Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-18
2001-03-13
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C514S313000, C546S153000, C546S158000, C546S165000, C546S166000, C546S168000, C546S171000
Reexamination Certificate
active
06200988
ABSTRACT:
The present invention relates to novel heterocyclic derivatives and pharmaceutical use thereof. More particularly, the present invention relates to novel heterocyclic derivatives having an indoline ring, indole ring or tetrahydroquinoline ring, which derivatives having an inhibitory activity on acyl CoA : cholesterol acyltransferase (hereinafter ACAT) and lipoperoxidation inhibitory activity, and to pharmaceutical use thereof.
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. A pharmaceutical agent which directly inhibits deposition of cholesterol in arterial walls has been desired as a pharmaceutical agent which effectively prevents or treats arterial sclerosis, and studies in this field are thriving. Yet, an ideal pharmaceutical agent has not been developed.
In recent years, it has been clarified that cholesterol in blood is accumulated in arterial walls in the ester form thereof, and that it 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 arterio-sclerosis, as a result of suppression of absorption of cholesterol in small intestine and accumulation of cholesterol in arterial walls.
Conventionally, there have been reported, for example, as such ACAT inhibitors, amide and urea derivatives [J. Med. Chem., 29 : 1131 (1986), Japanese Patent Unexamined Publication Nos. 117651/1990, 7259/1990, 234839/1992, 327564/1992 and 32666/1993]. However, creation and pharmacological studies of these compounds have been far from sufficient.
Meanwhile, hyperoxidation of low density lipoprotein (LDL) is also highly responsible for intracellular incorporation of cholesterol accumulated as cholesterol ester in arterial walls. In addition, it is known that hyperoxidation 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 an 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 living organisms, 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, as well as pharmaceutical use thereof, particularly ACAT inhibitor and lipoperoxidation inhibitor.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies to achieve the above-mentioned objects and found that a certain heterocyclic derivative having an indoline ring, indole ring or tetrahydroquinoline ring is superior in water solubility as-compared to conventional ACAT inhibitors, and has lipoperoxidation inhibitory activity in addition to strong ACAT inhibitory activity, and that said compound permits superior oral absorption, strong anti-hyperlipemia effect and anti-arteriosclerosis effect, which resulted in the completion of the present invention.
Thus, the present invention relates to heterocyclic derivatives of the formula (I)
wherein
one of R
1
, R
2
and R
5
is hydroxy, carboxy, alkoxycarbonyl, a group of the formula —NR
9
R
10
wherein R
9
and R
10
are each independently hydrogen atom or lower alkyl, or alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or a group of the formula —NR
9
R
10
wherein R
9
and R
10
are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy;
either R
3
or R4 is a group of the formula -NHCOR
7
wherein R
7
is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cyclo-alkylalkyl, aryl, arylalkyl or a group of the formula —NHR
8
wherein R
8
is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy;
R
6
is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl; and
Z is a binding group forming a 5- or 6-membered ring together with nitrogen atom substituted by R
6
, carbon atom-of benzene ring to which said nitrogen atom binds and carbon atom adjacent to said carbon atom,
and pharmaceutically acceptable salts thereof.
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 alkyl at R
1
, R
1a
, R
1b
, R
1c
, R
2
, R
2c
, R
3
, R
3a
, R
3b
, R
3c
, R
4
, R
4c
, R
5
, R
5c
, R
9
, R
9c
, R
10
and R
10c
may be linear or branched and has 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentylhexyl and the like.
Lower alkoxy at R
1
, R
1b
, R
1c
, R
2
, R
2c
, R
3
, R
3b
, R
3c
, R
4
, R
4c
, R
5
and R
5c
may be linear or branched and has 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
Alkyl at R
6
, R
6a
, R
6b
, R
6c
, R
7
, R
7a
, R
7b
, R
7c
, R
8
, R
8b
and R
8c
may be linear or branched and preferably has 1 to 20 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, icosyl, 1,1-dimethylpropyl, 1,1-dimethylbutyl, 1,1-dimethylhexyl, 1,1-dimethylheptyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl and the like.
In alkoxyalkyl at R
6
, R
6b
, R
6c
, R
7
, R
7b
and R
7c
, the alkoxy moiety thereof preferably has 1 to 6 carbon atoms and alkyl moiety thereof preferably has 1 to 6 carbon atoms. Examples of alkoxyalkyl include ethoxybutyl, ethoxyhexyl, butoxybutyl, butoxyhexyl, hexyloxybutyl, hexyloxyhexyl and the like.
In alkylthioalkyl at R
6
, R
6b
, R
6c
, R
7
, R
7b
and R
7c
, both alkyl moieties preferably have 1 to 6 carbon atoms. Examples of alkylthioalkyl include ethylthioethyl, ethylthiohexyl, butylthiobutyl, butylthiohexyl, hexylthiobutyl, hexylthiohexyl and the like.
Cycloalkyl at R
6
, R
6a
, R
6b
, R
6c
, R
7
, R
7a
, R
7b
, R
7c
, R
8
, R
8b
and R
8c
preferably has 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
In cycloalkylalkyl at R
6
, R
6a
, R
6b
, R
6c
, R
7
, R
7
&, R
7
b R
7
, R
8
, R
8b
and R
8c
,
Kamiya Shoji
Matsui Hiroshi
Nakamura Shohei
Shirahase Hiroaki
Wada Katsuo
Kyoto Pharmaceutical Industries, Ltd.
Rao Deepak R.
Shah Mukund J.
Wenderoth , Lind & Ponack, L.L.P.
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