) was >98% enantiomerically pure based on NMR analysis of the (lS,2R)-norephedrine salt; [a * - +18J, c = 8.8 in methanol. Method 10 (R -N-[2-Chloro-4-(phenylthio)phenyll-2-hvdroxy-2-methyl-3.3J-trifluoropropanamide Oxalyl chloride (0.063ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2- methyl-3,3,3-trifluoropropanoic acid (Method 9) (0J06g) in dichloromethane (2ml) containing DMF (1 drop). The mixture was stiπed at ambient temperature for 90 minutes and was then added to a solution of 2-chloro-4-phenylthioaniline (Method 11) (0.143 g) in dichloromethane (4ml) and stiπed a further 3 hours. Ethyl acetate (30ml) was added and the mixture was washed with water (2x30ml) and brine then dried. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 15% ethyl acetate/hexane to give the title compound (0J53g) as a gum. ΝMR: 1.57 (s, 3H), 7.26-7.41 (m, 6H), 7.44 (d, IH), 7.82 (s, IH), 7.95 (d, IH), 9.74 (s, IH); MS: 374 (M-H) " . Method 10a Using the procedure of Method 10, but using 2-hydroxy-2-trifluoromethylbutanoic acid as the starting material, the following compound was prepared. 67 Method Compound ΝMR 10a N-[2-chloro-4-(phenylthio)phenyl]-2- 0.9 (t, 3H), 1.8 (m, IH), 2J (m, IH), 7J8 hydroxy-2-trifluoromethyl- (m, 7H), 7.58 (br s, IH), 7.92 (d, IH), butanamide 9.65 (br s, IH) Method 11 2-Chloro-4-phenylthioaniline Tetrakis(triphenylphosphine)palladium(0) (0J 15g) was added to a deoxygenated mixture of 2-chloro-4-iodoaniline (0.507g), thiophenol (0.214ml) and sodium methoxide (0.227g) in ethanol (20ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stiπing under argon for 18 hours, cooled, diluted with ether (30ml) and filtered. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-15% ethyl acetate/hexane to give the title compound (0.443g) as a solid. M.p. 59-60°C; ΝMR: 5.78 (br s, 2H), 6.8 (t, IH), 7.04 (m, 2H), 7J5 (m, 2H), 7.2-7.35 (m, 3H); EA: C 12 H 10 C1ΝS requires C, 61.1; H, 4.3; N, 5.9; S, 13.6%; found: C, 60.8; H, 4.4; N, 5.7; S, 13.3%. Methods lla-d Using the procedure of Method 11, but using the appropriate starting materials, the following compounds were prepared. Method Compound Replacement for Replacement for thiophenol 2-chloro-4-iodoaniline 11a 1 (R)-N-[2-Chloro-4-(thien-2- 2-mercaptothiophene (R)-N-(2-chloro-4-iodo- y lthio)pheny 1] -2-hydroxy-2- phenyl)-2-hydroxy-2- methyl-3 ,3 ,3 -trifluoromethyl-3,3,3- propanamide trifluoropropanamide 68 lib (R)-N-[2-Chloro-4-(3- (R)-N-(2-chloro-4- 3-iodoanisole methoxypheny lthio)pheny 1] - mercaptophenyl)-2- 2-hydroxy-2-methyl-3 ,3,3- hydroxy-2-methyl-3,3,3 trifluoropropanamide -trifluoropropanamide 2 lie 3 (R)-N-[2-Chloro-4-(4-fluoro- 4-fluorobenzenethiol (R)-N-[2-chloro-4-iodo pheny lthio)phenyl] -2- phenyl]-2-hydroxy-2- hydroxy-2-methyl-3 ,3 ,3 - methyl-3 ,3,3 -trifluorotrifluoropropanamide propanamide lid 4 (R)-N-[2-Chloro-4-(4-bromo 4-bromobenzenethiol (R)-N-[2-chloro-4Jodo- phenylthio)phenyl]-2- phenyl]-2-hydroxy-2- hydroxy-2-methyl-3 ,3 ,3 - methy 1-3 ,3,3 -trifluorotrifluoropropanamide propanamide 1 Product was purified by chromatography on silica gel eluting with 20-30%) ethyl acetate/hexane. 2 Method 31. 3 Product contaminated with 2-chloro-4-(4-fluorophenylthio)aniline, removed after next step. 4 Product impure. Method 12 4-(4-Bromophenylsulphonyl -2-chloroaniline Iron powder (2.5g) was added to a stiπed mixture of 4-(4-bromophenylsulphonyl)-2- chloro-nitrobenzene (Method 13) (0.6g), water (2ml), concentrated hydrochloric acid (0.5ml) and ethanol (10ml). The mixture was heated under reflux for 1 hour then evaporated to near dryness and partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (3x15ml) and the organic extracts were combined and dried. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-25% ethyl acetate/liexane followed by trituration with ether to give the title compounde (0J lg) as a solid. ΝMR: 6.42 (s, 2H), 6.82 (d, IH), 7.5 (d, IH), 7.8 (m, 5H); MS: 346 (M-H) " . - 69 - Method 13 4-(4-Bromophenylsulphonyl)-2-chloro-nitrobenzene Hydrogen peroxide (0.9ml of a 30 wt. % solution in water) was added to a solution of 4-(4-bromophenylthio)-2-chloro-nitrobenzene (Method 14) (0.635g) in glacial acetic acid (4ml) and the mixture was stiπed and heated at 95°C for 75 minutes then poured into water (15ml) and extracted with ethyl acetate (3x10ml). The organic extracts were combined, washed with brine and then dried. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-25% ethyl acetate/hexane to give the title compound (0.61g). ΝMR: 7.9 (m, 2H), 8.0 (m, 2H), 8.1-8.3 (m, 2H), 8.4 (m, IH). Method 14 4-(4-Bromophenylthio)-2-chloro-mtrobenzene A solution of 2-amino-4-(4-bromophenylthio)nitrobenzene (Method 15) (2.25g) in warm glacial acetic acid (13ml) was poured onto ice (20ml). Concentrated hydrochloric acid (3.95ml) was added and the mixture was stiπed and cooled to <5°C. A solution of sodium nitrite (0.524g) in water (5ml) was added over 7 minutes and the mixture was stiπed for 2 hours at 0-5°C. Aqueous sulphamic acid solution (10% w/v) was added until a negative starch iodide test was observed. Meanwhile toluene was added to a solution of cuprous chloride (0.745g) in water (1ml) and concentrated hydrochloric acid (1.15ml) and the mixture was cooled to <0°C. The first preparation (diazonium salt) was then added to the cold cuprous chloride mixture over 5 minutes and the resultant mixture was stiπed at ambient temperature for 18 hours. The organic layer was separated and the aqueous layer was extracted with toluene (3x10ml). The organic extracts were combined, washed with water and brine then dried. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-15% ethyl acetate/hexane to give the title compound (0.644g). MS: 343 (M + ). Method 15 2-Amino-4-(4-bromophenylthio nitrobenzene Sodium (0.269g) was added to ethanol (20ml) and the resultant solution was allowed to cool to ambient temperature then 4-bromothiophenol (2.2 lg) was added. The mixture was - 70 - stiπed for 5 minutes then 5-chloro-2-nitroaniline (2g) was added. The mixture was then heated under reflux under argon for 3 hours then allowed to cool down. The resultant solid was collected by filtration, washed with ethanol then dried to give the title compound (2.36g) as a solid. NMR: 6.38 (dd, IH), 6.65 (m, IH), 7.42 (m, 4H), 7.7 (m, 2H), 7.9 (d, IH); MS: 327 (M+H) + . Method 15a Using the procedure of Method 15 followed by the procedure of Methods 14, 13 and 12 the following compound was prepared: Method Replacement for Compound Prepared 4-bromothiophenol 15a p-Thiocresol 4-(4-methylphenylsulphonyl)-2-chloroaniline Method 16 (R -N-r2-Bromo-4-(phenylthio)phenvn-2-hvdroxy-2-methyl-3,3J-trifluoropropanamide Oxalyl chloride (0.052ml) was added to a stiπed suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.095g) in dichloromethane (3ml) containing DMF (1 drop). The mixture was stiπed at ambient temperature for 2 hours and was then added to a solution of 2-bromo-4-phenylthioaniline (Method 17) (0J35g) and 2,6-di-tert-butylpyridine (0J4ml) in dichloromethane (5ml) and stiπed a further 3 hours. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-30% ethyl acetate/hexane to give the title compound (0.061g) as a waxy solid. ΝMR: 1.59 (s, 3H), 7.25-7.50 (bm, 6H), 7.59 (sJH), 7.82 (bs, IH), 7.98 (dJH), 9.79 (s, IH); MS: 420 ( M-H) " . Method 17 2-Bromo-4-phenylthioaniline Iron powder (1.2g) was added to a stiπed mixture 2-bromo-4-phenylthionitrobenzene (Method 18) (0.6g), water (1.6ml), concentrated hydrochloric acid (0.4ml) and ethanol (8ml). The mixture was heated under reflux for 40 minutes then evaporated to near dryness and partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (3x10ml) and the organic extracts were combined and - 71 - dried. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-35% ethyl acetate/hexane to give the title compound (0J45g) as a waxy solid. ΝMR: 5.65 (s,2H), 6.8 (dJH), 7.05 (d, 2H), 7J-7.3 (m, 4H), 7.42 (sJH); MS: 280 (M-H) " . Method 18 2-Bromo-4-phenylthionitrobenzene tert-Butyl nitrite (0.725ml) was added to a slurry of copper(II)bromide (1.04g) in acetonitrile (20ml) at 0°C. 2-.Amino-4-phenylthionitrobenzene (lg, prepared as described in J. Med. Chem., 1975, 18, 1164) was added portionwise over 5 minutes and the mixture was stiπed a further 2 hours at 0°C, allowed to warm to ambient temperature, and stiπed a further 16 hours. Nolatile material was removed by evaporation and the residue was purified by flash chromatography on silica gel eluting with 2% ethyl acetate/hexane to give the title compound (0.2g) as an oil. ΝMR: 7.2 (d, IH), 7.5-7.62 (m, 6H), 7.9 (d, IH); MS: 311 (M + ). Method 19 (R)-N-[2-Chloro-4-(2-methoxyphenylthio phenyl1-2-hvdroxy-2-methyl-3JJ-trifluoro- propanamide Tetrakis(triphenylphosphine)palladium(0) (0.03g) was added to a deoxygenated mixture of (R)-N-[2-chloro-4-iodophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 20) (0.2g), 2-methoxybenzenethiol (0.064ml) and sodium methoxide (0.058g) in ethanol (10ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stiπing under argon for 18 hours, treated with a further portion of tetrakis(triphenylphosphine)palladium(0) (0.03g), heated a further 24 hours then cooled and filtered. Nolatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-10%) ethyl acetate/hexane to give the title compound (0J66g) as an oil. ΝMR (CDC1 3 ): 1.75 (s, 3H), 3.7 (br s, IH), 3.85 (s, 3H), 6.9 (m, 2H), 7.2 (m, IH), 1.3 (dd, IH), 7.35 (m, 2H), 8.3 (d, IH), 9.8 (br s, IH); MS: 404 (M-H) ' . 72 Method 19a Using the procedure of Method 19 the following compound was prepared: Meth Replacement for (R)-N-[2-chloro- Replacement for Compound 4-iodophenyl]-2-hydroxy-2-methyl- 2-methoxy- Prepared 3,3 . 3-trifluoropropanamide benzenethiol 19a 4-bromo-3-fluoro-iodobenzene thiophenol (4-bromo-3 -fluoro- 1 -phenylthiobenzene) 1 Double the amount of palladium catalyst was used, and the compound was used without further purification. Method 20 (R)-N-[2-Chloro-4-iodophenyl1-2-hvdroxy-2-methyl-3J,3-trifluoropropanamide Oxalyl chloride (1.07ml) was added dropwise to a stiπed suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (1.95g) in dichloromethane (42ml) and DMF (0.8ml). The mixture was stiπed at ambient temperature for 2 hours and was then added over 35 minutes to a solution of 2-chloro-4-iodoaniline (2.5g) and 2,6-di-tert-butylpyridine (2.94ml) in dichloromethane (40ml) and stiπed a further 18 hours. Nolatile material was removed by evaporation and the residue was purified by flash chromatography on silica gel eluting with dichloromethane to give the title compound (2.85g) as a solid. ΝMR: 1.6 (s, 3H), 7.7 (m, 2H), 7.8 (d, IH), 7.9 (br s, IH); MS: 392 (M-H) ' . Methods 20a - 20e Using the procedure of Method 20 followed by the procedure of Method 19 the following compounds were prepared: Method Replacement for 2- Compound Prepared methoxybenzenethiol 20a 4-Methoxybenzenethiol R)-N-[2-chloro-4-(4-methoxyphenylthio)phenyl]-2- hydroxy-2-methy 1-3 ,3 ,3 -trifluoropropanamide 20b 2-Fluorothiophenol (R)-N-[2-chloro-4-(2-fluorophenylthio)phenyl]-2- hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide 73 20c 4-Fluorothiophenol (R)-N-[2-chloro-4-(4-fluorophenylthio)phenyl]-2- hydroxy-2-methyl-3,3,3-trifluoropropanamide 20d 3-Fluorothiophenol (R)-N-[2-chloro-4-(3-fluorophenylthio)phenyl]-2- hydroxy-2-methy 1-3 ,3,3 -trifluoropropanamide 20e ' 2-Fluorothiophenol (R)-N-[2-fluoro-4-(2-fluorophenylthio)phenyl]-2- hydroxy-2-methyl-3 ,3,3 -trifluoropropanamide 1 Double the amount of palladium catalyst was used for preparation of the starting material and 2-fluoro-4-iodoaniline was used in Method 20 in place of 2-chloro-4-iodoaniline. Method 21 2-Methoxy-4-phenylsulphonylaniline A solution of ammonium formate (0J83g) in water (2.5ml) was added to a mixture of 10%) palladium on carbon (0.03g) and 2-methoxy-4-phenylsulphonylnitrobenzene (Method 22) (0.213g) in methanol (10ml) and ethyl acetate (1ml). The mixture was heated and stirred under reflux under argon for 4 hours then cooled and filtered through diatomaceous earth. The filter was washed with ethyl acetate (2x5ml) and the filtrates were combined. The solution was concentrated by evaporation to approximately 2ml and the resultant solid was collected, washed with water (2x5ml) and dried in vacuo to give the title compound as a solid. M.pJ49-150.5°C; ΝMR: 3.8 (s, 3H), 5.78 (s, 2H), 6.67 (d, IH), 7.17 (s, IH), 7.26 (dd, IH), 7.5-7.62 (m, 3H), 7.84 (d, 2H); MS: 262 (M-H) " ; EA: C 13 H 13 ΝO 3 S requires C, 59.3; H, 5.0; N, 5.3; S, 12.2%; found: C, 59.1; H, 4.9; N, 5.2; S, 12.2%. Method 22 2-Methoxy-4-phenylsulphonylnitrobenzene Hydrogen peroxide (0.4ml of a 30 wt. % solution in water) was added to a solution of 2-methoxy-4-phenylthionitrobenzene (0.261g) in glacial acetic acid (1.0ml) and the mixture was stiπed and heated at 100°C for 2 hours. A few drops of water were added and the mixture was cooled and scratched to induce crystallisation. The resultant solid was collected, washed with water (2x5ml) then dried in vacuo to give the title compound (0.263g) as a solid. M.p. 128.5-129.5°C; NMR: 4.01 (s, 3H), 7.6-7.7 (m, 3H), 7.73 (t, IH), 7.81 (s, IH), 8.05 (apparent d, 3H); EA: C, 3 H„NO s S requires C, 53.2; H, 3.8; N, 4.8; S, 10.9%; found: C, 52.9; H, 3.8; N, 4.6; S, 10.8%. - 74 - Methods 23-25 Using the procedure of Example 2 the following compounds were prepared. Method Replacement for Compound Prepared 2-hydroxy-2-methyl-3,3 ? 3-triflu oropropanoic acid 23 3,3-Difluoro-2-hydroxy-2-methyl N-[2-chloro-4-(phenylthio)phenyl]-3,3- propanoic acid ' difluoro-2-hydroxy-2-methylpropanamide 24 ( 1 -Hydroxy- 1 -cyclopropy 1) N- [2-chloro-4-(phenylthio)phenyl] -( 1 -hydrox carboxylic acid y- 1 -cyclopropyl)carboxamide 25 2-Hydroxy-2-methylbutanoic acid N-[2-chloro-4-(phenylthio)phenyl]-2-hydroxy -2-methylbutanamide 1 Chemica 1 Abstracts, 53 :2078i 1959 Method 26 N-r2-Chloro-4-(phenylthio phenyl]-2-ethyl-2-hydroxybutanamide Acetyl chloride (0.785g) was added dropwise to a stiπed solution of 2-ethyl-2-hydroxybutanoic acid (0.528g) in dry toluene (10ml) whilst cooling in an ice/water bath. The mixture was heated at 80°C for 2 hours then volatile material was removed by evaporation and thionyl chloride (0.595g) was added to the residue. The resultant solution was heated at 80°C for 2 hours then volatile material was removed by evaporation to give 2-acetoxy-2-ethylbutanoyl chloride (0.700g). This material was dissolved in dry toluene then added slowly to a solution of 2-chloro-4-phenylthioaniline (Method 11) (0.235g), and pyridine (0.336g) in dry toluene (5ml). The mixture was heated at 100°C for 4 hours then dried. Nolatile material was removed by evaporation and the residue was dissolved in methanol (15ml) and lithium hydroxide monohydrate (0.200g) was added. The mixture was stiπed for 3 hours at ambient temperature then volatile material was removed by evaporation and the residue was partitioned between 2M aqueous hydrochloric acid and dichloromethane. The organic layer was dried and volatile material was removed by evaporation. The residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 5-10% ethyl acetate/hexane to give the title compound (0J9g) as a gum. MS: 348 (M-H) " . 75. Method 27 (R)-N-[ " 2-Chloro-4-(2-nitrophenylthio')phenyll-2-hvdroxy-2-methyl-3.3.3- trifluoropropanamide A mixture of (R)-N-(2-chloro-4-mercaptophenyl)-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide (OJg), l-iodo-2-nitrobenzene (0.086g), sodium methoxide (0.02 lg), and cuprous chloride (0.014g) in DMF (1ml) was stiπed and heated to 135°C for 2.5 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (5ml) and poured onto a Narian Chem Elut column. When the liquid had been adsorbed the column was eluted with ethyl acetate and the eluate was concentrated by evaporation. The residue was purified on a silica gel Mega Bond Elut column, eluting with 5-40%> ethyl acetate/hexane to give the title compound (0.085g) as a glass. MS: 419 (M-H) ' . Methods 27a-l Using the procedure of Method 27 the following compounds were prepared. Meth Replacement for Replacement for Compound Prepared l-iodo-2-nitrobenzene (R)-N-(2-chloro-4- mercapto-phenyl)-2- hydroxy-2-methyl-3,3 » 3- trifluoropropanam.de 27a (R)-N-[2-chloro-4-iodo- 4-Νitrothiophenol (R)-N-[2-chloro-4-(4-nitro phenyl] -2-hydroxy-2- -phenylthio)phenyl] -2- methyl-3 ,3 ,3-trifluoro- hydroxy-2-methyl-3,3,3- propanamide trifluoropropanamide 27b (R)-N-[2-chloro-4-iodo- 2-Mercaptopyrimidine (R)-N-[2-chloro-4- phenyl]-2-hydroxy-2- (pyrimidin-2-ylthio) methyl-3 ,3,3 -trifluorophenyl] -2-hydroxy-2- propanamide methyl-3 ,3 ,3 -trifluoropropanamide 76 c (R)-N-[2-chloro-4-iodo- 2-Mercaptothiazole (R)-N-[2-chloro-4-(thiazol phenyl]-2-hydroxy-2- -2-ylthio)phenyl]-2- methy 1-3 ,3 ,3 -trifluorohydroxy-2-methyl-3 ,3,3- propanamide trifluoropropanamide d (R)-N-[2-chloro-4-iodo- Sodium methanethiolate (R)-N-(2-chloro-4-methyl- phenyl]-2-hydroxy-2- thiophenyl)-2-hydroxy-2- methyl-3 ,3 ,3 -trifluoromethyl-3 ,3 ,3 -trifluoropropanamide propanamide e (R)-N-[2-chloro-4-iodo- 2-Trifluoromethyl- (R)-N-[2-chloro-4-(2-tri- phenyl]-2-hydroxy-2- thiophenol fluoromethylphenylthio) methyl-3 ,3 ,3 -trifluorophenyl]-2-hydroxy-2- propanamide methyl-3 ,3 ,3 -trifluoropropanamide f (R)-N-[2-chloro-4-iodo- 4-Trifluoromethylthio- (R)-N-[2-chloro-4-(4-tri- phenyl]-2-hydroxy-2- phenol fluoromethylphenylthio) methyl-3,3,3-trifluoro- phenyl]-2-hydroxy-2- propanamide methyl-3 ,3 ,3 -trifluoropropanamide g (R)-N-[2-chloro-4-iodo- 3 -Trifluoromethy lthio- (R)-N-[2-chloro-4-(3- phenyl]-2-hydroxy-2- phenol trifluoromethylphenylthio) methyl-3 ,3 ,3 -trifluorophenyl]-2-hydroxy-2- propanamide methy 1-3 ,3,3 -trifluoropropanamide h ' 2-Iodo-5-methylthiophene (R)-N-(2-chloro-4- (R)-N-[2-chloro-4-(5- mercapto-phenyl)-2- methyl-2-thienylthio) hydroxy-2-methy 1-3 ,3,3- phenyl]-2-hydroxy-2- trifluoropropanamide methyl-3,3,3-trifluoro- propanamide 77 . 27i (R)-N-[2-chloro-4-iodo- 2-Mercaptoimidazole (R)-N-[2-chloro-4-(imidaz phenyl]-2-hydroxy-2- ol-2-ylthio) phenyl]-2- methyl-3,3,3-trifluoro- hydroxy-2-methyl-3 ,3,3- propanamide trifluoro-propanamide 27j (R)-N-[2-chloro-4-iodo- 2-Mercaptopyridine (R)-N-[2-chloro-4-(pyrid- phenyl]-2-hydroxy-2- 2- methyl-3 ,3 ,3 -trifluoroylthio)phenyl]-2-hydroxy- propanamide 2-methyl-3,3,3- trifluoropropanamide 27k 3-Iodopyridine (R)-N-(2-chloro-4- (R)-N-[2-chloro-4-(pyrid- mercaptophenyl)-2- 3 -ylthio)phenyl]-2- hydroxy-2-methyl-3,3,3- hydroxy-2-methyl-3 ,3 ,3- trifluoropropanamide trifluoropropanamide 271 (R)-N-[2-chloro-4-iodo- 3 -mercapto-2-methylfuran (R)-N-[2-chloro-4- phenyl]-2-hydroxy-2- ((2-methylfuran-3 -yl)thio) methyl-3 ,3 ,3-trifluoro- phenyl] -2-hydroxy-2- propanamide methy 1-3 ,3,3 -trifluoropropanamide Product was purified by chromatography eluting with 25% ethyl acetate Tiexane Method 28 4-Phenylsulphonyl-2-fluorophenylethyne Bis(triphenylphosphine)palladium(II) chloride (0.06 lg) was added to a solution of ethynyltrimethylsilane (0.295ml) and 2-fluoro-4-phenylsulphonylbromobenzene (Method 29) (0.548g) in triethylamine (5.5ml) and DMF (2ml) and the mixture was heated at 70°C for 18 hours. The mixture was poured into water (70ml) and extracted with ethyl acetate (2 x 70ml) to give a solid (0.46g). A portion of this solid (0.30g) was dissolved in dichloromethane (20ml). Tetrabutylammonium fluoride (0.9 ml of a IM solution in THF) was added. After 10 minutes volatile material was removed by evaporation and the residue was dissolved in dichloromethane and washed with brine. Chromatography of the crude product eluting with 0-30%) ethyl acetate/hexane gave the title compound (0.208g) as a solid. ΝMR (CDC1 3 ): 3.42 - 78 - (s, IH), 7.5-7.7 (m, 6H), 7.94 (d, 2H); MS: 260 (M + ); EA: C 14 H 9 FO 2 S requires C, 64.6; H, 3.5%; found: C, 64.6; H, 3.6%. Method 29 5 2-Fluoro-4-phenylsulphonylbromobenzene Using an analogous procedure to that described in Example 42, 4-bromo-3-fluoro-l-phenylthiobenzene (Method 19a) as the starting material and 20% ethyl acetate/hexane as the eluant for the chromatographic purification there was thus obtained the title compound. NMR (CDC1 3 ): 7.5-7.75 (m, 6H), 7.94 (d, 2H); EA: C 12 H 8 BrFO 2 S requires C, 10 45.7; H, 2.6%; found: C, 46J; H, 2.4%. Method 30 (RVN-[2-Chloro-4-(3-nitrophenylthio phenyll-2-hvdroxy-2-methyl-3.3.3- trifluoropropanamide 15 A mixture of 3-niu-ophenyl disulphide (0.176g) and (R)-N-(2-chloro-4-iodophenyl)- 2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide (0J5g) in diphenyl ether (5ml) was heated and stiπed at 250°C for 2 days. The reaction mixture was cooled, diluted with isohexane (5ml) and purified by chromatography eluting with 10-100% dichloromethane/hexane to give the title compound (0.05g) as an oil. ΝMR (CDC1 3 ): 1.80 (s, 3H), 3.60 (s, IH), 7.40-7.55 (m, 20 4H), 8J0 (br s, 2H), 8.45 (d, IH), 9.05 (br s, IH); MS: 421 (M+H)J Method 31 (R -N-(2-Chloro-4-mercaptophenyl)-2-hvdroxy-2-methyl-3J.3-trifluoropropanamide Trifluoroacetic anhydride (5ml) was added to (R)-N-(2-chloro-4-methylsulphinyl- 25 phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 32)(0J88g). The mixture was stiπed and heated under reflux for 45 minutes then cooled and evaporated to dryness. A mixture of triethylamine (5ml) and methanol (5ml) was added to the residue. This mixture was stiπed for a further 45 minutes then evaporated to dryness. The residue was dissolved in chloroform (50ml), washed with saturated aqueous ammonium chloride solution (50ml), dried 30 and concentrated by evaporation to give the title compound (0J77g) as a gum which was used without purification. MS 298 (M-H) " . - 79 - Method 32 (RVN-(2-Chloro-4-methylsulphinylphenylV2-hvdroxy-2-methyl-3,3,3-trifluoroprop.anamide t-Butylhydroperoxide (0.42 ml of a 5.5M solution in hexanes) was added to a solution of (R)-N-(2-chloro-4-methylthiophenyl)-2-hydroxy-2-methyl-3 ,3 ,3-trifluoropropanamide (Method 27d) (0.304g) and camphorsulphonic acid (0.022g) in chloroform (7ml). The mixture was stiπed for 18 hours and then was purified directly by chromatography eluting with 90% ethyl acetate/hexane to give the title compound (0.294g) as a solid. ΝMR (CDC1 3 ): 1.77 (s, 3H), 2.74 (s, 3H), 4.7 and 4.75 (2 x br s, IH), 7.49 (t, IH), 7.74 (d, IH), 8.59 (m, IH), 9.3 (br d, IH); MS: 328 (M-H) " ; EA: C u H u ClF 3 ΝO 3 S.0J5 Et 2 O requires C, 40.9; H, 3.7; N, 4.1%; found: C, 40.7; H, 3.5; N, 3.9%. Example 62 The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), or a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I) or a pharmaceutically acceptable salt of said compound or said ester (hereafter compound X), for therapeutic or prophylactic use in humans: (a) Tablet I me/tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b) Tablet II mε/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyπolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 - 80 - (c) Tablet III me/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0 (d) Capsule mε/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium stearate 1.5 (e) Injection I (50 me ml) Compound X 5.0%) w/v IN Sodium hydroxide solution 15.0% v/v OJN Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f) Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6%) w/v OJN Sodium hydroxide solution 15.0% v/v Water for injection to 100% (g) Injection III (lmg/ml,buffered to pH6) Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38%) w/v Polyethylene glycol 400 3.5% w/v Water for injection to 100% - 81 - Note The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

Claims: - 82 - CLAIMS; What is claimed is: 1. The use of a compound of the formula (I): /( Rl )„ R 2 HO R3 (I) wherein: ring C is phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; wherein said phenyl or heteroaryl is substituted on carbon at one or both positions meta to the position of A-B attachment or on carbon at the position para to the position of A-B attachment by a group selected from cyano, trifluoromethyl, nitro, trifluoromethoxy, trifluoromethylthio and a group ArY; and further, wherein said phenyl or heteroaryl is substituted on carbon at any remaining meta position(s) or para position by a group or groups independently selected from hydrogen, (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (l-4C)alkenyloxy, cyano, nitro, halo, hydroxy and trifluoromethylthio; in which Ar is selected from the group consisting of phenyl, a carbon-linked six-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked five-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said phenyl or heteroaryl ring Ar is optionally substituted at carbon, with 1-4 substituents selected from (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo and trifluoromethylthio; Y is selected from carbonyl, sulphinyl and sulphonyl; A-B is selected from NHCO, OCH 2 , SCH 2 , NHCH 2 , trαra'-vinylene, and ethynylene; R 1 is linked to ring C at a carbon ortho to the position of A-B attachment and is selected from the group consisting of ( 1 -4C)alkyl, ( 1 -4C)haloalkyl, ( 1 -4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo, trifluoromethylthio and hydroxy; n is 1 or 2; R 2 and R 3 are independently (l-3C)alkyl optionally substituted by from 1 to 2k+l atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said (l-3C)alkyl, provided that R 2 and R 3 are not both methyl; or - 83 - R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring optionally substituted by from 1 to 2m-2 fluorine atoms wherein m is the number of carbon atoms in said ring; and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I); and a pharmaceutically acceptable salt of said compound or said ester; provided said compound is not N-(4-benzoyl-2,6-dimethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans. 2. The use of a compound of the formula (I) as claimed in claim 1 wherein ring C is phenyl and wherein said phenyl is substituted on carbon at the position para to the position of A-B attachment by a group selected from cyano, trifluoromethyl, nitro, trifluoromethoxy and a group ArY wherein A-B and ArY are as defined in claim 1. 3. The use of a compound of the formula (I) as claimed in claim 1 or 2 wherein Y is selected from sulphinyl and sulphonyl. 4. The use of a compoimd of the formula (I) as claimed in claim 1, 2 or 3 wherein A-B is ΝHCO. 5. The use of a compound of the formula (I) as claimed in claim 1, 2, 3 or 4 wherein R 1 is selected from methoxy, nitro, fluoro, chloro, bromo and hydroxy and n is 1. 6. The use of a compound of the formula (I) as claimed in claim 1, 2, 3, 4 or 5 wherein one of R 2 and R 3 is methyl and the other is trifluoromethyl. 7. A compound of the formula (I): ^ ^ l)n R2 Ci>- A - B HJO R R 3 - 84 - (I) wherein ring C, R 1 , n, A-B, R 2 and R 3 are as defined in claim 1 and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (I); and a pharmaceutically acceptable salt of said compound or said ester; provided said compound is not selected from N-(4-benzoyl-2,6-dimethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-fluorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(6-chloro-3-phenylsulfonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-N-[2-methoxy-4-(4-pyridylsulfonyl)phenyl]-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-2-methyl-N-[2-nitro-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoropropanamide, S-(-)-N-(4-benzoyl-2-methylphenyl)-2-hydroxy-2-methyl-3JJ-trifluoropropanamide, N-(4-benzoyl-2-chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-bromophenyl)-3,3-difluoro-2-(difluoromethyl)-2-hydroxypropanamide, N-(4-benzoyl-2-bromophenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-berιzoyl-2-cyanophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, N-(4-benzoyl-2-methoxyphenyl)-2-hydroxy-2-methyl-3 ,3 ,3 -trifluoropropanamide, N-(4-benzoyl-2-hydroxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, 2-hydroxy-N-[2-hydroxy-4-(4-pyridylsulfonyl)phenyl]-2-methyl-3J,3-trifluoropropanamide, N-(4-benzoyl-2,6-dimethylphenyl)-2-hydroxy-2-methyl-3 ,3 ,3-trifluoropropanamide, N-(2-Fluoro-5-nitrophenyl)-2-hydroxy-2-trifluoromethylbutanamide, N-(2-Fluoro-5-nitrophenyl)-2-hydroxy-2-difluoromethyl-3,3-difluoropropanamide, and 3-Hydroxy-3-trifluoromethyl-l-(2-chloro-5-trifluoromethylphenyl)-4,4,4-trifluorobut-l-yne, and pharmaceutically acceptable in vivo cleavable esters of said compounds, and pharmaceutically acceptable salts of said compounds and said esters. 8. A compound of the formula (le) : .O // \\ Are— S(O) y- rC -CF, R lε HO (le) - 85 - wherein: R le is fluoro, chloro or bromo; m is 1 or 2; Are is selected from the group consisting of a carbon-linked six-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked five-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said heteroaryl ring is optionally substituted at carbon, with 1-4 substituents selected from (l-4C)alkyl, (l-4C)haloalkyl, (l-4C)alkoxy, (l-4C)haloalkoxy, (2-4C)alkenyloxy, cyano, nitro, halo and trifluoromethylthio; and a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (le), and a pharmaceutically acceptable salt of said compound or said ester. 9. A compound as claimed in claim 8 which is selected from: (R)-N-[2-Chloro-4-(thien-2-yl-sulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide; (R)-N-[2-Chloro-4-(pyrimid-2-yl-sulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide (R)-N-[2-Chloro-4-(pyrid-4-ylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide; (R)-N-[2-(5-Methyl-thien-2-ylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide; (R)-N- [2-Chloro-4-(imidazol-2-y lsulphonyl)phenyl] -2-hydroxy-2-methy 1-3 ,3,3- trifluoropropanamide; (R)-N-[2-Chloro-4-(pyrid-2-ylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide; (R)-N-[2-Chloro-4-(pyrid-3-ylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide; (R)-N-[2-Chloro-4-(thiazol-2-ylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide; and (R)-N-[2-Chloro-4-(2-methylfur-3-ylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide; and a pharmaceutically acceptable in vivo cleavable ester of said compound; - 86 - and a pharmaceutically acceptable salt of said compound or said ester. 10. A pharmaceutical composition which comprises a compound of the formula (I) or (le) as defined in claim 7, 8 or 9 or a pharmaceutically acceptable in vivo cleavable ester of said compound of formula (le) or a pharmaceutically acceptable salt of said compound or said ester, in association with a pharmaceutically acceptable excipient or carrier. 11. A process for preparing a compound of formula (le) as claimed in claim 8 or 9 which comprises: (a) deprotecting a protected compound having foπnula (He): (He) wherein "Pg" is a suitable alcohol protecting group; (b) when S(O) m is sulphonyl: by treating a compound of formula (Ve): .0 // -N R l l e e u HnO CF ' (Ve) wherein G 1 is iodo, with a compound of formula ArSO 2 ' Na + in the presence of a Cu(I) catalyst; (c) by oxidizing a compound of formula (Ve) wherein G 1 is Are-S-; (d) by coupling a compound of formula (Vie): Are— S(O) V- NH, R le (Vie) with an acid of formula (Vile): - 87 - ,O HO-{ HO K CF> (Vile) (e) by coupling a compound of formula (Vie) with an activated acid derivative of an acid of formula (Vile); (f) by reacting an amide of formula (VHIe): O Are— S(O) H -CF, R H (VHIe) with a base and oxygen in the presence of a reducing agent; (g) by reacting a compound of formula (IXe): Are- ~Hal p ie R (IXe) where Hal is halogen substituent, with an alkali metal amide dianion having formula (Xe): O M + - NH rv O - CF 3 M + (Xe) wherein M is an alkali metal; (h) when S(O) m is sulphony 1: by treating a compound of foπnula (XHe): R le O (XHe) with a compound of formula MeM wherein M is an alkali metal or a compound of formula - 88 - MeMgBr or MeMgCl; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; or iii) forming a pharmaceutically acceptable salt or in vivo cleavable ester.

Inventors: BUTLIN ROGER JOHN, BUTLIN, ROGER, JOHN
Applicants: BUTLIN ROGER JOHN, ZENECA LTD, BUTLIN, ROGER, JOHN, ZENECA LIMITED
Application year: 1999
Main classification: A61K31
IPC codes: A61K31, A61P3, A61P43, C07C317, C07C323