The use of compounds of the formula (I), and salts thereof; and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I); and pharmaceutically acceptable salts of said compound or said prodrugs:

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 xcex2-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 xcex2-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 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, (Vary et al., 1988; Circ. Shock. 24: 3-18), has been shown to have the predicted effects in reducing glycaemia, (Stacpoole et al., 1978; N. 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; N. Engl. J. Med. 309: 390-396).
PDH is an intramitochondrial multienzyme complex consisting of multiple copies of several subunits including three enzyme activities E1, E2 and E3, required for the completion of the conversion of pyruvate to acetyl CoA (Patel and Roche 1990; FASEB J., 4: 3224-3233). E1 catalyses the non-reversible removal of CO2 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 E1 at three serine residues and a loosely-associated specific phosphatase which reverses the phosphorylation. Phosphorylation of a single one of the three serine residues renders the E1 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 Nos. 617010 and 524781 describes compounds which are capable of relaxing bladder smooth muscle and which may be used in the treatment of urge incontinence. We have found that the compounds of the present invention are very good at elevating PDH activity, a property nowhere disclosed in EP 0617010 and EP 524781.
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 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""s disease (AD) (J Neural Transm (1998) 105, 855-870).
According to one aspect of the present invention there is provided the use of compounds of the formula (I):
wherein:
ring C is as defined in (a) or (b);
R1 is as defined in (c) or (d);
n is 1 or 2;
R2 and R3 are as defined in (e) or (f);
Axe2x80x94B is as defined in (g) or (h) and
R4 is as defined in (i) or (j)
wherein
(a) 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 Axe2x80x94B attachment or on carbon at the position para to the position of Axe2x80x94B attachment by P1 or P2 (wherein P1 and P2 are as defined hereinafter), and further, wherein said phenyl or heteroaryl is optionally substituted on carbon at any remaining meta position(s) or para position by P1 or P3, (wherein P1 and P3 are as defined hereinafter);
(b) ring C is selected from the following five groups:
(i) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is unsubstituted except by (R1)n wherein R1 and n are as defined hereinafter;
(ii) a carbon-linked triazine optionally substituted on a ring carbon at a position meta or para to Axe2x80x94B attachment by 1 substituent selected from P1, P2, P3 and P4, wherein P1, P2, P3 and P4 are as defined hereinafter;
(iii) a 6-membered carbon-linked heteroaryl group containing 1-3 nitrogen atoms wherein one or more ring nitrogen atoms are oxidised to form the N-oxide, which heteroaryl group is optionally substituted at any of the positions meta or para to Axe2x80x94B attachment by 1-3 substituents selected from P1, P2, P3 and P4, wherein P1, P2, P3 and P4 are as defined hereinafter;
(iv) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is substituted at a position meta or para to Axe2x80x94B attachment by 1 substituent selected from P3 and P4, wherein P3 and P4 are as defined hereinafter; and
(v) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is substituted at any of the positions meta or para to Axe2x80x94B attachment by 2-3 substituents selected from P1, P2, P3 and P4, provided that if one or more of the substituents is P1 or P2 then at least one of the other substituents is P4, wherein
P1, P2, P3 and P4 are as defined hereinafter;
P1 is cyano, trifluoromethyl, nitro, trifluoromethoxy or trifluoromethylsulphanyl;
P2 is xe2x80x94Y1Ar1, wherein Ar1 is selected from the group consisting of phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms selected independently from O, N and S, wherein said phenyl or heteroaryl ring is optionally substituted at carbon, with 1-4 substituents selected from Q1, wherein Q1 is as defined hereinafter; and Y1 is selected from xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94 and xe2x80x94SO2xe2x80x94;
P3 is C1-4alkyl, haloC2-4alkyl, C1-4alkoxy, haloC2-4alkoxy, C2-4alkenyloxy, halo or hydroxy;
P4 is selected from the following eight groups:
xe2x80x831) halosulphonyl, cyanosulphanyl;
xe2x80x832) xe2x80x94X1xe2x80x94R5 wherein X1 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94N+Oxe2x88x92R6xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94OCONR9xe2x80x94, xe2x80x94CONR10SO2xe2x80x94, xe2x80x94NR11SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR12COOxe2x80x94, xe2x80x94CSNR13xe2x80x94, xe2x80x94NR14CSxe2x80x94, xe2x80x94NR15CSNR16xe2x80x94, NR17CONR18xe2x80x94 or xe2x80x94NR19CONR20SO2xe2x80x94 (wherein R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R5 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkynyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-4alkyl with the proviso that P4 is not trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
xe2x80x833) xe2x80x94X1xe2x80x94C1-6alkyl-X2xe2x80x94R21 wherein X1 is as defined hereinbefore, X2 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94NR22xe2x80x94, xe2x80x94N+Oxe2x88x92R22xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR23xe2x80x94, xe2x80x94NR24COxe2x80x94, xe2x80x94NR25COOxe2x80x94, xe2x80x94SO2NR26xe2x80x94, xe2x80x94NR27SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR28COxe2x80x94, xe2x80x94OCONR29xe2x80x94, xe2x80x94CSNR30xe2x80x94, xe2x80x94NR31CSxe2x80x94, xe2x80x94NR32CSNR33xe2x80x94, xe2x80x94NR34CONR35xe2x80x94, xe2x80x94CONR36SO2xe2x80x94, xe2x80x94NR37CONR38SO2xe2x80x94, xe2x80x94SO2NR39CONR40xe2x80x94 or xe2x80x94SO2NR39CNNR40xe2x80x94 (wherein R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39 and R40, each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R21 is hydrogen or C1-4alkyl which C1-4alkyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl or R21 is R41 wherein R41 is phenyl or a 4-12 membered heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S which heterocyclic moiety may be aromatic or non-aromatic and which phenyl or heterocyclic moiety is optionally substituted by 1-6 substituents selected from Q3 wherein Q3 is as defined hereinafter with the proviso that P4 is not C1-4alkyl, haloC1-4alkyl, C1-4alkoxy or haloC1-4alkoxy;
xe2x80x834) xe2x80x94X1xe2x80x94C2-6alkenyl-X2xe2x80x94R21 wherein X1, X2 and R21 are as defined hereinbefore with the proviso that P4 is not C2-4alkenyloxy;
xe2x80x835) xe2x80x94X1xe2x80x94C2-6alkynyl-X2xe2x80x94R21 wherein X1, X2 and R21 are as defined hereinbefore;
xe2x80x836) xe2x80x94X1xe2x80x94C3-7cycloalkyl-X2xe2x80x94R21 wherein X1, X2 and R21 are as defined hereinbefore;
xe2x80x837) xe2x80x94X1xe2x80x94C1-6alkylC3-7cycloalkyl-X2xe2x80x94R21 wherein X1, X2 and R21 are as defined hereinbefore; and
xe2x80x838) xe2x80x94Y2Ar2 wherein Y2 is X1 wherein X1 is as defined hereinbefore and Ar2 is selected from the following six groups:
(i) phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms selected independently from O, N and S, wherein said phenyl or heteroaryl ring is substituted at carbon, with 1-4 substituents selected from Q1 and Q2 including at least one substituent selected from Q2 wherein Q1 and Q2 are as defined hereinafter;
(ii) a carbon-linked triazine or a carbon-linked 5-membered heteroaryl ring containing 3-4 heteroatoms selected independently from O, N and S; wherein said heteroaryl ring is optionally substituted with 1-4 substituents selected from Q1 and Q2 wherein Q1 and Q2 are as defined hereinafter;
(iii) a 4-12 membered non-aromatic heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S wherein said heterocyclic moiety is optionally substituted with 1-6 substituents selected from Q3 wherein Q3 is as defined hereinafter, with the proviso that if Ar2 is a nitrogen linked heterocyclic ring Y2 is not xe2x80x94SO2xe2x80x94;
(iv) a 5-membered heteroaryl ring containing 1-4 heteroatoms selected independently from O, N and S, which heteroaryl ring contains at least one nitrogen atom substituted by a group selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, benzoyl or phenylsulphonyl and which heteroaryl ring is optionally substituted by 1-3 substituents selected from Q3 wherein Q3 is as defined hereinafter;
(v) a carbon linked 7-12 membered aromatic heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S wherein said heterocyclic moiety is optionally substituted with 1-6 substituents selected from Q3 wherein Q3 is as defined hereinafter; and
(vi) Ar1 with the proviso that if Ar2 has a value Ar1 then Y2 is not xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
Q1 is C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C2-4alkenyloxy, cyano, nitro, halo or trifluoromethylsulphanyl;
Q2 is selected from the following ten groups:
1) oxygen (forming an oxo group when linked to a ring carbon and forming an N-oxide when a ring nitrogen is oxidised);
2) halosulphonyl, cyanosulphanyl;
3) xe2x80x94X3xe2x80x94R5 wherein X3 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94NR42xe2x80x94, xe2x80x94N+Oxe2x88x92, R42xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR43xe2x80x94, xe2x80x94NR44COxe2x80x94, xe2x80x94NR45COOxe2x80x94, xe2x80x94SO2NR46xe2x80x94, xe2x80x94NR47SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR48COxe2x80x94, xe2x80x94OCONR49xe2x80x94, xe2x80x94CSNR50xe2x80x94, xe2x80x94NR51CSxe2x80x94, xe2x80x94NR52CSNR53xe2x80x94, xe2x80x94NR54CONR55xe2x80x94, xe2x80x94CONR56SO2xe2x80x94, xe2x80x94NR57CONR58SO2xe2x80x94, xe2x80x94SO2NR57CNNR58xe2x80x94 or xe2x80x94SO2NR59CONR60xe2x80x94 (wherein R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59 and R60 each independently represents hydrogen or C1-4alkyl which C1-4akyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R5 is as defined hereinbefore but with the proviso that Q2 is not trifluoromethylsulphanyl, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
4) R41 wherein R41 is as defined hereinbefore;
5) xe2x80x94X3xe2x80x94C1-6alkyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore but with the proviso that Q2 is not C1-4alkyl, haloC1-4alkyl, C1-4alkoxy or haloC1-4alkoxy;
6) xe2x80x94X3xe2x80x94C2-6alkenyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore but with the proviso that Q2 is C2-4alkenyloxy;
7) xe2x80x94X3xe2x80x94C2-6alkynyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore;
8) xe2x80x94X3xe2x80x94C3-7cycloalkyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore;
9) xe2x80x94X3xe2x80x94C1-6alkylC3-7cycloalkyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore; and
10) xe2x80x94X3xe2x80x94R41 wherein R41 and X3 are as defined hereinbefore;
Q3 is selected from the following four groups:
xe2x80x831) oxygen (forming an oxo group when linked to a ring carbon and forming an N-oxide when a ring nitrogen is oxidised);
xe2x80x832) cyano, nitro or halo;
xe2x80x833) halosulphonyl, cyanosulphanyl; and
xe2x80x834) xe2x80x94X4xe2x80x94R61 wherein X4 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94NR62xe2x80x94, xe2x80x94N+Oxe2x88x92, R62xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR63xe2x80x94, xe2x80x94NR64COxe2x80x94, xe2x80x94NR65COOxe2x80x94, xe2x80x94SO2NR66xe2x80x94, xe2x80x94NR67SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR68COxe2x80x94, xe2x80x94OCONR69xe2x80x94, xe2x80x94CSNR70xe2x80x94, xe2x80x94NR71CSxe2x80x94, xe2x80x94NR72CSNR73xe2x80x94, xe2x80x94NR74CONR75xe2x80x94, xe2x80x94CONR76SO2xe2x80x94, xe2x80x94NR77CONR78SO2xe2x80x94, xe2x80x94SO2NR79CNNR80xe2x80x94 or xe2x80x94SO2NR79CONR80xe2x80x94 (wherein R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79 and R80 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R61 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkynyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl;
(c) R1 is linked to ring C at a carbon ortho to the position of Axe2x80x94B attachment and is selected from the group consisting of C1-4alkyl, haloC1-4allyl, C1-4alkoxy, haloC1-4alkoxy, C2-4alkenyloxy, cyano, nitro, halo, trifluoromethylsulphanyl and hydroxy;
(d) R1 is linked to ring C at a ring carbon atom ortho to the position of Axe2x80x94B attachment and is selected from the following two groups:
1) xe2x80x94X5xe2x80x94R81 wherein X5 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94NR82xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR83xe2x80x94, xe2x80x94NR84COxe2x80x94, xe2x80x94NR85COOxe2x80x94, xe2x80x94SO2NR86xe2x80x94, xe2x80x94NR87SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR88COxe2x80x94, xe2x80x94OCONR89xe2x80x94, xe2x80x94CSNR90xe2x80x94, xe2x80x94NR91CSxe2x80x94, xe2x80x94NR92CSNR93xe2x80x94, xe2x80x94NR94CONR95xe2x80x94, xe2x80x94CONR96SO2xe2x80x94, xe2x80x94NR97CONR98SO2xe2x80x94, xe2x80x94SO2NR99CNNR100xe2x80x94 or xe2x80x94SO2NR99CONR100xe2x80x94 (wherein R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99 and R100 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R81 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkynyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl with the proviso that R1 is not trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy; and
2) xe2x80x94X6xe2x80x94R101 wherein X6 is selected from a direct bond, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 and xe2x80x94NR102xe2x80x94 (wherein R102 is hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R101 is phenyl which is optionally substituted by 1-4 substituents selected from cyano, nitro, trifluoromethylsulphanyl, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C2-6alkenyloxy, halo, hydroxy and amino;
n is 1 or 2;
(e) either R2 and R3 are independently C1-3alkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said C1-3alkyl, provided that R2 and R3 are not both methyl;
or R2 and R3, together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring optionally substituted by from 1 to 2mxe2x88x922 fluorine atoms wherein m is the number of carbon atoms in said ring;
(f) R2 and R3 are both methyl or one of R2 and R3 is hydrogen or halo and the other is halo or C1-3alkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said C1-3alkyl, with the proviso that when either R2 or R3 is halo R4 is not hydroxy and with the proviso that when either R2 or R3 is hydrogen, R4 is not hydrogen;
(g) Axe2x80x94B is selected from xe2x80x94NHCOxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94NHCH2xe2x80x94, trans-vinylene, and ethynylene;
(h) Axe2x80x94B is xe2x80x94NHCSxe2x80x94 or xe2x80x94COCH2xe2x80x94;
(i) R4 is hydroxy;
(j) R4 is hydrogen, halo, amino or methyl;
but excluding compounds wherein ring C is selected from (a) and R1 is selected only from (c) and R2 and R3 are selected from (e) and Axe2x80x94B is selected from (g) and R4 is selected from (i);
and salts thereof;
and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I);
and pharmaceutically acceptable salts of said compound or said prodrugs;
in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans.
Advantageously Q1 is C1-2alkyl, haloC1-2alkyl, C1-2alkoxy, cyano or halo.
In one embodiment of the present invention Ar1 is phenyl or 4-pyridyl and is optionally substituted as defined hereinbefore.
In another embodiment of the present invention Ar1 is phenyl and is optionally substituted as defined hereinbefore.
Preferably Y1 is xe2x80x94SO2xe2x80x94 or xe2x80x94SOxe2x80x94, more preferably xe2x80x94SO2xe2x80x94.
Advantageous values for X1 are a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94OCONR9xe2x80x94, xe2x80x94CONR10SO2xe2x80x94, xe2x80x94NR11SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR12COOxe2x80x94, xe2x80x94CSNR13xe2x80x94, xe2x80x94NR14CSxe2x80x94, xe2x80x94NR15CSNR16xe2x80x94, NR17CONR18xe2x80x94 and xe2x80x94NR19CONR20SO2xe2x80x94 (wherein R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferred values for X1 are xe2x80x94Oxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94NR11SO2xe2x80x94, xe2x80x94CH2xe2x80x94 and xe2x80x94NR12COOxe2x80x94 (wherein R6, R7, R8, R11 and R12 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
More preferred values of X1 are xe2x80x94SOxe2x80x94 and SO2xe2x80x94.
Advantageously R5 is selected from hydrogen, C1-4alkyl, C3-7cycoalkyl, C2-4alkenyl and C2-4alkynyl which C1-4alkyl, C3-7cycloalkyl, C2-4alkenyl or C2-4alkynyl is optionally substituted as defined hereinbefore.
Preferably R5 is selected from hydrogen, C1-4alkyl and C3-7cycloalkyl, which C1-4alkyl or C3-7cycloalkyl, is optionally substituted as defined hereinbefore.
Advantageous values for X2 are xe2x80x94Oxe2x80x94, xe2x80x94NR22xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 and SO2xe2x80x94, (wherein R22 is hydrogen or C1-4alkyl).
Preferred values for X2 are xe2x80x94Oxe2x80x94, xe2x80x94NR22xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 and xe2x80x94SO2xe2x80x94 (wherein R22 is hydrogen or C1-2alkyl).
More preferred values for X2 are xe2x80x94Oxe2x80x94 and xe2x80x94NR22xe2x80x94 (wherein R22 is hydrogen or C1-2alkyl).
Advantageous values for X4 are a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, SO2xe2x80x94, xe2x80x94NR62xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR63xe2x80x94, xe2x80x94NR64COxe2x80x94, xe2x80x94NR65COOxe2x80x94, xe2x80x94SO2NR66xe2x80x94, xe2x80x94NR67SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR68COxe2x80x94, xe2x80x94OCONR69xe2x80x94, xe2x80x94CSNR70xe2x80x94, xe2x80x94NR71CSxe2x80x94, xe2x80x94NR72CSNR73xe2x80x94, xe2x80x94NR74CONR75xe2x80x94, xe2x80x94CONR76SO2xe2x80x94, xe2x80x94NR77CONR78SO2xe2x80x94 and xe2x80x94SO2NR79CONR80xe2x80x94 (wherein R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R79, R79 and R80 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferred values for X4 are xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, SO2xe2x80x94, xe2x80x94NR62xe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94CONR63xe2x80x94, xe2x80x94NR64COxe2x80x94 and xe2x80x94NR67SO2xe2x80x94 (wherein R62, R63, R64 and R65 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
More preferred values for X4 are xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 and xe2x80x94SO2xe2x80x94.
In another aspect of the invention more preferred values for X4 are xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94CONR63xe2x80x94 and xe2x80x94SO2xe2x80x94.
Advantageously R61 is selected from hydrogen, C1-4alkyl, C3-7cycloalkyl, C2-4alkenyl and C2-4alkynyl which C1-4alkyl, C3-7cycloalkyl, C2-4alkenyl or C2-4alkynyl is optionally substituted as hereinbefore defined.
Preferably R61 is selected from hydrogen, C1-4allkyl and C3-7cycloalkyl, which C1-4alkyl or C3-7cycloalkyl is optionally substituted as hereinbefore defined.
Advantageously Q3 is selected from the following three groups:
(i) oxygen (formning an oxo group when linked to a ring carbon and forming an N-oxide when a ring nitrogen is oxidised);
(ii) cyano, nitro or halo; and
(iii) xe2x80x94X4xe2x80x94R61 wherein X4 and R61 are as defined hereinbefore.
Advantageously R41 is phenyl, a 5-6 membered heterocyclic aromatic ring containing 1-4 heteroatoms selected independently from O, N and S or a 5-7 membered heterocyclic non-aromatic moiety containing 1-2 heteroatoms selected independently from O, N and S which phenyl, heterocyclic aromatic ring or heterocyclic non-aromatic moiety is optionally substituted as defined hereinbefore.
Advantageously R21 is hydrogen or C1-4alkyl.
Advantageously X3 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR42xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR43xe2x80x94, xe2x80x94NR44COxe2x80x94, xe2x80x94NR45COOxe2x80x94, xe2x80x94SO2NR46xe2x80x94, xe2x80x94NR47SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR48COxe2x80x94, xe2x80x94OCONR49xe2x80x94, xe2x80x94CSNR50xe2x80x94, xe2x80x94NR51CSxe2x80x94, xe2x80x94NR52CSNR53xe2x80x94, xe2x80x94NR54CONR55xe2x80x94, xe2x80x94CONR56SO2xe2x80x94, xe2x80x94NR57CONR58SO2xe2x80x94 or xe2x80x94SO2NR59CONR60xe2x80x94 (wherein R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59 and R60 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR42xe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94CONR43xe2x80x94, xe2x80x94NR44COxe2x80x94, xe2x80x94SO2NR46xe2x80x94, xe2x80x94NR47SO2xe2x80x94, xe2x80x94SO2NR48COxe2x80x94 or xe2x80x94CONR56SO2xe2x80x94 (wherein R42, R43, R44, R46, R47, R48 and R56 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Advantageously Q2 is selected from the following seven groups:
1) oxygen (forming an oxo group when linked to a ring carbon and forming an N-oxide when a ring nitrogen is oxidised);
2) halosulphonyl, cyanosulphanyl:
3) xe2x80x94X3xe2x80x94R5 wherein X3 and R5 are as defined hereinbefore but with the proviso that Q2 is not trifluoromethylsulphanyl, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
4) R41 wherein R41 is as defined hereinbefore;
5) xe2x80x94X3xe2x80x94C1-4alkyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore;
6) xe2x80x94X3xe2x80x94C3-7cycloalkyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore; and
7) xe2x80x94X3xe2x80x94R41 wherein R41 and X3 are as defined hereinbefore.
Preferably Q2 is xe2x80x94X3xe2x80x94R5 wherein X3 and R5 are as defined hereinbefore but with the proviso that Q2 is not trifluoromethylsulphanyl, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy.
Advantageously Ar2 is selected from the following two groups:
1) phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms selected independently from O, N and S, wherein said phenyl or heteroaryl ring is substituted at carbon, with 1-4 substituents selected from Q1 and Q2 including at least one substituent selected from Q2 wherein Q1 and Q2 are as defined hereinafter; and
2) Ar1 with the proviso that if Ar2 has a value Ar1 then Y2 is not xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94.
Preferably Ar2 is phenyl substituted with one substituent selected from Q2.
Advantageously P4 is selected from the following five groups:
1) halosulphonyl, cyanosulphanyl;
2) xe2x80x94X1xe2x80x94R5 wherein X1 and R5 are as defined hereinbefore with the proviso that P4 is not trifluoromethyl, trifluoromethoxy, trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
3) xe2x80x94X1xe2x80x94C1-4alkyl-X2xe2x80x94R21 wherein X1, X2 and R21 are as defined hereinbefore;
4) xe2x80x94X1xe2x80x94C3-7cycloalkyl-X2xe2x80x94R21 wherein X1, X2 and R21 are as defined hereinbefore; and
5) xe2x80x94Y2Ar2 wherein Y2 and Ar2 are as defined hereinbefore.
Preferably P4 is selected from the following three groups:
1) halosulphonyl, cyanosulphanyl;
2) xe2x80x94X1xe2x80x94R5 wherein X1 and R5 are as defined hereinbefore with the proviso that P4 is not trifluoromethyl, trifluoromethoxy, trifluoromethylsulphanyl, hydroxy, C1-4alkyl, halo1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy; and
3) xe2x80x94Y2Ar2 wherein Y2 and Ar2 are as defined hereinbefore.
Advantageously R101 is phenyl which is optionally substituted by 1-4 substituents selected from cyano, nitro, trifluoromethylsulphanyl, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C2-4alkenyloxy, halo, hydroxy and amino.
Advantageously X6 is selected from a direct bond, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 and xe2x80x94NR102xe2x80x94 (wherein R102 is hydrogen or C1-2alkyl).
Advantageously R81 is selected from hydrogen, C1-4alkyl, C3-7cycloalkyl, C2-4alkenyl and C2-4alkynyl which C1-4alkyl, C3-7cycloalkyl, C2-4alkenyl or C2-4alkynyl is optionally substituted as defined hereinbefore.
Preferably R81 is selected from hydrogen, C1-4alkyl and C3-7cycloalkyl, which C1-4alkyl and C3-7cycloalkyl is optionally substituted as defined hereinbefore.
Advantageously X5 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR82xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR83xe2x80x94, xe2x80x94NR84COxe2x80x94, xe2x80x94NR85COOxe2x80x94, xe2x80x94SO2NR86xe2x80x94, xe2x80x94NR87SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR88COxe2x80x94, xe2x80x94OCONR89xe2x80x94, xe2x80x94CSNR90xe2x80x94, xe2x80x94NR91CSxe2x80x94, xe2x80x94NR92CSNR93xe2x80x94, xe2x80x94NR94CONR95xe2x80x94, xe2x80x94CONR96SO2xe2x80x94, xe2x80x94NR97CONR98SO2xe2x80x94 or xe2x80x94SO2NR99CONR100 (wherein R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99 and R100 each independently represents hydrogen C1-2alkyl or C1-2alkoxyethyl).
Preferably X5 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94NR82xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94CONR83xe2x80x94, xe2x80x94NR84COxe2x80x94, xe2x80x94NR87SOxe2x80x94 (wherein R82, R83, R84, and R87 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Advantageous values for R1 in group (c) are C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, cyano, nitro, halo and hydroxy.
Preferred values for R1 in group (c) are C1-2alkyl, C1-2alkoxy, cyano, nitro, halo and hydroxy.
More preferred values for R1 in group (c) are methyl, methoxy, nitro, fluoro, chloro, bromo and hydroxy.
Particular values for R1 in group (c) are methoxy, nitro, fluoro, chloro, bromo and hydroxy.
In one aspect of the invention preferably R1 is selected from halo, nitro, C1-4alkyl, C1-4alkoxy, C2-4alkenyl, C2-4alkynyl and hydrogen.
In another aspect of the invention preferably R1 is selected from C1-4alkoxy, halo, nitro or R1 is X5xe2x80x94R81 wherein X5 is a direct bond, xe2x80x94NHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NHSO2xe2x80x94 and R81 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl or R1 is xe2x80x94X6xe2x80x94R101 wherein xe2x80x94X6 is xe2x80x94COxe2x80x94 and R101 is phenyl substituted by halo.
In a further aspect of the invention preferably R1 is selected from fluoro and chloro.
In an additional aspect of the invention, preferably R1 is not hydrogen.
Preferably n is 1.
A preferred value for Axe2x80x94B in group (g) is NHCO.
Advantageous values for ring C in group (a) are:
phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted as defined hereinbefore.
More advantageous values for ring C in group (a) are:
phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of Axe2x80x94B attachment by a group selected from cyano, trifluoromethyl, nitro, triflouromethoxy trifluoromethylsulphanyl and a group P2 (wherein Axe2x80x94B and P2 are as defined hereinbefore).
Preferred values for ring C in group (a) are:
phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of Axe2x80x94B attachment by a group selected from cyano, trifluoromethyl, nitro and a group P2 (wherein Axe2x80x94B and P2 are as defined hereinbefore).
More preferred values for ring C in group (a) are:
phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted on carbon at the position para to the position of Axe2x80x94B attachment by a group P2 (wherein Axe2x80x94B and P2 are as defined hereinbefore).
A particular value for ring C in group (a) is phenyl which is substituted as defined hereinbefore.
A more particular value for ring C in group (a) is phenyl which is substituted on carbon at the position para to the position of Axe2x80x94B attachment by a group P2 (wherein Axe2x80x94B and P2 are as defined hereinbefore).
Advantageous values for ring C in group (b) are:
(i) phenyl or pyridyl wherein said phenyl or pyridyl is unsubstituted except by (R1)n wherein R1 and n are as defined hereinbefore;
(ii) a carbon-linked triazine optionally substituted on a ring carbon at a position para to Axe2x80x94B attachment by 1 substituent selected from P1, P2, P3 and P4, wherein Axe2x80x94B, P1, P2, P3 and P4 are as defined hereinbefore;
(iii) a 6-membered carbon-linked heteroaryl group containing 1-3 nitrogen atoms wherein one or more ring nitrogen atoms are oxidised to form the N-oxide, which heteroaryl group is optionally substituted at a position para to Axe2x80x94B attachment by 1 substituent selected from P1, P2, P3 and P4, wherein Axe2x80x94B, P1, P2, P3 and P4 are as defined hereinbefore;
(iv) phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted at a position para to Axe2x80x94B attachment by 1 substituent selected from P3 and P4, wherein Axe2x80x94B, P3 and P4 are as defined hereinbefore; and
(v) phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted at any of the positions meta or para to Axe2x80x94B attachment by 2-3 substituents selected from P1, P2, P3 and P4, provided that if one or more of the substituents is P1 or P2 then at least one of the other substituents is P4, wherein Axe2x80x94B, P1, P2, P3 and P4 are as defined hereinbefore.
More advantageous values for ring C in group (b) are:
(i) phenyl or pyridyl wherein said phenyl or pyridyl is unsubstituted except by (R1)n wherein R1 and n are as defined hereinbefore;
(ii) a 6-membered carbon-linked heteroaryl group containing 1-3 nitrogen atoms wherein one or more ring nitrogen atoms are oxidised to form the N-oxide, which heteroaryl group is optionally substituted at a position para to Axe2x80x94B attachment by 1 substituent selected from P1, P2, P3 and P4, wherein Axe2x80x94B, P1, P2, P3 and P4 are as defined hereinbefore; and
(iii) phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted at a position para to Axe2x80x94B attachment by 1 substituent selected from P3 and P4, wherein Axe2x80x94B, P3 and P4 are as defined hereinbefore.
Preferred values for ring C in group (b) are:
(i) phenyl or pyridyl wherein said phenyl or pyridyl is unsubstituted except by (R1)n wherein R1 and n are as defined hereinbefore; and
(ii) phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted at a position para to Axe2x80x94B attachment by 1 substituent selected from P3 and P4, wherein Axe2x80x94B, P3 and P4 are as defined hereinbefore.
More preferred values for ring C in group (b) are:
(i) phenyl or pyridyl wherein said phenyl or pyridyl is unsubstituted except by (R1)n wherein R1 and n are as defined hereinbefore;
(ii) phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl is substituted at a position para to Axe2x80x94B attachment by xe2x80x94Y2Ar2 wherein Axe2x80x94B, Y2 and Ar2 are as defined hereinbefore.
A particular value for ring C in group (b) is phenyl wherein said phenyl is substituted at a position para to Axe2x80x94B attachment by xe2x80x94Y2Ar2 wherein Axe2x80x94B, Y2 and Ar2 are as defined hereinbefore.
In an further feature of the invention preferably ring C is phenyl substituted by one group selected from P4 wherein P4 is as defined above.
More preferably ring C is phenyl substituted at a position para to Axe2x80x94B by a group selected from:
1) xe2x80x94X1xe2x80x94R5 wherein X1 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94 or xe2x80x94CONR7xe2x80x94 (wherein R6 and R7 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy or C1-6alkoxy) and R5 is selected from hydrogen and C1-6alkyl, which C1-6alkyl, is optionally substituted with one or more groups selected from hydroxy and C1-6alkoxy and hydroxyC1-6alkyl with the proviso that xe2x80x94X1xe2x80x94R5 is not hydroxy, C1-4alkyl or C1-4alkoxy;
2) xe2x80x94X1xe2x80x94C1-6alkyl-X2xe2x80x94R21 wherein X1 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94 or xe2x80x94CONR7xe2x80x94 (wherein R6 and R7 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy or C1-6alkoxy), X2 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR22xe2x80x94 or xe2x80x94CONR23xe2x80x94 (wherein R22 and R23 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy or C1-6alkoxy) and R21 is hydrogen or C1-4alkyl, which C1-4alkyl is optionally substituted with one or more groups selected from hydroxy or C1-6alkoxy or R21 is R41 wherein R41 is as defined hereinbefore with the proviso that xe2x80x94X1xe2x80x94C1-4alkyl-X2xe2x80x94R21 is not C1-4alkyl or C1-4alkoxy;
3) xe2x80x94Y2Ar2 wherein Y2 is X1 wherein X1 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94 or xe2x80x94CONR7xe2x80x94 (wherein R6 and R7 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy or C1-6alkoxy) and Ar2 is as defined hereinbefore.
Advantageously when selected from group (e) R2 and R3 are independently C1-3alkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro, wherein k is the number of carbon atoms in the said C1-3alkyl, provided that R2 and R3 are not both methyl; or
R2 and R3, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms.
Preferably when selected from group (e) R2 and R3 are independently C1-3alkyl optionally substituted by from 1 to 2k+1 fluorine atoms, wherein k is the number of carbon atoms in the said C1-3alkyl, provided that R2 and R3 are not both methyl; or
R2 and R3, 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 when selected from group (e) R2 and R3 are independently methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and perfluoroethyl provided that R2 and R3 are not both methyl; or
R2 and R3, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms.
Particularly when selected from group (e) R2 and R3 are independently methyl, fluoromethyl, difluoromethyl and trifluoromethyl, provided that R2 and R3 are not both methyl; or
R2 and R3, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms.
Advantageously when selected from group (f) R2 and R3 are both methyl or one of R2 and R3 is hydrogen or halo and the other is halo or C1-3alkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said C1-3alkyl, with the proviso that when either R2 or R3 is halo R4 is not hydroxy and with the proviso that when either R2 or R3 is hydrogen, R4 is not hydrogen.
More advantageously when selected from group (f) R2 and R3 are both methyl or one of R2 and R3 is hydrogen or chloro and the other is chloro or methyl with the proviso that when either R2 or R3 is chloro R4 is not hydroxy and with the proviso that when either R2 or R3 is hydrogen, R4 is not hydrogen.
Preferably when selected from group (f) R2 and R3 are both methyl or both chloro with the proviso that when R2 and R3 are both chloro R4 is not hydroxy.
More preferably when selected from group (f) R2 and R3 are both methyl.
Preferably when selected from group (j) R4 is hydrogen.
Where applicable, the R-configuration generally represents a preferred stereochemistry or compounds of formula (I).
Preferably R1 is selected from group (c) as defined hereinbefore.
Preferably Axe2x80x94B is selected from group (g) as defined hereinbefore.
Preferably R4 is selected from group (i) as defined hereinbefore.
In another aspect of the invention, preferably R4 is hydroxy, hydrogen or methyl.
Advantageously ring C is selected from the following values from group (a):
phenyl substituted at the position para to the position of Axe2x80x94B attachment by xe2x80x94Y1Ar1 wherein Y1 is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 and Ar1 is phenyl or 3-pyridyl which phenyl or 3-pyridyl is optionally substituted as defined hereinbefore;
or from the following values from group (b):
(i) phenyl unsubstituted except by (R1)n wherein R1 and n are as defined hereinbefore; and
(ii) phenyl substituted at the position para to Axe2x80x94B attachment by 1 substituent selected from P3 and P4 wherein P3 and P4 are as defined hereinbefore.
More advantageously ring C is selected from the following values from group (a):
phenyl substituted at the position para to the position of Axe2x80x94B attachment by xe2x80x94Y1Ar1 wherein Y1 is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 and Ar1 is phenyl or 3-pyridyl which phenyl or 3-pyridyl is optionally substituted as defined hereinbefore;
or from the following values from group (b):
(i) phenyl unsubstituted except by (R1)n wherein R1 and n are as defined hereinbefore; and
(ii) phenyl substituted at the position para to Axe2x80x94B attachment by 1 substituent selected from halo and P4 wherein P4 is selected from the three following groups:
1) halosulphonyl, cyanosulphanyl;
2) xe2x80x94X1xe2x80x94R1 wherein X1 and R5 are as defined hereinbefore with the proviso that P4 is not trifluoromethyl, trifluoromethoxy, trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy; and
3) xe2x80x94Y2Ar2 wherein Y2 and Ar2 are as defined hereinbefore.
Preferably ring C is selected from the following values from group (a):
phenyl substituted at the position para to the position of Axe2x80x94B attachment by xe2x80x94Y1Ar1 wherein Y1 is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 and Ar1 is phenyl or 3-pyridyl which phenyl or 3-pyridyl is optionally substituted as defined hereinbefore;
or from the following values from group (b):
(i) phenyl unsubstituted except by (R1)n wherein R1 and n are as defined hereinbefore; and
(ii) phenyl substituted at the position para to Axe2x80x94B attachment by 1 substituent selected from halo and P4 wherein P4 is selected from the three following groups:
1) halosulphonyl;
2) xe2x80x94X1xe2x80x94R5 wherein X1 and R5 are as defined hereinbefore with the proviso that P4 is not trifluoromethyl, trifluoromethoxy, trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy; and
3) xe2x80x94Y2Ar2 wherein either
(i) Ar1 is phenyl or 3-pyridyl wherein said phenyl or pyridyl is substituted at carbon with 1-4 substituents selected from Q1 and Q2 including at least one substituent selected from Q2 wherein Q1 and Q2 are as defined hereinbefore, and Y2 is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94CONR7xe2x80x94 wherein R7 is hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl; or
(ii) Ar2 is phenyl or 3-pyridyl wherein said phenyl or pyridyl is substituted at carbon with 1-4 substituents selected from Q1 wherein Q1 is as defined hereinbefore and Y2 is xe2x80x94Sxe2x80x94 or xe2x80x94CONR7xe2x80x94 wherein R7 is hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl.
Preferably R2 and R3 are selected from the following values from group (e):
R2 and R3 are independently methyl, fluoromethyl, difluoromethyl and trifluoromethyl, provided that R2 and R3 are not both methyl; or
R2 and R3 are selected from the following values from group (f):
R2 and R3 are both methyl.
More preferably one of R2 and R3 is trifluoromethyl and the other is methyl or both R2 and R3 are methyl.
In one aspect of the invention preferably R2 and R3 are independently Ckalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3,
or R2 and R3 together with the carbon atom to which they are attached, form a 3-membered cycloalkyl ring.
In another aspect of the invention preferably R2 and R3 are independently Ckalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3.
According to a further aspect of the present invention there are provided compounds of the formula (I), as defined hereinbefore,
and salts thereof;
and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I);
and pharmaceutically acceptable salts of said compound or said prodrugs;
but excluding the following compounds: 2-hydroxy-N-(2-methoxyphenyl)-2-methylpropanamide; 2-hydroxy-N-(2-methylphenyl)-2-methylpropanamide; 2-hydroxy-N-(2-methylphenyl)propanamide; N-(2,4-dimethylphenyl)-2-hydroxypropanamide; N-(2,5-dimethylphenyl)-2-hydroxypropanamide; N-(2,6-dimethylphenyl)-2-hydroxypropanamide; N-(2-chlorophenyl)-2-hydroxypropanamide; 2-hydroxy-N-(2-methoxyphenyl)propanamide; N-(2,5-dimethoxyphenyl)-2-hydroxypropanamide; N-(2-ethoxyphenyl)-2-hydroxypropanamide; N-(2,5-dimethoxyphenyl)-2-hydroxy-2-methylpropanamide; N-(2-ethoxyphenyl)-2-hydroxy-2-methylpropanamide; 3-chloro-N-(2,5-dichlorophenyl)-2-hydroxy-2-methylpropanamide; 3-chloro-N-(2,4-dichlorophenyl)-2-hydroxy-2-methylpropanamide; N-(2,3-dichloro-5-nitrophenyl)-2-hydroxy-2-methylpropanamide; 2-hydroxy-2-methyl-N-(2,3,4-trichlorophenyl)propanamide; 1-(2,5-dihydroxyphenyl)-3-hydroxy-3-methylbut-1-ene; 1-(2,4-dichlorophenyl)-3-hydroxy-4,4,4-trifluoro-3-trifluoromethylbut-1-ene; 2-hydroxy-N-(5-methoxycarbonyl-2-methylphenyl)-2-methylpropylamine; 1-(2,6-dimethoxyphenoxy)-2-isopropylpropan-2-ol; 1-(2,6-dimethoxyphenoxy)-2-methylpentan-2-ol; 1-(2,6-dimethoxyphenoxy)-2-methylbutan-2-ol; 1-(2,5-dimethoxyphenoxy)-2-methylpentan-2-ol; 1-(2,4-dimethoxyphenoxy)-2-methylpentan-2-ol; 1-(2,3-dimethoxyphenoxy)-2-methylpentan-2-ol; 1-(2,6-dimethoxyphenoxy)-2-ethylbutan-2-ol; 2-ethyl-1-(2-methylphenoxy)butan-2-ol; 1-(2-[2-ethyl-2-hydroxybutoxy]phenoxy)-2-ethylbutan-2-ol; 2-ethyl-1-(2-methoxyphenoxy)butan-2-ol; 1-(2-methoxyphenoxy)-2-methylbutan-2-ol and 2-ethyl-1-(2-methoxyphenoxy)pentan-2-ol; for use as medicaments.
According to a further aspect of the present invention there are provided compounds of the formula (I), as defined hereinbefore, with the provisos that:
(i) ring C bears a group other than hydrogen at the position para to Axe2x80x94B attachment;
(ii) when Axe2x80x94B is xe2x80x94COCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94OCH2xe2x80x94, trans-vinylene or ethynylene, ring C does not have an oxygen atom linked at a position ortho to Axe2x80x94B attachment;
(iii) when Axe2x80x94B is ethynylene, ring C does not have fluorine atoms linked at both of the positions ortho to Axe2x80x94B attachment;
(iv) when Axe2x80x94B is trans-vinylene, ring C does not bear methyl groups at both of the positions ortho to Axe2x80x94B attachment, and does not bear a formyl group at a position ortho to Axe2x80x94B attachment;
(v) when Axe2x80x94B is xe2x80x94COCH2xe2x80x94, ring C does not bear methyl groups at both of the positions ortho to Axe2x80x94B attachment;
(vi) when Axe2x80x94B is xe2x80x94OCH2xe2x80x94, ring C does not have chlorine atoms linked at both of the positions ortho to Axe2x80x94B attachment and does not bear nitro groups at both of the positions ortho to Axe2x80x94B attachment;
(vii) when Axe2x80x94B is xe2x80x94NHCH2xe2x80x94, ring C does not bear two nitro groups at positions ortho and para to Axe2x80x94B attachment and does not bear two methyl groups at positions meta and para to Axe2x80x94B attachment; and
(viii) when Axe2x80x94B is xe2x80x94SCH2xe2x80x94, ring C does not simultaneously bear an amino group at a position ortho to Axe2x80x94B attachment and a nitro group at the position para to Axe2x80x94B attachment; and excluding the following compounds: N-(4-chloro-2-nitrophenyl)-2-hydroxy-2-methylpropanamide; N-(4,5-dichloro-2-(2-hydroxy-2-methylpropanamido)phenyl)-2-hydroxy-2-methylpropanamide; N-(4-chloro-2-benzoylphenyl)-2-hydroxy-2-methylpropanamide; N-(2,4-dimethylphenyl)-2-hydroxypropanamide; 3-chloro-N-(2,4-dichlorophenyl)-2-hydroxy-2-methylpropanamide; 2-hydroxy-2-methyl-N-(2,3,4-trichlorophenyl)propanamide; 1-(2,4-dichlorophenyl)-3-hydroxy-4,4,4-trifluoro-3-trifluoromethylbut-1-ene; 1-(4-bromo-2-fluorophenyl)-3-hydroxy-3-methylbut-1-yne; 1-(2-fluoro-4-pent-1-enylphenyl)-3-hydroxy-3-methylbut-1-yne; 1-(4-[3-hydroxy-3-methylbut-1-yn-1-yl]-2-phenylphenyl)-3-hydroxy-3-methylbut-1-yne; 1-(2-fluoro-4-pentoxyphenyl)-3-hydroxy-3-methylbut-1-yne; 1-(2-fluoro-4-trifluoromethylphenyl)-3-hydroxy-3-methylbut-1-yne; 1-(2,5-dimethyl-4-[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)-3-hydroxy-3-methylbut-1-yne; 1-(2,4-di[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)-3-hydroxy-3-methylbut-1-yne; 3-hydroxy-3-methyl-1-(2,4,5-tri[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)but-1-yne; 3-hydroxy-3-methyl-1-(2,3,4,5-tetra[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)but-1-yne and 3-hydroxy-3-methyl-1-(2,3,4,5,6-penta[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)but-1-yne; and
salts thereof;
and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I);
and pharmaceutically acceptable salts of said compound or said prodrugs.
According to a further aspect of the present invention there are provided compounds of the formula (I), as defined hereinbefore, wherein Axe2x80x94B is xe2x80x94NHCOxe2x80x94 and with the proviso that ring C bears a group other than hydrogen at the position para to Axe2x80x94B attachment and excluding the following compounds: N-(4-chloro-2-nitrophenyl)-2-hydroxy-2-methylpropanamide; N-(4,5-dichloro-2-(2-hydroxy-2-methylpropanamido)phenyl)-2-hydroxy-2-methylpropanamide; N-(4-chloro-2-benzoylphenyl)-2-hydroxy-2-methylpropanamide; N-(2,4-dimethylphenyl)-2-hydroxypropanamide; 3-chloro-N-(2,4-dichlorophenyl)-2-hydroxy-2-methylpropanamide and 2-hydroxy-2-methyl-N-(2,3,4-trichlorophenyl)propanamide; and salts thereof;
and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I);
and pharmaceutically acceptable salts of said compound or said prodrugs.
According to a further aspect of the present invention there is provided the use of compounds of the formula (I):
wherein:
ring C is as defined in (a) or (b);
R1 is as defined in (c) or (d);
n is 1 or 2;
R2 and R3 are as defined in (e) or (f);
Axe2x80x94B is as defined in (g) or (h) and
R4 is as defined in (i) or (j)
xe2x80x83wherein
(a) 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 Axe2x80x94B attachment or on carbon at the position para to the position of Axe2x80x94B attachment by P1 or P2 (wherein P1 and P2 are as defined hereinafter), and further, wherein said phenyl or heteroaryl is optionally substituted on carbon at any remaining meta position(s) or para position by P1 or P3, (wherein P1 and P3 are as defined hereinafter);
(b) ring C is selected from the following five groups:
(i) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is unsubstituted except by (R1)n wherein R1 and n are as defined hereinafter;
(ii) a carbon-linked triazine optionally substituted on a ring carbon at a position meta or para to Axe2x80x94B attachment by 1 substituent selected from P1, P2, P3 and P4, wherein P1, P2, P3 and P4 are as defined hereinafter;
(iii) a 6-membered carbon-linked heteroaryl group containing 1-3 nitrogen atoms wherein one or more ring nitrogen atoms are oxidised to form the N-oxide, which heteroaryl group is optionally substituted at any of the positions meta or para to Axe2x80x94B attachment by 1-3 substituents selected from P1, P2, P3 and P4, wherein P1, P2, P3 and P4 are as defined hereinafter;
(iv) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is substituted at a position meta or para to Axe2x80x94B attachment by 1 substituent selected from P3 and P4, wherein P3 and P4 are as defined hereinafter; and
(v) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is substituted at any of the positions meta or para to Axe2x80x94B attachment by 2-3 substituents selected from P1, P2, P3 and P4, provided that if one or more of the substituents is P1 or P2 then at least one of the other substituents is P4, wherein P1, P2, P3 and P4 are as defined hereinafter;
P1 is cyano, trifluoromethyl, nitro, trifluoromethoxy or trifluoromethylsulphanyl;
P2 is xe2x80x94Y1Ar1, wherein Ar1 is selected from the group consisting of phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms selected independently from O, N and S, wherein said phenyl or heteroaryl ring is optionally substituted at carbon, with 1-4 substituents selected from Q1, wherein Q1 is as defined hereinafter; and Y1 is selected from xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94 and xe2x80x94SO2xe2x80x94;
P3 is C1-4alkyl, haloC2-4alkyl, C1-4alkoxy, haloC2-4alkoxy, C2-4alkenyloxy, halo or hydroxy;
P4 is selected from the following five groups:
xe2x80x831) halosulphonyl, cyanosulphanyl;
xe2x80x832) xe2x80x94X1xe2x80x94R5 wherein X1 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94OCONR9xe2x80x94, xe2x80x94CONR10SO2xe2x80x94, xe2x80x94NR11SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR12COOxe2x80x94, xe2x80x94CSNR13xe2x80x94, xe2x80x94NR14CSxe2x80x94, xe2x80x94NR15CSNR16xe2x80x94, NR17CONR18xe2x80x94 or xe2x80x94NR19CONR20SO2xe2x80x94 (wherein R6, R7, R8, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 each independently represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl) and R5 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl with the proviso that P4 is not trifluoromethyl, trifluoromethoxy, trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
xe2x80x833) xe2x80x94X1xe2x80x94C1-6alkyl-X2xe2x80x94R21 wherein X1 is as defined hereinbefore, X2 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR22xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR23xe2x80x94, xe2x80x94NR24COxe2x80x94, xe2x80x94NR25COOxe2x80x94, xe2x80x94SO2NR26xe2x80x94, xe2x80x94NR27SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR28COxe2x80x94, xe2x80x94OCONR29, xe2x80x94CSNR30xe2x80x94, xe2x80x94NR31CSxe2x80x94, NR32CSNR33, xe2x80x94NR34CONR35xe2x80x94, xe2x80x94CONR36SO2xe2x80x94, xe2x80x94NR37CONR38SO2xe2x80x94 or xe2x80x94SO2N39CONR40xe2x80x94 (wherein R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39 and R40, each independently represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl) and R21 is hydrogen, C1-4alkyl or R41 wherein R41 is phenyl or a 4-12 membered heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S which heterocyclic moiety may be aromatic or non-aromatic and which phenyl or heterocyclic moiety is optionally substituted by 1-6 substituents selected from Q3 wherein Q3 is as defined hereinafter;
xe2x80x834) xe2x80x94X1xe2x80x94C3-7cycloakyl-X2xe2x80x94R21 wherein X1, X2 and R21 are as defined hereinbefore; and
xe2x80x835) xe2x80x94Y2Ar2 wherein Y2 is X1 wherein X1 is as defined hereinbefore and Ar2 is selected from the following four groups:
(i) phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms selected independently from O, N and S, wherein said phenyl or heteroaryl ring is substituted at carbon, with 1-4 substituents selected from Q1 and Q2 including at least one substituent selected from Q2 wherein Q1 and Q2 are as defined hereinafter;
(ii) a carbon-linked triazine or a carbon-linked 5-membered heteroaryl ring containing 3-4 heteroatoms selected independently from O, N and S; wherein said heteroaryl ring is optionally substituted with 1-4 substituents selected from Q1 and Q2 wherein Q1 and Q2 are as defined hereinafter:
(iii) a 4-12 membered non-aromatic heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S wherein said heterocyclic moiety is optionally substituted with 1-6 substituents selected from Q3 wherein Q3 is as defined hereinafter, with the proviso that if Ar2 is a nitrogen linked heterocyclic ring Y2 is not xe2x80x94SO2xe2x80x94; and
(iv) Ar1 with the proviso that if Ar2 has a value Ar1 then Y2 is not xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
Q1 is C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C2-4alkenyloxy, cyano, nitro, halo or trifluoromethylsulphanyl;
Q2 is selected from the following seven groups:
xe2x80x831) oxygen (forming an oxo group when linked to a ring carbon and forming an N-oxide when a ring nitrogen is oxidised);
xe2x80x832) halosulphonyl, cyanosulphanyl;
xe2x80x833) xe2x80x94X3xe2x80x94R5 wherein X3 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR42xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR43xe2x80x94, xe2x80x94NR44COxe2x80x94, xe2x80x94NR45COOxe2x80x94, xe2x80x94SO2NR46xe2x80x94, xe2x80x94NR47SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR48COxe2x80x94, xe2x80x94OCONR49xe2x80x94, xe2x80x94CSNR50xe2x80x94, xe2x80x94NR51CSxe2x80x94, xe2x80x94NR52CSNR53xe2x80x94, xe2x80x94NR54CONR55xe2x80x94, xe2x80x94CONR56SO2xe2x80x94, or xe2x80x94SO2NR59CONR60xe2x80x94 (wherein R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59 and R60 each independently represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl) and R5 is as defined hereinbefore but with the proviso that Q2 is not trifluoromethylsulphanyl, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
xe2x80x834) R41 wherein R41 is as defined hereinbefore;
xe2x80x835) xe2x80x94X3xe2x80x94C1-6alkyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore;
xe2x80x836) xe2x80x94X3xe2x80x94C3-7cycloalkyl-X2xe2x80x94R21 wherein X3, X2 and R21 are as defined hereinbefore; and
xe2x80x837) xe2x80x94X3xe2x80x94R41 wherein R41 and X3 are as defined hereinbefore;
Q3 is selected from the following four groups:
xe2x80x831) oxygen (forming an oxo group when linked to a ring carbon and forming an N-oxide when a ring nitrogen is oxidised);
xe2x80x832) cyano, nitro or halo;
xe2x80x833) halosulphonyl, cyanosulphanyl; and
xe2x80x834) xe2x80x94X4xe2x80x94R61 wherein X4 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR62xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR63xe2x80x94, xe2x80x94NR64COxe2x80x94, xe2x80x94NR65COOxe2x80x94, xe2x80x94SO2NR66xe2x80x94, xe2x80x94NR67SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR68COxe2x80x94, xe2x80x94OCONR69xe2x80x94, xe2x80x94CSNR70xe2x80x94, xe2x80x94NR71CSxe2x80x94, xe2x80x94NR72CSNR73xe2x80x94, xe2x80x94NR74CONR75xe2x80x94, xe2x80x94CONR76SO2xe2x80x94, xe2x80x94NR77CONR78SO2xe2x80x94 or xe2x80x94SO2NR79CONR80xe2x80x94 (wherein R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79 and R80 each independently represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl) and R61 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkynyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl;
(c) R1 is linked to ring C at a carbon ortho to the position of Axe2x80x94B attachment and is selected from the group consisting of C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C2-4alkenyloxy, cyano, nitro, halo, trifluoromethylsulphanyl and hydroxy;
(d) R1 is linked to ring C at a ring carbon atom ortho to the position of Axe2x80x94B attachment and is selected from the following two groups:
1) xe2x80x94X5xe2x80x94R81 wherein X5 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2, xe2x80x94NR82xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR83xe2x80x94, xe2x80x94NR84COxe2x80x94, xe2x80x94NR85COOxe2x80x94, xe2x80x94SO2NR86xe2x80x94, xe2x80x94NR87SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2NR88COxe2x80x94, xe2x80x94OCONR89xe2x80x94, xe2x80x94CSNR90xe2x80x94, xe2x80x94NR91CSxe2x80x94, xe2x80x94NR92CSNR93xe2x80x94, xe2x80x94NR94CONR95xe2x80x94, xe2x80x94CONR96SO2xe2x80x94, xe2x80x94NR97CONR98SO2xe2x80x94 or xe2x80x94SO2NR99CONR100xe2x80x94 (wherein R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99 and R100 each independently represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl) and R81 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkynyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl with the proviso that R1 is not trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy; and
2) xe2x80x94X6xe2x80x94R101 wherein X6 is selected from a direct bond, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 and xe2x80x94NR102xe2x80x94 (wherein R102 is hydrogen or C1-4alkyl) and R101 is phenyl which is optionally substituted by 1-4 substituents selected from cyano, nitro, trifluoromethylsulphanyl, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C2-6alkenyloxy, halo, hydroxy and amino;
n is 1 or 2;
(e) either R2 and R3 are independently C1-3alkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said C1-3alkyl, provided that R2 and R3 are not both methyl;
or R2 and R3, together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring optionally substituted by from 1 to 2mxe2x88x922 fluorine atoms wherein m is the number of carbon atoms in said ring;
(f) R2 and R3 are both methyl or one of R2 and R3 is hydrogen or halo and the other is halo or C1-3alkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said C1-3alkyl, with the proviso that when either R2 or R3 is halo R4 is not hydroxy and with the proviso that when either R2 or R3 is hydrogen, R4 is not hydrogen;
(g) Axe2x80x94B is selected from xe2x80x94NHCOxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94NHCH2xe2x80x94, trans-vinylene, and ethynylene;
(h) Axe2x80x94B is xe2x80x94NHCSxe2x80x94 or xe2x80x94COCH2xe2x80x94;
(i) R4 is hydroxy;
(j) R4 is hydrogen, halo or methyl;
but excluding compounds wherein ring C is selected from (a) and R1 is selected only from (c) and R2 and R3 are selected from (e) and Axe2x80x94B is selected from (g) and R4 is selected from (i);
and salts thereof;
and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I);
and pharmaceutically acceptable salts of said compound or said prodrugs;
in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans.
In a further aspect of the invention there is provided a compound of formula (Ixe2x80x2):
wherein:
n is 1 or 2;
Ra is chloro, fluoro, bromo, nitro or methoxy;
Rb is C1-6alkyl optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy or C1-6alkoxy or Rb is phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms or a carbon-linked 5-membered heteroaryl ring containing 1-3 heteroatoms selected independently from O, N and S, wherein said phenyl or heteroaryl ring is substituted by one or more groups selected from i)-iii) and is optionally further substituted with a group selected from iv):
i) xe2x80x94Xaxe2x80x94Rc wherein Xa is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRexe2x80x94 (wherein Rd and Re each independently represents hydrogen or C1-4alkyl which C1-4alkyl is optionally substituted with one or more groups selected from hydroxy or C1-4alkoxy) and Rc is selected from hydrogen or C1-6alkyl which C1-6alkyl is optionally substituted with one or more hydroxy or C1-4alkoxy with the proviso that xe2x80x94Xaxe2x80x94Rc is not C1-4alkyl or C1-4alkoxy;
ii) a 4-12 membered heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S which heterocyclic moiety may be aromatic or non-aromatic and is optionally substituted with one or more groups selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl or cyano;
iii) xe2x80x94Xaxe2x80x94C1-6alkyl-Xbxe2x80x94Rc wherein Xa and Rc are as defined hereinbefore and Xb is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
iv) cyano, hydroxy, halo, C1-4alkoxy, C1-4alkyl; and
and salts thereof;
and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I);
and pharmaceutically acceptable salts of said compound or said prodrugs.
Preferable values for a compound of formula (Ixe2x80x2) are as follows:
Preferably Ra is chloro or fluoro.
More preferably Ra is chloro.
Preferably Rb is C1-4alkyl optionally substituted by one or more hydroxy or Rb is phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms or a carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms wherein said phenyl or heteroaryl ring is substituted by one or more groups selected from i)-iii):
i) xe2x80x94Xaxe2x80x94Rc wherein Xa is xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRexe2x80x94 (wherein Rd and Re each independently represents hydrogen or C1-4alkyl) and Rc is selected from hydrogen or C1-6alkyl which C1-6alkyl is optionally substituted with one or more hydroxy;
ii) a 4-12 membered heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S which heterocyclic moiety may be aromatic or non-aromatic;
iii) xe2x80x94Xaxe2x80x94C1-6alkyl-Xbxe2x80x94Rc wherein Xa and Rc are as defined hereinbefore and Xb is xe2x80x94Sxe2x80x94.
More preferably Rb is C1-4alkyl optionally substituted by hydroxy or Rb is phenyl wherein said phenyl is substituted by one group selected from i)-iii):
i) xe2x80x94Xaxe2x80x94Rc wherein Xa is xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRe (wherein Rd and Re each independently represents hydrogen or C1-4alkyl) and Rc is selected from hydrogen or C1-6alkyl which C1-6alkyl is optionally substituted with one or more hydroxy;
ii) a 4-12 membered heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S which heterocyclic moiety may be aromatic or non-aromatic;
iii) xe2x80x94Xaxe2x80x94C1-6alkyl-Xbxe2x80x94Rc wherein Xa and Rc are as defined hereinbefore and Xb is xe2x80x94Sxe2x80x94.
Particularly Rb is ethyl, 2-hydroxyethyl, 4-N,N-dimethylcarbamoylphenyl, 4-(2-hydroxyethlyamino)phenyl, 4-methylsulphinylphenyl, 4-mesylphenyl, 4-aminophenyl, 4-(2-oxopyrrolidi-1-yl)phenyl and 4-(2-methylthioethylamino)phenyl.
In one aspect of the invention preferably n is 1.
In another aspect of the invention preferably n is 2.
In one aspect of the invention preferably the group Rbxe2x80x94S(O)nxe2x80x94 is para to the xe2x80x94NHxe2x80x94C(O)xe2x80x94 group.
In another aspect of the invention preferably the group Rbxe2x80x94S(O)nxe2x80x94 is meta to the xe2x80x94NHxe2x80x94C(O)xe2x80x94 group.
Preferably the tertiary centre of formula (Ixe2x80x2) xe2x80x94C(OH)(CF3)(Me) has the R stereochemistry.
Preferred compounds of formula (I) or (Ixe2x80x2) are those of Examples 14, 43, 63, 71, 74, 87, 128, 144, 215 and 355 and salts thereof; and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I); and pharmaceutically acceptable salts of said compound or said prodrugs.
Compounds of the present invention include:
N-(2,6-dimethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-cyanophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-2-chloro-4-[(2-hydroxy-2-methyl-3,3,3-trifluoropropanamido]phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-2-nitro-4-[(2-hydroxy-2-methyl-3,3,3-trifluoropropanamido]phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-[2-(4-chlorobenzoyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-[2-carboxy-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-bromo-2-chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2,4-dichlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-fluorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(biphen-2-yl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-acetylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-bromophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
2-hydroxy-2-methyl-N-[2-(phenylsulphonyl)phenyl]-3,3,3-trifluoropropanamide;
N-(2-methoxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-hydroxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
(R)-N-(4-bromo-2,6-diclorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
(R)-N-[2-chloro-4-(phenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
(S)-N-[2-chloro-4-(phenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
(R)-N-[2-fluoro-4-(phenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
(R)-N-(4-bromo-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-[2-chloro-4-(phenylsulphonyl)phenyl]-2-hydroxypropanarmide;
N-(2-fluoro-4-iodophenyl)-2-hydroxypropanamide;
N-{4-[benzyloxycarbonyl)amino]-2-fluorophenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-[2-(hydroxymethyl)-4-iodophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-benzyl-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-carbamoyl-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-iodo-2-methoxycarbonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-iodo-2-nitrophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-bromo-4-methoxycarbonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-bromo-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-[2-chloro-4-(benzoylamino)phenyl]-2-hydroxy-2-methylpropanamide;
N-2-chloro-4-[(phenylsulphonyl)amino]phenyl-2-hydroxy-2-methylpropanamide;
N-(4-chloro-2-methoxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
2-hydroxy-N-(4-methoxy-2-methylphenyl)-2-methyl-3,3,3-trifluoropropanamide;
N-(2,3-dimethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(3-chloro-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-bromo-2-trifluoromethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-chloro-2-benzoylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-chloro-2-trifluoromethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropaiamide;
N-(4-chloro-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-chloro-4-mesylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-chloro-4-fluorosulphonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2,4-diiodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-bromo-4-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-bromo-4-butylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(2-chloro-4-thiocyanatophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-[2-fluoro-4-(allyloxycarbonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-[2-fluoro-4-{N-[(1,3-diethoxycarbonyl)propyl]carbarnoyl}phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
N-(4-amino-2-chlorophenyl)-2-hydroxy-2-methylpropanamide;
N-[2-chloro-4-(4-aminophenylsulphanyl)phenyl]-2-hydroxy-2-methylpropanamide;
and Examples 106, 108, 110, 113, 149, 151, 171, 173, 197 and 205;
and salts thereof and pharmaceutically acceptable in vivo cleavable esters or sulphides of said compounds; and pharmaceutically acceptable salts of said compounds or esters or sulphides.
Advantageous compounds of the present invention include Examples 184-186 and salts thereof and pharmaceutically acceptable in vivo cleavable esters or sulphides of said compounds; and pharmaceutically acceptable salts of said compounds or esters or sulphides.
Preferred compounds of the present invention include Examples 15, 114, 171, 172 and 182 and salts thereof and pharmaceutically acceptable in vivo cleavable esters or sulphides of said compounds; and pharmaceutically acceptable salts of said compounds or esters or sulphides.
More preferred compounds of the present invention include Examples 14 and 87 and salts thereof and pharmaceutically acceptable in vivo cleavable esters or sulphides of said compounds; and pharmaceutically acceptable salts of said compounds or esters or sulphides.
Particular compounds of the present invention include Examples 1, 2, 13, 16, 54, 86, 104, 212, 213 and 214 and salts thereof and pharmaceutically acceptable in vivo cleavable esters or sulphides of said compounds; and pharmaceutically acceptable salts of said compounds or esters or sulphides.
In another aspect of the invention, preferred compounds of the invention are any one of Examples 1-428 and salts thereof; and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I); and pharmaceutically acceptable salts of said compound or said prodrugs.
Preferred aspects of the invention are those which relate to the compound or a pharmaceutically acceptable salt thereof.
In this specification the term xe2x80x9calkylxe2x80x9d includes both straight and branched chain alkyl groups but references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chain version only. An analogous convention applies to other generic terms. Unless otherwise stated the term xe2x80x9calkylxe2x80x9d advantageously refers to chains with 1-6 carbon atoms, preferably 1-4 carbon atoms.
In this specification the term xe2x80x9calkoxyxe2x80x9d refers to an alkyl group as defined hereinbefore linked to an oxygen atom.
In this specification the term xe2x80x9ccycloalkylxe2x80x9d refers to cyclic non-aromatic rings of carbon atoms.
In this specification the term xe2x80x9ccycloalkoxyxe2x80x9d refers to a cycloalkyl group as defined hereinbefore linked to an oxygen atom.
In this specification the term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo unless stated otherwise.
In this specification the term xe2x80x9chaloalkylxe2x80x9d includes an alkyl group as defined hereinbefore substituted with one or more halo groups, including for example trifluoromethyl.
In this specification the term xe2x80x9chydroxyalkylxe2x80x9d includes an alkyl group as defined hereinbefore substituted with one or more hydroxy groups.
In this specification the term xe2x80x9carylxe2x80x9d includes C5-12aromatic groups which may, if desired and unless otherwise defined, carry one or more substituents selected from halo, alkyl, alkoxy, cyano, nitro or trifluoromethyl (wherein alkyl and alkoxy are as hereinbefore defined). Suitable values for aryl include phenyl and naphthyl.
The term xe2x80x9caryloxyxe2x80x9d means an aryl group as defined hereinbefore linked to an oxygen atom. Suitable values for aryloxy include phenoxy and naphth-1-yloxy.
The term xe2x80x9cheteroarylxe2x80x9d includes aryl groups, as defined hereinbefore, containing one or more heteroatoms selected from O, N and S.
Suitable values for xe2x80x9ca 6-membered carbon-linked heteroaryl group containing 1-3 nitrogen atoms wherein one or more ring nitrogen atoms are oxidised to form the N-oxidexe2x80x9d include pyridyl-N-oxide, pyrimidyl-N-oxide and pyrazinyl-N-oxide.
Suitable values for xe2x80x9ca carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atomsxe2x80x9d include pyridyl, pyrimidyl, pyrazinyl and pyridadzinyl.
Suitable values for xe2x80x9ca carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms selected independently from O, N and Sxe2x80x9d include fluryl, thienyl, pyrrolyl, thiazolyl, isoxazolyl, oxazolyl, imidazolyl and pyrazolyl.
Suitable values for xe2x80x9ca carbon-linked 5-membered heteroaryl ring containing 3-4 heteroatoms selected independently from O, N and Sxe2x80x9d include oxadiazolyl, furazanyl, triazolyl and thiadiazolyl.
Suitable values for a xe2x80x9c5-6 membered heterocyclic aromatic ring containing 1-4 heteroatoms selected independently from O, N and Sxe2x80x9d include furyl, thienyl, pyrrolyl, thiazolyl, isoxazolyl, oxazolyl and pyrazolyl, tetrazolyl, imidazolyl, oxadiazolyl, furazanyl, triazolyl, thiadiazolyl pyridyl, pyrimidyl, pyrazinyl and pyridazinyl.
Suitable values for a xe2x80x9c5-7 membered heterocyclic non-aromatic moiety containing 1-2 heteroatoms selected independently from O, N and Sxe2x80x9d include morpholino, piperazinyl, piperidinyl, homopiperazinyl, oxazolidinyl, thiazolinyl, oxaxolinyl, dihydropyranyl and tetrapyranyl.
Suitable values for xe2x80x9ca 5-membered heteroaryl ring containing 1-4 heteroatoms selected independently from O, N and Sxe2x80x9d include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl.
Suitable values for xe2x80x9ca carbon-linked 5-membered heteroaryl ring containing 1-3 heteroatomsxe2x80x9d include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl and triazolyl.
Suitable values for xe2x80x9ca 7-12 membered aromatic heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and Sxe2x80x9d include indolyl, benzofuryl, benzothienyl, benzimidazolyl, purinyl, quinolinyl and isoquinolinyl.
A xe2x80x9c4-12 membered heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S which heterocyclic moiety may be aromatic or non-aromaticxe2x80x9d is a saturated, partially saturated or unsaturated (including aromatic) mono or bicyclic ring, which may, unless otherwise specified, be carbon or nitrogen linked, and, unless otherwise specified, any (optional) substituents may be substituents on a ring carbon or nitrogen (where said ring is a ring containing an xe2x80x94NHxe2x80x94 moiety the substitution thus replacing the hydrogen), wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94C(O)xe2x80x94, a ring nitrogen atom may optionally bear a C1-6alkyl group and formn a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. Examples and suitable values of the term xe2x80x9cheterocyclic groupxe2x80x9d are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, oxazolinyl, oxazolidinyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.
A xe2x80x9c4-12 membered non-aromatic heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and Sxe2x80x9d is as defined in the above paragraph, but excludes those compounds which are fully aromatic.
In this specification xe2x80x9cnon-aromaticxe2x80x9d includes fully saturated rings as well as partially saturated rings but does not include aromatic unsaturated rings.
The term xe2x80x9cheterocyclicxe2x80x9d includes aromatic and non-aromatic cyclic moieties containing one or more heteroatoms selected from O, N and S.
In this specification unless stated otherwise the term xe2x80x9calkenylxe2x80x9d includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl are specific for the straight chain version only. In this specification unless stated otherwise the term xe2x80x9calkynylxe2x80x9d includes both straight and branched chain alkynyl groups but references to individual alkynyl groups such as 2-butynyl are specific for the straight chain version only.
For the avoidance of any doubt, it is to be understood that when X1 is, for example, a group of formula xe2x80x94NR8COxe2x80x94, it is the nitrogen atom bearing the R8 group which is attached to ring C and the carbonyl group is attached to R5, whereas when X1 is, for example, a group of formula xe2x80x94CONR7xe2x80x94, it is the carbonyl group which is attached to ring C and the nitrogen atom bearing the R7 group is attached to R5. When X1 is xe2x80x94NR11SO2xe2x80x94 it is the nitrogen atom bearing the R11 group which is attached to ring C and the sulphonyl group which is attached to R5. Analogous conventions apply to similar groups. When X1 is xe2x80x94NR6xe2x80x94 it is the nitrogen atom bearing the R6 group which is linked to ring C and to R5. When X1 is xe2x80x94OCOxe2x80x94 it is the first oxygen atom which is attached to ring C and the carbonyl group is attached to R5. When X1 is xe2x80x94COOxe2x80x94 it is the carbonyl group which is linked to ring C and the other oxygen atom is attached to R5. Analogous conventions apply to similar groups. It is further to be understood that when X1 represents xe2x80x94NR6xe2x80x94 and R6 is C1-3alkoxyC2-3alkyl it is the C2-3alkyl moiety which is linked to the nitrogen atom of X1 and an analogous convention applies to other groups.
When X3 is xe2x80x94OCONR49xe2x80x94 it is the first oxygen which is linked to ring Ar2 and the carbonyl group while the nitrogen atom is linked to the carbonyl group, R49 and R5.
When X3 is xe2x80x94NR47SO2xe2x80x94 it is the nitrogen atom which is linked to Ar2, R47 and the sulphonyl group, and it is the suiphonyl group which is linked to R5 and analogous conventions apply to similar groups.
For the avoidance of any doubt, it is to be understood that when a group C5-6alkyl carries a C1-4alkoxycarbonyl substituent it is the carbonyl moiety which is attached to C5-6alkyl and an analogous convention applies to other groups.
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 utilized 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.
In vivo cleavable prodrugs of compounds of formula (I) include for example in vivo hydrolysable esters of compounds of the formula (I) containing a carboxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid, for example, a pharmaceutically acceptable ester formed with a C1-6alcohol such as methanol, ethanol, ethylene glycol, propanol or butanol, or with a phenol or benzyl alcohol such as phenol or benzyl alcohol or a substituted phenol or benzyl alcohol wherein the substituent is, for example, a halo (such as fluoro or chloro), C1-4alkyl (such as methyl) or C1-4alkoxy (such as methoxy) group.
In vivo cleavable prodrugs of compounds of formula (I) also include for example in vivo hydrolysable amides of compounds of the formula (I) containing a carboxy group, for example, a Nxe2x80x94C1-6alkyl or N,N-di-C1-6alkyl amide such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.
It is also to be understood that certain compounds of the formula (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.
Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, which process (in which variable groups are as defined for formula (I) unless otherwise stated) comprises of:
(a) for compounds of formula (I) where R4 is hydroxy; deprotecting a protected compound of formula (II):
where Pg is an alcohol protecting group;
(b) for compounds of formula (I) where Y1, Y2 or X1 is xe2x80x94C(O)xe2x80x94: oxidising a corresponding alcohol of formula (III):
wherein ring D1 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) and Ra1 is a group attached to Y1, Y2 or X1 (possible valued as defined above);
(c) for compounds of formula (I) where Y1, Y2 or X1 is xe2x80x94C(O)xe2x80x94: deprotecting a corresponding compound of formula (IV):
wherein ring D2 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 Arxe2x80x94C(xe2x80x94Oxe2x80x94(CH2)3xe2x80x94Oxe2x80x94)xe2x80x94 and Ra1 is as defined above;
(d) for compounds of formula (I) where Ring C has an Ra2xe2x80x94CH2xe2x80x94 substituent attached to it wherein Ra2 is a group that is attached via xe2x80x94CH2xe2x80x94 moiety to ring C (possible values as defined above): reduction of a compound of formula (III) or (V):
wherein ring D1 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 ArC(O)xe2x80x94;
(e) for compounds of formula (I) where ring C has a Ra3xe2x80x94C(O)xe2x80x94 substituent wherein Ra3 is and aromatic moiety or alkenyl moiety (possible values as defined above): treating a compound of formula (VI):
wherein ring D3 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 G1 and G1 is a leaving group; with carbon monoxide and a tin compound having the formula (R6)p1Sn(Ra3)p2 (wherein R6 is C1-4alkyl and p1+p2=4) or an aluminium compound having the formula (R6)p3Al(Ra3)p4 (wherein R6 is C1-4alkyl and p3+p4=3);
(f) for compounds of formula (I) where Ring C has an Ra4S(O)xe2x80x94 or Ra4S(O)2xe2x80x94 substituent. Ra4 is a group attached through a sulphoxide or sulphone moiety (possible values as defined above) and Axe2x80x94B is not SCH2 or NHCH2: oxidising a compound of formula (VI) wherein G1 is Ra4S;
(g) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94NHC(O)xe2x80x94: coupling compounds of formula (VII):
wherein J is NH2, with an acid of formula (VIII):
wherein X is OH;
(h) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94NHC(O)xe2x80x94: coupling an aniline of formula (VII) wherein J is xe2x80x94NH2 with an activated acid derivative of formula (VIII);
(i) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94NHC(O)xe2x80x94 or xe2x80x94NHC(S)xe2x80x94 and R4 is hydroxy: reacting a compound of formula (IX):
wherein X is O or S: with a base to yield the dianion, followed by treatment of the dianion with oxygen in the presence of a reducing agent; or by treatment with a peroxyacid;
(j) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94NHC(O)xe2x80x94: reacting a compound of formula (VII) wherein J is chloro or fluoro, with an alkali metal amide anion having formula (X):
wherein M is an alkali metal;
(k) for a compound of formula (I) that contains no carbonyl moieties, R4 is hydroxy and R2xe2x95x90R3: reacting a compound of formula (XI):
wherein R4 is C1-4alkyl, with a Grignard reagent of formula R2MgBr or R2MgCl or an organolithium reagent of formula LiR2;
(l) for a compound of formula (I) that contains no carbonyl moieties and R4 is hydroxy: reacting a compound of formula (XII):
with a compound of formula R2M wherein M is an alkali metal or a Grignard compound of formula R2MgBr or R2MgCl;
(m) for a compound of formula (I) which has an N-linked sulphonamide, an N-linked N-alkyl sulphonamide or a sulphinate ester substituent attached to ring C: treating a corresponding compound of formula (XIII):
wherein ring D3 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 G2 wherein G2 is amino or hydroxy with a sulphonyl chloride;
(n) for a compound of formula (I) in which Axe2x80x94B is ethynylene and R4 is not chloro and when R4 is hydroxy it is protected: coupling a corresponding compound of formula (VII) wherein J is a leaving group, with a corresponding acetylene of formula (XIV):
(o) for a compound of formula (I) in which Axe2x80x94B is ethynylene and R4 is hydroxy: reacting a corresponding alkyne of formula (XV):
wherein Z is hydrogen, with a base, followed by treatment with a ketone of formula (XVI):
(p) for a compound of formula (I) in which Axe2x80x94B is trans-vinylene: reducing a corresponding ompound of formula (I) in which Axe2x80x94B is ethynylene with a suitable reducing agent;
(q) for a compound of formula (I) in which Axe2x80x94B is trans-vinylene: dehydration of a compound of formula (XVII):
(r) for a compound of formula (I) in which Axe2x80x94B is trans-vinylene and R4 is hydroxy: base catalysed opening of an epoxide of formula (XVIII):
(s) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94NHCH2xe2x80x94: reducing a corresponding compound of formula (I) in which Axe2x80x94B is xe2x80x94NHC(O)xe2x80x94;
(t) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94 or xe2x80x94NHCH2: reacting an ethylene oxide of formula (XIX):
with a corresponding compound of formula (VII) where J is xe2x80x94OH, xe2x80x94SH or xe2x80x94NH2;
(u) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94NHC(S)xe2x80x94: reacting a compound of formula (I) in which Axe2x80x94B is xe2x80x94NHC(O)xe2x80x94 with a sulphonating reagent;
(v) a compound of formula (I) in which ring C is substituted by ArC(O)xe2x80x94 wherein Ar is an aromatic group (possible values as defined for formula (I) above) and Axe2x80x94B is xe2x80x94NHCOxe2x80x94: by acylation of a compound of formula (I):
w) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94C(O)CH2xe2x80x94 and R4 is hydroxy: reacting a ketone of formula (XX):
with a strong base followed by reaction with a ketone of formula (XVI);
x) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94C(O)CH2xe2x80x94 and R4 is hydroxy: reaction of a compound of formula (XXI):
wherein Rxe2x80x3 is a C1-6alkyl group, with a ketone of formula (XVI);
y) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94C(O)CH2xe2x80x94: reaction of a compound of formula (VII) wherein J is Li with a compound of formula (XXII):
z) for a compound of formula (I) in which Axe2x80x94B is xe2x80x94C(O)CH2xe2x80x94: reaction of a compound of formula (XXIII):
with a compound of formula (XXIV):
a1) for compounds of formula (I) where Ring C has an PhSxe2x80x94 substituent: treatment of a compound of formula (VI), wherein G1 is a leaving group, with a thiophenol in the presence of a catalyst;
b1) for compounds of formula (I) where Ring C has an ArSxe2x80x94 substituent wherein Ar as defined above: treating a compound of formula (VI), wherein G1 is SH with an aromatic compound containing a displaceable group, in the presence of a catalyst;
c1) for compounds of formula (I) where Ring C has an ArSxe2x80x94 substituent wherein Ar is as defined above and Axe2x80x94B is not NHCO: treating a compound of formula (VI), wherein G1 is a leaving group with a compound of formula ArSH in the presence of a base;
d1) for compounds of formula (I) where ring C has a Ra2xe2x80x94NC(O)xe2x80x94 substituent wherein Ra2 is a group that is attached through an amide linker (possible values as defined above): treating a compound of formula (VI) wherein ring D3 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 G1 and G1 is a leaving group; with carbon monoxide and an amine having the formula xe2x80x94NRa2; and
e1) for compounds of formula (I) where ring C has a Ra2xe2x80x94OSO2xe2x80x94 substituent wherein Ra2 is a group that is attached through a sulphinate ester linker (possible values as defined above): treating a compound of formula (VI) wherein ring D3 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 G1 and G1 is a sulphonyl chloride ClO2Sxe2x80x94; with an alcohol having the formula xe2x80x94ORa2;
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 hydrolysable ester.
Examples of reactions to convert a compound of the formula (I) into another compound of the formula (I) are known in the art. By way of illustration these include:
(i) formation of a hydroxy as a substituent on an aryl or heteroaryl group by cleaving the corresponding alkyl ether or acyloxy ester. 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; and the cleavage of an acetate group using for example lithium hydroxide in a lower alcohol (such as for example methanol or ethanol);
(ii) formation of R4 as hydroxy. For example, a compound of formula (I) where R4 is chloro can be prepared by reaction of a compound of formula (I) in which R4 is hydroxy with a reagent such as thionyl chloride in a suitable solvent such as dichloromethane or tetrahydrofuran and at a temperature in the range of 0 to 70xc2x0 C. The reaction can optionally be carried out in the presence of a catalyst such as N,N-dimethylformamide.
Pg is an alcohol protecting group suitable values for Pg are groups such as a benzyl groups, silyl groups or a acetyl protecting groups.
When G1 is a leaving group suitable values are brom odo or triflate.
Where formula (VIII) is an activated acid derivative, uitable values for X include halo (for example chworo or bromo), anhydrides and aryloxy (for example phenoxy or pentafluorophenoxy).
In formula (X) M is an alkali metal, suitable values for M include sodium or lithiumn. Suitable values for M in formula (XII) include lithium.
In formula (VII) wherein J is a leaving group suitabl values are bromo, iodo or triflate.
Specific conditions of the above reactions are as follows:
(a) Examples of suitable reagents for deprotecting an alcohol of formula (II) are:
1) when Pg is benzyl:
(i) hydrogen in the presence of palladium/carbon catalyst, i.e. hydrogenolysis; or
(ii) hydrogen bromide or hydrogen iodide;
2) when Pg is a silyl protecting group:
(i) tetrabutylammonium fluoride; or
(ii) aqueous hydrofluoric acid;
3) when Pg is acetyl:
i) mild aqueous base for example lithium hydroxide.
The reaction can be conducted in a suitable solvent such as ethanol, methanol, acetonitrile, or dimethylsulphoxide and may conveniently be performed at a temperature in the range of xe2x88x9240 to 100xc2x0 C.
(b) These conditions are well known in the art for example suitable oxidising agents such as pyridinium dichromate and solvents such as methanol or dichloromethane, may be employed.
(c) A saturated aqueous acid such as oxalic or a mineral acid such as hydrochloric acid or sulphuric acid may conveniently be employed for this deprotection. The reaction may conveniently be performed at a temperature in the range of 0 to 100xc2x0 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 or water/acetone.
(d) Reducing agents such as sodium borohydride (for compouns of formula (V) yielding compounds of formula (III)) and triethylsilane (for compounds of formula (III)) may be used. A reduction involving sodium borohydride is conveniently carried out in solvents such as for example a lower alcohol (e.g. methanol or ethanol) and a reduction using triethylsilane is conveniently carried out in a solvent such as trifluoromethylsulphonic acid.
(e) This reaction with the tin compound is conveniently performed in the presence of a suitable catalyst such as for example bis(triphenylphosphine)palladium dichloride, and at a temperature in the range of 0 to 100xc2x0 C. and in a solvent such as for example tetrahydrofuran, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, or dimethyl sulphoxide. The reaction with the aluminium compound is conveniently performed in the presence of a similar catalyst and temperature and in a solvent such as for example diethyl ether, benzene, toluene, or tetrahydrofuran.
(f) Suitable oxidising agents include potassium permanganate, OXONE, sodium periodate, tert-butyl hydroperoxide (as solution in toluene), peracids (such as for example 3-chloroperoxybenzoic acid), hydrogen peroxide, TPAP (tetrapropylammonium perruthenate) or oxygen. 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 these solvents. The reaction may conveniently be performed at a termperature in the range of xe2x88x9240 to 100xc2x0 C.
(g) The reaction can be conducted in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, for example dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, pyridine, or 2,6-di-alkyl-pyridines (such as 2,6-lutidine or 2,6-di-tert-butylpyridine) or 2,6-diphenylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of xe2x88x9240 to 40xc2x0 C.
(h) This coupling may be achieved optionally in the presence of a base for example triethylamine, pyridine, 2,6-di-alkyl-pyridines (such as 2,6-lutidine or 2,6-di-tert-butylpyridine) or 2,6-diphenylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of xe2x88x9240 to 40xc2x0 C.
(i) Suitable bases to yield a dianion are strong bases such as lithium dialkylamides (for example lithium diisopropyl amide). Suitable reducing agents include triphenylphosphine.
Suitable peroxyacids include 3-chloroperoxybenzoic acid. The reactions may conveniently be performed at a temperature in the range of xe2x88x92100xc2x0 C. to room temperature, in a suitable solvent such as tetrahydrofuiran or diethyl ether.
(j) The reaction may conveniently be performed at a temperature in the range of xe2x88x9240 to 100xc2x0 C. and in a suitable solvent such as dimethylformamide, DMSO, or tetrahydrofuran. Where R4 is hydroxy the corresponding dianion is formed.
(k) The reaction may conveniently be performed at a temperature in the range of xe2x88x92100 to 20xc2x0 C., preferably at a temperature in the range of xe2x88x9220 to 20xc2x0 C., in a suitable solvent such as tetrahydrofuran or diethyl ether.
(l) The reaction may conveniently be performed at a temperature in the range of xe2x88x92100 to 25xc2x0 C. and in a solvent such as tetrahydrofuran, diethyl ether, or 1,2-(dimethoxyethane.
(m) The reaction may be conveniently carried out in the presence of a base such as for example pyridine, triethylamine or potassium carbonate, at a temperature in the range of 0 to 120xc2x0 C. in a suitable solvent such as for example N,N-dimethylformamide, or acetonitrile. For N-linked N-alkylsulphonamides this is followed by alkylation with, for example, an alkyl iodide or bromide. The alkylation reaction may conveniently be performed at a temperature in the range of 0 to 1 20xc2x0 C. in a suitable solvent such as for example N,N-dimethylformamide, or acetone in the presence of a base such as for example potassium carbonate.
(n) The reaction may be conveniently carried out in the presence of a catalyst such as a combination of cuprous iodide and bis(triphenyl-phosphine)palladium dichloride or palladium(II) acetate. 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 xe2x88x9220 to 110xc2x0 C.
(o) Suitable bases include lithium diisopropylamide (LDA), n-butyllithium or tert-butyllithium. The reaction may be performed at a temperature in the range of xe2x88x92100 to xe2x88x9240xc2x0 C. preferably at a temperature in the range of xe2x88x9270 to xe2x88x9240xc2x0 C.; and in a solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane.
(p) Suitable reducing agents are, for example, lithium aluminium hydride or sodium bis(methoxyethoxy)aluminium hydride. The reaction can be conducted in a suitable solvent such as tetrahydrofuran or diethyl ether, and at a temperature in the range of 0 to 50xc2x0 C.
(q) This reaction may be conveniently performed in the presence of an acid catalyst (for example p-toluenesulphonic acid), in a solvent such as toluene or dichloromethane at a temperature in the range of 0 to 200xc2x0 C. preferably a temperature in the range of 20 to 1 00xc2x0 C.
(r) The opening may be carried out in a suitable organic solve it for example, ethers or toluene. Ethers such as tetrahydrofuran are preferred. Suitable bases include potassium tert-butoxide or sodium hydride. The opening may be carried out at a temperature in the range of xe2x88x9250 to 100xc2x0 C., preferably at a temperature in the range of 0 to50xc2x0 C.
(s) Suitable reducing agent include lithium aluminium hydride or borane. The reaction can conveniently be carried out at a temperature in the range of 0xc2x0 C. to reflux, in solvents such as for example diethyl ether, tetrahydrofuran, or 1,2-dimethoxyethane.
(t) Where J is xe2x80x94OH or xe2x80x94SH; the reaction may be conveniently carried out in the presence of a base for example sodium hydride or triethylamine. The reacticn can be conducted at a temperature of 0xc2x0 C. to reflux in a solvent such as dichloromethane, tetrahydrofuran, or diethyl ether. Where J is xe2x80x94NH2; the reaction may be conveniently carried out by the procedure as described in JOC (1999), 64, p.287-289 using copper (I) triflate as a catalyst.
(u) Suitable sulphonating reagents are for example phosphorus pentasulphide or Lawesson""s reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide). The reaction may optionally be carried out in the presence of a suitable base such as for example pyridine or triethylamine. Suitable solvents for the reaction include for example toluene, tetrahydrofuran, 1,3-dioxane or acetonitrile. The reaction is coveniently performed at a temperature in the range of from 0xc2x0 C. to reflux.
(v) Acylating reagents such as carboxylic 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 200xc2x0 C. employing a solvent such as N,N-dimethylformamide, 1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H)-pyrimidinone, DMSO, or ethylene glycol if required, followed by (2) the formation of an amide as described in (g) or (h) hereinbefore (Staskum, B., J. Org. Chem. (1964), 29, 2856-2860; Ohmrnacht C., J. Med. Chem. (1996), 39, 4592-4601).
(w) suitable strong bases are for example:
i) sodium hydride in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide. The reaction is conveniently performed at a temperature in the range of from xe2x88x9278xc2x0 C. to 25xc2x0 C.
ii) lithium diisopropylamide in a suitable solvent such as tetraydrofuran. The reaction is conveniently performed at a temperature in the range of from xe2x88x9278 to 25xc2x0 C.
(x) Rxe2x80x3 is preferably methyl. This reaction may be carried out in the presence of a Lewis acid such as titanium tetrachloride in a suitable solvent such as dicloromethane. This reaction is conveniently performed at a temperature in the range of xe2x88x9278 to 50xc2x0 C.
(y) This reaction is preferably carried out in a suitable solvent, for example tetrahydrofuran at a temperature of xe2x88x9278 to 100xc2x0 C.
(z) This reaction is conveniently performed under standard Friedel Crafts conditions, for example in the presence of aluminium trichloride in a solvent such as dichloromethane or nitrobenzene at a temperature of 0 to 150xc2x0 C.
a1) Suitable catalysts include tetrakis(triphenylphosphine)palldium(0), cuprous chloride or a stoichlometric amount of cupurous oxide. The reaction may conveniently be conducted in a suitable inert solvent such as a lower alcohol, a mixture of pyridine and quinoline, dimethylformamide, N-methylpyrrolidinone or toluene and optionally in the presence of a base such as for example sodium methoxide or potassium carbonate.
b1) Suitable displaceable groups include halo or triflate. Suitable catalysts include tetrakis(triphenylphosphine)palladium(0), cuprous chloride or a stoichlometric amount of cupurous oxide. The reaction may conveniently be conducted in a suitable inert solvent such as a lower alcohol or a mixture of pyridine and quinoline or N-methylpyrrolidinone or dimethylformamide and in the presence of a base such as for example sodium methoxide if required at a temperature of 25-180xc2x0 C.
c1) A suitable leaving group is fluoro. A suitable base is potassium carbonate. The reaction may conveniently be performed at a temperature in the range of 30 to 200xc2x0 C. and in a solvent such as N,N-dimethylformamide, 1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H)-pyrimidinone, DMSO, or ethylene glycol.
d1) This reaction with an amine is conveniently performed in the presence of a suitable catalyst such as for example bis(triphenylphosphine palladium dichloride or dichlorobis-(triphenylphosphine) palladium(II), and at a temperature in the range of 0xc2x0 C. to reflux and in a solvent such as for example tetrahydrofuran, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, dimethyl sulphoxide or using an amine as the required solvent such as for example tributylamine.
e2) The reaction may be conveniently carried out in the presence of a base such as for example pyridine, triethylamine or potassium carbonate, at a temperature in the range of 0 to 120xc2x0 C. in a suitable solvent such as for example dichloromethane, diethyl ether, N,N-dimethylformamide, or acetonitrile.
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, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples.
For example, it will be appreciated that certain of the optional aromatic substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acylhalide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by, for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl using, for example, hydrogen peroxide in acetic acid with heating or 3-chloroperoxybenzoic acid.
Specific examples of the techniques used to make the starting materials described above are illustrated, but not limited by, the following example in which variable groups are as defined for formula (I) unless otherwise stated.
1) Preparation of Compounds of Formula (II).
a) compounds of formula (II) in which Axe2x80x94B is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94 or xe2x80x94NHCH2xe2x80x94 may be made by treating the corresponding compound of formula (VII) where in J is xe2x80x94OH, xe2x80x94SH or xe2x80x94NH2 with a compound of formula (XXV):
where Z is a leaving group for example mesylate; in the presence of a base such as an alkali metal hydride (e.g. sodium hydride), in a solvent such as tetrahydrofuran, dimethyl sulphoxide, N,N-dimethylformamide or 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and at a temperature of room temperature to reflux.
A compound of formula (XXV), wherein Z is mesylate may be prepared by reacting a compound of formula (XXV) wherein Z is OH with methanesulphonyl chloride in the presence of a base such as triethylamine, in a solvent such as dichloromethane, and at a temperature of about xe2x88x9278 to 25xc2x0 C.
Compounds of formula (XXV) wherein Z is OH are prepared by reducing a compound of formula (VIII) wherein X is OH and R4 is a protected hydroxy group or a compound of formula (XXVI):
where E is a carboxy protecting group (e.g. Me) and R4 is a protected hydroxy group with a suitable reducing agent such as lithium aluminium hydride in a solvent such as diethyl ether or tetrahydrofuran and at a temperature of about 0 to about 25xc2x0 C.
b) A compound of formula (II), wherein Axe2x80x94B is xe2x80x94NHC(O)xe2x80x94, may be made by coupling a compound of formula (VII) wherein J is xe2x80x94NH2 with a compound of formula (VIII) wherein X is OH and R4 is a protected hydroxy group in a manner analogous to that described for procedure (g) or (h) of preparations of a compound of formula (I) hereinabove.
Compounds of formula (VIII) wherein X is OH and R4 is a protected hydroxy group may be made by conventional procedures. For example, cleavage of the ester group of a compound of formula (XXVI) where E is a carboxy protecting group (e.g. Me), under standard conditions such as mild alkaline conditions, for example, aqueous lithium hydroxide.
Compounds of formula (XXVI) where R4 is protected hydroxy may be prepared by protecting a compound of formula (XXVI) where R4 is hydroxy by reaction with a compound such as benzyl chloride or benzyl bromide (in the presence of a suitable base such as sodium hydride and optionally with a catalyst such as sodium or ammonium iodide, to provide a benzyl protecting group) or any of the conventional silylating agents known and used for such purpose (for example 2-trimethylsilylethoxymethyl chloride, in the presence of a suitable base such as triethylamine optionally in the presence of a catalyst such as N,N-dimethylaminopyridine).
Compounds of formula (XXVI) where R4 is hydroxy are prepared by esterifying an acid of formula (VIII) wherein X is OH by a conventional esterification procedure such as reaction with a C1-4alcohol (e.g. methanol) in the presence of an acid catalyst (for example sulphuric acid).
c) A compound of formula (II), wherein Axe2x80x94B is ethynylene, may be made by reacting a compound of formula (VII) wherein J is a leaving group such as bromo, iodo, or triflate, with an acetylene of formula (XXVII)
wherein if R4 is protected hydroxy in the presence of a catalyst such as a combination of copper(I) iodide and bis(triphenylphosphine)palladium dichloride or palladium(II) acetate. The reaction can be conducted in an inert solvent such as tetrahydrofuran, benzene, or toluene, or in a basic solvent such as diethylamine or triethylamine, and at a temperature in the range of xe2x88x9220 to 110xc2x0 C.
A compound of formula (XXVII) wherein R4 is a protected hydroxy group may be made by reacting a compound of formula (XXVII) where R4 is OH with a conventional hydroxy protecting group reagent such as those described herein before and herein after.
d) A compound of formula (II), wherein Axe2x80x94B is trans-vinylene, may be made by reacting a compound of formula (XXVIII):
where M is an alkylmetal group such as a trialkyltin (for example tributyl- or trimethyl-tin) or a bisalkyloxyborane (for example catecholborane) and R4 is protected hydroxy with a compound of formula (VII), wherein J is a leaving group for example iodide, bromide or triflate in the presence of a catalyst such as bis(triphenylphosphine)palladium dichloride or tetrakis(triphenylphosphine)palladium(0). The reaction may conveniently be conducted in a suitable inert solvent such as a tetrahydrofuran or dimethylformamide at a temperature of 0-150xc2x0 C. under an inert atmosphere.
A compound of formula (XXVIII) may be made by a reaction of a compound of formula (XXVII)
i) with an agent such as catecholborane, to form the vinylborane compound of formula (XXVIII) where M is catecholborane; or
ii) a trialkyltinhydride in the presence of a catalytic amount of a radical chain initiator such as, for example, aza-bis-isobutyronitrile or by using trialkyltinhydride pre-treated with a strong base (such as an alkyllithium) and copper(I) cyanide, or by using a transition metal catalyst such as, for example, tetrakis(triphenylphosphine)palladium(0) to form a compound of formula (XXVIII) where M is trialkyltin.
These reactions may conveniently be conducted in a suitable inert solvent such as tetrahydrofuran, toluene or xylene at a temperature of from 0-150xc2x0 C. under an inert atmosphere.
Compounds of formula (XXVII) may be made by reacting a compound of formula (XVI) 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 xe2x88x92100 to 25xc2x0 C.
2) Preparation of a Compound of Formula (IV):
a) A compound of formula (IV), wherein Axe2x80x94B is ethynylene and R4 is OH, may be made by reacting a corresponding compound of formula (XXIX):
wherein ring D5 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(xe2x80x94Cxe2x80x94Oxe2x80x94(CH2)3xe2x80x94Oxe2x80x94)xe2x80x94 with a base such as an alkyllithium (for example, butyllithium) followed by addition of a ketone having the formula (XVI). The reaction may be conducted at a temperature of from about xe2x88x92100 to about xe2x88x9240xc2x0 C. and in a solvent such as tetrahydrofuran, dimethyl ether, or 1,2-dimethoxyethane.
b) A compound of formula (IV), wherein Axe2x80x94B is trans-vinylene, may be made by reducing a corresponding compound of formula (IV), wherein Axe2x80x94B is ethynylene, with a suitable reducing agent such as lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminium, in a solvent such as tetrahydrofuran. The reaction may be conducted at a temperature of from about 40 to about 40xc2x0 C.
c) a compound of formula (XXIX) may be made by treating the corresponding ketone with 1,3-propanediol in the presence of an acid catalyst such as p-toluenesulphonic acid (TsOH) and in a refluxing solvent such as toluene using a Dean Stark apparatus or dried Molecular Sives.
3) Preparation of a Compound of Formula (VI):
a) A compound of formula (VI) wherein G1 is halo, such as for example bromo or iodo may be made by (1) treating a corresponding compound of formula (VI), wherein G1 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 sulphuric acid or tert-butyl nitrite to effect diazotization, and thereafter (3) treating the diazotized compound with a corresponding copper(I)halide such as for example cuprous bromide or potassium iodide.
b) A compound of formula (VI), wherein G1 is SH can be made by: (1) coupling of a compound of formula (VI) wherein G1 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 xe2x88x9278 to about 25xc2x0 C.; or (2) by Pummerer rearrangement as described in Tet. Let. (1984), 4), 25 (17), p. 1753 of a compound of formula (VI) wherein G1 is CH3S(O)xe2x80x94, which can be made from a compound of formula (VI) wherein G1 is a leaving group such as halo of triflate, 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 (VI), wherein G1 is SO2Cl, 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, dimethylformamide, followed by an acidic workup.
c) a compound of formula (VI), wherein G1 is SO2Cl can be made by treatment with chlorosulphonic acid of a compound of formula (VI), wherein G1 is H, under standard conditions.
4) Preparation of Compounds of Formula (XII).
A compound of formula (XII), wherein Axe2x80x94B is ethynylene, may be made by treating a corresponding compound of formula (XV) wherein Z is a protecting group such as, for example, trimethylsilyl with a fluoride base (for example, tetrabutylammonium fluoride (TBAF)) and an acid chloride of formula R3xe2x80x94COxe2x80x94Cl, thereby making the desired compound.
5) Preparation of Compounds of Formula (VII).
A compound of formula (VII), wherein J is halo, may be made by treating a corresponding compound of formula (VII), wherein J is nitro, with (1) as tin(II) chloride or (2) iron dust and concentrated hydrochloric acid in 95% ethanol to reduce the nitro group and thereby form the corresponding amine; (2) the amine may the be treated for example with a nitrite (such as tert-butyl nitrite or sodium nitrite in the presence of a mineral acid) to form the corresponding diazonium salt which may in turn be treated with a copper(I) salt (such as copper(I)bromide or copper(I)chloride) or potassium iodide. The diazotization and displacement reactions may be conducted in a solvent such as acetonitrile and at a temperature of from 0 to 25xc2x0 C.
6) Preparation of Compounds of Formula (XIV).
A compound of formula (XIV) wherein R4 is OH may be made by reacting a corresponding ketone having the formula (XVI) 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 xe2x88x92100 to about 25xc2x0 C.
7) Preparation of Compounds of Formula (XIII).
A compound of formula (XIII), wherein G2 is amino and Axe2x80x94B is NHCO may be made by treating a compound of formula (XIII), wherein G2 is nitro, under standard conditions for example by a reducing agent such as tin(II) chloride or iron dust in conjunction with concentrated acid, or using palladium metal supported on charcoal and hydrogen gas in a solvent such as a lower alcohol (methanol or ethanol) or ethyl acetate.
8) Preparation of Compounds of Formula (VII).
i) a compound of formula (VII) wherein R1 is ortho-halo or ortho-hydroxy and J is xe2x80x94NH2, may be made by treatment of a compound of formula (XXX):
wherein the amino group is in a position ortho to the nitro group, with (I) a combination of nitric acid and sulphuric acid or tert-butyl nitrite 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 corresponding phenol, followed by (3) reduction of the nitro group (see 8) ii) or 7)). The diazotization and displacement reactions may be conducted in a solvent such as acetonitrile and at a temperature of from 0-25xc2x0 C. A compound of formula (XXX) may be made for example according to procedures similar to those described in J. Med. Chem., (1975), 18, 1164.
ii) a compound of formula (VII) wherein J is NH2 may be prepared by reducing a compound of formula (XXXI):
under standard conditions for example by a reducing agent such as tin(II) chloride or iron dust in conjunction with concentrated acid, or using palladium metal supported on charcoal and hydrogen gas in a solvent such as a lower alcohol (methanol or ethanol) or ethyl acetate.
iii) a compound of formula (VII) wherein J is NH2, R1 is xe2x80x94NO2 and ring C is substituted by ArSO2: reacting a compound of formula (XXXII):
wherein ring D4 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 ArSO2, with nitric acid, followed by treating the nitrated compound under mild alkaline conditions (i.e. employing a base such as lithium hydroxide) to cleave the acetate group to yield the amine.
iv) a compound of formula (VII) wherein J is xe2x80x94OH, may be prepared by diazotizing a compound of formula (VII) wherein J is xe2x80x94NH2 under standard conditions followed by heating the resulting compound in dilute sulphuric acid.
v) a compound of formula (VII), wherein J is xe2x80x94SH, may be prepared by reacting a compound of formula (VII) where J is a leaving group (for example fluoro or chloro) with an excess of methanethiol in the presence of sodium hydride.
vi) a compounds of formula (VII) wherein J is Li may be prepared by
a) halogen metal exchange. For example by treatment of a compound of formula (VII) wherein J is Br or I; with an organolithium reagent such as n-butyl lithium or t-butyllithium in a solvent such as tetrahydrofuran at low temperature such as xe2x88x92100-xe2x88x9250xc2x0 C.
b) for compounds where R1 is an ortho directing metallating substituent by treatment of a compound of formula (XXIII) with an alkyl lithium base. Reactions of this type are reviewed in V. Snieckus, Chem Rev, 1990, 90, 879-933.
9) Resolution of Compounds of Formula (VIII) wherein X is OH.
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 {for example WO 9738124}, by enzymatic resolution, 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)-(xe2x88x92) acid, i.e. using the classical resolution method described in European Patent Application Publication No. EP 0524781, also for preparation of the (S)-(xe2x88x92) acid, except that (1S,2R)-norephedrine may be used in place of (S)-(xe2x88x92)-1-phenylethylamine.
10) Preparation of Compounds of Formula (XV).
A compound of formula (XV) wherein Z is H, may be prepared by reacting a compound of formula (VII), wherein J is a leaving group such as bromo, iodo or triflate 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 potassium carbonate) in a C1-6alcohol (such as methanol) as the solvent to remove the trimethylsilyl group.
11) Preparation of Compounds of Formula (XVII).
A compound of formula (XVII) may be prepared from a compound of formula (XXXIII):
by reduction under standard conditions for example by using a hydride, such as sodium borohydride.
A compound of formula (XXXIII) may be prepared by deprotonation of a compound of formula (VII) where J is Me, with a strong base, for example lithium diisopropyl amide in an organic solvent, for example tetrahydrofuran at a temperature of xe2x88x9278 to 100xc2x0 C. followed by addition of an amide of formula (XXXIV):
in which R19 and R20 are each independently C1-6alkyl, preferably methyl, or together with the atoms to which they are attached form a 5-7 membered ring.
An amide of formula (XXXIV) may be prepared from an acid of formula (VIII), or a reactive derivative thereof, by reaction with a hydroxyamine of formula R19(R20O)NH under standard conditions such as those described in process (g) or (h) for preparation of a compound of formula (I) hereinabove.
12) Preparation of Compounds of Formula (XVIII).
A compound of formula (XVIII) may be prepared from a diol of formula (XXXV):
using a suitable dehydrating agent, for example bis[xcex1,xcex1-bis(trifluoromethyl)benzene methanolato]diphenyl sulphur.
13) Preparation of Compounds of Formula (XIX).
A compound of formula (XIX) may be made by treating a compound of formula (XVI) with a trimethylsulphonium salt (such as trimethylsulphonium iodide) and a base (such as an alkali metal hydroxide) in a solvent such as dichloromethane.
14) Preparation of Compounds of Formula (XX).
Compounds of formula (XX) can be made by synthetic reactions well known in the art for example:
i) a Friedel Crafts acylation of a compound of formula (XXIII) with acetyl chloride under conditions such as those described in (z) above.
ii) reaction of a compound of formula (VII) wherein J is Li with an amide of formula (XXXVI):
under conditions such as those described in 8)vi)b) hereinabove.
iii) oxidation of a compound of formula (XXXVII):
15) Preparation of Compounds of Formula (XXI).
Compounds of formula (XXI) can be prepared from compounds of formula (XX) by treatment with a base such as lithium diisopropylamide or triethylamine and a silylating agent such as trimethylsilyl chloride in a solvent such as tetrahydrofuran or trimethylsilyl triflate in a solvent such as dichloromethane. The reaction can conveniently be performed at a temperature in the range of xe2x88x9278 to 70xc2x0 C.
16) Preparation of Compounds of Formula (XXII).
Compounds of formula (XXII) can be prepared from an acid of formula (XXXVIII):
or a reactive derivative thereof, by reaction with a hydroxyamine of formula R19(R20O)NH under standard conditions such as those described in process (g) or (h) for preparation of a compound of formula (I) hereinabove.
According to a further feature of the invention, there is provided a process for preparing a compound of formula (Ixe2x80x2) using any one of processes a), f), g), h), i) or l); and thereafter if necessary:
i) converting a compound of the formula (Ixe2x80x2) into another compound of the formula (Ixe2x80x2);
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 as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a phenol is, for example, an alkylether, for example, methyl, a silyl ether, for example, trimethylsilyl ether or t-butyldimethylsilyl ether, an oxyalkylether, for example, methoxymethyl ether or methoxyethoxymethyl ether or an ester, for example acetate or benzoate. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an alkylether may be removed by treatment with a suitable reagent such as iodotrimethylsilane or a suitable Lewis acid such as borontribromide. Alternatively a silyl ether may be removed by acid- or fluoride ion-catalysed hydrolysis. Alternatively oxyalkylethers may be removed by treatment with a suitable acid such as acetic acid or hydrochloric acid. Alternatively esters may be removed by hydrolysis by a suitable acid or a suitable base.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
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, methanesulphonate, acetate, tartrate, citrate, succinate benzoate, ascorbate, xcex1-ketoglutarate, and xcex1-glycerophosphate. Suitable inorganic salts may also be formed such as sulphate, 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 envisaged and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg 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 salt thereof is defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
According to an additional aspect of the present invention there is provided a compound of the formula (Ixe2x80x2) or a pharmaceutically acceptable salt there of as defined hereinbefore for use in a method of treatment of the human or animal body by the 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 (Ixe2x80x2), or a pharmaceutically acceptable salt thereof, for use as a medicament, conveniently a compound of formula (Ixe2x80x2), or a pharmaceutically acceptable salt thereof, for use as a medicament for producing an elevation of PDH activity in a warm-blooded animal such as a human being.
A further feature of the present invention is a compound of formula (Ixe2x80x2), or a pharmaceutically acceptable salt thereof, for use as a medicament, conveniently a compound of formula (Ixe2x80x2), or a pharmaceutically acceptable salt thereof, 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 salt thereof 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.
Thus according to an additional aspect of the invention there is provided the use of a compound of the formula (Ixe2x80x2), or a pharmaceutically acceptable salt thereof 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 salt thereof as defined hereinbefore. ester) with a suitable acid affording a physiologically acceptable anion. It is also possible with most compounds of the invention to make a corresponding 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.
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 PDHkinaseII (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 1.3 kb fragment encoding the protein was isolated by PCR from rat liver cDNA and cloned into a vector (for example pQE32xe2x80x94Quiagen Ltd.). The recombinant construct was transformed into E. coli (for example M15pRep4xe2x80x94Quiagen 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 Cloningxe2x80x94A Laboratory Manual , 2nd 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 xcexcM isopropylthio-xcex2-galactosidase. Cells were grown for 18 hours at 18xc2x0 C. and harvested by centrifugation. The resuspended cell paste was lysed by homogenisation and insoluble material removed by centrifugation at 24000xc3x97g 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, 0.15 M sodium chloride pH 8.0. Eluted fractions containing 6-His protein were pooled and stored in aliquots at xe2x88x9280xc2x0 C. in 10% glycerol.
Each new batch of stock enzyme was titrated in the assay to determine a concentration giving approximately 90% inhibition of PDH in the conditions of the assay. For a typical batch, stock enzyme was diluted to 7.5 xcexcg/ml.
For assay of the activity of novel compounds, compounds were diluted with 10% dimethylsulphoxide (DMSO) and 10 xcexcl transferred to individual wells of 96-well assay plates. Control wells contained 20 xcexcl 10% DMSO instead of compound. 40 xcexcl Buffer containing 50 mM potassium phosphate buffer pH 7.0, 10 mM ethylene glycol-bis(xcex2-aminoethyl ether)-N,N,N,N-tetracetic acid (EGTA), 1 mM benzamidine, 1 mM phenylmethylsulphonyl fluoride (PMSF), 0.3mM tosyl-L-lysine chloromethyl ketone (TLCK), 2 mM 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 rTPDHKII. PDH kinase activity was then initiated by the addition of 5 xcexcM ATP, 2 mM magnesium chloride and 0.04 U/ml PDH (porcine heart PDH Sigma P7032) in a total volume of 50 xcexcl and plates incubated at ambient temperature for a further 45 minutes. The residual activity of the PDH was then determined by the addition of substrates (2.5 mM coenzyme A, 2.5 mM thiamine pyrophosphate (cocarboxylase), 2.5 mM sodium pyruvate, 6 mM NAD in a total volume of 80 xcexcl and the plates incubates for 90 minutes at ambient temperature. The production of reduced NAD (NADH) was established by measured optical density at 340 nm using a plate reading spectrophotometer. The ED50 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 37xc2x0 C. in 5% CO2, the medium was replaced with Minimum Essential Medium (MEM, Gibco BRL) containing NEAA and penicillin/streptomycin as above in addition to 10 nM dexamethasone and 10 nM insulin.
The following day cells were washed with phosphate buffered saline (PBS) and medium replaced with 1 ml HEPES-buffered Krebs solution (25 mM HEPES, 0.15M sodium chloride, 25 mM sodium hydrogen carbonate, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium sulphate, 1 mM potassium dihydrogen phosphate) containing the compound to be tested at the required concentration in 0.1% DMSO. Control wells contained 0.1% DMSO only and a maximum response was determined using a 10 xcexcM treatment of a known active compound. After a preincubation period of 40 minutes at 37xc2x0 C. in 5% CO2, cells were pulsed with sodium pyruvate to a final concentration of 0.5 mM (containing 1-14C sodium pyruvate (Amersham product CFA85) 0.18 Ci/mmole) for 12 minutes. The medium was then removed and transferred 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 CO2 in the medium released by the addition of 0.2 xcexcl 60% (w/v) perchloric acid (PCA). Released 14CO2 trapped in the absorbent was determined by liquid scintillation counting. The ED50 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 (Vary 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 140-180 g) 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 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 m EDTA, 2 mM DTT, 1% Triton X-100, 10 mM sodium pyruvate, 10 xcexcM phenylmethylsulphonyl chloride (PMSF) and 2 xcexcg/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 xcexcl extract, 40 xcexcl phosphatase (1:20 dilution), in a final volume of 125 xcexcl 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. 3. (1976)154, 225). 50 xcexcl Extract is incubate with 0.75 mM NAD, 0.2 mM CoA, 1.5 mM thiamine pyrophosphate (TPP) and 1.5 mM sodium pyruvate in the presence of 20 xcexcg/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, 50 mM sodium fluoride, 5 mM 2-mercaptoethanol and 1 mM 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 5 mM.
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 salt thereof, 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 (Ixe2x80x2) as defined hereinbefore or a pharmaceutically acceptable salt thereof, 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 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg. A unit dose in the range, for example, 1-10 mg/kg, preferably 1-50 mg/kg is
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 1-50 mg/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;
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 reperfusion, muscle weakness, hyperlipidaemias, Alzheimer""s disease and 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 xe2x80x9cetherxe2x80x9d is used anywhere in this specification it refers to diethyl ether.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (xc2x0 C.); operation were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25xc2x0 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 carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of up to 60xc2x0 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 referred to, this means a column containing 10 g or 20 g of silica of 40 micron particle size, the silica being contained in a 60 ml disposable syringe and supported by a porous disc, obtained from Varian. Harbor City, Calif., USA under the name xe2x80x9cMeg Bond Elut SIxe2x80x9d; xe2x80x9cMega Bond Elutxe2x80x9d is a trademark;
(iv) where a Chem Elut column is referred to this means a xe2x80x9cHydromatrixxe2x80x9d 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 Varian, Harbor City, Calif., USA under the name of xe2x80x9cExtube, Chem Elutxe2x80x9d; xe2x80x9cExtubexe2x80x9d is a registered trademark of International Sorbent Technology Limited;
(v) where an ISOLUTE column is referred to, this means an xe2x80x9cion exchangexe2x80x9d extraction cartridge for adsorption of basic or acid material, i.e. a polypropylene tube containing a special grade of ion exchange sorbent, high purity, surface to pHxcx9c7, incorporating a phase-separation filtering material, used according to the manufacturers instructions, obtained from Varian, Harbor City, Calif., USA under the name of xe2x80x9cExtube, Chem Elut, ISOLUTExe2x80x9d; xe2x80x9cExtubexe2x80x9d is a registered trademark of International Sorbent Technology Limited;
(vi) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
(vii) melting points are uncorrected 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;
(viii) final products had satisfactory proton nuclear magnetic resonance NMR) spectra and/or mass spectral data;
(ix) 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;
(x) where given, NMR 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-xcex46) as solvent unless otherwise indicated, other solvents (where indicated in the text) include deuterated chloroform-CDCl3 and deuterated acetic acid AcOH-xcex44; coupling constants (J) are given in Hz; Ar designates an aromatic proton when such an assignment is made;
(xi) chemical symbols have their usual meanings; SI units and symbols are used;
(xii) reduced pressures are given as absolute pressures in Pascals (Pa); elevated pressures are given as gauge pressures in bars;
(xiii) solvent ratios are given in volume: volume (v/v) terms
(xiv) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported and unless otherwise stated the value quoted is (Mxe2x88x92H)xe2x88x92;
(xv) Oxone is a Trademark of E.I. du Pont de Nemours and Co., Inc., and refers to potassium peroxymonosulphate;
(xvi) The following abbreviations are used:
(xvii) HPLC Methods referred to in the text are as follows:
(xviii) where (R) or (S) stereochemistry is quoted at the beginning of a name, unless further clarified, it is to be understood that the indicated stereochemistry refers to the A-B-C*(R2)(R3)(R4) centre as depicted in formula (I).

Use of compounds for the elevation of pyruvate dehydrogenase activity

Abstract: wherein:

Abstract: Ring C is phenyl or a carbon linked heteroaryl ring substituted as defmed within;

Abstract: R1 is an ortho substituent as defined within;

Abstract: n is 1 or 2;

Abstract: Axe2x80x94B is a linking group as defined within;

Abstract: R2 and R3 are as defined within;

Abstract: R4 is hydroxy, hydrogen, halo, amino or methyl; in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans is described. Pharmaceutical compositions, methods and processes for preparation of compounds of formula (I) are also described.