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| United States Patent |
6,204,392
|
|
Matsui
, et al.
|
March 20, 2001
|
Heterocyclic derivatives, method of production thereof and pharmaceutical
use thereof
Abstract
Heterocyclic derivatives of the formula (I)
##STR1##
wherein each symbol is as defined in the specification, pharmaceutically
acceptable salts thereof and method of producing them. Pharmaceutical
compositions containing the heterocyclic derivative or a pharmaceutically
acceptable salt thereof, particularly, ACAT inhibitors and
lipoperoxidation inhibitors. The heterocyclic derivatives and
pharmaceutically acceptable salts thereof of the present invention show
superior ACAT inhibitory activity and lipoperoxidation inhibitory
activity, and are useful as ACAT inhibitors and hyperlipemia inhibitors.
To be specific, they are useful for the prevention and treatment of
arteriosclerotic lesions of arteriosclerosis, hyperlipemia and diabetes,
as well as ischemic diseases of brain, heart and the like.
| Inventors:
|
Matsui; Hiroshi (Nara, JP);
Kamiya; Shoji (Kyoto, JP);
Shirahase; Hiroaki (Nagaokakyo, JP);
Nakamura; Shohei (Kyoto, JP)
|
| Assignee:
|
Sankyo Company, Limited (Tokyo, JP)
|
| Appl. No.:
|
283525 |
| Filed:
|
April 1, 1999 |
Foreign Application Priority Data
| Intern'l Class: |
C07D 209/26; C07D 403/06 |
| Field of Search: |
548/490,491,106,113
546/268.1,184
544/106,336
|
References Cited
U.S. Patent Documents
| 3824230 | Jul., 1974 | Hester, Jr. | 540/450.
|
| 5143919 | Sep., 1992 | Meguro et al. | 544/291.
|
| 5254919 | Oct., 1993 | Malen et al. | 318/560.
|
| 5256782 | Oct., 1993 | Meguro et al. | 546/114.
|
| Foreign Patent Documents |
| 0 354 994 | Feb., 1990 | EP.
| |
| 0 375 133 | Jun., 1990 | EP.
| |
| 0 427 860 | May., 1991 | EP.
| |
| 2-117651 | May., 1990 | JP.
| |
| 3-7259 | Jan., 1991 | JP.
| |
| 4-66568 | Mar., 1992 | JP.
| |
| WO 94/14801 | Jul., 1994 | WO.
| |
| WO 97/12860 | Apr., 1997 | WO.
| |
Other References
De Vries et al., "Potential Antiatherosclerotic Agents. 5. An Acyl-CoA:
Cholesterol .omicron.-Acyltransferase Inhibitor with Hypocholesterolemic
Activity", J. Med. Chem., 29, pp. 1131-1133 (1986).
Mazza et al., "N-Acylindolines with phytotoxic activity," Farmaco, Ed.
Sci., vol. 32, No. 1, pp. 54-66, 1977.*
Cram & Hammond "Organic Chemistry" McGraw-Hill Book Co New York, pp 76, 77,
255, 304, 305, 361 and 362, (2nd Ed.) 1964.
|
Primary Examiner: Ford; John M.
Assistant Examiner: Sridada; Pavanaram K
Attorney, Agent or Firm: Leydig, Voit & Mayer, Ltd.
Parent Case Text
This is a divisional of application Ser. No. 08/809,242, filed on Mar. 19,
1997 U.S. Pat. No. 5,990,150 which is a PCT/JP95/018 Sep. 26, 1995.
Claims
What is claimed is:
1. A method of preparing a compound of the formula
##STR43##
wherein
R.sup.1 and R.sup.3 are methyl,
R.sup.2 is hydrogen, R.sup.4 is --NHCO--R.sup.6,
R.sup.6 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl,
cyclo C.sub.3 -C.sub.6 alkyl, cyclo C.sub.3 -C.sub.6 alkyl C.sub.1
-C.sub.3 alkyl, phenyl, naphthyl, phenyl C.sub.1 -C.sub.4 alkyl, naphthyl
C.sub.1 -C.sub.4 alkyl, pyriolidinyl, piperidyl, piperidino, morpholinyl,
morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl
C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8 alkyl, piperidino
C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8 allyl, morpholino
C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8 alkyl, pyrrolyl
C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl, pyridyl C.sub.1
-C.sub.8 alkyl (wherein any of the foregoing is unsubstituted or
substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, di(C.sub.1
-C.sub.4)alkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy,
carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl,
C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C.sub.1
-C.sub.4)alkylamino), --R.sup.A SO.sub.3 A, --R.sup.B PO.sub.3 B where
R.sup.A and R.sup.B are each alkylene and A and B are each alkali metal or
hydrogen atom, --NR.sup.7 R.sup.8 where R.sup.7 is selected from the group
consisting of C.sub.1 -C.sub.12 alkyl, cyclo C.sub.3 -C.sub.6 alkyl, cyclo
C.sub.3 -C.sub.6 alkyl C.sub.1 -C.sub.3 alkyl, phenyl, naphthyl, phenyl
C.sub.1 -C.sub.4 alkyl, and naphthyl C.sub.1 -C.sub.4 alkyl (wherein any
of the foregoing is optionally substituted with a C.sub.1 -C.sub.4 alkyl,
amino, hydroxy, di(C.sub.1 -C.sub.4)alkylamino, C.sub.1 -C.sub.4
aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4
alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy,
phenyl, phenoxy, halogen, or phenyl (C.sub.1 -C.sub.4)dialkylamino), and
R.sup.8 is hydrogen atom or C.sub.1 -C.sub.4 alkyl, or --R.sup.9
--OCOR.sup.10 where R.sup.9 is alkylene and R.sup.10 is selected from the
group consisting of C.sub.1 -C.sub.12 alkyl, pyrrolidinyl, piperidyl,
piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl,
pyridyl, pyrrolidinyl C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8
alkyl, piperidino C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8
alkyl, morpholino C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8
alkyl, pyrrolyl C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl,
pyridyl C.sub.1 -C.sub.8 alkyl (wherein any of the foregoing is optionally
substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, C.sub.1
-C.sub.4 dialkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4
alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4
carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or
phenyl di(C.sub.1 -C.sub.4)alkylamino), and the remaining three of
R.sup.1, R.sup.2, R.sup.3, or R.sup.4 may be the same or different and
each is independently a hydrogen atom, a C.sub.1 -C.sub.4 alkyl or a
C.sub.1 -C.sub.4 alkoxy,
R.sup.5 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl,
cyclo C.sub.3 -C.sub.6 alkyl, cyclo C.sub.3 -C.sub.6 alkyl C.sub.1
-C.sub.3 alkyl, phenyl, naphthyl, phenyl C.sub.1 -C.sub.4 alkyl, naphthyl
C.sub.1 -C.sub.4 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl,
morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl
C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8 alkyl, piperidino
C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8 alkyl, morpholino
C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8 alkyl, pyrrolyl
C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl, pyridyl C.sub.1
-C.sub.8 alkyl (wherein any of the foregoing is optionally substituted
with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, C.sub.1 -C.sub.4
dialkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy,
carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl,
C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C.sub.1
-C.sub.4)alkylamino), an alkenyl, an alkynyl, a dialkylaminoacyloxyalkyl,
--R.sup.D SO.sub.3 D or --R.sup.E PO.sub.3 E where R.sup.D and R.sup.E are
each alkylene and D and E are each alkali metal or hydrogen atom, and
m is 1,
said method comprising:
providing 1-acetyl-5-bromo4,6dimethylindoline;
introducing a nitro substituent to the 7- position of said
1-acetyl-5-bromo-4,dimethylindoline;
reducing said nitro substituent to an amino substituent;
converting said amino substituent to an amide group of the formula R.sup.6
C(O)--, wherein R.sup.6 is as defined above,
reductively removing the bromine atom at the 5-position; and
removing the acetyl substituent at the 1-position and thereafter covalently
bonding R.sup.5 to the indoline nitrogen at the 1-position.
2. The method of claim 1, wherein said amino substituent is converted to an
amide group of the formula R.sup.6 C(O)-- by reacting said amino with an
acid of the formula R.sup.6 CO.sub.2 H or an acid halide of the formula
R.sup.6 COX, wherein X is a halogen atom.
3. The method of claim 2, wherein X is chloride.
4. The method of claim 1, wherein said amino substituent is converted to an
amide group of the formula R.sup.6 C(O)-- by converting said amino group
to an isocyanate and reacting said isocyanate with an amine of the formula
HNR.sup.7 R.sup.8.
5. The method of claim 1, wherein said amino substituent is converted to an
amide group of the formula R.sup.6 C(O)-- by reacting the amino group with
an isocyanate of the formula R.sup.7 --NCO.
6. The method of claim 1, wherein said acetyl is removed via base
hydrolysis.
7. The method of claim 6, wherein said base is hydroxide ion.
8. The method of claim 1, wherein said R.sup.5 is covalently bonded to said
indoline nitrogen by reacting said indoline nitrogen with a compound of
the formula R.sup.5 X, wherein X is a halogen atom.
9. The method of claim 8, wherein R.sup.5 is unsubstituted.
10. The method of claim 8, wherein R.sup.5 is substituted with alkyl,
amino, hydroxy, dialkylamino, aminoalkyl, alkoxy, carboxyl,
alkoxycarbonyl, carboxyalkyl, acyloxy, phenyl, phenoxy or halogen.
11. The method of claim 1, wherein said bromine atom at the 5-position is
reductively removed in the presence of a catalyst.
12. The method of claim 11, wherein said catalyst is palladium.
13. The method of claim 1, wherein said nitro substituent is reduced to an
amino substituent, and said bromine atom at the 5-position is reductively
removed, in one step.
14. The method of claim 13, wherein said amino substituent is converted to
an amide group of the formula R.sup.6 C(O)--by reacting the amino at the
7-position with an acid halide of the formula R.sup.6 COX, wherein X is a
halogen atom.
15. The method of claim 14, wherein said amino substituent is converted to
an amide group of the formula R.sup.6 C(O)-- by converting the amino at
the 7-position to an isocyanate and reacting said isocyanate with an amine
of the formula HNR.sup.7 R.sup.8.
16. A method of preparing a compound of the formula
##STR44##
wherein
R.sup.1 and R.sup.3 are methyl,
R.sup.2 is hydrogen,
R.sup.4 is --NHCO--R.sup.6,
R.sup.5 is acetyl,
R.sup.6 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl,
cyclo C.sub.3 -C.sub.6 alkyl, cyclo C.sub.3 -C.sub.6 alkyl C.sub.1
-C.sub.3 alkyl, phenyl, naphthyl, phenyl C.sub.1 -C.sub.4 alkyl, naphthyl
C.sub.1 -C.sub.4 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl,
morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl
C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8 alkyl, piperidino
C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8 alkyl, morpholino
C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8 alkyl, pyrrolyl
C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl, pyridyl C.sub.1
-C.sub.8 alkyl (wherein any of the foregoing is unsubstitated or
substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, di(C.sub.1
-C.sub.4)alkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy,
carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl,
C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C.sub.1
-C.sub.4)alkylamino), --R.sup.A SO.sub.3 A, --R.sup.B PO.sub.3 B where
R.sup.A and R.sup.B are each alkylene and A and B are each alkali metal or
hydrogen atom, --NR.sup.7 R.sup.8 where R.sup.7 is selected from the group
consisting of C.sub.1 -C.sub.12 alkyl, cyclo C.sub.3 -C.sub.6 alkyl, cyclo
C.sub.3 -C.sub.6 alkyl C.sub.1 -C.sub.3 alkyl, phenyl, naphthyl, phenyl
C.sub.1 -C.sub.4 alkyl, and naphthyl C.sub.1 -C.sub.4 alkyl (wherein any
of the foregoing is optionally substituted with a C.sub.1 -C.sub.4 alkyl,
amino, hydroxy, di(C.sub.1 -C.sub.4)alkylamino, C.sub.1 -C.sub.4
aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4
alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy,
phenyl, phenoxy, halogen, or phenyl (C.sub.1 -C.sub.4)dialkylamino), and
R.sup.8 is hydrogen atom or C.sub.1 -C.sub.4 alkyl, or --R.sup.9
--OCOR.sup.10 where R.sup.9 is alkylene and R.sup.10 is selected from the
group consisting of C.sub.1 -C.sub.12 alkyl, pyrrolidinyl, piperidyl,
piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl,
pyridyl, pyrrolidinyl C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8
alkyl, piperidino C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8
alkyl, morpholino C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8
alkyl, pyrrolyl C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl,
pyridyl C.sub.1 -C.sub.8 alkyl (wherein any of the foregoing is optionally
substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, C.sub.1
-C.sub.4 dialkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4
alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4
carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or
phenyl di(C.sub.1 -C.sub.4)alkylamino), and the remaining three of
R.sup.1, R.sup.2, R.sup.3, or R.sup.4 may be the same or different and
each is independently a hydrogen atom, a C.sub.1 -C.sub.4 alkyl or a
C.sub.1 -C.sub.4 alkoxy, and
m is 1,
said method comprising:
providing 1-acetyl-5-bromo4,6-dimethylindoline;
introducing a nitro substituent to the 7-position of said
1-acetyl-5-bromo4,6-dimethylindoline;
reducing said nitro substituent to an amino substituent;
converting said amino substituent to an amide group of the formula R.sup.6
C(O)--, wherein R.sup.6 is as defined above; and
reductively removing the bromine atom at the 5-position.
Description
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, 7259/1990,
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)
##STR2##
wherein
one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is a group of the formula
--NHCO--R.sup.6 wherein R.sup.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.sup.A SO.sub.3 A, --R.sup.B PO.sub.3 B where R.sup.A and R.sup.B are
each alkylene and A and B are each alkali metal or hydrogen atom,
--NR.sup.7 R.sup.8 where R.sup.7 is optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted aryl or optionally substituted arylalkyl and
R.sup.8 is hydrogen atom or lower alkyl, or --R.sup.9 --OCOR.sup.10 where
R.sup.9 is alkylene and R.sup.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.sup.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.sup.D SO.sub.3 D or
--R.sup.E PO.sub.3 E where R.sup.D and R.sup.E are each alkylene and D and
E are each alkali metal or hydrogen atom, provided that when R.sup.4 is
--NHCO--R.sup.6, R.sup.5 and R.sup.6 optionally combinedly form a ring;
and
m is 1 or 2, [hereinafter this compound is also referred to as Compound
(I)] and a 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
1+L reacting an amine of the formula (II)
##STR3##
wherein R.sup.11, R.sup.12 and R.sup.13 may be the same or different and
each is independently hydrogen atom, lower alkyl or lower alkoxy, and
R.sup.5 and m are as defined above [hereinafter also referred to as
Compound (II)], and an isocyanate of the formula (III)
R.sup.7 NCO (III)
wherein R.sup.7 is as defined above [hereinafter also referred to as
Compound (III)];
2 reacting Compound (II) and a halogen compound of the formula (IV)
R.sup.6 --COX (IV)
wherein X is halogen atom and R.sup.6 is as defined above [hereinafter also
referred to as Compound (IV)];
3 reacting Compound (II) and a carboxylic acid of the formula (V)
R.sup.6' COOH (V)
wherein R.sup.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;
4 reacting an isocyanate of the formula (VI)
##STR4##
wherein R.sup.5, R.sup.11, R.sup.12, R.sup.13 and m are as defined above
[hereinafter also referred to as Compound (VI)], and an amine of the
formula (VII)
HNR.sup.7 R.sup.8 (VII)
wherein R.sup.7 and R.sup.8 are as defined above [hereinafter also referred
to as Compound (VII)]; or
5 reacting a compound of the formula (VIII)
##STR5##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and m are as defined above
[hereinafter also referred to as Compound (VIII)], and a compound of the
formula (IX)
R.sup.5 X (IX)
wherein R.sup.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 alkyl at R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.8, R.sup.11,
R.sup.12 and R.sup.13 may be linear or branched and preferably has 1 to 4
carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl and the like.
Lower alkoxy at R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 may be linear or branched and preferably has 1 to 4 carbon atoms.
Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, tert-butoxy and the like.
Alkyl at R.sup.5, R.sup.6, R.sup.6', R.sup.7 and R.sup.10 may be linear or
branched and preferably has 1 to 12 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, 1,1-dimethylpropyl, 1,1-dimethylbutyl, 1,1-dimethylpentyl,
1,1-dimethylhexyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl and the like.
Cycloalkyl at R.sup.5, R.sup.6, R.sup.6' and R.sup.7 preferably has 3 to 6
carbon atoms. Examples thereof include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and the like.
With regard to cycloalkylalkyl at R.sup.5, R.sup.6, R.sup.6' and R.sup.7,
its cycloalkyl moiety preferably has 3 to 6 carbon atoms and alkyl moiety
preferably has 1 to 3 carbon atoms. Examples of cycloalkylalkyl include
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
cyclopropylethyl, cyclopropylpropyl and the like.
Examples of aryl at R.sup.5, R.sup.6, R.sup.6' and R.sup.7 include phenyl,
naphthyl and the like.
Arylalkyl at R.sup.5, R.sup.6, R.sup.6' and R.sup.7 has an aryl moiety as
exemplified above and its alkyl moiety preferably has 1 to 4 carbon atoms.
Examples of arylalkyl include benzyl, 1-phenylethyl, 2-phenylethyl,
1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and the like.
Heterocycle group at R.sup.5, R.sup.6, R.sup.6' and R.sup.10 is a
monovalent group which occurs as a result of liberation of one hydrogen
atom bonded to the ring of heterocyclic compound and may be aliphatic or
aromatic. Examples thereof include pyrrolidinyl, piperidyl, piperidino,
morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl and
the like.
Heterocyclic alkyl at R.sup.5, R.sup.6, R.sup.6', and R.sup.10 has a
heterocyclic moiety as exemplified above and its alkyl moiety preferably
has 1 to 8 carbon atoms. Examples thereof include (1-pyrrolidinyl)butyl,
morpholinopropyl, 1,1-dimethyl-2-(1-pyrrolidinyl)ethyl,
1,1-dimethyl-2-piperidinoethyl, 1,1-dimethyl-3-(imidazol-1-yl)propyl,
(2,6-dimethylpiperidino)methyl, (2,6-dimethylpiperidino)ethyl,
(2,6-dimethylpiperidino)propyl and the like.
The above-mentioned alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocycle and heterocyclic alkyl may be substituted. Examples of the
substituent include alkyl, amino, hydroxy, dialkylamino, aminoalkyl,
alkoxy, carboxyl, alkoxycarbonyl, carboxyalkyl, acyloxy, phenyl, phenoxy,
halogen atom and the like.
Alkyl in alkyl, dialkylamino, aminoalkyl and carboxyalkyl is exemplified by
the above-mentioned lower alkyl. Alkoxy in alkoxy and alkoxycarbonyl is
exemplified by the above-mentioned lower alkoxy. Acyloxy may be linear or
branched and preferably has 2 to 5 carbon atoms. Examples thereof include
acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy and the like.
Halogen atom is exemplified by those to be mentioned later. Alkyl in
dialkylamino may be substituted by phenyl.
Alkenyl at R.sup.5 may be linear or branched and preferably has 2 to 8
carbon atoms. Examples thereof include ethenyl, propenyl, isopropenyl,
butenyl, pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl and
the like.
Alkynyl at R.sup.5 may be linear or branched and preferably has 2 to 8
carbon atoms. Examples thereof include ethynyl, propynyl, butynyl,
pentynyl, hexynyl, heptynyl, octynyl, 3,3-dimethyl-2-propynyl and the
like.
Alkyl moiety of dialkylaminoacyloxyalkyl at R.sup.5 preferably has 1 to 8
carbon atoms, and its acyl moiety may be linear or branched and preferably
has 2 to 5 carbon atoms. Examples thereof include acetyl, propionyl,
butyryl, valeryl, pivaloyl and the like. The dialkylaminoacyloxyalkyl is
specifically exemplified by N,N-dimethylaminoacetoxyethyl,
N,N-dimethylaminoacetoxypropyl and the like.
Alkylene at R.sup.A, R.sup.B, R.sup.D, R.sup.E and R.sup.9 may be linear or
branched and preferably has 1 to 8 carbon atoms. Examples thereof include
methylene, ethylene, trimethylene, propylene, tetramethylene,
pentamethylene, hexamethylene, 1,1-dimethylethylene, 2,2-dimethylpropylene
and the like.
Alkali metal at A, B, D and E is preferably sodium, potassium and the like.
Halogen atom at X is exemplified by chlorine atom, bromine atom, iodine
atom and the like.
When R.sup.4 is --NHCO--R.sup.6, R.sup.6 and R.sup.5 may combinedly form a
ring. The group (--R.sup.6 --R.sup.5 --) formed by R.sup.6 and R.sup.5 in
combination may be linear or branched and preferably has 2 to 12 carbon
atoms. Examples thereof include alkylene such as 1,1-dimethyltrimethylene,
1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene,
1,1-dimethylpentamethylene, 2,2-dimethylpentamethylene and the like, and
alkylene having --OCO-- bond, such as --C(CH.sub.3).sub.2 CH.sub.2
OCO(CH.sub.2).sub.3 --, --C(CH.sub.3).sub.2 CH.sub.2 OCOC(CH.sub.3).sub.2
(CH.sub.2).sub.3 -- and the like.
The preferable Compound (I) of the present invention includes, for example,
1-butyl-3-(1-hexyl-4, 6-dimethylindolin-5-yl)urea,
1-butyl-3-(1-hexyl-4,6-dimethylindolin-7-yl)urea,
N-(1-hexyl-4,6-dimethylindolin-5-yl)-2,2-dimethylpropa namide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-isobutyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylbutanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpentanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-cyclohexanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-3-ethoxypropanamide,
N-(1-ethoxypropyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-3-piperidinopropanamide,
N-(1-piperidinopropyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,6-dimethylpiperidinopropanamide, and
the like, and pharmaceutically acceptable salts thereof.
The Compound (I) may be converted to a pharmaceutically acceptable salt
thereof.
The Compound (I) may be converted to an acid addition salt, since it has a
basic group, and the acid to form this acid addition salt includes, for
example, an inorganic acid such as hydrochloric acid, sulfuric acid,
phosphoric acid, nitric acid and the like; an organic acid such as oxalic
acid, fumaric acid, maleic acid, citric acid, tartaric acid,
methanesulfonic acid, toluenesulfonic acid and the like; and the like.
When Compound (I) has an acidic group such as carboxyl, it can form an
alkali metal salt such as sodium salt, potassium salt and the like;
alkaline earth metal salt such as calcium salt, magnesium salt and the
like; organic base salt such as triethylamine salt, dicyclohexylamine
salt, pyridine salt and the like; and the like.
The Compound (I) and pharmaceutically acceptable salts thereof can be
produced, for example, by the following methods.
PRODUCTION METHOD 1
Compound (II) and compound (III) are reacted.
This method produces a compound of the formula (I) wherein R.sup.6 is
--NR.sup.7 R.sup.8 where R.sup.8 is hydrogen atom.
This reaction generally proceeds in an inert solvent. Examples of the inert
solvent include acetone, dioxane, acetonitrile, chloroform, benzene,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine,
4-dimethylaminopyridine, potassium carbonate and the like may be added.
The reaction temperature is generally from -10.degree. C. to 160.degree.
C., preferably 20-100.degree. C., and the reaction time is generally from
30 minutes to 10 hours.
The starting compound (II) can be prepared, for example, by the following
method.
A nitro group is introduced into a compound of the general formula (X)
##STR6##
wherein R.sup.11, R.sup.12, R.sup.13 and m are as defined above and
R.sup.14 is an amino-protecting group [see J. Eric. Mordlander, et al., J.
Org. Chem., 46, 778-782 (1981)], (introduction of nitro onto benzene ring)
using nitric acid in a mixed solvent of acetic acid and sulfuric acid, and
the amino-protecting group is eliminated.. The compound thus obtained and
compound (IX) are reacted, and nitro group is reduced using a catalyst
such as palladium-carbon and the like to give starting compound (II).
Examples of the amino-protecting group at R.sup.14 include acyl such as
formyl, acetyl, monochloroacetyl, dichloroacetyl, trichloroacetyl,
trifluoroacetyl, propionyl, benzoyl and the like.
Said amino-protecting group is eliminated by a method known per se. For
example, it is eliminated by the action of an acid (e.g., hydrochloric
acid, formic acid, trifluoroacetic acid and the like) or an alkali (e.g.,
sodium hydroxide, potassium hydroxide, sodium carbonate, sodium
hydrogencarbonate and the like), or other method.
PRODUCTION METHOD 2
Compound (II) and compound (IV) are reacted.
This method produces a compound of the formula (I) wherein R.sup.6 can be
any one of those defined above.
This reaction generally proceeds in an inert solvent. Examples of the inert
solvent include acetone, dioxane, acetonitrile, chloroform, benzene,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine,
4-dimethylaminopyridine, potassium carbonate and the like may be added.
The reaction temperature is generally from -10.degree. C. to 100.degree.
C., preferably 0-60.degree. C., and the reaction time is generally from 30
minutes to 10 hours.
PRODUCTION METHOD 3
Compound (II) and compound (V) or a reactive derivative thereof are
reacted.
This method produces a compound of the formula (I) wherein R.sup.6 is
R.sup.6'.
This reaction generally proceeds in an inert solvent. Examples of the inert
solvent include acetone, dioxane, acetonitrile, chloroform, benzene,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine,
4-dimethylaminopyridine, potassium carbonate and the like may be added.
The reaction temperature is generally from -10.degree. C. to 100.degree.
C., preferably 0-60.degree. C., and the reaction time is generally from 30
minutes to 10 hours.
Compound (V) is subjected to said reaction as, for example, a free acid; a
salt such as sodium, potassium, calcium, triethylamine, pyridine and the
like; or a reactive derivative such as acid anhydride, mixed acid
anhydride [e.g., substituted phosphoric acid (e.g., dialkylphosphoric
acid), alkyl carbonate (e.g., monoethyl carbonate) and the like], active
amide (e.g., amide with imidazole etc.), ester (e.g., cyanomethyl ester,
4-nitrophenyl ester and the like), and the like.
When Compound (V) is used as a free acid or salt in this reaction, the
reaction is preferably carried out in the presence of a condensing agent.
Examples of the condensing agent include dehydrating agent such as
N,N'-di-substituted-carbodiimides (e.g., N,N'-dicyclohexylcarbodiimide),
carbodiimide compounds (e.g.,
1-ethyl-3-(3'-dimethylamino-propyl)carbodiimide,
N-cyclohexyl-N'-morpholinoethylcarbodiimide and
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide), azolide compounds
(e.g., N,N'-carbonyldiimidazole and N,N'-thionyldiimidazole) and the like.
When these condensing agents are used, the reaction is considered to
proceed via a reactive derivative of carboxylic acid.
PRODUCTION METHOD 4
Compound (VI) and compound (VII) are reacted.
This method produces a compound of the formula (I) wherein R.sup.6 is
--NR.sup.7 R.sup.8.
This reaction generally proceeds in an inert solvent. Examples of the inert
solvent include acetone, dioxane, acetonitrile, chloroform, benzene,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine,
4-dimethylaminopyridine, potassium carbonate and the like may be added.
The reaction temperature is generally from -10.degree. C. to 160.degree.
C., preferably 10-100.degree. C., and the reaction time is generally from
30 minutes to 10 hours.
The starting compound (VI) can be produced, for example, by dissolving
compound (II) in an inert solvent and bubbling in phosgene.
PRODUCTION METHOD 5
Compound (VIII) and compound (IX) are reacted.
This reaction generally proceeds in an inert solvent. Examples of the inert
solvent include acetone, dioxane, acetonitrile, chloroform, benzene,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine,
4-dimethylaminopyridine, potassium carbonate, sodium hydride and the like
may be added.
The reaction temperature is generally from -10.degree. C. to 100.degree.
C., preferably 0-60.degree. C., and the reaction time is generally from 30
minutes to 10 hours.
The starting compound (VIII) can be prepared, for example, by the method
wherein a nitro group is introduced into a compound of the formula (X)
(introduction of nitro onto benzene ring), and the nitro group is reduced
using a catalyst such as palladium-carbon and the like to give a compound
of the formula (XI)
##STR7##
wherein R.sup.11, R.sup.12, R.sup.13, R.sup.14 and m are as defined above.
Using this compound as a starting compound and according to Production
Method 2, a compound of the formula (XII)
##STR8##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.14 and m are as defined
above, is obtained. This compound is deprotected to give compound (VIII).
The Compound (I) of the present invention obtained as in the above can be
purified by a method conventionally known, such as chromatography and
recrystallization.
This Compound (I) can be converted to a pharmaceutically acceptable salt by
a method known per se.
The Compound (I) and pharmaceutically acceptable salts thereof of the
present invention show superior ACAT inhibitory activity and
lipoperoxidation inhibitory activity in mammals (e.g., human, cow, horse,
dog, cat, rabbit, rat, mouse, hamster and the like) and are useful as ACAT
inhibitors and hyperlipemia inhibitors. To be specific, they are useful
for the prevention and treatment of arteriosclerotic lesions such as
arteriosclerosis, hyperlipemia and diabetes, as well as ischemic diseases
of brain, heart and the like.
A pharmaceutical composition containing Compound (I) or a pharmaceutically
acceptable salt thereof of the present invention may contain an additive.
Examples of the additive include excipients (e.g., starch, lactose, sugar,
calcium carbonate and calcium phosphate), binders (e.g., starch, gum
arabic, carboxymethylcellulose, hydroxypropylcellulose and crystalline
cellulose), lubricants (e.g., magnesium stearate and talc), disintegrators
(e.g., calcium carboxymethylcellulose and talc), and the like.
The above-mentioned ingredients are mixed, and the mixture can be
formulated into an oral preparation such as capsule, tablet, fine
granules, granules, dry syrup and the like, or a parenteral preparation
such as injection, suppository and the like by a method conventionally
known.
While the dose of Compound (I) and pharmaceutically acceptable salts
thereof of the present invention varies depending on administration
target, symptom and other factors, it is generally about 0.1-50 mg/kg body
weight per dose for an adult patient with hypercholesterolemia by oral
administration in about one to three times a day.
The present invention is described in more detail in the following by way
of Examples, to which the present invention is not limited.
EXAMPLE 1
1-butyl-3-(1-hexyl-4,6-dimethylindolin-5-yl)urea
(1) 1-acetyl-4,6-dimethylindoline
4,6-Dimethylindole (1.08 g) was dissolved in acetic acid (20 ml), and
sodium cyanoborohydride (2.3 g) was added portionwise at 15.degree. C. The
mixture was stirred at said temperature for one hour and poured into ice
water. Saturated aqueous sodium hydrogencarbonate was added to neutralize
the mixture and the mixture was extracted with ethyl acetate. The extract
was washed with saturated brine and dried over sodium sulfate. The solvent
was evaporated under reduced pressure. The residue was dissolved in
benzene, and acetic anhydride (840 mg) was added, which was followed by
stirring at room temperature for one hour. The reaction mixture was washed
with saturated aqueous sodium hydrogencarbonate and saturated brine, and
dried over sodium sulfate. The solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chromatography
(developing solvent:chloroform-methanol=1:0-10:1) to give 1.3 g of the
title compound (1).
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.18 (6H, s, --CH.sub.3, --COCH.sub.3),
2.30 (3H, s, --CH.sub.3), 3.00 (2H, t, J=8.3Hz, C.sub.3 -H.sub.2), 4.03
(2H, t, J=8.3Hz, C.sub.2 -H.sub.2), 6.66 (1H, s, C.sub.5 -H), 7.89 (1H, s,
C.sub.7 -H)
(2) 1-acetyl-4,6-dimethyl-5-nitroindoline
1-Acetyl-4,6-dimethylindoline (2.6 g) was dissolved in acetic anhydride (35
ml), and nitric acid (d=1.5, 0.92 ml) dissolved in acetic anhydride (15
ml) was added dropwise at 0.degree. C. The mixture was stirred at room
temperature for one hour and poured into ice water. Saturated aqueous
sodium hydrogencarbonate was added to neutralize the mixture, and the
mixture was extracted with chloroform. The extract was washed with
saturated brine and dried over sodium sulfate. The solvent was evaporated
under reduced pressure. The residue was purified by silica gel column
chromatography (developing solvent : chloroform-methanol=1:0-100:1) to
give 2.4 g of the title compound (2).
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.17 (3H, s, --COCH.sub.3), 2.24 (3H, s,
--CH.sub.3), 2.30 (3H, s, --CH.sub.3), 3.08 (2H, t, J=8.4Hz, C.sub.3
-H.sub.2), 4.14 (2H, t, J=8.3Hz, C.sub.2 -H.sub.2), 8.00 (1H, s, C.sub.7
-H)
(3) 4,6-dimethyl-1-hexyl-5-nitroindoline
1-Acetyl-4,6-dimethyl-5-nitroindoline (2.4 g) obtained in (2) was dissolved
in methanol (25 ml) and 6N hydrochloric acid (20 ml) was added, which was
followed by refluxing for 15 hours. After the completion of the reaction,
the solvent was evaporated under reduced pressure. The residue was
dissolved in chloroform, and the mixture was washed with saturated aqueous
sodium hydrogencarbonate and saturated brine, and dried over sodium
sulfate. The solvent was evaporated under reduced pressure. Indoline (1.8
g) thus obtained was dissolved in dimethylformamide (20 ml), and sodium
hydride (abt. 60% in oil suspension, 457 mg) was added at 0.degree. C. The
mixture was stirred at said temperature for 0.5 hour and hexyl bromide
(1.8 g) was added to the reaction mixture, which was followed by stirring
at room temperature for 3 hours. Water was added to the reaction mixture,
and the mixture was extracted with ethyl acetate. The extract was washed
with saturated brine and dried over sodium sulfate. The solvent was
evaporated under reduced pressure. The residue was purified by silica gel
column chromatography (developing solvent : hexane-ethyl acetate=1:0-10:1)
to give 2.8 g of the title compound (3).
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.90 (3H, br-t, --CH.sub.3), 1.2-1.8
(8H, m, --(CH.sub.2).sub.4 --), 2.17 (3H, s, --CH.sub.3), 2.30 (3H, s,
--CH.sub.3), 3.00 (2H, t, J=8.4Hz, C.sub.3 -H.sub.2), 3.09 (2H, t,
J=7.2Hz, N--CH.sub.2), 3.51 (2H, t, J=8.3Hz, C.sub.2 -H.sub.2), 5.99 (1H,
s, C.sub.7 -H)
(4) 1-butyl-3-(1-hexyl-4,6-dimethylindolin-5-yl)urea
4,6-Dimethyl-1-hexyl-5-nitroindoline (1.0 g) obtained in (3) was dissolved
in benzene (40 ml) and 10% palladium-carbon (100 mg) was added to allow
hydrogenation at 40.degree. C. After the completion of the reaction,
palladium-carbon was filtered off, and the filtrate was washed with
saturated aqueous sodium hydrogencarbonate and saturated brine, and dried
over sodium sulfate. The solvent was evaporated under reduced pressure.
5-Amino-4,6-dimethyl-1-hexylindoline thus obtained was dissolved in
chloroform (20 ml) and butyl isocyanate (400 mg) was added to the reaction
mixture, which was followed by stirring at room temperature for 18 hours.
Water was added to the reaction mixture, and the mixture was washed with
saturated brine and dried over sodium sulfate. The solvent was evaporated
under reduced pressure. The residue was purified by silica gel column
chromatography (developing solvent:chloroform-methanol=1:0-50:1) and
recrystallized from ethanol to give 650 mg of the title compound (4).
.sup.1 H-NMR (CDCl.sub.3).delta.: 0.91 (6H, br-t, --CH.sub.3), 1.0-2.0
(12H, m, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.2 --), 2.09 (3H, s,
--CH.sub.3), 2.19 (3H, s, --CH.sub.3), 2.6-3.6 (8H, m, CO--CH.sub.2,
C.sub.3 -H.sub.2, N--CH.sub.2, C.sub.2 -H.sub.2), 4.29 (1H, br, NH), 5.45
(1H, br, NH), 6.18 (lH, S, C.sub.7 -H)
EXAMPLE 2
N-(1-hexyl-4,6-dimethylindolin-5-yl)-2,2-dimethylpropanamide
5-Amino-4,6-dimethyl-1-hexylindoline (880 mg) was dissolved in chloroform
(20 ml), and triethylamine (370 mg) and pivaloyl chloride (430 mg) were
added, which was followed by stirring at room temperature for 1 hour.
Water was added to the reaction mixture, and the mixture was washed with
saturated brine and dried over sodium sulfate. The solvent was evaporated
under reduced pressure. The residue was purified by silica gel column
chromatography (developing solvent:chloroform-methanol=1:0-50:1) and
recrystallized from ethanol to give 650 mg of the title compound.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.84 (3H, br-t, --CH.sub.3), 1.1-1.8
(8H, m, --(CH.sub.2).sub.4 --), 1.33 (9H, s, --(CH.sub.3).sub.3), 2.00
(3H, s, --CH.sub.3), 2.11 (3H, s, --CH.sub.3), 2.82 (2H, t, J=7.8Hz,
C.sub.3 -H.sub.2), 2.99 (2H, t, J=7.2Hz, N--CH.sub.2), 3.33 (2H, t,
J=7.8Hz, C.sub.2 -H.sub.2), 6.16 (1H, s, C.sub.7 -H), 6.70 (1H, br, N--H)
EXAMPLE 3
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide
(1) 1-acetyl-5-bromo-4,6-dimethylindoline
1-Acetyl-4,6-dimethylindoline (5.5 g) was dissolved in acetic acid (150
ml), and bromine (2.2 ml) was added dropwise at room temperature. The
mixture was stirred at room temperature for 1 hour, and poured into ice
water. The precipitated solid was collected by filtration, and
recrystallized from methanol to give 6.5 g of the title compound (1).
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.19 (3H, s, --COCH.sub.3), 2.27 (3H,
s, --CH.sub.3), 2.39 (3H, s, --CH.sub.3), 3.06 (2H, t, J=8.4Hz, C.sub.3
-H.sub.2), 4.03 (2H, t, J=8.4Hz, C.sub.2 -H.sub.2), 7.99 (1H, S, C.sub.7
-H)
(2) 5-bromo-4,6-dimethyl-7-nitroindoline
Concentrated sulfuric acid (25 ml) and nitric acid (d=1.56, 1.46 ml) were
added to acetic acid (25 ml), and 1-acetyl-5-bromo-4,6-dimethylindoline
(6.5 g) obtained in (1) was added while stirring the mixture at 0.degree.
C., which was followed by stirring at said temperature for 18 hours. The
reaction mixture was poured into ice water, and the precipitated solid was
collected by filtration and washed thoroughly with water. The obtained
solid was suspended in ethanol (50 ml) and water (10 ml). Sodium hydroxide
(20 g) was added and the mixture was refluxed for 3 hours. The solvent was
evaporated under reduced pressure and chloroform was added. The mixture
was washed with saturated brine and dried over sodium sulfate. The solvent
was evaporated under reduced pressure. The residue was purified by silica
gel column chromatography (developing solvent:benzene) to give 4.8 g of
the title compound (2).
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.29 (3H, s, C.sub.4 --CH.sub.3), 2.65
(3H, s, C.sub.6 --CH.sub.3), 3.10 (2H, t, J=8.4Hz, C.sub.3 -H.sub.2), 3.82
(2H, t, J=8.4Hz, C.sub.2 -H.sub.2), 9.0 (1H, br, N--H)
(3) N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide
5-Bromo-4,6-dimethyl-7-nitroindoline (3.0 g) obtained in (2) was dissolved
in dimethylformamide (60 ml) and sodium hydride (abt. 60% in oil
suspension, 530 mg) was added at 0.degree. C., which was followed by
stirring at said temperature for 0.5 hour. Hexyl bromide (1.8 g) was added
to the reaction mixture and the mixture was stirred at room temperature
for 12 hours. Water was added to the reaction mixture, and the mixture was
extracted with ethyl acetate. The extract was washed with saturated brine
and dried over sodium sulfate. The solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chromatography
(developing solvent:hexane-ethyl acetate=1:0-10:1). The obtained solid was
dissolved in benzene (40 ml) and 10% palladium-carbon (100 mg) was added
to allow hydrogenation at 40.degree. C. After the completion of the
reaction, palladium-carbon was filtered off, and the filtrate was washed
with saturated aqueous sodium hydrogencarbonate and saturated brine, and
dried over sodium sulfate. The solvent was evaporated under reduced
pressure.
7-Amino-4,6-dimethyl-1-hexylindoline thus obtained was dissolved in
chloroform (20 ml), and triethylamine (1.0 g) and pivaloyl chloride (1.0
g) were added to the reaction mixture, which was followed by stirring at
room temperature for 1 hour. Water was added to the reaction mixture, and
the mixture was washed with saturated brine and dried over sodium sulfate.
The solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (developing
solvent:chloroform-methanol=1:0-50:1). The obtained compound (3) was
dissolved in ethanol and 10N hydrochloric acid/ethanol (1 ml) was added.
The solvent was evaporated under reduced pressure. The residue was
recrystallized from ethanol to give 700 mg of hydrochloride of the title
compound (3).
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.90 (3H, br-t, --CH.sub.3), 1.1-1.6
(8H, m, --(CH.sub.2).sub.4 --), 1.41 (9H, s, --(CH.sub.3)3), 2.15 (3H, S,
--CH.sub.3), 2.25 (3H, s, --CH.sub.3), 3.15 (4H, m, C.sub.3 -H.sub.2,
N--CH.sub.2), 3.70 (1H, m, C.sub.2 -H), 4.00 (1H, m, C.sub.2 -H), 7.12
(1H, s, C.sub.5 -H), 9.2 (1H, br, N--H)
EXAMPLE 4
1-butyl-3-(1-hexyl-4,6-dimethylindolin-7-yl)urea
7-Amino-4,6-dimethyl-1-hexylindoline (800 mg) was dissolved in chloroform
(20 ml) and butyl isocyanate (400 mg) was added, which was followed by
stirring at room temperature for 18 hours. Water was added to the reaction
mixture, and the mixture was washed with saturated brine and dried over
sodium sulfate. The solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (developing
solvent : chloroform-methanol=1:0-50:1) and recrystallized from ethanol to
give 450 mg of the title compound.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.88 (6H, br-t, --CH.sub.3), 1.0-1.8
(12H, m, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.2 --), 2.13 (6H, S,
--CH.sub.3.times.2), 2.83 (2H, t, J=8.3Hz, C.sub.3 -H.sub.2), 3.20 (4H,
N--CH.sub.2.times.2), 3.43 (2H, t, J=8.3Hz, C.sub.2 -H.sub.2), 4.80 (1H,
br-t, NH--CH.sub.2), 5.52 (1H, br-s, C.sub.7 -NH), 6.40 (1H, s, C.sub.5
-H)
EXAMPLES 5-36
In the same manner as in any one of the above-mentioned Examples 1-4, the
compounds shown in Tables 1 and 2 were obtained.
TABLE 1
##STR9##
R.sup.4 = --NHCO--R.sup.6
Example R.sup.1 R.sup.2 R.sup.3 R.sup.6 R.sup.5
5 --H --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5
CH.sub.3
6 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.8
CH.sub.3 --CH.sub.2 CH.sub.3
7 --OCH.sub.3 --H --OCH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5
CH.sub.3
8 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.3
CH.sub.3
9 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.3
CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
10 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.5
CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
11 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.7 CH.sub.3
12 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --CH.sub.2
CH.sub.3
13 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.5
CH.sub.3 --CH.sub.2 CH.sub.3
14 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.3
CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3
15 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.5
CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3
16 --CH.sub.3 --H --CH.sub.3 --CH.sub.3 --(CH.sub.2).sub.5
CH.sub.3
17 --CH.sub.3 --H --CH.sub.3 --CH(CH.sub.3).sub.2
--(CH.sub.2).sub.5 CH.sub.3
18 --CH.sub.3 --H --CH.sub.3 --CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2
COOH --(CH.sub.2).sub.5 CH.sub.3
19 --CH.sub.2 CH.sub.3 --H --CH.sub.2 CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.5 CH.sub.3
20 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.2
COOH --(CH.sub.2).sub.5 CH.sub.3
TABLE 2
##STR10##
R.sup.4 = --NHCO--R.sup.6
Example R.sup.1 R.sup.2 R.sup.3 R.sup.6 R.sup.5
21 --CH.sub.3 --H --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
--(CH.sub.2).sub.5 CH.sub.3
22 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.2 OCOCH.sub.3
23 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.2 OCH.sub.3
24 --CH.sub.3 --H --CH.sub.2 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.2 OC.sub.2 H.sub.5
25 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --C.sub.5
H.sub.11
26 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.5 COOH
27 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --C.sub.7
H.sub.15
28 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2 OH
--C.sub.6 H.sub.13
29 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2
OCOCH.sub.3 --C.sub.6 H.sub.13
30 --CH.sub.3 --H --CH.sub.3
##STR11##
--C.sub.6 H.sub.13
31 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.2 CH(CH.sub.3).sub.2
32 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --CH.sub.2
CH(CH.sub.3).sub.2
33 --CH.sub.3 --H --CH.sub.3
##STR12##
--C.sub.6 H.sub.13
34 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2 OC.sub.2
H.sub.5 --C.sub.6 H.sub.13
35 --CH.sub.3 --H --CH.sub.3
##STR13##
--C.sub.6 H.sub.13
36 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --C.sub.3
H.sub.7
The .sup.1 H-NMR data of the compounds of the above Examples 5-36 are shown
in the following.
.sup.1 H-NMR (CDCl.sub.3) .delta.:
EXAMPLE 5
(hydrochloride) 0.91 (3H, br-t), 1.1-1.8 (8H, m), 1.34 (9H, s), 2.09 (3H,
s), 2.93-3.48 (4H, m), 3.48-3.82 (1H, m), 3.82-4.35 (1H, m), 7.12 (1H, d),
7.32 (1H, d), 9.36 (1H, br-s)
EXAMPLE 6
0.93 (3H, br-t), 1.0-2.0 (19H, m), 1.35 (6H, s), 2.12 (3H, s), 2.19 (3H,
s), 2.98 (2H, t), 3.25 (2H, t), 3.65 (2H, t), 6.80 (1H, s), 8.09 (1H,
br-s)
EXAMPLE 7
0.87 (3H, br-t), 1.1-1.8 (8H, m), 1.31 (9H, s), 2.84 (2H, t), 3.16 (2H, t),
3.44 (2H, t), 3.74 (3H, s), 3.79 (3H, s), 5.86 (1H, s)
EXAMPLE 8
0.92 (3H, br-t), 1.39 (9H, s), 1.2-1.9 (4H, m), 2.08 (3H, s), 2.15 (3H, s),
2.80-3.30 (4H, m), 3.60 (2H., t), 6.68 (1H, s), 7.78 (1H, br-s)
EXAMPLE 9
0.90 (3H, br-t), 0.92 (3H, br-t), 1.08-1.88 (10H, m), 1.29 (6H, s), 2.05
(3H, s), 2.12 (3H, s), 2.81 (2H, t), 3.13 (2H, t), 3.40 (2H, t), 6.39 (1H,
s), 6.74 (1H, br-s)
EXAMPLE 10
0.63-1.05 (6H, m), 1.05-1.82 (14H, m), 1.29 (6H, s), 2.08 (3H, s), 2.10
(3H, s), 2.82 (2H, s), 3.13 (2H, t), 3.41 (2H, t), 6.41 (1H, s), 6.77 (1H,
br-s)
EXAMPLE 11
0.88 (3H, br-t), 1.01-1.87 (12H, m), 1.35 (9H, s), 2.09 (3H, s), 2.14 (3H,
s), 2.82 (2H, t), 3.13 (2H, t), 3.52 (2H, t), 6.60 (1H, br-s)
EXAMPLE 12
1.18 (3H, t), 1.35 (9H, s), 2.09 (3H, s), 2.15 (3H, s), 2.92 (2H, t), 3.22
(2H, q), 3.56 (2H, t), 6.62 (1H, s), 7.57 (1H, br-s)
EXAMPLE 13
0.88 (3H, br-t), 1.08 (3H, t), 1.29 (6H, s), 1.1-1.9 (10H, m), 2.08 (3H,
s), 2.22 (3H, s), 2.82 (2H, t), 3.21 (2H, q), 3.33 (2H, t), 6.43 (1H, s),
6.84 (1H, br-s)
EXAMPLE 14
0.90 (3H, br-t), 0.92 (3H, br-t), 1.08-1.88 (14H, m), 1.29 (6H, s), 2.05
(3H, s), 2.12 (3H, s), 2.81 (2H, t), 3.13 (2H, t), 3.40 (2H, t), 6.39 (1H,
s), 6.74 (1H, br-s)
EXAMPLE 15
0.63-1.05 (6H, m), 1.05-1.82 (18H, m), 1.34 (6H, s), 2.11 (3H, s), 2.17
(3H, s), 2.95 (2H, s), 3.13 (2H, t), 3.60 (2H, t), 6.72 (1H, s), 7.8 (1H,
br)
EXAMPLE 16
0.89 (3H, br-t), 1.05-1.70 (8H, m), 1.81 (3H, s), 2.11 (3H, s), 2.15 (3H,
s), 2.81 (2H, br-t), 2.6-3.8 (4H, m), 6.39 (1H, s), 6.58 (1H, br), 6.72
(1H, br)
EXAMPLE 17
0.87 (3H, br-t), 1.05-1.90 (8H, m), 1.25 (3H, s), 1.32 (3H, s), 2.11 (31,
s), 2.17 (3H, s), 2.67 (1H, m), 2.7-3.4 (4H, m), 3.59 (2H, t), 6.69 (1H,
s), 7.83 (1H, br-s)
EXAMPLE 18
0.87 (3H, br-t), 1.05 -1.80 (8H, m), 1.21 (6H, s), 2.17 (6H, s), 2.48 (2H,
s), 2.55 (2H, s), 3.01 (2H, t), 3.10 (2H, t), 3.54 (2H, t), 6.70 (1H, s),
6.8-8.2 (1H, br-s), 8.72 (1H, br-s)
EXAMPLE 19
0.87 (3H, br-t), 1.05-1.80 (8H, m), 1.17 (3H, t), 1.20 (3H, t), 1.35 (9H,
s), 2.22-2.62 (4H, m), 2.91 (2H, t), 3.04 (2H, t), 3.48 (2H, br-t), 6.56
(1H, s), 7.25 (1H, br-s)
EXAMPLE 20
0.85 (3H, br-t), 1.05-1.80 (8H, m), 1.27 (6H, s), 1.80-2.25 (2H, m), 2.10
(3H, s), 2.16 (33H, s), 2.25-2.55 (2H, m), 2.90 (2H, t), 3.04 (2H, t),
3.47 (2H, t), 6.69 (1H, s), 8.49 (1H, br-s), 8.95 (1H, br-s)
EXAMPLE 21
0.83 (3H, br-t), 0.87 (3H, br-t), 1.1-1.8 (11H, m), 2.11 (3H, s), 2.16 (3H,
s), 2.29 (1H, t), 2.85 (2H, t), 3.22 (2H, t), 3.55 (21H, t), 6.49 (1H, s),
6.68 (1H, br)
EXAMPLE 22
1.27 (9H, s), 2.04 (6H, s), 2.13 (3H, s), 3.06 (2H, t), 3.43 (2H, t), 3.75
(2H, t), 4.29 (2H, t), 6.87 (1H, s), 9.15 (1H, br-s)
EXAMPLE 23
1.33 (9H, s), 2.04 (3H, s), 2.09 (3H, s), 2.8-2.9 (4H, m), 3.38 (3H, s),
3.4-3.6 (4H, m), 6.36 (1H, s), 7.35 (1H, br-s)
EXAMPLE 24
1.16 (3H, t), 1.32 (9H, s), 2.04 (3H, s), 2.09 (3H, s), 2.82 (2H, t),
3.3-3.6 (8H, m), 6.53 (1H, s), 7.40 (1H, br-s)
EXAMPLE 25
0.88 (3H, br-t), 1.35 (9H, s), 1.2-1.9 (6H, m), 2.08 (3H, s), 2.15 (3H, s),
2.92 (2H, t), 3.13 (2H, t), 3.55 (2H, t), 6.23 (1H, s), 7.60 (1H, br-s)
EXAMPLE 26
1.1-1.9 (6H, m), 1.39 (9H, s), 2.07 (3H, s), 2.13 (3H, s), 2.29 (2H, t),
2.84 (2H.sub.1, t), 3.11 (2H, t), 3.43 (2H, t), 5.40 (1H, br), 6.52 (1H,
s), 7.30 (1H, br-s)
EXAMPLE 27
0.87 (3H, br-t), 1.1-1.8 (10H, m), 1.34 (9H, s), 2.07 (3H, s), 2.13 (3H,
s), 2.87 (2H, t), 3.13 (2H, t), 3.49 (2H, t), 6.52 (1H, s), 7.20 (1H,
br-s)
EXAMPLE 28
0.87 (3H, br-t), 1.1-1.8 (8H, m), 1.26 (6H, s), 1.99 (3H, s), 2.08 (3H, s),
2.78 (2H, t), 3.10 (2H, t), 3.37 (2H, t), 3.48 (2H, s), 4.00 (1H, br-s),
6.35 (1H, s), 7.81 (1H, s)
EXAMPLE 29
0.87 (3H, br-t), 1.1-1.8 (8H, m), 1.28 (6H, s), 2.07 (6H, s), 2.12 (3H, s),
2.84 (2H, t), 3.14 (2H, t), 3.43 (2H, t), 4.20 (2H, s), 6.48 (1H, s), 7.35
(1H, s)
EXAMPLE 30
0.87 (3H, br-t), 1.1-1.8 (8H, m), 2.15 (6H, s), 2.82 (2H, t), 3.16 (2H, t),
3.43 (2H, t), 6.43 (1H, s), 7.42 (2H, m), 8.22 (1H, m), 8.75 (1H, m), 9.16
(1H, br-s)
EXAMPLE 31
0.90 (6H, d), 1.3-1.8 (3H, m), 1.36 (9H, s), 2.09 (31, s), 2.16 (3H, s),
2.92 (2H, t), 3.16 (2H, t), 3.54 (2H, t), 6.65 (1H, s), 7.65 (1H, br-s)
EXAMPLE 32
0.94 (6H, d), 1.33 (9H, s), 1.7-2.0 (1H, m), 2.04 (3H, s), 2.10 (3H, s),
2.82 (2H, t), 2.94 (2H, t), 3.38 (2H, t), 6.37 (1H, s), 6.70 (1H, br-s)
EXAMPLE 33
0.85 (3H, br-t), 1.1-1.8 (8H, m), 1.44 (6H, s), 2.03 (3H, s), 2.08 (3H, s),
2.80 (2H, t), 3.14 (2H, t), 3.41 (2H, t), 4.50 (2H, s), 6.37 (11, s), 7.04
(1H, br-s), 7.40 (2H, m), 8.28 (11, m), 8.75 (1H, m), 9.21 (1H, d)
EXAMPLE 34
0.88 (3H, br-t), 1.1-1.8 (8H, m), 1.23 (3H, t), 1.27 (6H, s), 2.07 (3H, s),
2.10 (3H, s), 2.81 (2H, t), 3.18 (2H, t), 3.41 (2H, t), 3.48 (2H, s), 3.55
(2H, q), 6.37 (1H, s), 8.00 (1H, br-s)
EXAMPLE 35
0.88 (3H, br-t), 1.1-1.8 (14H, m), 1.24 (6H, s), 2.10 (6H, s), 2.50 (2H,
t), 2.90 (2H, t), 2.8-3.6 (8H, m), 6.39 (1H, s), 7.00 (1H, br-s)
EXAMPLE 36
0.87 (3H, br-t), 1.2-1.9 (2H, m), 1.35 (9H, s), 2.08.(3H, s), 2.15 (3H, s),
2.93 (2H, t), 3.12 (2H, t), 3.50 (2H, t), 6.30 (1H, s), 7.40 (1H, br-s)
In the same manner as in any one of the above-mentioned Examples 1-1, the
compounds shown in Tables 3 to 9 can be obtained.
TABLE 3
##STR14##
R.sup.4 = --NHCO--R.sup.6
Example R.sup.1 R.sup.2 R.sup.3 R.sup.6
R.sup.5
37 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--CH.sub.2 --CH.dbd.C(CH.sub.3).sub.2
38 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.4 SO.sub.3 Na
39 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
##STR15##
40 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
##STR16##
41 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
##STR17##
42 --CH.sub.3 --H --CH.sub.3
##STR18##
--CH.sub.2 CH.sub.3
43 --CH.sub.3 --H --CH.sub.3
##STR19##
--(CH.sub.2).sub.3 CH.sub.3
44 --CH.sub.3 --H --CH.sub.3
##STR20##
--(CH.sub.2).sub.5 CH.sub.3
45 --CH.sub.3 --H --CH.sub.3
##STR21##
--(CH.sub.2).sub.5 COOH
46 --CH.sub.3 --H --CH.sub.3
##STR22##
--(CH.sub.2).sub.5 CH.sub.3
47 --CH.sub.3 --H --CH.sub.3
##STR23##
--(CH.sub.2).sub.5 CH.sub.3
48 --CH.sub.3 --H --CH.sub.3
##STR24##
--(CH.sub.2).sub.5 CH.sub.3
49 --CH.sub.3 --H --CH.sub.3
##STR25##
--(CH.sub.2).sub.5 CH.sub.3
50 --CH.sub.3 --H --CH.sub.3
##STR26##
--(CH.sub.2).sub.5 CH.sub.3
51 --CH.sub.3 --H --CH.sub.3
##STR27##
--CH.sub.2 CH.sub.3
52 --CH.sub.3 --H --CH.sub.3 --(CH.sub.2).sub.4 OC(CH.sub.3).sub.3
--(CH.sub.2).sub.3 CH.sub.3
53 --CH.sub.3 --H --CH.sub.3
##STR28##
--(CH.sub.2).sub.3 CH.sub.3
TABLE 4
##STR29##
R.sup.4 = --NHCO--R.sup.6
Example R.sup.1 R.sup.2 R.sup.3 R.sup.6
R.sup.5
54 --CH.sub.3 --H --CH.sub.3
##STR30##
--CH.sub.2 CH.sub.3
55 --CH.sub.3 --H --CH.sub.3
##STR31##
--CH.sub.2 CH.sub.3
56 --CH.sub.3 --H --CH.sub.3
##STR32##
--CH.sub.2 CH.sub.3
57 --CH.sub.3 --H --CH.sub.3 --CH.sub.2 C(CH.sub.3).sub.3
--(CH.sub.2).sub.5 CH.sub.3
58 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.2
SO.sub.3 Na --(CH.sub.2).sub.5 CH.sub.3
59 --CH.sub.3 --H --CH.sub.3 --CH.sub.2 C(CH.sub.3).sub.2
(CH.sub.2).sub.2 SO.sub.3 Na --(CH.sub.2).sub.5 CH.sub.3
60 --CH.sub.3 --H --CH.sub.3
##STR33##
--(CH.sub.2).sub.5 CH.sub.3
61 --CH.sub.3 --H --CH.sub.3
##STR34##
--(CH.sub.2).sub.5 CH.sub.3
62 --H --H --OCH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.6 CH.sub.3
63 --H --H --OCH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.4 CH.sub.3
64 --H --H --OCH(CH.sub.3).sub.2 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.5 CH.sub.3
65 --H --H --OCH(CH.sub.3).sub.2 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.4 CH.sub.3
66 --H --H --OCH(CH.sub.3).sub.2 --(CH.sub.2).sub.3 CH.sub.3
--(CH.sub.2).sub.5 CH.sub.3
67 --H --H --OCH(CH.sub.3).sub.2 --(CH.sub.2).sub.5 CH.sub.3
--(CH.sub.2).sub.5 CH.sub.3
TABLE 5
##STR35##
R.sup.4 = --NHCO--R.sup.6
Ex-
am-
ple R.sup.1 R.sup.2 R.sup.3 --R.sup.6 --R.sup.5 --
68 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.2 --
69 --CH.sub.3 --H --CH.sub.3 --CH.sub.2 C(CH.sub.3).sub.2
(CH.sub.2).sub.2 --
70 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2
OCO(CH.sub.2).sub.3 --
71 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2
OCOC(CH.sub.3).sub.2 (CH.sub.2).sub.3 --
TABLE 6
##STR36##
R.sup.4 = --NHCONH--R.sup.7
Ex-
am-
ple R.sup.1 R.sup.2 R.sup.3 R.sup.7 R.sup.5
72 --H --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5
CH.sub.3
73 --CH.sub.3 --H --CH.sub.3
##STR37##
--(CH.sub.2).sub.5 CH.sub.3
74 --OCH.sub.3 --H --OCH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.5 CH.sub.3
75 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.3
CH.sub.3
76 --CH.sub.3 --H --CH.sub.3
##STR38##
--(CH.sub.2).sub.3 CH.sub.3
77 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.7
CH.sub.3
78 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --CH.sub.2 CH.sub.3
79 --CH.sub.3 --H --CH.sub.3
##STR39##
--CH.sub.2 CH.sub.3
80 --CH.sub.3 --H --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3
--(CH.sub.2).sub.5 CH.sub.3
81 --H --H --CH.sub.3 --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3
82 --H --H --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2).sub.5
CH.sub.3
83 --H --H --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2).sub.5
CH.sub.3
84 --H --H --CH.sub.3 --CH.sub.3 --(CH.sub.2).sub.7 CH.sub.3
85 --H --H --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2).sub.7
CH.sub.3
86 --H --H --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2).sub.7
CH.sub.3
87 --H --H --OCH.sub.3 --CH.sub.3 --CH.sub.2 CH.sub.3
88 --H --H --OCH.sub.3 --(CH.sub.2).sub.3 CH.sub.3 --CH.sub.2
CH.sub.3
89 --H --H --OCH.sub.3 --(CH.sub.2).sub.5 CH.sub.3 --CH.sub.2
CH.sub.3
90 --H --H --OCH.sub.3 --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
91 --H --H --OCH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
--(CH.sub.2).sub.3 CH.sub.3
92 --H --H --OCH.sub.3 --(CH.sub.2).sub.5 CH.sub.3
--(CH.sub.2).sub.3 CH.sub.3
TABLE 7
##STR40##
R.sup.2 = --NHCONH--R.sup.7
Example R.sup.1 R.sup.3 R.sup.4 R.sup.7 R.sup.5
93 --H --CH.sub.3 --H --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5
CH.sub.3
94 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.2 (CH.sub.2).sub.8
CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3
95 --OCH.sub.3 --OCH.sub.3 --H --C(CH.sub.3).sub.3
--(CH.sub.2).sub.5 CH.sub.3
96 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.3
--(CH.sub.2).sub.3 CH.sub.3
97 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.2 (CH.sub.2).sub.3
CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
98 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.2 (CH.sub.2).sub.5
CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
99 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.3
--(CH.sub.2).sub.7 CH.sub.3
100 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.3 --CH.sub.2 CH.sub.3
101 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.2 (CH.sub.2).sub.5
CH.sub.3 --CH.sub.2 CH.sub.3
102 --CH.sub.3 --CH.sub.3 --H --(CH.sub.2).sub.3 CH.sub.3
--(CH.sub.2).sub.5 CH.sub.3
103 --CH.sub.3 --CH.sub.3 --H --(CH.sub.2).sub.5 CH.sub.3
--(CH.sub.2).sub.5 CH.sub.3
TABLE 8
##STR41##
R.sup.2 = --NHCO--R.sup.6
Example R.sup.1 R.sup.3 R.sup.4 R.sup.6 R.sup.5
104 --H --OCH.sub.3 --H --CH.sub.3 --CH.sub.2 CH.sub.3
105 --H --OCH.sub.3 --H --(CH.sub.2).sub.3 CH.sub.3 --CH.sub.2
CH.sub.3
106 --H --OCH.sub.3 --H --(CH.sub.2).sub.5 CH.sub.3 --CH.sub.2
CH.sub.3
107 --H --OCH.sub.3 --H --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
108 --H --OCH.sub.3 --H --(CH.sub.2).sub.3 CH.sub.3
--(CH.sub.2).sub.3 CH.sub.3
TABLE 9
##STR42##
R.sup.4 = --NHCO--R.sup.6
Example R.sup.1 R.sup.2 R.sup.3 R.sup.6 R.sup.5
109 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.5 CH.sub.3
110 --H --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5
CH.sub.3
111 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.8
CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3
112 --OCH.sub.3 --H --OCH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.5 CH.sub.3
113 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.3 CH.sub.3
114 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.3
CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
115 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.2).sub.2 (CH.sub.2).sub.5
CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3
116 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3
--(CH.sub.2).sub.7 CH.sub.3
117 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --CH.sub.2
CH.sub.3
118 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.5
CH.sub.3 --CH.sub.2 CH.sub.3
EXPERIMENTAL EXAMPLE 1
ACAT Inhibitory Activity
A high cholesterol feed [a feed added with cholesterol (1%), Clea Japan,
Inc.] was fed to male Japanese white rabbits weighing 2-2.5 kg at 100 g
per day and the rabbits were bred for 4 weeks. The rabbits were killed by
bleeding under anesthesia and small intestine was removed. The mucous
membrane of small intestine was peeled, collected and homogenated. The
homogenate was centrifuged at 4.degree. C. and 10,000 rpm for 15 min. The
obtained supernatant was further centrifuged at 40.degree. C. and 41,000
rpm for 30 minutes to give microsomal fractions. Using this microsomal
suspension as an enzyme sample, dimethyl sulfoxide (DMSO, 5 .mu.l) or a
test compound dissolved in DMSO (test compound solution, 5 .mu.l), and a
reaction substrate [1-.sup.14 C]-oleoyl CoA were added to a reaction
buffer. After incubation at 37.degree. C. for 5 minutes, a
chloroform-methanol mixture was added to stop the reaction. Water was
added thereto and mixed, and chloroform layer was separated. The solvent
was evaporated to dryness, and the residue was dissolved in hexane. The
mixture was subjected to thin layer chromatography using a silica gel
plate. The spots of cholesteryl oleate on the silica gel plate were
scraped, and quantitatively assayed on a liquid scintillation counter. The
ACAT inhibitory activity of the test compound was expressed as a
proportion (%) of inhibition of cholesteryl oleate, namely, the proportion
of inhibition of cholesteryl oleate production as compared to control.
The results are shown in Tables 10-11.
EXPERIMENTAL EXAMPLE 2
Serum Total Cholesterol Reducing Effect
Male Wister rats weighing 180-200 g were bred under free access to a high
cholesterol feed [added with cholesterol (1%), cholic acid (0.5%) and
coconut oil (10%), Clea Japan, Inc.] for 3 days, during which period a
test compound (10-100 mg/kg) suspended in 5% gum arabic solution was
forcibly administered once a day orally for 3 days. Only 5% gum arabic
solution was administered to control animals. After final administration,
the test animals were fasted for 5 hours and the blood was taken. The
serum total cholesterol level was determined using a commercially
available assay kit (cholesterol-E-Test Wako, Wako Pure Chemical
Industries, Ltd.). The activity of the test compound was expressed as a
proportion (%) of reduction of serum total cholesterol level, namely, the
proportion of reduction of serum total cholesterol as compared to control.
The results are shown in Tables 10-11.
EXPERIMENTAL EXAMPLE 3
LDL Peroxidation Inhibitory Effect
Male Japanese white rabbits weighing 2-2.5 kg were bred on 100 g per day of
a high cholesterol feed [added with cholesterol (1%), Clea Japan, Inc.]
for 4 weeks. The blood was taken from carotid and plasma was obtained.
Then, LDL was fractionated from the plasma by ultracentrifugation,
dialyzed for one day and preserved at 4.degree. C. LDL (400 .mu.g) and
aqueous copper sulfate solution (final concentration 5 .mu.M) were added
to bufferized Ham F-10 medium (2 ml, GBICO, USA). DMSO or a solution (20
.mu.l) of test compound dissolved in DMSO was added and the mixture was
incubated at 37.degree. C. for 24 hours. After the completion of the
incubation, LDL peroxide in medium was allowed to develop color by
thiobarbituric acid method and assayed as malondialdehyde. The activity of
the test compound was expressed as malondialdehyde production inhibitory
ratio (%), namely, the proportion of inhibition of production of
malondialdehyde as compared to control.
The results are shown in Tables 10-11.
EXPERIMENTAL EXAMPLE 4
Plasma Lipoperoxidation Inhibitory Effect
The blood was taken from male Japanese white rabbits weighing 2-2.5 kg
under anesthesia and heparinized plasma was separated by a conventional
method. To the plasma (2.0 ml) was added DMSO or a solution (20 .mu.l,
final concentration 10.sup.-5 M) of test compound dissolved in DMSO, and
aqueous copper sulfate solution (final concentration 5 mM) was added
immediately thereafter. The mixture was incubated at 37.degree. C. for 3
hours. After the completion of the incubation, 20% trichloroacetic acid
was added to stop the reaction. Then, the mixture was centrifuged at
4.degree. C., 4,500 rpm for 15 minutes. The lipoperoxide in the
supernatant thus obtained was assayed as malondialdehyde upon color
development by thiobarbituric acid method. The activity of the test
compound was expressed as malondialdehyde production inhibitory ratio (%),
namely, the proportion of inhibition of production of malondialdehyde as
compared to control.
The results are shown in Tables 10-11.
TABLE 10
Result of Result of Result of Result of
Exp. Ex. 1 Exp. Ex. 2 Exp. Ex. 3 Exp. Ex. 4
Test compound (%) *1 (%) *2 (%) *3 (%) *4
Example 1 76.6 ** 12.9 *** 99.2 94.3
Example 2 59.9 ** -- 99.5 95.8
Example 3 97.5 ** 54.4 ** 93.3 90.4
Example 4 94.9 ** 21.4 ** 59.5 92.0
Example 6 99.8 ** 53.3 ** 24.8 37.4
Example 7 96.2 ** 19.2 ** 86.6 86.4
Example 8 99.7 ** 48.0 ** 91.9 85.1
Example 9 81.3 ** 51.3 ** 93.7 81.6
Example 10 98.7 ** 55.2 ** 18.3 82.6
Example 11 99.2 ** 59.5 * 91.6 78.8
Example 12 71.9 ** 30.3 ** 90.3 74.9
Example 13 96.0 ** 28.4 ** 82.4 87.1
Example 14 96.6 ** 53.9 ** 88.3 93.1
Example 15 93.1 ** 35.0 * 12.3 90.1
Example 17 96.7 ** 27.0 * 89.6 91.1
Example 18 69.6 * 22.3 ** 34.0 87.1
Example 20 22.7 * 7.8 * 67.8 91.1
Example 21 94.4 ** 28.3 * 92.1 91.4
Example 22 78.5 ** 38.6 *** 40.6 92.8
Example 23 88.8 ** 23.6 ** 54.8 90.5
*1ACAT inhibition (concentration *: 10.sup.-4 M, **: 10.sup.-5 M)
*2reduction of serum total cholesterol (dose *: 10 mg/kg/day, **: 30
mg/kg/day, ***: 100 mg/kg/day)
*3LDL peroxidation inhibition (concentration : 10.sup.-5 M)
*4plasma lipoperoxidation inhibition (concentration : 10.sup.-5 M)
TABLE 11
Result of Result of Result of Result of
Exp. Ex. 1 Exp. Ex. 2 Exp. Ex. 3 Exp. Ex. 4
Test compound (%) *1 (%) *2 (%) *3 (%) *4
Example 24 97.1 ** 28.3 ** 42.2 90.5
Example 25 96.8 ** 50.5 ** 92.2 93.1
Example 26 26.5 ** 37.4 ** 43.3 90.1
Example 27 95.5 ** 56.9 *** 92.2 91.1
Example 28 79.4 ** 20.8 *** 92.2 91.1
Example 29 86.6 ** 6.9 ** 91.9 91.1
Example 30 83.0 ** 25.7 *** 94.1 91.8
Example 31 93.8 ** 49.0 ** 90.3 90.8
Example 32 93.9 ** 57.4 ** 85.3 89.1
Example 33 82.2 ** 7.2 ** 87.0 89.5
Example 34 91.0 ** 50.2 ** 82.9 89.8
Example 35 84.6 ** 20.8 ** 71.9 91.4
Example 36 95.9 ** 50.2 ** 83.2 89.1
YM-750 92.3 ** 43.8 ** 0 --
Probucol 3.4 ** 7.3 * 89.4 87.5
*1ACAT inhibition (concentration *: 10.sup.-4 M, **: 10.sup.-5 M)
*2reduction of serum total cholesterol (dose *: 10 mg/kg/day, **: 30
mg/kg/day, ***: 100 mg/kg/day)
*3LDL peroxidation inhibition (concentration : 10.sup.-5 M)
*4plasma lipoperoxidation inhibition (concentration : 10.sup.-5 M)
YM-750 1-cycloheptyl-1-[(2-fluorenyl)methyl]-3- (2,4,6-trimethylphenyl)
urea
Probucol 4,4'-isopropylidenedithiobis (2, 6-di-t-butylphenol)
Formulation Example 1
Tablets having the following composition are prepared by a conventional
method.
Compound of Example 3 25 mg
Polyvinylpyrrolidone 20 mg
Starch 75 mg
Magnesium stearate 2 mg
Formulation Example 2
Capsules having the following composition are prepared by a conventional
capsule packing method.
Compound of Example 6 100 mg
Lactose 25 mg
Magnesium stearate 1 mg
The heterocyclic derivative and pharmaceutically acceptable salts thereof
of the present invention show superior ACAT inhibitory activity and
lipoperoxidation inhibitory activity, and are useful as ACAT inhibitors or
hyperlipemia inhibitors. To be specific, they are useful for the
prevention and treatment of arteriosclerotic lesions such as
arteriosclerosis, hyperlipemia and diabetes, as well as ischemic diseases
of brain, heart and the like.
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