Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-06-23
1997-08-05
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546133, 546136, 546137, A01N 4390, C07D45302
Patent
active
056543158
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
This invention relates to novel heterocyclic derivatives and, more particularly to novel heterocyclic derivatives which possess the pharmacologically useful property of inhibiting squalene synthase. The invention also relates to pharmaceutical compositions for use in treating diseases or medical conditions such as hypercholesterolemia and atherosclerosis, as well as other diseases and conditions in which inhibition of squalene synthase is desirable. The invention also relates to processes for the preparation of the novel heterocyclic derivatives, and to their use in medicine.
BACKGROUND
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, inter alia, in a lowering of circulating blood cholesterol levels.
Squalene synthase is a microsomal enzyme which catalyses the first committed step of cholesterol biosynthesis. Two molecules of farnesyl pyrophosphate (FPP) 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 cardiovascular disease. Thus, an agent which inhibits squalene synthase should be useful in treating diseases and medical conditions in which a reduction in the level 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.
Certain quinuclidine derivatives are reported in EP 458,214 to be muscarinic agonists.
SUMMARY OF INVENTION
The present invention is based on the discovery that certain heterocyclic derivatives 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--, --OCH.sub.2 --, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 CO--, --COCH.sub.2 --, --CH.dbd.N--, --N.dbd.CH--, --CH.sub.2 S--, --SCH.sub.2 --, wherein the sulphur atom in the latter two groups may optionally bear one or two oxygen atoms; and independently substituted by one or more substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[(1-6C)alkyl]carbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)a
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: 5494918 (1996-02-01), Neuenschwander et al.
WO A 9 215 579, Sep. 17, 1992-pp. 36 and 37-claims.
Warawa et al, Quinuclidine Chemistry2.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.
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.
De Vito et al., Synthesis and Pharmacological Evaluation of Some Novel 13-[N,N-dialkylamino-alkyl]benzo[g][2]benzopyrano[43-b]indol-5[13H]ones, 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.
Mikhlina et al., Stereochemistry of Benzo[b]quinuclidines . . . , Khim. Geterosikl Soedin, 6, (1973), pp. 839-843.
Fleet et al., Complex Quinuclidines (1-Azabicyclo[2,2,2]octanes) from 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.
Brown George Robert
Harrison, deceased Peter John
Mallion Keith Blakeney
Hartley Michael G.
Hollinden Gary E.
Imperial Chemical Industries plc
LandOfFree
Quinuclidine compounds useful in treating diseases does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Quinuclidine compounds useful in treating diseases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Quinuclidine compounds useful in treating diseases will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1075086