JPH1135545A - Urethane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition having an excellent low density lipoprotein receptor gene expression-reinforcing action and useful for preventing and treating hyperlipemia, atherosclerosis, etc., by including a specific compound having a urethane skeleton. SOLUTION: This medicinal composition contains a compound, such as a urethane derivative of formula II [R<1> is a (substituted) heterocyclic group, etc.; R<2> is H, etc.; R<3> is a (substituted) alkyl, etc.], containing a urethane skeleton of formula I, having a low density lipoprotein receptor expression-reinforcing action, or its pharmacologically acceptable salt as an active ingredient. The compound of formula II includes (quinolin-3-yl) carbamic acid cyclopentyl ester obtained by reacting cyclopentanol with the reaction product of 3-aminoquinoline with N,N' -carbonyldiimidazole in the presence of an acid-removing agent in a solvent at -10 to 30 deg.C. The compound of formula II is preferably administered at a daily dose of about 5-20 mg/kg as an injection or at a daily dose of about 10-100 mg/kg as an oral agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition comprising a compound having a low specific gravity lipoprotein (LDL) receptor expression enhancing action and having a urethane skeleton as an active ingredient, a novel urethane derivative, and a method for producing the same.

[0002]

2. Description of the Related Art Arteriosclerosis causes myocardial infarction due to circulatory obstruction, stroke and cerebral malacia due to cerebrovascular disorders.
Atherosclerosis is often caused by atherosclerosis, and its cause is considered to be abnormal lipid metabolism, especially blood cholesterol increase as an important factor. 60-75% of blood cholesterol is present as low density lipoprotein (LDL). LDL in the blood is taken up via LDL receptors in the liver.

[0003] It has been reported that LDL receptor expression is increased in transgenic mice into which the human LDL receptor gene has been introduced, and that blood cholesterol is significantly reduced on a high fat diet as compared with normal rats. (M. Yokode et al., Science
nce), vol. 250, pp. 1273-1275, 199
0 years).

[0004] Drugs for lowering blood LDL include 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase (3-hydroxy-3-methylgluta), a rate-limiting enzyme of cholesterol synthase.
RMG-CoA reducer; HMG-CoA
Inhibitors of reductase (eg, mevalotin (generic name; pravastatin sodium) and mevacol (generic name: lovastatin)) are known. These substances inhibit cholesterol synthesis in the liver,
Secondaryly increase the number of LDL receptors, resulting in blood LD
It is believed that L uptake is promoted and lowers its blood concentration. However, cholesterol inhibitors can limit the supply of essential cholesterol, and there are concerns about side effects. Therefore, a substance having an LDL lowering action having a different action mechanism is desired.

[0005]

SUMMARY OF THE INVENTION The present invention provides an excellent LD
An object of the present invention is to provide a compound having an L receptor expression enhancing action and a pharmaceutical composition comprising such a compound as an active ingredient.

[0006]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a series of compounds having a urethane skeleton is LDL.
The present inventors have found that they have a receptor expression enhancing action, and have completed the present invention.

That is, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a urethane derivative or a pharmaceutically acceptable salt thereof useful for the prevention and treatment of hyperlipidemia, atherosclerosis, etc., and an LDL receptor. It is intended to provide a novel urethane derivative having a body expression enhancing action.

Further, a novel urethane derivative useful as an LDL receptor expression enhancer, that is, the present invention relates to a compound represented by the general formula [I-
a]:

[0009]

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(Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group, (2) a substituted or unsubstituted alkyl group,
(3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ² represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ³¹
Is (1) substituted or unsubstituted alkyl group, (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted heterocyclic group, (4) bridged cyclic hydrocarbon group, (5) substituted or unsubstituted Represents an alkenyl group or (6) a substituted or unsubstituted cycloalkyl group. However, when R ¹ is a substituted or unsubstituted 2-quinolyl group, R ³¹ is (1) a straight-chain alkyl group having 4 or more carbon atoms or 1 to 3 carbon atoms substituted with a heterocyclic group. A substituted or unsubstituted branched or unsubstituted C 4 or more carbon atom alkyl group (excluding tert-butyl group), (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted A heterocyclic group, (4) a bridged cyclic hydrocarbon group, or (5) a substituted or unsubstituted cycloalkyl group. Or a pharmacologically acceptable salt thereof, and a method for producing these compounds.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION As the pharmaceutical composition of the present invention, L
A pharmaceutical composition comprising a compound having a DL receptor expression enhancing action and having a urethane skeleton or a pharmacologically acceptable salt thereof as an active ingredient is exemplified. Specifically, LD
Has an L receptor expression enhancing action, and has the formula:

[0012]

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[0013] Pharmaceutical compositions comprising a compound having the partial structure represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. Further, the compounds represented by the general formulas [I] and / or
Or a pharmaceutical composition comprising, as an active ingredient, a urethane derivative represented by the general formula [Ia] or a pharmaceutically acceptable salt thereof.

That is, the pharmaceutical composition of the present invention comprises an LDL receptor expression enhancer, a lipid lowering agent, and a preventive / hyperlipidemic agent.
It is useful as a therapeutic agent or a prophylactic / therapeutic agent for a prophylactic / therapeutic agent for atherosclerosis.

The urethane derivatives of the present invention include:
The compound represented by the general formula [Ia] or a pharmaceutically acceptable salt thereof is exemplified.

The urethane derivative [Ia] of the present invention or a pharmaceutically acceptable salt thereof has an excellent LDL receptor expression enhancing action, and is therefore useful as an LDL receptor expression enhancer. Furthermore, the urethane derivative [Ia] or a pharmaceutically acceptable salt thereof is an excellent lipid-lowering agent, and is useful as an agent for preventing and treating hyperlipidemia and an agent for preventing and treating atherosclerosis. It is.

In the urethane derivative [I] and / or [Ia] of the present invention, the heterocyclic group includes, for example,
Monocyclic, bicyclic or tricyclic aliphatic or aromatic heterocyclic groups which may be partially saturated. Examples of the aromatic heterocyclic group include a monocyclic or bicyclic 5- to 12-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Preferably
For example, pyrrolyl group, imidazolyl group, furyl group, thienyl group, thiazolyl group, isoxazolyl group, oxazolyl group, oxazolinyl group, pyrazolyl group, quinazolinyl group, thienopyrimidinyl group, pyridyl group, chromanyl group, chromenyl group, pyrimidinyl group, pyridazinyl group ,
Pyrazinyl group, triazinyl group, tetrazolyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, benzothienyl group, benzothiazolyl group, benzoxazolyl,
Examples include an indolyl group, an indazolyl group, an isoindolyl group or a benzimidazolyl group, and a ring in which a part thereof is saturated.

The ring in which a part of the aromatic heterocyclic group is saturated includes, for example, imidazolinyl group, thiazolinyl group, oxazolinyl group, pyrrolinyl group, indolinyl group, pyrazolinyl group, isoindolinyl group, 1,2,2
Examples include a 3,4-tetrahydroquinolyl group.

The aliphatic heterocyclic group is a monocyclic or bicyclic 5- to 12-membered aliphatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Certain ones are preferable, and examples thereof include a piperazinyl group, a pyrrolidinyl group, a piperidyl group, a piperidino group, a homopiperidyl group, a thiomorpholino group, a tetrahydrofuryl group, and a morpholino group.

However, in the urethane derivative [Ia], R ¹ is a substituted or unsubstituted 2-quinolyl group, and R ³¹ is a heterocyclic group-substituted linear alkyl having 1 to 3 carbon atoms. When it is a group, the heterocyclic group includes the above-mentioned heterocyclic group, and more specifically, a monocyclic or bicyclic nitrogen-containing 5- to 12-membered heterocyclic group is preferable,
Particularly, a nitrogen-containing monocyclic 5- to 7-membered heterocyclic group such as a pyridyl group is preferable.

Examples of the aryl group include a monocyclic ring which may be partially saturated, a bicyclic or tricyclic hydrocarbon group having 15 or less carbon atoms which may be partially or wholly saturated. Is mentioned. The monocyclic hydrocarbon group preferably has 5 to 8 carbon atoms, and more specifically, a phenyl group, a cyclopentenyl group, a cyclohexenyl group, and the like.

The bicyclic hydrocarbon group has 9 carbon atoms.
To 11 are preferable, and more specifically, a naphthyl group,
In addition to an indenyl group and an azulenyl group, a decahydronaphthyl group and the like can be mentioned.

The tricyclic hydrocarbon group preferably has 12 to 15 carbon atoms, and more specifically includes a fluorenyl group, a phenanthryl group, an anthryl group, an acenaphthylenyl group, a biphenylenyl group and the like.

Further, examples of the crosslinked cyclic hydrocarbon group include bicyclic or polycyclic C7 to C15 carbon atoms which may be partially or wholly saturated.
Those which are bicyclic or tricyclic bridged cyclic saturated hydrocarbon groups are preferred. The bicyclic bridged cyclic hydrocarbon group preferably has 7 to 15 carbon atoms, and more specifically, a bicycloheptyl group, a bicyclooctyl group and the like.

The tricyclic bridged cyclic hydrocarbon group preferably has 8 to 15 carbon atoms, and more specifically, an adamantyl group and the like.

On the other hand, in the urethane derivatives [I] and / or [Ia], when R ¹ is a substituted heterocyclic group, examples of the substituent on the heterocyclic group include:
Halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, optionally protected amino group, aryl group, cyano group, arylthio group, lower alkoxy group, halogen atom, lower alkyl group, nitro group,
An aryloxy group optionally substituted with a group selected from a carboxyl group, a lower alkoxycarbonyl group and an amino group; a lower aralkyloxy group; an oxo group;
A nitro group; a carboxyl group; a lower alkoxycarbonyl group; an alkenyl group.

When R ¹ is a substituted heterocyclic group, the substituent on the heterocyclic group is an “aryl group”,
When it is an "arylthio group", an "aryloxy group" or a "lower aralkyloxy group", the aryl group includes a phenyl group or a naphthyl group.

As the substituent on the alkyl group, for example,
Examples include a phenyl group, a pyridyl group, an indolyl group, an optionally protected carboxy group-substituted phenyl group, a furyl group, and a cyclo-lower alkyl group.

Examples of the substituent on the alkoxy group include a phenyl group and a pyridyl group.

Examples of the substituent on the alkenyl group include a phenyl-substituted lower alkyl group, a nitro-substituted phenyl group, a lower alkoxy-substituted phenyl group, a mono- or dihalogenophenyl group, a phenyl group, a pyridyl group, and a furyl group. Is mentioned.

As the substituent on the aryl group, for example,
Examples include a hydroxyl group, a carboxyl group, and an amino group.

R ¹ is a heterocyclic group, an alkyl group,
In the case of an alkoxy group, an alkenyl group or an aryl group, these groups may have the same or different substituents and may have 1 to 3 substituents.

Further, when R ² is an alkyl group, examples of the substituent on the alkyl group include a pyridyl group, a carboxyl group which may be protected, a phenyl group and the like.

When R ² is an alkyl group, the alkyl group may have 1 to 3 identical or different substituents.

The urethane derivative [I] and / or [I-
In a), when R ³ and / or R ³¹ is an alkyl group, examples of the substituent on the alkyl group include a cyclo lower alkyl group; a phenyl group; an oxo group, an amino group, and a carboxyl group. A monocyclic or bicyclic nitrogen-containing compound which may be substituted with
Examples include a 12-membered heterocyclic group.

When R ³ and / or R ³¹ is an alkyl group, when the substituent on the alkyl group is a monocyclic or bicyclic nitrogen-containing 5- to 12-membered heterocyclic group, As the cyclic or bicyclic nitrogen-containing 5- to 12-membered heterocyclic group, a nitrogen-containing monocyclic 5- to 7-membered heterocyclic group is preferable.

As the substituent on the aryl group, for example,
Examples include a hydroxyl group, a carboxyl group, an amino group, and a nitro group.

As the substituent on the heterocyclic group, for example,
Lower alkyl group, halogen atom, amino group, cyano group,
Examples include a nitro group and a carboxyl group.

Examples of the substituent on the alkenyl group include a phenyl group, a pyridyl group and a quinolyl group.

Examples of the substituent on the cycloalkyl group include a lower alkyl group, an oxo group and a carboxyl group.

When R ³ and / or R ³¹ is an alkyl group, an aryl group, a heterocyclic group, an alkenyl or a cycloalkyl group, these groups may be the same or different from each other and have 1 to 3 substituents. You may have.

In the urethane derivative [I], preferred compounds are those in which R ¹ is (1) a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group,
A monocyclic or dicyclic group which may be substituted with a group selected from an optionally protected amino group, aryl group, cyano group, arylthio group, substituted or unsubstituted aryloxy group, lower aralkyloxy group, oxo group and hydroxyl group; Cyclic 5- to 12-membered heterocyclic group, (2) substituted with a group selected from a phenyl group, a pyridyl group, an indolyl group, an optionally protected carboxy-substituted phenyl group, a furyl group and a cyclo-lower alkyl group. A lower alkyl group, (3) a lower alkoxy group, (4) a phenyl group-substituted lower alkyl group, a nitro group-substituted phenyl group, a lower alkoxy group-substituted phenyl group, a mono- or dihalogenophenyl group, a phenyl group, a pyridyl group, Lower alkenyl group which may be substituted with a group selected from a furyl group, (5) hydroxyl group and carboxyl From a group substituted by two may be cyclic 9-11 membered aryl group or (6) a benzenesulfonyl group or a tosyl group selected, R ² is selected from the carboxyl group which may be pyridyl group and protection A lower alkyl group or a hydrogen atom which may be substituted with a group, wherein R ³ is (1) a cyclo-lower alkyl group, a phenyl group, an isoindolinyl group, a pyridyl group, a piperidino group substituted with one or two oxo groups; An alkyl group which may be substituted with a group selected from oxo group-substituted pyrrolidinyl groups, (2) a bicyclic 9-11-membered aryl group,
(3) a nitrogen-containing or oxygen-containing monocyclic 5- to 7-membered heterocyclic group which may be substituted by a lower alkyl group, (4) a bi- or tricyclic cross-linked cyclic saturated hydrocarbon group, (5) a lower Compounds that are alkenyl groups or (6) cycloalkyl groups are mentioned.

In the urethane derivative [Ia], a preferable compound is a monocyclic or bicyclic 5- to 12-membered monocyclic or bicyclic compound in which R ¹ may be substituted by a group selected from (1) an oxo group and a hydroxyl group. A heterocyclic group, (2) a lower alkyl group optionally substituted with a group selected from a phenyl group, a pyridyl group, an indolyl group, an optionally protected carboxyl group, a substituted phenyl group, a furyl group and a cyclo-lower alkyl group. A group selected from the group consisting of (3) a lower alkoxy group, (4) a phenyl group-substituted lower alkyl group, a nitro group-substituted phenyl group, a lower alkoxy group-substituted phenyl group, a mono- or dihalogenophenyl group, a phenyl group, a pyridyl group and a furyl group. And (5) a alkenyl group which may be substituted with a group selected from a hydroxyl group and a carboxyl group. An expression 9-11-membered aryl group or (6) a benzenesulfonyl group or a tosyl group,
R ² is a lower alkyl group or a hydrogen atom which may be substituted with a group selected from a pyridyl group and an optionally protected carboxyl group, and R ³¹ is (1) a cyclo lower alkyl group, a phenyl group, An alkyl group optionally substituted with an isoindolinyl group, a pyridyl group, a piperidino group, and an oxo group-substituted pyrrolidinyl group substituted with two oxo groups, (2) a bicyclic 9-11 membered aryl group, (3) a nitrogen-containing or oxygen-containing monocyclic 5- to 7-membered heterocyclic group which may be substituted with a lower alkyl group,
(4) a bi- or tricyclic bridged cyclic saturated hydrocarbon group,
Compounds that are (5) lower alkenyl groups or (6) cycloalkyl groups are mentioned.

Of these, preferred compounds are
A monocyclic or bicyclic 5-12 membered heterocyclic group or a bicyclic 9-11 membered aryl group has the formula:

[0045]

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The compounds represented by

Particularly preferred compounds are a monocyclic or bicyclic 5- to 12-membered heterocyclic group having a quinolyl group, a benzimidazolyl group, a benzothiazolyl group, a pyridyl group,
A chromenyl group, a quinoxalinyl group or an indazolyl group, wherein the bicyclic 9-11 membered aryl group is an indanyl group,
A naphthyl group or a decahydronaphthyl group, a nitrogen-containing or oxygen-containing monocyclic 5- to 7-membered heterocyclic group is a piperidyl group or a tetrahydrofuryl group, and a bi- or tricyclic cross-linked cyclic saturated hydrocarbon group is adamantyl. The compound is a group.

Further, among the compounds represented by the urethane derivatives [I] and / or [Ia], as other preferred compounds, R ¹ is a heterocyclic group or an aryl group, and R ³ and / or R Compounds in which ³¹ is an aryl group are exemplified.

Among the other preferred compounds, particularly preferred compounds are those wherein R ¹ is a bicyclic heterocyclic group or a bicyclic aryl group, and R ³ and / or R ³
Examples include compounds in which ³¹ is a bicyclic aryl group, more specifically, a bicyclic heterocyclic group or a bicyclic aryl group has the formula:

[0050]

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R ³ and / or R
Compounds wherein ³¹ is a bicyclic saturated aryl group.

Further, in the urethane derivatives [I] and / or [Ia], preferred compounds from the viewpoint of efficacy include a lower alkenyl group in which R ¹ is substituted with a group selected from nitro-substituted phenyl and pyridyl groups, and quinolyl. Group,
A pyridyl-substituted lower alkyl group or an oxo-substituted chromenyl group, R ³ and / or R ³¹ are a lower alkyl group,
Compounds that are a cyclo-lower alkyl group, a cyclo-lower alkyl group-substituted lower alkyl group or a decahydronaphthyl group are exemplified.

[0053] Among them, as the efficacy the especially preferred compounds, R ¹ has the formula:

[0054]

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Compounds which are groups represented by

As the protecting group for the amino group, a conventional protecting group which can be a protecting group for the amino group can be used. For example, a substituted or unsubstituted lower alkoxycarbonyl group,
Specific examples include a lower alkanoyl group and the like. Specific examples include a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2,-
Examples include a trichloroethyloxycarbonyl group, a formyl group, an acetyl group, a propionyl group, and a butyryl group.

As the carboxyl-protecting group, a conventional protecting group which can be used as a carboxyl-protecting group can be used. Examples thereof include a lower alkyl group and an aryl-substituted lower alkyl group. Examples include a methyl group, an ethyl group, a tert-butyl group, and a benzyl group.

The carboxyl-protecting group can be easily removed by a known method, for example, a conventional method such as catalytic reduction.

The urethane derivatives [I] and / or [Ia] of the present invention can be formed by the groups R ¹ , R ² , R ³ and / or R
^{When 31} has an asymmetric carbon atom, it may exist as an optical isomer based on the asymmetric carbon, and the present invention includes any of these optical isomers and a mixture thereof.

The urethane derivatives [I] and / or [Ia] of the present invention can be used in a free form or in the form of a pharmaceutically acceptable salt for pharmaceutical use. Such pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate or hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfonate,
Organic acid salts such as tosylate or maleate are exemplified. When the compound has a substituent such as a carboxyl group, a salt with a base (for example, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt) is exemplified.

The urethane derivative [I] and / or [Ia] of the present invention or a pharmaceutically acceptable salt thereof may be any one of an inner salt, an adduct, a solvate and a hydrate. Is also included.

The urethane derivative [I] and / or [Ia] or a pharmaceutically acceptable salt thereof of the present invention can be administered orally or parenterally. , Tablets, granules, capsules, powders, injections, and inhalants.

The dosage form for oral administration may be a solid such as tablets, granules, capsules and powders, or a liquid such as solution and suspension, and is suitable for oral administration. It can be used as a pharmaceutical formulation together with a pharmaceutical carrier. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar,
Corn starch, potassium phosphate, sorbite, glycine, etc.), lubricants (magnesium stearate, talc,
Any of conventional materials such as polyethylene glycol, silica, etc., disintegrants (potato starch, etc.) or wetting agents (sodium lauryl sulfate, etc.) can be used.

On the other hand, the dosage form for parenteral administration is preferably an injection or drip injection using, for example, distilled water for injection, physiological saline, aqueous glucose solution, or the like.

The dose of the urethane derivative [I] and / or [Ia] or a pharmaceutically acceptable salt thereof of the present invention varies depending on the administration method, age, weight and condition of the patient. As an agent, usually about 1-50mg per day
/ Kg, especially about 5 to 20 mg / kg, and for oral preparation, usually about 10 to 300 mg / kg, especially about 10 to 200 mg / kg per day.

According to the present invention, the urethane derivatives [I] and / or [Ia] can be produced according to the following (Method A), (Method B) and (Method C).

(Method A): Among the compounds [I], the general formula [Ia]:

[0068]

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(Wherein R ¹ represents (1) a substituted or unsubstituted heterocyclic group, (2) a substituted or unsubstituted alkyl group,
(3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ² represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ³¹
Is (1) substituted or unsubstituted alkyl group, (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted heterocyclic group, (4) bridged cyclic hydrocarbon group, (5) substituted or unsubstituted Represents an alkenyl group or (6) a substituted or unsubstituted cycloalkyl group. However, when R ¹ is a substituted or unsubstituted 2-quinolyl group, R ³¹ is (1) a straight-chain alkyl group having 4 or more carbon atoms or 1 to 3 carbon atoms substituted with a heterocyclic group. A substituted or unsubstituted branched or unsubstituted C 4 or more carbon atom alkyl group (excluding tert-butyl group), (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted A heterocyclic group, (4) a bridged cyclic hydrocarbon group, or (5) a substituted or unsubstituted cycloalkyl group. The compound represented by the general formula [II]:

[0070]

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(Wherein the symbols have the same meanings as described above) or a salt thereof, and a compound represented by the general formula [II
I]:

[0072]

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(Wherein the symbols have the same meanings as described above), by reacting the compound with a reactive derivative at the carboxyl group or a salt thereof.

(Method B): Of the compound [I], a compound represented by the general formula [Ia-1]:

[0075]

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(Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group, (2) a substituted or unsubstituted alkyl group,
(3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ³¹
Is (1) substituted or unsubstituted alkyl group, (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted heterocyclic group, (4) bridged cyclic hydrocarbon group, (5) substituted or unsubstituted Represents an alkenyl group or (6) a substituted or unsubstituted cycloalkyl group. However, when R ¹ is a substituted or unsubstituted 2-quinolyl group, R ³¹ is (1) a straight-chain alkyl group having 4 or more carbon atoms or 1 to 3 carbon atoms substituted with a heterocyclic group. A substituted or unsubstituted branched or unsubstituted C 4 or more carbon atom alkyl group (excluding tert-butyl group), (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted A heterocyclic group, (4) a bridged cyclic hydrocarbon group, or (5) a substituted or unsubstituted cycloalkyl group. The compound represented by the general formula [IV]:

[0077]

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(Wherein the symbols have the same meanings as described above) or a salt thereof and a general formula [ii]
i]:

[0079]

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(Wherein the symbols have the same meanings as described above) or a salt thereof.

(Method C): Among the compounds [I], the general formula [Ia]:

[0082]

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(Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group, (2) a substituted or unsubstituted alkyl group,
(3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ² represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ³¹
Is (1) substituted or unsubstituted alkyl group, (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted heterocyclic group, (4) bridged cyclic hydrocarbon group, (5) substituted or unsubstituted Represents an alkenyl group or (6) a substituted or unsubstituted cycloalkyl group. However, when R ¹ is a substituted or unsubstituted 2-quinolyl group, R ³¹ is (1) a straight-chain alkyl group having 4 or more carbon atoms or 1 to 3 carbon atoms substituted with a heterocyclic group. A substituted or unsubstituted branched or unsubstituted C 4 or more carbon atom alkyl group (excluding tert-butyl group), (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted A heterocyclic group, (4) a bridged cyclic hydrocarbon group, or (5) a substituted or unsubstituted cycloalkyl group. The compound represented by the general formula [V]:

[0084]

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(Wherein X represents a leaving group, and other symbols have the same meanings as described above) or a salt thereof and a general formula [iii]:

[0086]

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(Wherein the symbols have the same meanings as described above) or a salt thereof.

The following methods (A), (B) and (C)
Method) will be described in detail.

(Method A): The reaction of compound [II] or a salt thereof with a reactive derivative of compound [III] is carried out in the presence or absence of a deoxidizing agent in a suitable solvent or without a solvent. Can be. As the deoxidizing agent, for example, triethylamine, pyridine, 4- (N, N-dimethylamino)
Organic bases such as pyridine; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; Any inert solvent which does not participate in the reaction may be used. For example, dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, N-methylpyrrolidone and the like can be used. This reaction proceeds, for example, at -50 to 50C, particularly at -10 to 20C.

The reactive derivative of the compound [III] includes a compound represented by the formula:

[0091]

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(Wherein the symbols have the same meanings as described above). Further, the chloroformate of the compound [III] includes a compound represented by the general formula [iii]:

[0093]

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(Wherein the symbols have the same meanings as described above) can be reacted with phosgene or triphosgene.

(Method B): The reaction of compound [IV] or a salt thereof with compound [iii] or a salt thereof can be carried out in the presence or absence of a deoxidizing agent in a suitable solvent or without a solvent. it can. Examples of the deoxidizing agent include organic bases such as triethylamine, pyridine and 4- (N, N-dimethylamino) pyridine, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate and the like. Alkali metal bicarbonate, sodium carbonate, alkali metal carbonate such as potassium carbonate and the like,
Examples of the solvent include dimethyl sulfoxide, N, N
-Dimethylacetamide, dimethylformamide, hexamethylphosphoramide, sulfolane, 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, dichloromethane, diethyl ether and the like can be used. This reaction proceeds, for example, at -50 to 50C, particularly at -10 to 30C.

Further, the compound [IV] has the general formula [iv]

[0097]

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(Wherein the symbols have the same meanings as described above), and reacted with diphenylphosphoric azide (DPPA) in the presence of a deoxidizing agent (eg, triethylamine, diisopropylethylamine, etc.). can do.

(Method C): The reaction of compound [V] or a salt thereof with compound [iii] or a salt thereof can be carried out in the presence or absence of a deoxidizing agent in a suitable solvent or without a solvent. it can. Examples of the deoxidizing agent include organic bases such as triethylamine, pyridine and 4- (N, N-dimethylamino) pyridine, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate and the like. Alkali metal bicarbonate, sodium carbonate, alkali metal carbonate such as potassium carbonate and the like,
Examples of the solvent include dimethyl sulfoxide, N, N
-Dimethylacetamide, dimethylformamide, hexamethylphosphoramide, sulfolane, 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, dichloromethane, diethyl ether and the like can be used. This reaction proceeds, for example, at -50 to 50C, particularly at -10 to 30C.

Further, the compound [V] has the general formula [II]

[0101]

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(Wherein the symbols have the same meanings as described above) and a compound of the general formula [VI]

[0103]

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(Wherein the symbols have the same meanings as described above) or a salt thereof.

However, as the compound [VI], the compound [V] can be produced, and the group X substantially proceeds when the compound [V] is reacted with the compound [iii]. Any leaving group may be used, for example, N, N'-carbonyldiimidazole, triphosgene and the like can be suitably used.

The compound [Ia] according to the present invention and / or
Alternatively, upon production of compound [I-a-1], compounds [II], [III], [IV], [iii] and [V] can be used in the form of a salt. Are, for example, alkali metal salts such as sodium, potassium, lithium, pyridine, triethylamine, N
-Salts with organic bases such as methylmorpholine, salts with inorganic acids such as hydrogen chloride, hydrogen bromide and sulfuric acid, salts with organic acids such as acetic acid, formic acid, oxalic acid, citric acid and malonic acid. .

The compound [Ia] of the present invention is obtained by substituting the substituents R ¹ , R ² and / or R
It can also be produced by converting ³¹ into another substituent of interest. The method for converting such a substituent may be appropriately selected according to the type of the desired substituent. For example, the method can be carried out as in the following (method a) to (c method).

(Method a): a group containing a heterocyclic group in which the group R ¹ represented by the general formula [Ia] is substituted with an oxo group (for example, a nitrogen-containing heterocyclic group substituted with an oxo group) Groups,
More specifically, a quinolyl group substituted with an oxo group, etc.)
Can be produced by oxidizing the corresponding compound [Ia] in which the group R ¹ is a group containing a heterocyclic group. This oxidation reaction can be carried out using an oxidizing agent. Examples of such an oxidizing agent include peroxides such as 3-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, and pertrifluoroacetic acid, sodium periodate, Osmium oxide and sodium bromite are exemplified. The reaction is, for example,
It proceeds at -50 to 20C, especially at -10 to 30C.

[0109] (b) method: general formula [I-a] the desired product group R ² is a substituted or unsubstituted alkyl group represented by [I], the corresponding compound group R ² is a hydrogen atom [I-
a) in the presence or absence of a deoxidizing agent, an alkyl halide in which an alkyl moiety may be substituted or an alkyl lower alkane sulfonate in which an alkyl moiety may be substituted (for example, alkyl methane sulfonate and the like);
It can be produced by reacting with an alkylating agent such as an alkylarylsulfonate (eg, alkyl p-toluenesulfonate). Examples of the deoxidizing agent include alkali metal hydroxides such as sodium hydroxide, alkali metal hydrogencarbonates such as sodium hydrogencarbonate, alkali metal carbonates such as sodium carbonate, and organic bases such as triethylamine and pyridine. This reaction is performed, for example, at -20 to 100 ° C.
In particular, it proceeds at -10 to 50C.

(Method c): The target product [Ia] in which the group R ¹ represented by the general formula [Ia] is a substituted or unsubstituted alkyl group (for example, a substituted or unsubstituted ethyl group) is A corresponding compound [I- wherein R ¹ is a substituted or unsubstituted alkenyl group (eg, a substituted or unsubstituted ethylene group)
a) can be produced by catalytic reduction. The catalytic reduction is carried out by a conventional method by hydrogenation using a catalyst. As the catalyst, conventionally known catalysts can be widely used, and examples thereof include palladium catalysts such as palladium carbon and palladium black, and platinum catalysts such as a platinum wire. The process proceeds at 3 atm, and the temperature is 10 to 50 ° C, especially 20
Proceed at ３０30 ° C.

In the present invention, the alkyl, alkoxy and alkenyl groups have 1 to 16 carbon atoms.
Particularly, a linear or branched one having 1 to 8 carbon atoms is mentioned, and a lower alkyl group and a lower alkoxy group are those having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms.
Examples of the lower alkenyl group and the lower alkanoyl group include linear or branched ones having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms. Further, examples of the cycloalkyl group include those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms.
Halogen atoms include chlorine, bromine, fluorine or iodine.

[0112]

EXAMPLES The present invention will be described more specifically with reference to the following experimental examples and examples, but the present invention is not limited to these examples.

Experimental Example 1 LDL Receptor Gene Expression Enhancing Activity (Luciferase Assay) The reaction was carried out according to the method of de Whet et al. (Molecular).
and Cellular Biology, 7, 7
25-737, 1987). That is, L
A plasmid was prepared by linking a 472 base pair promoter region 5 'upstream of the translation start point of the DL receptor gene to a firefly luciferase gene, and this was used to introduce a gene into a CHO cell derived from Chinese hamster ovary (Bio-Rad Inc.). ). The expression level of the LDL receptor gene in the obtained recombinant cells can be measured as luciferase activity.

The above recombinant cells are suspended in a Ham's (Ham's) F12 medium (manufactured by Gibco) containing 10% FCS (fetal calf serum) and seeded in a 96-well plate in an appropriate number. 2
After culturing for one day, the medium was cultured in Ham's F containing 10% LPDS (Lipoprotein Defectient Serum).
The medium is exchanged for 12 media, and the compound obtained in Example 42 described later is added. After further culturing for 2 days, pickagene luciferase assay kit (manufactured by Toyo Ink Co., Ltd.)
Was used to prepare a cell extract, and its luciferase activity was measured. When 100 μM and 10 μM of the compound obtained in Example 42 described later were added to the medium, the luciferase activity was increased about 20-fold and about 5-fold, respectively, as compared with the control without addition of the sample.

Table 1 shows the concentrations at which the luciferase activity was increased 5-fold as compared with the control without the addition of the sample.

[0116]

[Table 1]

Experimental Example 2 LDL Receptor Expression Enhancing Activity (LDL Binding Assay) Human liver-derived HepG2 cells were suspended in MEM-E medium (manufactured by Gibco) containing 10% FCS (fetal calf serum).
Seed the appropriate number in a 24-well plate. After culturing for 1 day, 10
The medium is replaced with a MEM-E medium containing% LPDS, and the compound obtained in Example 42 described later is added. After culturing for 48 hours, L
Provide for DL binding assay.

The culture solution prepared by the above operation was added to ¹²⁵ I
-Add 2 μg / well of LDL. In order to measure non-specific binding, unlabeled LDL was further added to 100%.
Add μg / ml. Thereafter, the cells are cultured at 37 ° C. for 3 hours. The cells were washed with a washing solution containing 2 mg / ml BSA (bovine serum albumin) (50 mM Tris-HCl [pH
7.5], 0.15 M NaCl) three times and BSA-free wash twice, then 1N NaOH 0.1.
The cells are lysed with 5 ml, and the radioactivity and the protein concentration of the lysate are measured. The number of bound ¹²⁵ I-LDL per protein amount is determined as LDL binding activity. As a result, Example 4 described later was used.
The compound obtained in 2 increased LDL binding about 2-fold at the addition of 2 μM as compared with the control without addition of the sample.

Experimental Example 3 Cholesterol lowering action High cholesterol diet (10% coconut oil, 0.
After hamsters were bred for 2 weeks on hamsters normally fed with 12% cholesterol (additional feed), the test compound was reduced to 0.1%
They were bred for one week on the added high cholesterol diet. After fasting for one day, aortic blood was collected under ether anesthesia. The amount of cholesterol in the serum separated from the collected blood was measured by the cholesterol oxidase method (Cholesterol E-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.). as a result,
The compound obtained in Example 42 described later suppressed a rise in serum cholesterol by about 40%.

Example 1 6.0 g of 3-aminoquinoline and 10 g of tetrahydrofuran 10
7. N, N'-carbonyldiimidazole in 0 ml solution.
0 g and 6.3 ml of triethylamine are sequentially added, and the mixture is refluxed for 14 hours. 3.6 g of cyclopentanol was added to the reaction solution.
Of tetrahydrofuran in 10 ml, and the mixture is refluxed under heating for 3 hours. After the completion of the reaction, the solvent was distilled off, and ethyl acetate was added to the residue. The organic layer was washed successively with a 5% aqueous solution of potassium hydrogen sulfate, water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride and dried. After distilling off the solvent, 9.11 g of a colorless solid was obtained. The solid was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 2: 1), and then re-used with isopropyl ether. By crystallization, 8.0 g of colorless prism-shaped (quinolin-3-yl) carbamic acid cyclopentyl ester is obtained. m. p: 114-116 ° C. Example 2-13 The corresponding starting material is treated in the same manner as in Example 1 to obtain the compound shown in Table 2.

[0121]

[Table 2]

[0122]

[Table 3]

Example 14 To a dichloromethane solution of 188 mg of the desired compound of Example 1 (quinolin-3-yl) carbamic acid cyclopentyl ester) was added 200 mg of metachloroperbenzoic acid under ice cooling, followed by stirring for 4 hours. A 5% aqueous solution of sodium thiosulfate is added to the reaction solution, and the mixture is extracted with ethyl acetate after completion of the reaction. The extract layer was washed successively with an aqueous sodium carbonate solution and a saturated saline solution, dried, and then evaporated to remove a light yellow powder.
After obtaining 23 mg, the powder was subjected to silica gel column chromatography (solvent; chloroform: ethyl acetate = 1: 1).
By purifying in 3), 188 mg of a light yellow powder of (1-oxy-quinolin-3-yl) carbamic acid cyclopentyl ester is obtained. m. p: 168-170 ° C (decomposition) Example 15 To a solution of 1.22 g of the target compound of Example 8 (quinolin-3-yl-carbamic acid cycloheptyl ester) in 15 ml of dimethylformamide was added tert-bromoacetic acid at room temperature.
1.0 g of t-butyl and 3.0 g of potassium carbonate are sequentially added, and the mixture is further stirred at room temperature for 3 hours. Ethyl acetate is added to the reaction solution, and the mixture is washed with a 10% aqueous citric acid solution, water, a saturated aqueous sodium carbonate solution, and a saturated saline solution. After drying the organic layer, the solvent was distilled off to obtain a pale yellow powder, and the powder was recrystallized from n-hexane to give N- (cycloheptyloxycarbonyl) -N- (quinoline-3). −
Ill) 1.31 g of colorless needles of glycine tert-butyl ester are obtained. m. p: 113-115 ° C. Example 16 Target compound of Example 15 (N- (cycloheptyloxycarbonyl) -N-quinolin-3-yl) glycine t
2.4 g of trifluoroacetic acid was added to 990 mg of tert-butyl ester) in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution is distilled off, chloroform is added to the residue, and the mixture is washed with a 10% aqueous citric acid solution, dried, and then the solvent is distilled off to obtain a colorless amorphous substance. Furthermore, silica gel column chromatography (solvent;
Chloroform: methanol = 19: 1,9: 1,5:
By purifying in 1), 830 mg of a colorless amorphous of N- (cycloheptyloxycarbonyl) -N- (quinolin-3-yl) glycine is obtained. m. p: 77-80 ° C Example 17 The target compound ((quinolin-3-yl) carbamic acid cycloheptyl ester) of Example 8 and the corresponding starting compound were treated in the same manner as in Example 15 to give N- (2- Pyridylmethyl) -N- (quinolin-3-yl) carbamic acid cycloheptyl ester is obtained. m. p: 92-94 ° C Examples 18-41 The corresponding starting compounds are treated in the same manner as in Example 1 to give the compounds described in Tables 3, 4 and 5.

[0124]

[Table 4]

[0125]

[Table 5]

[0126]

[Table 6]

Example 42 To a toluene solution of 2.5 g of dihydrocinnamic acid, 3.8 ml of diphenylphosphoric acid azide and 2.9 ml of triethylamine were sequentially added, followed by stirring at 80 ° C. for 2.5 hours. After allowing the reaction solution to cool, 3.1 ml of n-butanol and 2.9 ml of triethylamine were added, and the mixture was stirred at room temperature for 14 hours.
And stir for 4.5 hours. Ethyl acetate was added to the reaction solution,
Wash sequentially with 5% aqueous potassium hydrogen sulfate, water, saturated aqueous sodium carbonate, and saturated aqueous sodium chloride.
After drying the organic layer, the solvent is distilled off to obtain a pale orange oil. The oily substance is purified by silica gel chromatography (solvent: hexane: ethyl acetate = 5: 1) to obtain 3.6 g of a colorless oily substance of phenethylcarbamic acid n-butyl ester. Examples 43 to 79 By treating the corresponding starting compounds in the same manner as in Example 42, the compounds described in Tables 6, 7, 8 and 9 are obtained.

[0128]

[Table 7]

[0129]

[Table 8]

[0130]

[Table 9]

[0131]

[Table 10]

[0132]

[Table 11]

[0133]

[Table 12]

Example 80 A solution of 0.23 g of the desired compound of Example 51 ((quinolin-2-yl) carbamic acid 2- (pyridin-2-yl) ethyl ester) in 3 ml of dichloromethane was added under ice-cooling.
1.5 ml of a normal hydrochloric acid-dioxane solution is added, and the mixture is heated to room temperature and stirred for 1 hour. Diethyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with diethyl ether, and dried to give (quinolin-2-yl) carbamic acid 2- (pyridin-2-yl) ethyl ester. 22 g are obtained.

M. p: 154-156 ° C Example 81 Target compound of Example 66 ([2- (furan-2-yl)
[Vinyl] carbamic acid butyl ester) To a solution of 89 mg of tetrahydrone in 2 ml of 10% palladium-carbon 45 was added.
mg, and the mixture is stirred at room temperature for 1 hour under a hydrogen atmosphere. The insolubles in the reaction solution are removed from the furnace, and the furnace solution is distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (solvent; hexane: ethyl acetate = 4: 1) to give [2- (furan-
16 mg of a colorless oil of 2-yl) ethyl] carbamic acid butyl ester are obtained. Example 82 By treating 535 mg of m-carboxymethyldihydrocinnamic acid and the corresponding starting compound in the same manner as in Example 42,
2- [2- (isobutoxycarbonylamino) ethyl]
486 mg of methyl benzoate) are obtained. 2.5 ml of a 2N aqueous sodium hydroxide solution is added to 5 ml of a methanol solution of the product at room temperature, and the mixture is further stirred at room temperature overnight. After adding hydrochloric acid to the reaction solution, extraction with ethyl acetate is performed. After washing and drying the extract layer, the solvent is distilled off to obtain colorless crystals. The crystals are purified by silica gel column chromatography (solvent; ethyl acetate: chloroform = 3: 1) to obtain 113 mg of colorless crystals of 2- [2- (isobutoxycarbonylamino) ethyl] benzoic acid. m. p: 103-105 ° C Example 83 3-aminoquinoline 288m in a solution of 440mg of di-tert-butyl carbonate in 6ml of tetrahydrofuran
g and stirred at room temperature for 2 hours. 4- (N,
After adding 14 mg of N-dimethylamino) pyridine and stirring at room temperature for 6 hours, 270 mg of di-tert-butyl carbonate and 244 mg of 4- (N, N-dimethylaminopyridine) are further added, and the mixture is stirred at room temperature overnight. After completion, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent; n-hexane: ethyl acetate = 4: 1).
After obtaining 350 mg of a colorless solid by refining in the above, the solid was further recrystallized with a mixed solution of hexane-ethyl acetate to give (quinolin-3-yl) carbamic acid tert-butyl ester. Colorless needles 29
6 mg are obtained. m. p: 154-156 ° C Examples 84-91 The corresponding starting compounds are treated in the same manner as in Example 83, to give the compounds described in Table 10.

[0136]

[Table 13]

Example 92 The target compound of Example 85 (phenethylcarbamic acid t)
tert-butyl ester) and the corresponding starting compound in Example 1
By treating in the same manner as in 5, an oil of N-methyl-N-phenethylcarbamic acid tert-butyl ester is obtained. Example 93 A mixture of 5 ml of a dichloromethane solution of 273 mg of isobutoxycarbonyl chloride and 1.5 ml of a 2N aqueous sodium hydroxide solution was added under ice-cooling, and phenethylamine 2
Add 51 μl and stir for 2 hours while warming to room temperature.
After completion of the reaction, chloroform and water are added for extraction. After washing and drying the extract, the solvent is distilled off to obtain 341 mg of phenethylcarbamic acid isobutyl ester as a colorless oil.

Examples 94 to 97 By treating the corresponding starting compounds in the same manner as in Example 93, the compounds described in Table 11 are obtained.

[0139]

[Table 14]

Example 98 550 μl of n-butanol, 418 μ of triethylamine
To a solution of 1 in toluene (6 ml) was added 40 μl of benzenesulfonyl isocyanate under ice cooling, followed by stirring at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) to give N- (n-butoxycarbonyl) -benzenesulfonamide as a pale yellow color. 104 mg of an oil are obtained. Reference Example 1 (1) A solution of 22.4 g of ethyl diethylphosphonoacetate in 100 ml of tetrahydrofuran was vigorously stirred and cooled with ice, and sodium hydride (60% oil-suspepe) was used.
nsion) 3.87 g is slowly added and stirred for 1 hour.
70 ml of a tetrahydrofuran solution of 10.0 g of 4-pyridinealdehyde is slowly added to the reaction solution, and the mixture is stirred at room temperature for 3 hours. Further, ethyl acetate was added to the reaction solution,
The organic layer is sequentially washed with water and saturated saline, dried, and the solvent is distilled off. The residue was washed with n-hexane and air-dried to give 3- (pyridin-4-yl) acrylic acid.
15.2 g of a colorless solid of the ethyl ester are obtained.

M. p: 64-65 ° C (2) To a solution of 7.50 g of this product in 120 ml of ethanol,
At room temperature, 25 ml of a 2N aqueous sodium hydroxide solution is added, and the mixture is stirred for 3 hours. After completion of the reaction, the solvent is distilled off, and a saturated aqueous solution of citric acid is added to the residue to adjust the solution to neutrality, and the precipitated crystals are collected by furnace. The precipitated crystals are washed with a small amount of cold water and dried to obtain 5.91 g of colorless powder of (3-pyridin-4-yl) acrylic acid.

M. p: 263-268 ° C (decomposition)

[0143]

Industrial Applicability The urethane derivative of the present invention has a low density lipoprotein (LDL) receptor expression-enhancing action, and is useful for hyperlipidemia such as hypercholesterolemia due to disorders of lipid metabolism and atherosclerosis. It is useful as a prophylactic / therapeutic agent.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/40 A61K 31/40 31/415 31/415 31/425 31/425 31/44 31/44 31/445 31/445 31/47 ADN 31/47 ADN AED AED 31/505 31/505 C07D 207/27 C07D 207/27 Z 209/16 209/16 209/48 213/36 213/36 213/40 213/40 215/54 215 / 54 231/56 Z 231/56 235/30 235/30 241/20 241/20 277/82 277/82 295/08 Z 295/08 307/20 307/20 307/52 307/52 333/66 333 / 66 335/06 335/06 339/06 339/06 401/12 209 401/12 209 211 211 213 213 209/48 Z (72) Inventor Kenji Omori 33-1 Miyagayacho, Takatsuki-shi, Osaka (72) Inventor Tetsuo Onuki 3-83-3 Kahinata, Satte City, Saitama Prefecture (72) Inventor Yasushi Oguchi 2-385 Kitabukuro, Omiya City, Saitama Prefecture Tanabe Pharmaceutical Omiya Dormitory (72) Inventor Yasuyuki Asai San, Urawa City, Saitama Prefecture 2250 Grand Palace Yayoi 103, Room

Claims (17)

[Claims] The present invention has a low-density lipoprotein (LDL) receptor expression enhancing action, and has the following formula: A pharmaceutical composition comprising, as an active ingredient, a compound having a urethane skeleton represented by or a pharmacologically acceptable salt thereof. 2. A compound of the general formula [I]: (Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group,
(2) a substituted or unsubstituted alkyl group, (3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ² is A hydrogen atom or a substituted or unsubstituted alkyl group, R ³ represents (1) a substituted or unsubstituted alkyl group, (2) a substituted or unsubstituted aryl group, (3) a substituted or unsubstituted heterocyclic group, (4)
A bridged cyclic hydrocarbon group, (5) a substituted or unsubstituted alkenyl group or (6) a substituted or unsubstituted cycloalkyl group. A pharmaceutical composition comprising, as an active ingredient, the urethane derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof. 3. A compound of the general formula [Ia]: (Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group,
(2) a substituted or unsubstituted alkyl group, (3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ² is A hydrogen atom or a substituted or unsubstituted alkyl group, R ³¹ represents (1) a substituted or unsubstituted alkyl group, (2) a substituted or unsubstituted aryl group, (3) a substituted or unsubstituted heterocyclic group,
(4) a bridged cyclic hydrocarbon group, (5) a substituted or unsubstituted alkenyl group, or (6) a substituted or unsubstituted cycloalkyl group. Provided that R ¹ is substituted or unsubstituted 2
-When it is a quinolyl group, R ³¹ is (1) carbon number 4
The above-mentioned straight-chain alkyl group, a straight-chain alkyl group having 1 to 3 carbon atoms substituted by a heterocyclic group or a substituted or unsubstituted branched-chain alkyl group having 4 or more carbon atoms (provided that tert is
-Excluding a butyl group), (2) a substituted or unsubstituted aryl group, (3) a substituted or unsubstituted heterocyclic group, (4) a bridged cyclic hydrocarbon group, or (5) a substituted or unsubstituted cycloalkyl group. is there. A pharmaceutical composition comprising, as an active ingredient, the urethane derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof. 4. R ¹ is (1) a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, an optionally protected amino group, an aryl group, a cyano group,
A mono- or bicyclic 5- to 12-membered heterocyclic group which may be substituted with a group selected from an arylthio group, a substituted or unsubstituted aryloxy group, a lower aralkyloxy group, an oxo group and a hydroxyl group, (2) phenyl Group, pyridyl group, indolyl group, optionally protected carboxy group-substituted phenyl group, furyl group and lower alkyl group optionally substituted with a group selected from cyclo lower alkyl group, (3) lower alkoxy group, 4) phenyl group-substituted lower alkyl group, nitro group-substituted phenyl group, lower alkoxy group-substituted phenyl group, mono- or dihalogenophenyl group, phenyl group, pyridyl group, and lower alkenyl optionally substituted with a group selected from furyl groups Group, (5) bicyclic 9-11 which may be substituted with a group selected from a hydroxyl group and a carboxyl group An aryl group or (6) a benzenesulfonyl group or a tosyl group, R ² is a pyridyl group and protected optionally substituted by a group also selected from a carboxyl group which have a lower alkyl group or a hydrogen atom, R ³ is an alkyl optionally substituted with (1) a cyclo lower alkyl group, a phenyl group, an isoindolinyl group substituted with one or two oxo groups, a pyridyl group, a piperidino group, and an oxo group-substituted pyrrolidinyl group. A group, (2) a bicyclic 9-11 membered aryl group,
(3) a nitrogen-containing or oxygen-containing monocyclic 5- to 7-membered heterocyclic group which may be substituted by a lower alkyl group, (4) a bi- or tricyclic cross-linked cyclic saturated hydrocarbon group, (5) a lower The pharmaceutical composition according to claim 2, which is an alkenyl group or a (6) cycloalkyl group. 5. A monocyclic or bicyclic 5 in which R ¹ may be substituted by (1) a group selected from an oxo group and a hydroxyl group.
12-membered heterocyclic group, (2) phenyl group, pyridyl group,
An indolyl group, an optionally protected carboxyl group-substituted phenyl group, a lower alkyl group which may be substituted with a group selected from a furyl group and a cyclo lower alkyl group,
(3) lower alkoxy group, (4) phenyl group-substituted lower alkyl group, nitro group-substituted phenyl group, lower alkoxy group-substituted phenyl group, mono- or dihalogenophenyl group,
A lower alkenyl group which may be substituted with a group selected from a phenyl group, a pyridyl group and a furyl group; (5) a bicyclic 9-11-membered aryl group which may be substituted with a group selected from a hydroxyl group and a carboxyl group; Or (6) a benzenesulfonyl group or a tosyl group, wherein R ² is a lower alkyl group or a hydrogen atom which may be substituted with a group selected from a pyridyl group and an optionally protected carboxyl group, and R ³¹ is (1) an alkyl group optionally substituted by a group selected from a cyclo lower alkyl group, a phenyl group, an isoindolinyl group substituted with one or two oxo groups, a pyridyl group, a piperidino group, and an oxo group-substituted pyrrolidinyl group; (2) a bicyclic 9-11 membered aryl group, (3)
A nitrogen-containing or oxygen-containing monocyclic 5- to 7-membered heterocyclic group which may be substituted with a lower alkyl group, (4) a bi- or tricyclic bridged cyclic saturated hydrocarbon group, (5) a lower alkenyl group or (6) The pharmaceutical composition according to claim 3, which is a cycloalkyl group. 6. The monocyclic or bicyclic 5- to 12-membered heterocyclic group is a quinolyl group, a benzimidazolyl group, a benzothiazolyl group, a pyridyl group, a chromenyl group, a quinoxalinyl group or an indazolyl group, and the bicyclic 9 to 11-membered group. The aryl group is an indanyl group, a naphthyl group or a decahydronaphthyl group; the nitrogen-containing or oxygen-containing monocyclic 5- to 7-membered heterocyclic group is a piperidyl group or a tetrahydrofuryl group; The pharmaceutical composition according to claim 4, wherein the saturated hydrocarbon group is an adamantyl group. 7. The pharmaceutical composition according to claim 2, which is a low-density lipoprotein (LDL) receptor expression enhancer. 8. The method according to claim 1, which is a lipid-lowering agent.
The pharmaceutical composition according to 4, 5 or 6. 9. The pharmaceutical composition according to claim 1, which is an agent for preventing or treating hyperlipidemia. 10. The pharmaceutical composition according to claim 1, which is a prophylactic / therapeutic agent for atherosclerosis. 11. A compound of the general formula [Ia]: (Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group,
(2) a substituted or unsubstituted alkyl group, (3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ² is A hydrogen atom or a substituted or unsubstituted alkyl group, R ³¹ represents (1) a substituted or unsubstituted alkyl group, (2) a substituted or unsubstituted aryl group, (3) a substituted or unsubstituted heterocyclic group,
(4) a bridged cyclic hydrocarbon group, (5) a substituted or unsubstituted alkenyl group, or (6) a substituted or unsubstituted cycloalkyl group. Provided that R ¹ is substituted or unsubstituted 2
-When it is a quinolyl group, R ³¹ is (1) carbon number 4
The above-mentioned straight-chain alkyl group, a straight-chain alkyl group having 1 to 3 carbon atoms substituted by a heterocyclic group or a substituted or unsubstituted branched-chain alkyl group having 4 or more carbon atoms (provided that tert is
-Excluding a butyl group), (2) a substituted or unsubstituted aryl group, (3) a substituted or unsubstituted heterocyclic group, (4) a bridged cyclic hydrocarbon group, or (5) a substituted or unsubstituted cycloalkyl group. is there. Or a pharmacologically acceptable salt thereof. 12. R ¹ is (1) a monocyclic or bicyclic 5- to 12-membered heterocyclic group which may be substituted with a group selected from an oxo group and a hydroxyl group, (2) a phenyl group, a pyridyl group, An indolyl group, an optionally protected carboxy group-substituted phenyl group, a lower alkyl group optionally substituted by a group selected from a furyl group and a cyclo-lower alkyl group, (3) a lower alkoxy group, and (4) a phenyl group substitution (5) a lower alkenyl group which may be substituted with a group selected from a lower alkyl group, a nitro group-substituted phenyl group, a lower alkoxy group-substituted phenyl group, a mono- or dihalogenophenyl group, a phenyl group, a pyridyl group and a furyl group; A bicyclic 9-11-membered aryl group which may be substituted with a group selected from a hydroxyl group and a carboxyl group, or (6) a benzenesulfonyl group or A sill group, R ² is a pyridyl group and protected optionally substituted by a group also selected from a carboxyl group which have a lower alkyl group or a hydrogen atom, R ³¹ is (1) a lower cycloalkyl group,
A phenyl group, an alkyl group which may be substituted with a group selected from an isoindolinyl group substituted with one or two oxo groups, a pyridyl group, a piperidino group and an oxo-substituted pyrrolidinyl group, (2) bicyclic 9- 11-membered aryl group,
(3) a nitrogen-containing or oxygen-containing monocyclic 5- to 7-membered heterocyclic group which may be substituted by a lower alkyl group, (4) a bi- or tricyclic cross-linked cyclic saturated hydrocarbon group, (5) a lower 12. An alkenyl group or (6) a cycloalkyl group.
A compound as described. 13. A monocyclic or bicyclic 5-12 membered heterocyclic group or a bicyclic 9-12 membered aryl group having the formula: The compound according to claim 12, which is a group represented by the formula: 14. The monocyclic or bicyclic 5- to 12-membered heterocyclic group is a quinolyl group, benzimidazolyl group, benzothiazolyl group, pyridyl group, chromenyl group, quinoxalinyl group or indazolyl group, and a bicyclic 9 to 11-membered group. The aryl group is an indanyl group, a naphthyl group or a decahydronaphthyl group; the nitrogen-containing or oxygen-containing monocyclic 5- to 7-membered heterocyclic group is a piperidyl group or a tetrahydrofuryl group; 13. The compound according to claim 12, wherein the saturated hydrocarbon group is an adamantyl group. 15. A compound of the general formula [II]: (Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group,
(2) a substituted or unsubstituted alkyl group, (3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ² is Represents a hydrogen atom or a substituted or unsubstituted alkyl group. Or a salt thereof and a general formula [III]: (Wherein R ³¹ is (1) a substituted or unsubstituted alkyl group, (2) a substituted or unsubstituted aryl group, (3) a substituted or unsubstituted heterocyclic group, (4) a bridged cyclic hydrocarbon group, 5) represents a substituted or unsubstituted alkenyl group or (6) a substituted or unsubstituted cycloalkyl group.
Reacting with a reactive derivative at the carboxyl group of the compound represented by the general formula [Ia], wherein the product is converted into a pharmacologically acceptable salt, if desired. (Wherein the symbols have the same meanings as described above. However, when R ¹ is a substituted or unsubstituted 2-quinolyl group,
R ³¹ is (1) a linear alkyl group having 4 or more carbon atoms, a linear alkyl group having 1 to 3 carbon atoms substituted with a heterocyclic group, or a substituted or unsubstituted branched chain having 4 or more carbon atoms. Alkyl group (excluding tert-butyl group), (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted heterocyclic group, (4) bridged cyclic hydrocarbon group, or (5)
It is a substituted or unsubstituted cycloalkyl group. ) Or a pharmacologically acceptable salt thereof. 16. A compound of the general formula [IV]: (Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group,
(2) a substituted or unsubstituted alkyl group, (3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group, or (6) an arylsulfonyl group. ) Or a salt thereof and a general formula [iii]: (Wherein R ³¹ is (1) a substituted or unsubstituted alkyl group, (2) a substituted or unsubstituted aryl group, (3) a substituted or unsubstituted heterocyclic group, (4) a bridged cyclic hydrocarbon group, 5) represents a substituted or unsubstituted alkenyl group or (6) a substituted or unsubstituted cycloalkyl group.
Or a salt thereof, if desired, to give a pharmacologically acceptable salt of the product, if desired, of the general formula [Ia-1]: (Wherein the symbols have the same meanings as described above. However, when R ¹ is a substituted or unsubstituted 2-quinolyl group,
R ³¹ is (1) a linear alkyl group having 4 or more carbon atoms, a linear alkyl group having 1 to 3 carbon atoms substituted with a heterocyclic group, or a substituted or unsubstituted branched chain having 4 or more carbon atoms. Alkyl group (excluding tert-butyl group), (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted heterocyclic group, (4) bridged cyclic hydrocarbon group, or (5)
It is a substituted or unsubstituted cycloalkyl group. ) Or a pharmacologically acceptable salt thereof. 17. A compound of the general formula [V]: (Wherein R ¹ is (1) a substituted or unsubstituted heterocyclic group,
(2) a substituted or unsubstituted alkyl group, (3) a substituted or unsubstituted alkoxy group, (4) a substituted or unsubstituted alkenyl group, (5) a substituted or unsubstituted aryl group or (6) an arylsulfonyl group, R ² is X represents a hydrogen atom or a substituted or unsubstituted alkyl group; )
And a salt thereof and a general formula [iii]: (Wherein R ³¹ is (1) a substituted or unsubstituted alkyl group, (2) a substituted or unsubstituted aryl group, (3) a substituted or unsubstituted heterocyclic group, (4) a bridged cyclic hydrocarbon group, 5) represents a substituted or unsubstituted alkenyl group or (6) a substituted or unsubstituted cycloalkyl group.
Wherein the compound is reacted with a compound of the formula (Ia) or a salt thereof, if desired, to give a pharmacologically acceptable salt of the product. (Wherein the symbols have the same meanings as described above. However, when R ¹ is a substituted or unsubstituted 2-quinolyl group,
R ³¹ is (1) a linear alkyl group having 4 or more carbon atoms, a linear alkyl group having 1 to 3 carbon atoms substituted with a heterocyclic group, or a substituted or unsubstituted branched chain having 4 or more carbon atoms. Alkyl group (excluding tert-butyl group), (2) substituted or unsubstituted aryl group, (3) substituted or unsubstituted heterocyclic group, (4) bridged cyclic hydrocarbon group, or (5) substituted or unsubstituted It is a cycloalkyl group. ) Or a pharmacologically acceptable salt thereof.