Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-19
2003-07-29
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S133000, C546S137000, C544S061000, C544S333000, C544S405000, C514S228200, C514S253030, C514S256000
Reexamination Certificate
active
06599917
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel compound, a method for producing the novel compound, a squalene-synthesizing enzyme inhibitor, a cholesterol biosynthesis inhibitor and a triglyceride biosynthesis inhibitor containing such a novel compound and also to a medicinal composition containing them. More specifically, the present invention relates to preventive and curative agents for hyper lipidemia including arterial sclerosis diseases and ischemic heart diseases.
PRIOR ART
Cholesterol is a sterol which is biosynthesized in all animal cells except for a red blood cell and is a factor essential for maintaining a plasma membrane and for the creation of a steroid hormone. Cholesterol is liposoluble and exists as hypobaric lipoprotein (LDL), hyperbaric lipoprotein (HDL) and the like in blood. LDL in blood is incorporated into cells through an acceptor on the surface of the cells and regenerates free cholesterol after decomposed. This is a major route for incorporating cholesterol from the outside of cells. Also, it has been known that a major enzyme which participates in the biosynthesis of LDL acceptor protein and cholesterol undergoes feedback of the concentration of cholesterol which is the harvested product. In this manner, the level of cholesterol in cells is maintained and controlled exquisitely by the feedback control mechanism of the LDL acceptor and biosynthetic type enzyme on the basis of a balance between the biosynthesis of a cell itself and the incorporation of LDL from the outside of a cell.
In recent years, cholesterol has been recognized as the main culprit of hyper lipidemia and also as the most dangerous factor causing arterial sclerosis diseases (e.g., coronary diseases, cerebrovascular diseases, aortic diseases and peripheral arterial diseases) and ischemic heart diseases (e.g., angina pectoris and cardiac infarction), giving rise to a serious problem. Hyper lipidemia is defined as one showing any one or two or more of the followings: cholesterol in blood is 220 mg/dl or more, neutral lipid is 150 mg/dl or more and hyperbaric lipoprotein (HDL)-cholesterol is less than 35 mg/dl (Guideline of Japan Society of Arterial Sclerosis) and is catastrophic diseases causing arterial sclerosis and the like. One of the major reasons is a rise in the level of LDL-cholesterol in blood (high cholesteremia) and the deposition of cholesterol on the inner wall of a blood vessel. At present, treatment performed to reduce serum cholesterol has come to be thought effective to prevent the development and progress of arterial sclerosis and the like. A cholesterol biosynthesis inhibitor, especially, an inhibitor of 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) reducing enzyme such as pravastatin has obtained good results as a medicine for reducing serum cholesterol in recent years instead of conventional fibrate type drugs and nicotinic acid preparations. The HMG-CoA reducing enzyme inhibitor competitively inhibits the HMG-CoA reducing enzyme which is an enzyme limiting the rate of biosynthesis of cholesterol in the liver to decrease the rate of biosynthesis of cholesterol, whereby the liver is increased in the ability to synthesize LDL acceptors, with the result that the serum LDL is decreased. However, the inhibition of the production of mevalonic acid based on the inhibition of the HMG-CoA reducing enzyme affects the production of isoprene including farnecyl diphosphoric acid (FPP). Therefore, there is a fear as to an influence on, for example, other metabolic substances, such as ubiquinone, dolichol, heme A, isopentenyl tRNA and prenyl protein, produced through isoprene as a synthetic intermediate. Further, risks of side effects such as cataract and myopathy have been pointed out.
The squalene synthesizing enzyme is a membrane-bound enzyme of 47-kDa and reducibly catalyzes the head-to-head condensation of two molecules of FPP to synthesize squalene which is an intermediate for the synthesis of cholesterol. In a cholesterol-biosynthesizing system, the squalene synthesizing enzyme is positioned downstream of a system generating the HMG-CoA reducing enzyme and isoprene and therefore the squalene synthesizing enzyme inhibitor is considered to have almost no effect on metabolic systems other than cholesterol and is therefore expected to work as a new cholesterol depressor which will solve the problems concerning the HMG-CoA reducing enzyme inhibitor. A squalene synthesizing enzyme inhibitor which was reported first is analogous compounds of FPP and squalene. However, these analogous compounds has an activity inhibiting the formation of prenyl protein and the like in addition to squalene synthesizing enzyme inhibitive action and it is difficult to put these analogous compounds to practical use. In the meantime, it has been disclosed recently that a certain type substituted phenylethynylquinuclidine compound and substituted pyridinylethynylquinuclidine compound are useful as a squalene synthesizing enzyme inhibitor in JP-A 7-502283, 8-502731, 8-504803 (U.S. Pat. No. 5,731,323) and 8-509488. However, no squalene synthesizing enzyme inhibitor which can produce an effect as a medicine for hyper lipidemia has been created so far.
That is, an object of the present invention is to search and to find a compound which has stronger squalene synthesizing enzyme inhibitive activities and cholesterol depressing action over those currently in use and is useful as a remedy for hyper lipidemia.
DISCLOSURE OF THE INVENTION
In view of the above situation, the inventors of the present invention have made earnest studies and as a result, found that a specific quinuclidine compound and its salt have unprecedented strong squalene synthesizing inhibitive activities. The inventors have also found that these compounds and their salts have strong cholesterol biosynthesizing inhibitive activities, triglyceride biosynthesizing inhibitive activities and serum cholesterol depressing action and serum triglyceride depressing action based on the squalene synthesizing inhibitive activities. The present invention has been thus completed. A compound according to the present invention is useful as a remedy for hyper lipidemia.
Accordingly, the present invention relates to:
(1) a compound (I) represented by the following formula:
(in which R
1
represents (1) hydrogen atom or (2) hydroxyl group; HAr represents an aromatic heterocycle which may be substituted with 1 to 3 groups; Ar represents an optionally substituted aromatic ring; W represents a chain represented by (1) —CH
2
—CH
2
— which may be substituted, (2) —CH═CH— which may be substituted, (3) —C≡C—, (4) —NH—CO—, (5) —CO—NH—, (6) —NH—CH
2
—, (7) —CH
2
—NH—, (8) —CH
2
—CO—, (9) —CO—CH
2
—, (10) —NH—S(O)
l
—, (11) —S(O)
l
—NH—, (12) —CH
2
—S(O)
l
— or (13) —S(O)
l
—CH
2
— (l denotes 0, 1 or 2); and X represents a chain represented by (1) a single bond, (2) an optionally substituted C
1-6
alkylene chain, (3) an optionally substituted C
2-6
alkenylene chain, (4) an optionally substituted C
2-6
alkynylene chain, (5) a formula —Q— (wherein Q represents oxygen atom, sulfur atom, CO or N(R
2
) (wherein R
2
represents a C
1-6
alkyl group or a C
1-6
alkoxy group)), (6) —NH—CO—, (7) —CO—NH—, (8) —NH—CH
2
—, (9) —CH
2
—NH—, (10) —CH
2
—CO—, (11) —CO—CH
2
—, (12) —NH—S(O)
m
—, (13) —S(O)
m
—NH—, (14) —CH
2
—S(O)
m
—, (15) —S(O)
m
—CH
2
— (wherein m denotes 0, 1 or 2) or (16) —(CH
2
)
n
—O— (wherein n denotes an integer from 1 to 6)), a salt thereof or a hydrate of them,
(2) the compound described in (1), a salt thereof or a hydrate of them, wherein R
1
represents (1) hydrogen atom or (2) hydroxyl group; HAr is a 5- to 14-membered aromatic heterocycle which contains 1 to 4 atoms selected from nitrogen atom, sulfur atom and oxygen atom and may be substituted with 1 to 3 groups selected from (1) a halogen atom, (2) hydroxyl group, (3) thiol group, (4) nitro group, (5) nitrile group, (6) a C
1-6
chain hydrocarbon group which may be substituted, (7) a C
3-8
cyclic hydrocarbon group which may be substituted, (8) a C
6-14
aromatic cyclic hydrocarbon
Hiyoshi Hironobu
Ikuta Hironori
Ito Masashi
Kurusu Nobuyuki
Miyazaki Kazuki
Aulakh Charanjit S.
Birch & Stewart Kolasch & Birch, LLP
Eisai Co. Ltd.
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