1. Field of the Invention
The present invention relates to novel diphenyl methane derivatives having improved pharmacological properties when used for the therapy of hypercholesterolemia and hyperlipidemia and more particularly to chlorobenzyl phenoxy alkoxylates wherein the oxyalkoxylic moiety is in ortho position of the phenyl ring and has an asymmetric carbon atom as the link between the phenoxy moiety and the carboxylic function.
2. Description of the Prior Art
Ethyl p-chlorophenoxyisobutyrate (generic name: Clofibrate) having the formula ##STR2## disclosed by Glynn M. Jones et al. in U.S. Pat. No. 3,262,850 is a widely accepted therapeutic agent used for reducing the concentration of cholesterol in the blood serum. The relatively high toxicity (LD.sub.50 2350 mg/kg, mice) of Clofibrate and the necessity to use it in relatively high doses because of its low therapeutic effectiveness has triggered the search for other therapeutical agents suitable for treatment of hypercholesterolemia and having improved pharmacological properties.
The above mentioned U.S. Pat. No. 3,262,850 to Jones discloses other compound structures that include the phenoxyisobutyric moiety of the formula (10) ##STR3## in which Z is at least one substituent in para, meta or ortho position and Y.sup.1 is hydrogen or lower alkyl. For reasons explained below, the box A shown in dashed lines indicates the link between phenoxy carboxy.
Fukami et al. in German Published Specification No. 2,356,655 then disclosed anti-hypercholerolemic compounds of the formula ##STR4## in which Y.sup.2 is lower alkyl or a N,N-diloweralkyl substituted aminoalkylene group. It is to be noted that link A of the Fukami compounds (11) is the same as that of the Jones compounds (10).
Applicants have previously disclosed (e.g. in German Published Specification No. 2,461,069) that certain asymmetric homologues of the Jones compounds (10) and the Fukami compounds (11) of the formula (12) ##STR5## in which R' is hydrogen, halogen, lower alkyl or lower alkoxy and X is lower alkyl, provide for substantial improvements, notably an improved therapeutic ratio (LD.sub.50 divided by cholesterol lowering effectiveness) if link A.sup.1 is asymmetric; preferably, R" and R"' are different lower alkyls having a combined total of at least 3 carbon atoms, e.g. methyl/ethyl, methyl/propyl, etc.
When reviewing other parameters except link A.sup.1 of the above formula (12) compounds, both the art referred to above as well as experimental evidence reported below seemed to indicate that the linear arrangement of the formula (12) structure between link A.sup.1 and ring B was critical, notably with regard to the paraposition of the methylene and the oxy substituent of Ring C. For example, while some non-linear structures are disclosed in the Jones Patent mentioned above as well as in U.S. Pat. No. 3,362,997 to Bolhofer, and while non-linear structures of the general class of compounds referred to above are disclosed as herbicides in U.S. Pat. No. 4,088,474 to Matterstock et al., linear structures predominate and have been preferred for cholesterol-lowering agents according to the pertinent art.
On the other hand, experimental evidence indicates that relatively low toxicity data (i.e. high LD.sub.50 values) of compounds of the above classes found to have satisfactory cholesterol lowering effectiveness (i.e. low ED.sub.25 values) may not be a sufficient criterion in the evaluation of an optimum balance of properties. One generally accepted criterion in the context of drug-testing is the effect of the drug on size and weight of the liver, notably the hepatomegalitic or liver weight increasing effect. This factor is typically measured in terms of the increase of the weight of the hepata (liver) of test animals (e.g. rats) after a period of drug administration. It has been observed that compounds believed to be suitable for treatment of hypercholesterolemia or hyperlipidemia may have an undesirable high hepatomegalitic effect, i.e. cause a significant or even substantial increase of the liver weight of the test animals after a period of drug administration even though the LD.sub.50 toxicity of such compounds may be acceptably low.
USPTO Backgrounds
USPTO Backgrounds