Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-03-08
1998-03-31
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514308, 514310, 514313, 514332, 514352, 514415, 514471, 514596, 546140, 546143, 546162, 546265, 546309, 548483, 549472, 549480, 564 48, 564 50, 564305, 564336, A01N 4728
Patent
active
057339317
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP94/01475 filed Sep. 7, 1994.
TECHNICAL FIELD
The present invention relates to cyclohexanediurea derivatives which potently lower cholesterol and thus are useful as effective medicines for hyperlipidemia, atherosclerosis, etc.
BACKGROUND ART
Lipometabolism disorders in hyperlipidemia, atherosclerosis, etc. are considered as a risk factor which closely relates to cerebral apoplexy, myocardial infarction, etc. Recent research has shown that cholesterol is esterified before its intestinal absorption and that esterification of cholesterol is also necessary for its accumulation on the endarterium or in the liver. It has been further elucidated that the enzyme which catalyzes the esterification of cholesterol is Acyl-CoA: cholesterol acyltransferase (hereinafter referred to as "ACAT"). Since the compounds inhibiting the activities of ACAT can inhibit the esterification of cholesterol, they are expected to prevent intestinal absorption of cholesterol or cholesterol accumulation on the endarterium and considered as very potential medicines for hyperlipidemia and atherosclerosis and various diseases caused by them. Conventional ACAT enzyme inhibitors can be classified based on the chemical structure into three groups: amido derivatives (Japanese Unexamined Patent Publications Nos. 23848/1988 and 278038/1990), urea derivatives (Japanese Unexamined Patent Publications Nos. 6455/1990, 294256/1991 and 220168/1991) and diurea derivatives (Japanese Unexamined Patent Publications Nos. 203360/1989 and 117651/1990). There has been no report of the diurea compound in which urea groups are linked to a cyclohexane ring through alkylene chains, which is the chemical structure according to the present invention.
In search of a new ACAT enzyme inhibitor more powerful than those of the prior art and effective as a medicine for hyperlipidemia, atherosclerosis, etc., the inventors of the present invention studied 1,2-, 1,3- and 1,4-positions on the cyclohexane ring and cis- or trans- isomers of diurea compounds in these positions and finally found that some isomers of cyclohexanediurea derivatives in specific positions are the compounds which fulfill the above-mentioned requirements. The present invention has been accomplished based on this finding.
DISCLOSURE OF THE INVENTION
The present invention provides a cyclohexanediurea derivative represented by the following formula (I): ##STR2## wherein R.sup.1 and R.sup.2 are the same or different and they each represent a straight-chain or branched alkyl group having at least 3 carbons, a cycloalkyl group, a cycloalkyl group having a bridge head, a furyl group, a furyl lower alkyl or an aralkyl group and A.sub.1 and A.sub.2 are the same or different and they each represent a phenyl, pyridyl, quinolyl, isoquinolyl or indolyl group which may have substituent(s); or a salt thereof.
The present invention also provides a cyclohexanediamine derivative represented by the following formula (II): ##STR3## wherein R.sup.1 and R.sup.2 are as defined above; or a salt thereof.
The present invention further provides an ACAT enzyme inhibitor which comprises an effective amount of the cyclohexanediurea derivative of formula (I) or its salt and a pharmaceutically acceptable carrier.
The present invention also provides a medicine for hyperlipidemia which comprises an effective amount of the cyclohexanediurea derivative of formula (I) or its salt and a pharmaceutically acceptable carrier.
The present invention further provides a medicine for atherosclerosis which comprises an effective amount of the cyclohexanediurea derivative of formula (I) or its salt and a pharmaceutically acceptable carrier.
Furthermore, the present invention provides a method for inhibiting an ACAT enzyme which comprises administering an effective amount of the cyclohexanediurea derivative of formula (I) or its salt to a patient.
The present invention also provides a method for treating hyperlipidemia which comprises administering an effective amount of the cyclohexanediurea derivative of for
REFERENCES:
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patent: 5166429 (1992-11-01), Ito et al.
patent: 5384425 (1995-01-01), Ito et al.
Humber, L. G., J. Med. Chem. 1965, 8, pp. 401-404.
Furumoto Shiho
Ikemoto Kiyohito
Kobayashi Kazuhiro
Nobuhara Yoichi
Takagi Ichinari
Dahlen Garth M.
Ivy C. Warren
Nissin Food Products Co., Ltd.
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