Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-09
2002-07-16
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S122000
Reexamination Certificate
active
06420381
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a compound, a prodrug thereof, or a pharmaceutically acceptable salt of the same, which exhibits acyl-CoA: cholesterol acyl transferase (ACAT) inhibitory activity, and is useful as an agent for treatment of hyperlipidemia and atherosclerosis, and a use thereof.
PRIOR ART
Cerebral vessel disorders such as stroke and myocardial infarction, which rank in high in causes of death in developed countries, break out with being accompanied by atherosclerosis as basal disease. From the results of epidemiology research, it is pointed out that hypercholesterolemia is one of risk factors for atherosclerosis, and there are mainly used anti-hyperlipidemic agents, which can reduce cholesterol level in blood, in the prophylaxis or treatment thereof. However, there is no sufficiently effective agent in terms of the efficacy thereof. Recently, it is observed that cells derived from macrophage accumulate cholesterol ester droplet within the cells and become foam cells in atherosclerotic lesions, and it is clarified that these foam cells deeply participate in the developments of atherosclerotic lesions (Arteriosclerosis, 10, 164-177, 1990). In addition, it is reported that ACAT activity is increased and cholesterol esters are accumulated in the vascular wall of atherosclerotic lesions (Biochem. Biophys. Acta, 617, 458-471, 1980). Therefore, an inhibitor of ACAT, which catalyses cholesterol esterification, is expected to suppress the formation or the development of atherosclerotic lesions as a result of the inhibition of foam cell formation and of cholesterol; ester accumulation in lesions.
On the other hand, cholesterol in food is absorbed in the free form at intestinal epidermal cells, and then released in the form of chylomicron esterified by ACAT into the blood. Therefore, an inhibitor of ACAT is expected to reduce the cholesterol level in the blood by the inhibition of absorption of cholesterol in food at the intestine and of reabsorption of cholesterol released into the intestine (J. Lipid. Research, 34, 279-294, 1993).
JP-A-9-48780 discloses a naphthyridine derivative having an ACAT inhibitory activity. Some of the compounds of the present invention are included within the scope of said patent publication, but said publication never discloses concretely those compounds in Examples, etc.
DISCLOSURE OF INVENTION
An object of the present invention is to provide a compound having an ACAT inhibitory activity and being useful as an agent for treatment of hyperlipidemia and atherosclerosis.
The present inventors have intensively studied in order to solve the above-mentioned problems, and have found that a compound of the following formula (1) or (51), a prodrug thereof, and a pharmaceutically acceptable salt of the same (hereinafter, referred to as “the present compound”) exhibits a potent ACAT inhibitory activity, and have accomplished the present invention. That is, the present invention relates to the following:
[1] A compound of the formula (I):
wherein Ring A is a substituted or unsubstituted pyridine ring,
Y is a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted aromatic group,
R
1
is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted cycloalkyl group,
R
2
is a hydrogen atom or a lower alkyl group,
R
3
is a lower alkyl group,
Z is
1) —D
1
—Q wherein D
1
is a direct bond or a divalent hydrocarbon group having 1 to 8 carbon atoms and optionally containing an unsaturated bond, Q is a hydroxy group, a carboxyl group, a substituted or unsubstituted heteroaryl group, or a group of the formula: —NR
4
R
5
(R
4
and R
5
are independently a hydrogen atom, a lower alkoxy-substituted or unsubstituted lower alkyl group, a cycloalkyl group, or an aralkyl group, or R
4
and R
5
may combine each other, and with the adjacent nitrogen atom to which they bond, form a saturated cyclic amino group having 4 to 8 carbon atoms as ones forming the said ring, and optionally having one —NR
8
— (R
8
is a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, or a lower alkoxycarbonyl group) or one oxygen atom in the cycle thereof), provided that when Q is a substituted or unsubstituted heteroaryl group, then D
1
is not a direct bond, or
2) —D
2
—M—W wherein D
2
is a direct bond or a divalent hydrocarbon group having 1 to 8 carbon atoms and optionally containing an unsaturated bond, M is an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group, or a group of the formula: —NHC(═O)—, —C(═O)NH— or —NR
6
— (R
6
is a hydrogen atom or a lower alkyl group), E is a direct bond or a divalent hydrocarbon group having 1 to 8 carbon atoms and optionally containing an unsaturated bond, W is a hydroxyl group, a carboxyl group, a substituted or unsubstituted heteroaryl group, or a group of the formula: —NR
4
R
5
(R
4
and R
5
are as defined above), provided that when W is a hydroxy group, a carboxyl group or a group of the formula: —NR
4
R
5
, then E is not a direct bond,
or a prodrug thereof, or a pharmaceutically acceptable salt of the same;
[2] The compound according to the above [1], or a prodrug thereof, or a pharmaceutically acceptable salt of the same, wherein Ring A is oneof the groups of the following formulae (a), (b) and (c).
[3] The compound according to the above [2], or a prodrug thereof, or a pharmaceutically acceptable salt of the same, wherein Y is a substituted or unsubstituted aromatic group.
[4] The compound according to the above [3], or a prodrug thereof, or a pharmaceutically acceptable salt of the same, wherein R
1
is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkenyl group.
[5] The compound according to the above [4], or a prodrug thereof, or a pharmaceutically acceptable salt of the same, wherein Ring A is an unsubstituted pyridine ring.
[6] The compound according to the above [5], or a prodrug thereof, or a pharmaceutically acceptable salt of the same, wherein Y is a phenyl group being substituted by a lower al,yl group or a lower alkoxy group, or a pyridyl group being substituted by a lower alkyl group or a lower alkoxy group.
[7] The compound according to the above [6], or a prodrug thereof, or a pharmaceutically acceptable salt of the same, wherein Z is a group of the formula: —D
1
—Q, D
1
is a divalent hydrocarbon group having 1 to 4 carbon atoms, Q is a hydroxy group, a substituted or unsubstituted heteroaryl group, or a group of the formula: —NR
4
R
5
.
[8] The compound according to the above [6], or a prodrug thereof, or a pharmaceutically acceptable salt of the same, wherein Z is a group of the formula: —D
1
—Q, D
1
is a methylene group or an ethylene group, Q is a hydroxy group, a substituted or unsubstituted heteroaryl group, or a group of the formula: —NR
4
R
5
(R
4
and R
5
are independently a lower alkyl group, or R
4
and R
5
may combine each other, and with the adjacent nitrogen atom to which they. bond, form a saturated cyclic amino group having 5 or 6 atoms as ones forming the said ring, and optionally having one —NR
8
— (R
8
is a hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxycarbonyl group, or a benzyl group) or one oxygen atom in the cycle thereof.
[9] The compound according to the above [5] or [6], or a prodrug thereof, or a pharmaceutically acceptable salt of the same, wherein Z is a hydroxymethyl group, (1-pyrazolyl)methyl group, 2-(1-pyrazolyl)ethyl group, (3,5-dimethyl-1-pyrazolyl)methyl group, (1-imidazolyl)methyl group, 2-(1-imidazolyl)ethyl group, (2-methyl-1-imidazolyl)methyl group, (1,2,4-triazol-1-yl)methyl group, 2-(1,2,4-triazol-1-yl)ethyl group
Ban Hitoshi
Muraoka Masami
Ohashi Naohito
Dentz Bernard
Sumitomo Pharmaceuticals Company Limited
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