1. Field of the Invention
The present invention is directed to a process for controlling hyperlipidemia. More specifically, the present invention is directed to a process for controlling hyperlipidemia in mammals by treating that condition with a generic class of 2,3-dihydrophthalazine-1,4-diones, the species of which include novel compounds.
2. Background of the Prior Art
Hyperlipidemia, a condition associated with elevated serum cholesterol, phospholipid and/or triglyceride blood levels, is the base cause of a whole class of illnesses which exact a terrible toll in death and infirmity as well economic loss associated with lost productive activity and expensive medical treatment. It is only necessary to mention one of the most serious conditions known in man, atherosclerosis, a hyperlipidemic induced illness, to appreciate the importance of developing treatment regimes effective in controlling this condition. Recent scientific studies indeed establish that coronary heart disease is related to blood lipid concentration. J. Am. Med. Assn., Vol. 251, 351-373, Jan. 20, 1984; N. Engl. J. Med., Vol. 314, 138-144, Jan. 16, 1986.
Because of the importance of hyperlipidemia, many compounds have been proposed to lower serum cholesterol, phospholipid and triglyceride blood levels in mammals. For example, U.S. Pat. No. 4,499,303 discloses a novel class of N-benzoyl, N-benzoylsulfamates and benzoylsulfonamides useful in this application.
Another class of compounds disclosed as useful in reducing serum cholesterol and triglyceride blood levels in mammals is set forth in U.S. Pat. No. 4,395,417. This patent describes the use of cyclic imides, diones, reduced diones and analogs thereof useful in this application.
Certain compounds within the generic class conveniently referred to as 2,3-dihydrophthalazine-1,4-diones are known in the art. N. T. Buu-Hoi et al., Rec. Trav. Chim., Vol. 70, 1099-1104 (1951) disclose the use of 2,3-dihydro phthalazine-1,4-dione as a reactant with propyl halide or N-butyl halide in the presence of aqueous sodium hydroxide, to form 2-propyl-4-propoxyphthalazine-1(2H)-one and 2-butyl-4-butoxyphthalazine-1(2H)-one. Buu-Hoi et al. further teaches that these N,O-dialkyl products can be converted into 2-propyl-2,3-dihydrophthalazine-1,4-dione and 2-butyl-2,3-dihydrophthalazine-1,4-dione, respectively by treating the two above-reacted products with pyridinium hydrochloride. The Buu-Hoi et al. teaching is devoid of any suggestion that any of these synthesized compounds can be utilized for controlling hyperlipidemia.
U.S. Pat. No. 2,420,702, issued to Drewitt et al., describes a process for producing amino-hydrazines. In this process a byproduct of the reaction is 2,3-dihydrophthalazine-1,4-dione or a 3-hydrocarbyl substituted compound thereof. No disclosure is made of the utility of this byproduct.
U.S. Pat. No. 2,453,578, issued to Lacey et al. discloses a similar, albeit structurally distinguished, compound. This is 5-amino-1,4-dioxotetrahydrophthalazine which is recited to possess chemiluminescent activity. An intermediate in its production is 5-nitro-1,4-dioxotetrahydrophthalazine.
U.S. Pat. No. 3,433,641, issued to Margot, sets forth phthalazinone derivatives structurally similar to but outside the contemplation of the generic class of 2,3-dihydrophthalazine-1,4-diones utilized in the present invention. Margot states that these compounds have utility as growth-promoting additives for animal feed.
U.S. Pat. No. 3,497,512, issued to Hofer et al. teaches phthalazine derivatives which provide stability against ultraviolet radiation and heat. These compounds, distinguished from the compounds utilized in the process of the present invention, are formed from phthalazone derivatives similar to the compounds within the contemplation of the process of this invention.
A group of patents issued to Inoue et al., U.S. Pat. Nos. 3,864,343; 3,870,792; and 3,963,716, set forth phthalazone derivatives, structurally far removed from the compounds of the present invention. These patents are of interest because they are recited to prevent atherosclerosis. Inoue et al. states that this disease is prevented by inhibiting cholesterol deposition on arterial walls. The compounds of these patents are characterized by hydroxymethyl or substituted hydroxymethyl at the 1-position. The compounds of the present invention are all oxo-substituted at this position.
U.S. Pat. No. 4,226,993, issued to Buckler et al., sets forth a class of amino-functionalized phthalhydrazides. Not only are these compounds structurally distinguished by the substitutions on the fused phenyl ring but, in addition, are recited to have utility as intermediates in the synthesis of chemiluminescent phthalhydrazide-labeled conjugates.
U.S. Pat. No. 4,289,774, issued to Schacht et al. sets forth a class of compounds which in one embodiment is specifically a fused six-sided saturated ring. However, instead of an oxo substitution at the 4-position of the heterocyclic ring there is biphenyl, phenoxyphenyl, p-halobiphenyl or p-halophenoxyphenyl.
Finally, U.S. Pat. No. 4,293,553, issued to Ishikawa et al., describes 1-phthalazone derivatives useful for treating thrombotic disease. These compounds are either unsubstituted in the 1-position or 1-substituted with an alkyl or a hydroxymethyl group.
The above extensive analysis of the prior art is provided in order to establish that there is no disclosure of hypolipidemic agents whose structures are closely related to those of the present invention. Thus, there is no suggestion in the art for providing a new class of 2,3-dihydrophthalazine-1,4-diones useful in the treatment of hyperlipidemia.