Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-11-04
1995-09-05
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514570, 549295, 549313, 562470, A61K 3134
Patent
active
054479541
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/01071 filed Apr. 29, 1993.
The present invention relates to certain novel compounds, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.
It is now widely accepted that treatment of even moderate type II hypercholesterolaemia results in a reduction in mortality and morbidity due to coronary heart disease (CHD). Increased plasma concentrations of low density lipoprotein (LDL), the hallmark of type II hypercholesterolaemia are due to a variety of genetic and environmental factors resulting in increased LDL synthesis, decreased LDL catabolism or combinations of both. Current therapies for treatment of hypercholesterolaemia are directed towards stimulation of LDL catabolism (bile acid sequestrants and HMGCoA reductase inhibitors) as well as inhibition of LDL synthesis (nicotinic acid and maxepa fish oil).
The present invention relates to a new class of compounds which are expected to be of use in the treatment of hyperlipidaemia and preventing the development of consequent disorders like atherosclerosis and pancreatitis, as well as treatment of metabolic disorders like obesity. The compounds act by inhibition of the enzyme ATP citrate lyase, so inhibiting cholesterol synthesis and fatty acid synthesis resulting in lowered plasma cholesterol and triglyceride levels. In particular, it is expected that the compounds will be particularly useful in the treatment of mixed hyperlipidaemia (type IIb).
The present invention therefore provides, in a first aspect, compounds of structure (I) : ##STR2## in which, each group R.sup.1 is independently a lipophilic and/or electron withdrawing group; hydroxy and R.sup.5 is CH(R.sup.6)R.sup.7 in which R.sup.6 is hydrogen or hydroxy and R.sup.7 is a carboxyl group or a carboxylic acid ester group hydrolysable to a carboxyl group; or R.sup.4 is hydrogen and R.sup.5 is hydrogen or hydroxy, R.sup.2 is hydroxy and R.sup.3 is a carboxyl group or a carboxylic acid ester group hydrolysable to a carboxyl group; or R.sup.2 and R.sup.3 are hydrogen and R.sup.4 and R.sup.5 together form a group =C(R.sup.6)R.sup.7 in which R.sup.6 and R.sup.7 are as defined above,
The term "lipophilic and/or electron withdrawing group" refers to groups such as halogen, in particular chlorine, nitro, cyano, C.sub.1-4 alkanoyl, optionally substituted phenylC.sub.1-4 alkanoyl and fluorinated C.sub.1-4 alkyl such as trifluoromethyl. Other examples of such groups will be apparent to those skilled in the art. Suitable C.sub.1-4 alkanoyl groups include CH.sub.3 CO-- and C.sub.3 H.sub.7 CO--. Suitable phenylC.sub.1-4 alkanoyl groups include, for example, phenylCO-(benzoyl).
"Carboxylic acid ester groups hydrolysable to a carboxyl group" as defined for R.sup.3 and R.sup.7 include, for example, groups of formula C.sub.2 R.sup.8 in which R.sup.8 is C.sub.1-6 alkyl, benzyl, acetoxymethyl and pivaloyloxymethyl; preferably C.sub.1-6 alkyl such as methyl. Other examples of such groups will be apparent to those skilled in the art.
Suitably, each group R.sup.1 is independently a lipophilic and/or electron withdrawing group. Preferably each group R.sup.1 is the same and positioned in the 2,3- or 2,4-positions of the ring, in particular the 2,4-positions. More preferably each group R.sup.1 is the same and is halogen, in particular chlorine in the 2,4-positions of the ring.
Suitably, n is 5 to 8, preferably 6 or 7.
Suitably, R.sup.2 and R.sup.3 are both hydrogen, R.sup.4 is hydrogen or hydroxy and R.sup.5 is CH(R.sup.6)R.sup.7 in which R.sup.6 is hydrogen or hydroxy and R.sup.7 is a carboxyl group or a carboxylic acid ester group hydrolysable to a carboxyl group; or R.sup.4 is hydrogen and R.sup.5 is hydrogen or hydroxy, R.sup.2 is hydroxy and R.sup.3 is a carboxyl group or a carboxylic acid ester group hydrolysable to a carboxyl group; or R.sup.2 and R.sup.3 are hydrogen and R.sup.4 and R.sup.5 together form a group =C(R.sup.6)R.sup.7 in which R.sup.6 and R.sup.7 are as defined above.
Preferably, R.sup.2 and R.sup.3 ar
REFERENCES:
patent: 3248187 (1966-04-01), Bell
patent: 3261782 (1966-07-01), Anderson et al.
Journal of Medicinal Chemistry, vol. 25, No. 6, Jun. 1982.
Dolle Roland E.
Gribble Andrew D.
Groot Pieter H. E.
Shaw Antony N.
Dustman Wayne J.
Ivy C. Warren
Lentz Edward T.
Owens Amelia
SmithKline Beecham p.l.c.
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