Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-12
2002-07-02
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S824000, C514S866000
Reexamination Certificate
active
06414012
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel heterocyclic derivatives, a method of production thereof and pharmaceutical use thereof. More particularly, the present invention relates to novel heterocyclic derivatives having an indoline ring or tetrahydroquinoline ring, a method of production thereof and pharmaceutical use thereof, specifically acyl-CoA:cholesterol acyltransferase (hereinafter ACAT) inhibitors and lipoperoxidation inhibitors.
BACKGROUND ART
It is a well-known fact that arteriosclerosis is an extremely important factor causing various circulatory diseases, and active studies have been undertaken in an attempt to achieve suppression of the evolution of arterial sclerosis or regression thereof. In particular, although the usefulness of a pharmaceutical agent which reduces cholesterol in blood or arterial walls has been acknowledged, an ideal pharmaceutical agent exhibiting positive clinical effects while causing less side-effects has not been realized.
In recent years, it has been clarified that cholesterol accumulated in arterial walls in the ester form thereof significantly evolves arteriosclerosis. A decrease in cholesterol level in blood leads to the reduction of accumulation of cholesterol ester in arterial walls, and is effective for the suppression of evolution of arteriosclerosis and regression thereof.
Cholesterol in food is esterified in mucous membrane of small intestine, and taken into blood as chylomicron. ACAT is known to play an important role in the generation of cholesterol ester in mucous membrane of small intestine. Thus, if esterification of cholesterol can be suppressed by inhibiting ACAT in mucous membrane of small intestine, absorption of cholesterol by mucous membrane and into blood can be presumably prevented to ultimately result in lower cholesterol level in blood.
In arterial walls, ACAT esterifies cholesterol and causes accumulation of cholesterol ester. Inhibition of ACAT in arterial walls is expected to effectively suppress accumulation of cholesterol ester.
From the foregoing, it is concluded that an ACAT inhibitor will make an effective pharmaceutical agent for hyperlipemia and arteriosclerosis, as a result of suppression of absorption of cholesterol in small intestine and accumulation of cholesterol in arterial walls.
Conventionally, for example, there have been reported, as such ACAT inhibitors, amide and urea derivatives [J. Med. Chem., 29: 1131 (1986), Japanese Patent Unexamined Publication Nos. 117651/1990, 7259/1991, 32666/1993 and 327564/1992].
However, creation and pharmacological studies of these compounds have been far from sufficient.
Meanwhile, peroxidation of low density lipoprotein (LDL) is also highly responsible for accumulation of cholesterol ester in arterial walls. In addition, it is known that peroxidation of lipids in a living body is deeply concerned with the onset of arteriosclerosis and cerebrovascular and cardiovascular ischemic diseases.
Accordingly, a compound having both ACAT inhibitory activity and lipoperoxidation inhibitory activity is highly useful as a pharmaceutical product, since it effectively reduces accumulation of cholesterol ester in arterial walls and inhibits lipoperoxidation in the living body, thereby preventing and treating various vascular diseases caused thereby.
It is therefore an object of the present invention to provide a compound having ACAT inhibitory activity and lipoperoxidation inhibitory activity, a method for production thereof and pharmaceutical use thereof, particularly as an ACAT inhibitor and lipoperoxidation inhibitor.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies with the aim of accomplishing the above-mentioned object and found that a certain heterocyclic derivative having an indoline ring or tetrahydroquinoline ring has lipoperoxidation inhibitory activity in addition to strong ACAT inhibitory activity, and that said compound has strong anti-hyperlipemia effect and anti-arteriosclerosis effect, which resulted in the completion of the invention.
Thus, the present invention relates to a heterocyclic derivative of the formula (I)
wherein
one of R
1
, R
2
, R
3
and R
4
is a group of the formula —NHCO—R
6
wherein R
6
is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycle, optionally substituted heterocyclic alkyl, —R
A
SO
3
A, —R
B
PO
3
B where R
A
and R
B
are each alkylene and A and B are each alkali metal or hydrogen atom, —NR
7
R
8
where R
7
is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl or optionally substituted arylalkyl and R
8
is hydrogen atom or lower alkyl, or —R
9
—OCOR
10
where R
9
is alkylene and R
10
is optionally substituted alkyl, optionally substituted heterocycle or optionally substituted heterocyclic alkyl, and the remaining three may be the same or different and each is independently a hydrogen atom, a lower alkyl or a lower alkoxy;
R
5
is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heterocycle, an optionally substituted heterocyclic alkyl, an alkenyl, an alkynyl, a dialkylaminoacyloxyalkyl, —R
D
SO
3
D or —R
E
PO
3
E where R
D
and R
E
are each alkylene and D and E are each alkali metal or hydrogen atom, provided that when R
4
is —NHCO—R
6
, R
5
and R
6
optionally combinedly form a ring; and
m is 1 or 2,
[hereinafter this compound is also referred to as Compound (I)] and a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for producing the above-mentioned heterocyclic derivative or a pharmaceutically acceptable salt thereof, which comprises a step of
{circle around (1)} reacting an amine of the formula (II)
wherein R
11
, R
12
and R
13
may be the same or different and each is independently hydrogen atom, lower alkyl or lower alkoxy, and R
5
and m are as defined above [hereinafter also referred to as Compound (II)], and an isocyanate of the formula (III)
R
7
NCO (III)
wherein R
7
is as defined above [hereinafter also referred to as Compound (III);
{circle around (2)} reacting Compound (II) and a halogen compound of the formula (IV)
R
6
COX (IV)
wherein X is halogen atom and R
6
is as defined above [hereinafter also referred to as Compound (IV)];
{circle around (3)} reacting Compound (II) and a carboxylic acid of the formula (V)
R
6
′ COOH (V)
wherein R
6
′ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycle or optionally substituted heterocyclic alkyl [hereinafter also referred to as Compound (V)] or a reactive derivative thereof;
{circle around (4)} reacting an isocyanate of the formula (VI)
wherein R
5
, R
11
, R
12
, R
13
and m are as defined above [hereinafter also referred to as Compound (VI)], and an amine of the formula (VII)
HNR
7
R
8
(vii)
wherein R
7
and R
8
are as defined above [hereinafter also referred to as Compound (VII)]; or
{circle around (5)} reacting a compound of the formula (VIII)
wherein R
1
, R
2
, R
3
, R
4
and m are as defined above [hereinafter also referred to as Compound (VIII)], and a compound of the formula (IX)
R
5
X (IX)
wherein R
5
and X are as defined above [hereinafter also referred to as Compound (IX)].
The present invention also relates to pharmaceutical compositions, ACAT inhibitors and lipoperoxidation inhibitors containing the above-mentioned heterocyclic derivative or a pharmaceutically acceptable salt thereof.
In the present specification, each symbol denotes the following.
Lower alky
Kamiya Shoji
Matsui Hiroshi
Nakamura Shohei
Shirahase Hiroaki
Wada Katsuo
Leydig , Voit & Mayer, Ltd.
Nguyen Helen
Sankyo Company Limited
Webman Edward J.
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