Chemical compounds

Details Chemical compounds Chemical compounds

2002-06-17

2003-04-22

O'Sullivan, Peter (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C514S238800, C514S327000, C514S352000, C514S425000, C514S604000, C544S159000, C546S220000, C546S305000, C548S542000, C564S086000, C564S087000

Reexamination Certificate

active

06552225

ABSTRACT:

This application is a 371 of PCT/GB00/03303 filed Aug. 30, 2000.
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, in particular the treatment of diabetes mellitus, peripheral vascular disease and myocardial ischaemia in warm-blooded animals such as humans, more particularly to their use in the manufacture of medicaments for use in the treatment of diabetes mellitus 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 &bgr;-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 &bgr;-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 CO
2
from pyruvate; E2 forms acetyl CoA and E3 reduces NAD to NADH. Two additional enzyme activities are associated with the complex: a specific kinase which is capable of phosphorylating 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 No. 625516 refers to compounds which are capable of relaxing bladder smooth muscle and which may be used in the treatment of urge incontinence. We have found, surprisingly, that compounds also containing a sulphonamide moiety disclosed in the present invention are very good at elevating PDH activity, a property nowhere disclosed in EP 625516. 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 disease (AD) (J Neural Transm (1998) 105:855-870).
Accordingly, the present invention provides a compound of formula (I):
wherein:
R
1
and R
2
are each selected independently from hydrogen, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q, C
3-6
cycloalkyl optionally substituted by one or more Q, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkyl optionally substituted by one or more Q, R
8
T—, R
9
C
1-6
alkylT— and a heterocyclic group optionally substituted on a ring carbon by one or more Q and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D,
or R
1
and R
2
together with the nitrogen atom to which they are attached form a group Het which is optionally substituted on a ring carbon by one or more Q and wherein if group Het contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D;
R
3
and R
4
are independently C
k
alkyl optionally substituted by 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3;
or R
3
and R
4
together with the carbon atom to which they are attached, form a C
m
cycloalkyl ring optionally substituted by 1 to 2m-2 fluorine atoms wherein m is 3-5;
R
5
is hydrogen, C
1-6
alkyl, haloC
1-6
alkyl, C
1-6
alkoxy, haloC
1-6
alkoxy, cyano, nitro, C
2-6
alkenyloxy, trifluoromethylthio, halo, hydroxy, amino, N—(C
1-6
alkyl)amino, N—(C
1-6
alkyl)
2
amino, C
1-6
alkanoylamino, C
1-6
alkanoyl(N—C
1-6
alkyl)amino, C
1-6
alkylsulphonylamino, C
1-6
alkylsulphonyl(N—C
1-6
alkyl)amino, thiol, C
1-6
alkylsulphanyl, C
1-6
alkylsulphinyl, C
1-6
alkylsulphonyl, sulphamoyl, N—(C
1-6
alkyl)aminosulphonyl, N—(C
1-6
alkyl)
2
aminosulphonyl, carboxy, carbamoyl, N—(C
1-6
alkyl)carbamoyl, N—(C
1-6
alkyl)
2
carbamoyl, C
1-6
alkoxycarbonyl, formyl, C
1-6
alkanoyl, C
1-6
alkanoyloxy, C
2-6
alkenyl or C
2-6
alkynyl;
R
6
is hydrogen or Q;
R
7
is hydrogen, trifluoromethyl, C
1-4
alkyl, halo, hydroxy, trifluoromethoxy, cyano, C
1-4
alkoxy, formyl, C
1-4
alkanoyl, C
1-4
alkanoyloxy, amino, N—(C
1-4
alkyl)amino, N—(C
1-4
alkyl)
2
amino, C
1-

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