Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-02-28
1998-02-03
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546133, 546137, A61K 31435, C07D45302
Patent
active
057144966
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/GB93/01802, filed Aug. 24, 1993.
FIELD OF THE INVENTION
This invention concerns heterocyclic compounds which are useful in inhibiting squalene synthase, processes for their preparation and pharmaceutical compositions containing them. The present invention is also concerned with methods of using such heterocyclic compounds in treating diseases and medical conditions where inhibition of squalene synthase is desirable, for example in treating diseases or medical conditions such as hypercholesterolemia and atherosclerosis.
BACKGROUND TO INVENTION
Several different classes of compounds have been reported to possess the capability of being able to lower cholesterol levels in blood plasma. For example agents which inhibit the enzyme HMG CoA reductase, which is essential for the production of cholesterol, have been reported to reduce levels of serum cholesterol. Illustrative of this class of compounds is the HMG CoA reductase inhibitor known as lovastatin which is disclosed in U.S. Pat. No 4,231,938. Other agents which are reported to lower serum cholesterol include those which act by complexing with bile acids in the intestinal system and which are hence termed "bile acid sequestrants". It is believed that many of such agents act by sequestering bile acids within the intestinal tract. This results in a lowering of the levels of bile acid circulating in the enteroheptatic system and promoting replacement of bile acids by synthesis in the liver from cholesterol, which synthesis results in an upregulation of the heptatic LDL receptor and thus in a lowering of circulating blood cholesterol levels.
Squalene synthase (also referred to in the art as squalene synthetase) is a microsomal enzyme which catalyses the first committed step of cholesterol biosynthesis. Two molecules of farnesyl pyrophosphate (FFP) are condensed in the presence of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA. Elevated cholesterol levels are known to be one of the main risk factors for ischaemic cardiovacsular disease. Thus, an agent which inhibits squalene synthase should be useful in treating diseases and medical conditions in which a reduction in the levels of cholesterol is desirable, for example hypercholesterolemia and atherosclerosis.
Thus far, the design of squalene synthase inhibitors has concentrated on the preparation of analogues of the substrate farnesyl pyrophosphate (FPP), and hence on compounds which contain phosphorus groups. For example, the preparation of phosphorous-containing squalene synthase inhibitors is reported in published European Patent Application No. 409,181; and the preparation of isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthase is reported by Biller et al, J. Med. Chem., 1988, 31, 1869.
Recently, certain quinuclidine derivatives have been reported to inhibit squalene synthase (PCT Patent Application No. WO 92/15579, published 17 Sep. 1992).
DISCLOSURE OF INVENTION
The present invention is based on the discovery that certain heterocyclic compounds are inhibitors of squalene synthase, and are hence useful in treating diseases and medical conditions in which inhibition of squalene synthase is desirable.
According to the present invention there is provided a compound of formula I (formula set out hereinafter together with the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, wherein: double bond; --CH.sub.2 O--, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 CO--, --COCH.sub.2 --, --CH.sub.2 S-- and --SCH.sub.2 --; more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, carboxy(1-6C)alkyl and (1-6C)alkanoylamino; -- and --SCH.sub.2
REFERENCES:
patent: 3405134 (1968-10-01), Judd
patent: 3534053 (1970-10-01), Sallay et al.
patent: 3586694 (1971-06-01), Shen et al.
patent: 3655675 (1972-04-01), Carabateas
patent: 3679690 (1972-07-01), Carabateas
patent: 3725410 (1973-04-01), Potoski et al.
patent: 3763168 (1973-10-01), Carabateas
patent: 3857848 (1974-12-01), Mauvernay et al.
patent: 4038402 (1977-07-01), Kaminka et al.
patent: 4599344 (1986-07-01), Morgan
patent: 5135935 (1992-08-01), Alberts et al.
patent: 5242914 (1993-09-01), Kawamoto et al.
patent: 5286864 (1994-02-01), Walther et al.
patent: 5385912 (1995-01-01), Neuenschwander et al.
patent: 5554613 (1996-09-01), Mallion
Saudman RA and McHugh WC (1977), 66(6) 890-1.
March J. in `Advanced Organic Chemistry` Second Edition (1977) p. 434 McGraw Hill, N.Y.
Warawa et al, Quinuclidine Chemistry.2..sup.1 Synthesis and Antiinflammatory Properties of 2-Substituted Benzhydryl-3-quinuclidinols, J. Med. Chem. 17(5), (1974), 497-501.
Sterling et al, quaternary and Tertiary Quinuclidine Derivatives as Inhibitors of Choline Uptake, J. Pharm. Sciences, 80(8), (1991), 785-789.
Saunders et al, Novel Quinuclidine-Based Ligands for the Muscarinic Cholinergic Receptor, J. Med. Chem. 33(4), (1990), 1128-1137.
Turchin et al, Stereochemistry of Quinuclidines Containing a Substituent with Aryl (Heteroaryl) Nuclei at Position Three Khimiko-farmatsevticheskii Zhurnal, 1986, vol. 20, pp. 65-72.
Bondarenko et al, Khim. Farm, 12(11), 1978, pp. 56-60.
Khim, Farm, 7(8), 1973, 20-24.
Ricciardi et al, Facile Synthesis of Styrylquinuclidines, Heterocycles, 24, (1986), pp. 971-977.
Khim. Geterosikl Soedin, 3, (1983), 381-385.
Mikhlina et al, Synthesis and Properties of (3-Quinuclidyl)diarylcarbinols, Khim. Geterosikl Soedin, 7,1976;776-780.
Sekine et al., Effect of Sulfur Containing Purine Nucleosides on Immunological Reaction in Mice, Japan. J. Exp. Med., 1973, vol. 43, 5, pp. 369-375.
DeVito et al., Synthesis and Pharmacological Evaluation of Some Novel Med. Chem. Res. 1(1), (1991), pp. 47-51.
Ermakov et al, Application of Mass Spectrometry in Structural and Stereochemical Investigations . . . , Khim. Geterosikl Soedin, 10, (1975), 1376-1383. Geterosikl Soedin, 6, (1973), pp. 839-843. Sugars: Synthesis of 1.alpha.,3.alpha.,4.alpha.,5.alpha.)-Quinuclidine-3-,5-diol from D-Glucose, J. Chem. Soc. Perkin. Trans. 1(5), (1989), 1067-1068.
Brittain David Robert
Brown George Robert
Mallion Keith Blakeney
Whittamore Paul Robert Owen
Huang Evelyn
Ivy C. Warren
Zeneca Limited
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