Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1994-05-19
1999-02-02
O'Sullivan, Peter
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514522, 514538, 514563, 514597, 514603, 514618, 514620, 514629, 514654, 514824, 558414, 560 45, 564 49, 564 51, 564 86, 564124, 564126, 564127, 564162, 564164, 564165, 564221, 564223, 564353, 564354, A61K 31165, A61K 3119, A61K 3117, A61K 31275
Patent
active
058666117
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/GB93/00742 filed 8 Apr. 1993.
FIELD OF THE INVENTION
This invention relates to phenoxypropylamine derivatives which possess the pharmacologically useful property of inhibiting squalene synthase and are hence useful 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 present invention relates to the use of such derivatives in medicine, pharmaceutical compositions containing phenoxypropylamine derivatives, novel phenoxypropylamine derivatives and processes for the preparation of novel phenoxypropylamine derivatives.
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 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 (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 whieh 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.
DISCLOSURE OF INVENTION
The present invention is based on the discovery that certain phenoxypropylamine derivatives are capable of inhibiting the enzyme 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 the use of 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: (3-10C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, phenyl(1-4C)alkyl and (2-10C)alkenyl; or R.sup.1 and R.sup.2 together define the group --DZB--, thereby completing a ring which includes the adjacent nitrogen atom, in which D and B are independently selected from ethylene and trimethylene, Z is a direct bond between D and B, or an oxy, thio, methylene, ethylidene or isopropylidene link or a group of formula .dbd.NR3 in which R3 is hydrogen, (1-6C)alkyl, phenyl or benzyl; (1-
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Brown George Robert
Eakin Murdoch Allan
Harrison, deceased Peter John
Mallion Keith Blakeney
O'Sullivan Peter
Zeneca Limited
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