Pyridone derivatives and process for preparing the same

Details Pyridone derivatives and process for preparing the same Pyridone derivatives and process for preparing the same

2001-05-14

2002-09-17

Dentz, Bernard (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S292000

Reexamination Certificate

active

06452008

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a pyridone derivative or a salt thereof, which exhibits acyl-CoA: cholesterol acyl transferase (ACAT) inhibitory activity, and is useful as an agent for treatment of hyperlipidemia and atherosclerosis, and a process for preparing the same.
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-3-181465, JP-A-3-223254 and JP-A-6-501025 disclose some kinds of quinoline derivatives having an ACAT inhibitory activity, and JP-A-5-32666 discloses some kinds of thienopyridine derivatives having an ACAT inhibitory activity, and further JP-A-9-48780 discloses some kinds of naphthyridine derivatives having an ACAT inhibitory activity.
These patent publications disclose processes for preparation of these compounds, for example, in the above JP-A-9-48780, an ureidonaphthyridine derivative which is a pyridone derivative and its intermediate, an amino derivative are prepared by the following process.
wherein Ring A is a substituted or unsubstituted pyridine ring; R
1
is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y
1
is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; L is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group.
That is, a carboxy derivative of the formula (11) is azidated with an azidating agent, and subsequently heated to convert into an isocyanate derivative of the formula (12), which is further reacted with an amine derivative of the formula (3) to give an ureido derivative of the formula (13), or alternatively the isocyanate derivative (12) is hydrolyzed to give an amine derivative of the formula (14).
DISCLOSURE OF INVENTION
However, the present inventors have found that the azidating agents used in the above process and the compounds prepared by azidating the carboxyl derivative of the formula (II) have a risk of explosion and therefore, they are not suitable for large-scale production with respect to safety.
An object of the present invention is to provide a process for preparing pyridone derivatives and aminopyridone derivatives, especially a preferable process thereof with respect to safety, and to provide a novel pyridone derivative.
The present inventors have intensively studied in order to solve the above problems, and have found that pyridone derivatives and aminopyridone derivatives can safely be prepared by the following Processes [1] to [37], and further have found that novel pyridone derivatives of the following [38] to [54] exhibit a potent ACAT inhibitory activity, and then have accomplished the present invention.
That is, the gist of the present invention is as follows.
[1] A process for preparing a pyridone derivative of the formula (4):
wherein R
1
is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y
1
is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; Y
2
and Y
3
are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkyithio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, or Y
2
and Y
3
may combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring; and L is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group,
which comprises reacting a compound of the formula (1):
wherein R
1
, Y
1
, Y
2
and Y
3
are as defined above, with a hypochlorite or a hypobromite or with lead tetraacetate to give a compound of the formula (2):
wherein R
1
, Y
1
, Y
2
and Y
3
are as defined above, followed by reacting the compound (2) with a compound of the formula (3):
L—NH
2
  (3)
wherein L is as defined above.
[2] The process according to the above [1], wherein a sodium hypochlorite or a sodium hypobromite is used in the reaction from the compound (1) to the compound (2).
[3] The process according to the above [1], wherein lead tetraacetate is used in the reaction from the compound (1) to the compound (2).
[4] The process for preparing the pyridone derivative according to any one of the above [1] to [3], wherein Y
2
and Y
3
combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a), (b) or (c):
[5] The process for preparing the pyridone derivative according to any one of the above [1] to [3], wherein Y
2
and Y
3
combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a):
[6] The process for preparing the pyridone derivative according to the above [4] or [5], wherein Y
1
and L are a substituted aromatic group, and R
1
is a substituted or unsubstituted alkyl group.
[7] The process for preparing the pyridone derivative according to the above [6], wherein Y
1
is a 3-methoxyphenyl group, L is a 2,6-diisopropylphenyl group, and R
1
is a butyl group.
[8] A process for preparing a pyridone derivative of the formula (4):
wherein R
1
is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group

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