JP2001187789A - Dioxolane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a dioxolane derivative and its salt exhibiting strong squalene synthetase inhibiting action and useful as a drug for the prevention and/or treatment of hypercholesterolemia, hyperlipemia and arteriosclerosis. SOLUTION: This dioxolane derivative and its salt are expressed by formula (1) [A1 and A2 are each a bivalent hydrocarbon group; A3 is single bond or a bivalent hydrocarbon group; a1 and a2 are each O or N(A4); Q1 and Q2 are each a cyclic hydrocarbon group or a heteroaromatic group; Q3 is H, OH, an alkyl, an alkoxyl, cyano, a heterocyclic group, carbamoyl, an acylcarbamoyl or a carboxyl; and R1 and R2 are each an alkyl or form a carbonyl group or an aliphatic ring together with C atom bonding to R1 and R2].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a dioxolane derivative and a salt thereof, and more particularly to a prophylactic and / or therapeutic agent for hypercholesterolemia, hyperlipidemia, arteriosclerosis and the like based on squalene synthase inhibitory action. The present invention relates to a dioxolane derivative useful as a medicament and a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Hypercholesterolemia is one of the greatest risk factors for arteriosclerosis, and as a treatment for this, administration of drugs that lower blood cholesterol is effective. is there. Current,
Lovastatin (U.S. Pat. No. 4,231,938), Pravastatin (U.S. Pat.
No. 46227), simvastatin (U.S. Pat.
No. 784), etc., and a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor is mainly used. HMG-CoA reductase is one of the rate-limiting enzymes involved in cholesterol biosynthesis, and is an enzyme located relatively upstream in the cholesterol biosynthesis pathway. The major product produced downstream is farnesyl pyrophosphate, but cholesterol is biosynthesized in several steps from the farnesyl pyrophosphate. here,
Also known to be biosynthesized with farnesyl pyrophosphate as the major intermediate produced are non-sterol products such as ubiquinone, dolichol, heme A and the like. Ubiquinone plays a very important role in vivo as a component of the mitochondrial respiratory chain, and dolichol plays a very important role in vivo as a long-chain alcohol involved in glycoprotein synthesis. Therefore, administration of the HMG-CoA reductase inhibitor has a high possibility of inhibiting not only cholesterol but also the biosynthesis of other essential biological components, and there is a concern about side effects due to this. From this, HMG
-CoA reductase inhibitors are not always the best cholesterol lowering agents.

In order to suppress the biosynthesis of cholesterol without impairing the biosynthesis of essential components such as ubiquinone and dolichol, it is desirable to target an enzyme downstream of farnesyl pyrophosphate in the cholesterol biosynthesis pathway. In particular, it is desirable to inhibit squalene synthase, which is the first enzyme involved in sterol biosynthesis. Compounds that inhibit squalene synthase include Zaragodic acid (Tetrahedron, 48, 47, 10221-).
10226, 1992) and squalestatin (The Journ
al of Antibiotics, 45, 5, 639-647, 19
92), and 4,1-benzoxazepine derivatives (European Patent 5670) as synthetic compounds
No. 26), substituted amic acid derivatives (EP 6117)
No. 49), α-phosphonosulfonic acid derivative (Journa
l of Medicinal Chemistry, 39, 661-664, 1
996) and the like are known. However,
In any compound group, it is hard to say that sufficient oral cholesterol synthesis inhibitory action or blood cholesterol lowering action has been shown, and it has been provided as a pharmaceutical such that the selectivity of action has not been clarified. Questions remain.

[0004]

Means for Solving the Problems The present inventors have proposed a method for preventing hypercholesterolemia, hyperlipidemia and arteriosclerosis having a cholesterol synthesis inhibitory action or a blood cholesterol lowering action by inhibiting squalene synthase. As a result of intensive studies for the purpose of providing a therapeutic agent, the present inventors have found that a compound represented by the following formula (1) or a salt thereof achieves the object and completed the present invention.

That is, the present invention provides the following equation (1)

Embedded image

Wherein A ¹ and A ² are the same or different and each represent a divalent hydrocarbon group having 4 to 7 carbon atoms which may have a substituent; A ³ has a single bond or a substituent also represents a divalent hydrocarbon group having 1 to 4 carbon atoms; a ¹ and a ² are the same or different single bond, -O- or -
N (A ⁴ )-(where A ⁴ represents a hydrogen atom, a hydroxyl group or a hydrocarbon group which may have a substituent);
¹ and Q ² are the same or different and each represents a cyclic hydrocarbon group which may have a substituent or a heteroaromatic group which may have a substituent; Q ³ represents a hydrogen atom, a hydroxyl group,
To 7 alkyl groups, C1 to C7 alkoxyl groups, cyano groups, heterocyclic groups which may have a substituent, heterocyclic groups having a hydrogen atom which can be deprotonated, and carbamoyl groups which may have a substituent Represents an acylcarbamoyl group which may have a substituent or a carboxyl group which may be esterified; R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, or R ¹ and R ² and the carbon atom to which they are attached may form a carbonyl group or may form a 3- to 7-membered aliphatic ring. ] The dioxolane derivative represented by these, or its salt is provided.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, substituents in a dioxolane derivative represented by the formula (1) of the present invention will be described.

The divalent hydrocarbon group having 4 to 7 carbon atoms which may have a substituent and is represented by A ¹ or A ² includes a linear or branched alkylene group which may have a substituent. , A straight-chain or branched alkenylene group, a straight-chain or branched alkynylene group, and the like.

Examples of the linear or branched alkylene group include a tetramethylene group, a butylene group, a pentamethylene group, a hexamethylene group, and a heptamethylene group. Examples of the linear or branched alkenylene group include a 1-butenylene group, a 2-butenylene group, a 1-pentenylene group, a 2-pentenylene group, a 1-hexenylene group, a 2-hexenylene group, and a 3-hexenylene group. be able to. Examples of the linear or branched alkynylene group include a 1-butynylene group, a 2-butynylene group, and a 1-butynylene group.
Examples thereof include a pentynylene group, a 2-pentynylene group, a 1-hexynylene group, a 2-hexynylene group, and a 3-hexynylene group. Of these, pentamethylene group, 2-
A pentenylene group and a 2-pentynylene group are preferred, and a pentamethylene group is particularly preferred.

Examples of the divalent hydrocarbon group having 1 to 4 carbon atoms which may have a substituent represented by A ³ include a linear or branched alkylene group and a linear or branched alkenylene. Groups, linear or branched alkynylene groups and the like. As a linear or branched alkylene group, a methylene group, an ethylene group, a trimethylene group,
Examples include a propylene group, a tetramethylene group, and a butylene group. Examples of the linear or branched alkenylene group include a propenylene group, a 1-butenylene group, and a 2-butenylene group. Examples of the linear or branched alkynylene group include a propynylene group, a 1-butynylene group, and a 2-butynylene group.
Among them, a methylene group, an ethylene group and a trimethylene group are preferred.

The alkylene group having 1 to 4 carbon atoms which may have a substituent represented by A ⁴ means a linear or branched alkylene group, specifically, a methylene group,
Examples include an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, and a butylene group.

The above substituents A ¹ , A ² , A ³ and A ⁴ are
It may further have a substituent, and as a substituent to be substituted for these, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an amino group, an alkylamino group, a carbamoyl group, an alkanoyl group, or an alkyl group which may have a substituent. Examples thereof include 1 to 5 arbitrarily selected from a group, an alkoxyl group, a carboxyl group which may be esterified, an aryl group, an aryloxy group and an aroyl group. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the alkylamino group include a mono- or di-alkylamino group, and specifically, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, an n-butylamino group, a dimethylamino group, Mono- or di-C _1-7 alkylamino groups such as diethylamino group and ethylmethylamino group can be exemplified.
The carbamoyl group which may have a substituent includes a carbamoyl group, an N-methylcarbamoyl group,
An ethylcarbamoyl group, an N-propylcarbamoyl group,
C such as N, N-dimethylcarbamoyl, N-hydroxycarbamoyl, N-hydroxy-N-methylcarbamoyl, N-hydroxy-N-ethylcarbamoyl, etc.
_A carbamoyl group which may be substituted by a _1-7 alkyl group and / or a hydroxyl group can be given. Examples of the alkanoyl group include C _1-7 alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, and hexanoyl group. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group,
Examples thereof include C _1-7 alkyl groups such as isopropyl group and tert-butyl group. As the alkoxyl group,
Examples thereof include C _1-7 alkoxyl groups such as methoxyl, ethoxyl, propoxyl, isopropoxyl, and tert-butoxyl. Examples of the carboxyl group that may be esterified include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group,
and C _1-7 alkoxycarbonyl groups such as tert-butoxycarbonyl group. Examples of the aryl group include a phenyl group and a naphthyl group.Examples of the aryloxy group include a phenoxy group and a naphthoxy group.Examples of the aroyl group include a benzoyl group, a toluoyl group, and a naphthoyl group. Can be mentioned.

Examples of the cyclic hydrocarbon group which may have a substituent represented by Q ¹ and Q ² include a saturated or unsaturated monocyclic or condensed polycyclic hydrocarbon group having 6 to 18 carbon atoms. For example, phenyl group, naphthyl group, anthryl group, phenanthryl group, indanyl group,
And an indenyl group. If there is structural isomerism in these groups, they are all included in the present invention. In the present invention, a phenyl group, a 2-naphthyl group and the like are particularly preferable.

The substituents of these cyclic hydrocarbon groups include a hydroxyl group, a nitro group, a cyano group, a halogen atom, an amino group, an alkylamino group, a carbamoyl group, an alkanoyl group, an alkyl group and an alkoxyl group which may have a substituent. Group, carboxyl group which may be esterified,
There may be mentioned 1 to 5 arbitrarily selected from an aryl group, an aryloxy group and an aroyl group. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the alkylamino group include a mono- or dialkylamino group, and specifically, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, an n-
Mono- or di-C _1-7 such as butylamino group, dimethylamino group, diethylamino group, ethylmethylamino group, etc.
Examples thereof include an alkylamino group. Examples of the carbamoyl group which may have a substituent include an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-propylcarbamoyl group, an N, N-dimethylcarbamoyl group,
N-hydroxycarbamoyl group, N-hydroxy-N-
Examples thereof include a carbamoyl group which may be substituted by a C _1-7 alkyl group such as a methylcarbamoyl group, an N-hydroxy-N-ethylcarbamoyl group and / or a hydroxyl group. Examples of the alkanoyl group include C _1-7 alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, and hexanoyl group. Examples of the alkyl group include a C _1-7 alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a tert-butyl group. Examples of the alkoxyl group include a C _1-7 alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group, an isopropoxyl group, and a tert-butoxyl group. Examples of the carboxyl group that may be esterified include, in addition to the carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group,
Examples thereof include C _1-7 alkoxycarbonyl groups such as a sec-butoxycarbonyl group and a tert-butoxycarbonyl group. Examples of the aryl group include a phenyl group and a naphthyl group.Examples of the aryloxy group include a phenoxy group and a naphthoxy group.Examples of the aroyl group include a benzoyl group, a toluoyl group, and a naphthoyl group. Can be mentioned.

The heteroaromatic groups which may have the substituents represented by Q ¹ and Q ² include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and imidazolyl. , A pyrazolyl group, a 1,2,3-oxadiazolyl group,
1,2,4-oxadiazolyl group, furzanyl group, 1,
2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, benzofuranyl Group, isobenzofuranyl group, benzo [b] thienyl group,
Indolyl group, isoindolyl group, 1H-indazolyl group, benzimidazolyl group, benzoxazolyl group,
1,2-benzisoxazolyl group, benzothiazolyl group, 1,2-isobenzothiazolyl group, 1H-benzotriazolyl group, imidazopyridyl group, quinolyl group, isoquinolyl group, cinnolyl group, quinazolinyl group, quinoxalinyl Group, phthalazinyl group, naphthyridinyl group, purinyl group, pteridinyl group, carbazolyl group, α-carbolinyl group, β-carbolinyl group, γ-carbolinyl group, etc., among which oxazolyl group, imidazolyl group, thiazolyl group, pyridyl group Are preferred.

The alkyl group having 1 to 7 carbon atoms represented by Q ³ means a linear or branched alkyl group.
Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a tert-butyl group.

The alkoxyl group having 1 to 7 carbon atoms represented by Q ³ means a linear or branched alkoxyl group, such as methoxyl, ethoxyl, propoxyl, isopropoxyl, tert- Butoxyl group and the like.

The heterocyclic group which may have a substituent represented by Q ³ means a heteroaromatic group and other heterocyclic groups. The heteroaromatic group means the same as those represented by Q ¹ and Q ² above. Other heterocyclic groups include a pyrrolidyl group, a piperidinyl group, a morpholinyl group,
Examples thereof include a piperazinyl group, and among them, a pyrrolidyl group and a morpholinyl group are preferable.

The substituents on the heterocyclic or heteroaromatic groups represented by Q ¹ , Q ² and Q ³ include cyano, halogen, amino, alkylamino, alkyl, alkoxyl and esterified. Arbitrary 1 to 5 groups selected from carboxyl groups which may be mentioned can be mentioned. Here, examples of the halogen atom, amino group, alkylamino group, alkyl group, alkoxy group and carboxyl group which may be esterified include the same as those described above.

The carbamoyl group which may have a substituent represented by Q ³ includes an N-methylcarbamoyl group,
C _1- such as N-ethylcarbamoyl, N-propylcarbamoyl, N, N-dimethylcarbamoyl, N-hydroxycarbamoyl, N-hydroxy-N-methylcarbamoyl, N-hydroxy-N-ethylcarbamoyl, etc. ₇ Carbamoyl groups which may be substituted by an alkyl group and / or a hydroxyl group can be mentioned.

The heterocyclic group having a deprotonatable hydrogen atom represented by Q ³ includes a tetrazolyl group, 4,5
-Dihydro-5-oxo-1,2,4-oxadiazolyl group, 4,5-dihydro-5-thioxo-1,2,4-
Oxadiazolyl group, 2,3-dihydro-3-oxo-
1,2,4-oxadiazolyl group, 2,3-dihydro-
3-thioxo-1,2,4-oxadiazolyl group, 3,
5-dioxo-1,2,4-oxadiazolidinyl group,
4,5-dihydro-5-oxo-isoxazolyl group,
4,5-dihydro-5-thioxo-isoxazolyl group, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl group, 2,3-dihydro-3-oxo-1,
2,4-triazolyl group, 2,3-dihydro-3-thioxo-1,2,4-triazolyl group, 2,5-dihydro-5-oxo-1,2,4-thiadiazolyl group and the like can be mentioned. Among them, a tetrazolyl group, a 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl group,
A 2,5-dihydro-5-oxo-1,2,4-thiadiazolyl group is preferred.

The acylcarbamoyl group which may have a substituent represented by Q ³ is, for example, represented by the following formula:

[0023]

Embedded image

And the like. Where R ³
Examples thereof include those meaning a hydrogen atom or a linear or branched alkyl group. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group and a tert- group.
A butyl group and the like can be mentioned. Among them, R ³ is preferably a hydrogen atom. Examples of R ⁴ include those meaning a linear or branched alkyl group or aryl group. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group and a tert-butyl group, and the aryl group includes a phenyl group,
Examples include a 4-methylphenyl group and a naphthyl group. Among them, R ⁴ is preferably an alkyl group, more preferably a methyl group.

Examples of the carboxyl group which may be esterified and represented by Q ³ include, in addition to the carboxyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkanoyloxyalkoxycarbonyl group, an alkoxycarbonyloxyalkoxycarbonyl group, a carbamoyloxy group. Examples thereof include an alkoxycarbonyl group.

Here, the alkoxycarbonyl group includes, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl And C _1-7 alkoxycarbonyl groups. Examples of the alkenyloxycarbonyl group include a C _2-7 alkenyloxycarbonyl group such as an allyloxycarbonyl group and a 2-butenyloxycarbonyl group. Examples of the alkanoyloxyalkoxycarbonyl group include, for example, C _2-7 alkanoyloxy C such as acetoxymethoxycarbonyl group, 1-acetoxyethoxycarbonyl group, pivaloyloxymethoxycarbonyl group, and 1-pivaloyloxyethoxycarbonyl group.
_1-7 alkoxycarbonyl groups can be mentioned. The alkoxycarbonyloxy alkoxycarbonyl group, for example, include 1- (ethoxycarbonyloxy) ethoxycarbonyl group, 1-C _1-7 alkoxycarbonyloxy C _1-7 alkoxycarbonyl group such as (cyclohexyl) ethoxy group be able to. Examples of the carbamoyloxyalkoxycarbonyl group include a carbamoyloxy C _1-7 alkoxycarbonyl group such as a carbamoyloxymethoxycarbonyl group. Other than these, (4-methyl-2-oxo-1,3-dioxole-
5-yl) methoxycarbonyl group.

The alkyl groups having 1 to 7 carbon atoms represented by R ¹ and R ² are the same as those represented by Q ³ described above.

In R ¹ and R ² , the 3- to 7-membered aliphatic ring formed with R ¹ , R ² and the carbon atom to which they are bonded may be a 3- to 7-membered saturated ring or a saturated ring. It may be a saturated ring or any of them.

The salt of the succinamic acid derivative represented by the formula (1) of the present invention is not particularly limited as long as it is pharmacologically acceptable. For example, metal salts such as sodium salt, potassium salt, calcium salt and magnesium salt, for example, ammonium salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tert-butylamine Organic amine salts such as salts can be mentioned.

The dioxolane derivative represented by the formula (1) of the present invention has a structure in which stereoisomers such as optical isomers, diastereoisomers, and geometric isomers exist based on the asymmetric carbon in the structure. However, in the present invention, all of these stereoisomers and a mixture thereof are also included. The dioxolane derivative represented by the formula (1) or a salt thereof may be present as a hydrate or various solvates, but the present invention also includes these.

Among the dioxolane derivatives represented by the formula (1) of the present invention, preferred specific examples include the following compounds, salts thereof, stereoisomers thereof, hydrates and solvates thereof. Can be.

N- [3- [N-[(R) -2- [5-
(3,4-dimethylphenyl) pentyloxy] -2-
[(R) -4-oxo-1,3-dioxolan-5-yl] acetyl] -N- [5- (2-naphthyl) pentyl] amino] propionyl] methanesulfonamide N- [2- [N- [ (R) -2- [5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -4-
Oxo-1,3-dioxolan-5-yl] acetyl]
-N- [5- (2-naphthyl) pentyl] amino] acetyl] methanesulfonamide 5- [2- [N-[(R) -2- [5- (3,4-dimethylphenyl) pentyloxy]- 2-[(R) -4-
Oxo-1,3-dioxolan-5-yl] acetyl]
-N- [5- (2-naphthyl) pentyl] amino] ethyl] -1H-tetrazole 5-[[N-[(R) -2- [5- (3,4-dimethylphenyl) pentyloxy] -2] -[(R) -4-oxo-1,3-dioxolan-5-yl] acetyl] -N
-[5- (2-Naphthyl) pentyl] amino] methyl]
-1H-tetrazole (R) -N- [5- (2-naphthyl) pentyl] -2
-[5- (3,4-Dimethylphenyl) pentyloxy] -2-[(R) -4-oxo-1,3-dioxolan-5-yl] acetohydroxamic acid (R) -N-methyl-N- [5- (2-Naphthyl) pentyl] -2- [5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -4-oxo-1,3-
Dioxolan-5-yl] acetamide (R) -N- [5- (2-naphthyl) pentyl] -2
-[5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -2,2-dimethyl-4-oxo-
1,3-dioxolan-5-yl] acetamide (R) -N-methyl-N- [5- (2-naphthyl) pentyl] -2- [5- (3,4-dimethylphenyl) pentyloxy] -2 -[(R) -2,4-dioxo-
1,3-dioxolan-5-yl] acetamide N-[(R) -2- [5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -4-oxo-
1,3-dioxolan-5-yl] acetyl] -N-
[5- (2-naphthyl) pentyl] glycine

Although there are still many unclear points about the mechanism of arteriosclerosis, it is pointed out that the importance of low-density lipoprotein (LDL) being oxidized and denatured to oxidized LDL is pointed out. I have. In other words, oxidized LDL which has been oxidized in the vascular endothelium is taken up by macrophage, and this uptake increases and macrophages themselves accumulate a large amount of cholesterol ester therein and eventually foam. This causes the vascular endothelium to break down. This is the initial stage of arteriosclerosis. Therefore, measures to suppress the development of arteriosclerosis include suppressing the biosynthesis of cholesterol, thereby suppressing the amount of LDL produced, and actively oxidizing LDL with antioxidants such as radical scavengers. It is considered to be desirable to inhibit (denaturation) or to suppress the generation of active oxygen or the like that causes oxidation by, for example, chelation of iron ions. From the above viewpoint, reducing cholesterol without impairing the biosynthesis of ubiquinone and dolichol, which are antioxidants in vivo, like squalene synthetase inhibitors, is important from the viewpoint of efficacy and safety In addition, a compound having an antioxidant effect on squalene synthase inhibitory activity, that is, a compound having an LDL oxidation (denaturation) inhibitory effect, can be expected to have higher efficacy. The compounds of the present invention also include compounds having an antioxidant action as described above.

The method for producing the dioxolane derivative of the present invention represented by the formula (1) or a salt thereof will be described below.

The dioxolane derivative of the present invention represented by the formula (1) or a salt thereof (hereinafter sometimes referred to as a compound and (1), and the same applies to other derivatives) is described, for example, in WO 98/29380. It can be manufactured according to the method described in Japanese Unexamined Patent Publication, or a method analogous thereto.

For example, compound (1) can be produced according to the following reaction formula (A). [Reaction formula (A)]

[0037]

Embedded image

[In the formula, R ⁵ represents a carboxylic acid ester group, and R ⁶ represents a hydroxyl-protecting group. R ¹ , R ² ,
A ¹ , A ² , A ³ , Q ¹ , Q ² , Q ³ , a ¹ and a ² are the same as described above. ]

Compound (2) can be obtained from International Publication WO98 / 29
It can be produced according to the method described in JP-A-380.

The method for producing the compound (4) from the compound (2) and the compound (3) is carried out in an inert solvent.
The reaction is carried out by reacting 1 mol or an excess, preferably 1 to 2 mol, of the compound (3) with 1 mol, together with a condensing agent. If necessary, the reaction may be carried out in the presence of a base such as triethylamine, 4-dimethylaminopyridine or diisopropylethylamine.
Reaction with N-hydroxy compounds such as hydroxybenzotriazole, N-hydroxysuccinimide and N-hydroxyphthalimide or phenol compounds such as 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol and pentachlorophenol It can be added as an accelerator. Examples of the inert solvent include solvents such as methylene chloride, chloroform, dichloroethane, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, N, N-dimethylformamide, acetonitrile, acetone, and ethyl acetate, and mixtures thereof. Can be Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, benzotriazolyloxy-tris [pyrrolidino] -phosphonium hexafluorophosphate, and the like. In general, the condensing agent is used in an amount of 1 mol or an excess, preferably 1 to 3 mol, per 1 mol of the compound (2). The reaction temperature is usually −100 ° C.
Or up to the boiling point of the solvent used in the reaction, preferably -20.
C. to 30 ° C., and the reaction time is usually from 10 minutes to 4
8 hours, preferably 30 minutes to 24 hours.

R of compound (4)^FiveAnd R⁶Excluding each
The method of converting to the compound (5) by leaving^Five
And the protecting group R⁶The removal method differs depending on the type of
Has a method described in the literature [Protective Groups
N Organic Synthesis (Protective
 Groups in Organic Synthe
sis), 2nd edition, T.M. W. Green (TW Gre)
en), p. G. FIG. M. Utz (PGM Wuts)
Author, John Wiley & Sons (1991)
Year)] or an equivalent method.
it can. For example, R ^FiveIs a tert-butyl group,
It can be easily removed by trifluoroacetic acid.
In an inert solvent such as methylene chloride, 1 mole of compound (4)
Molar excess of trifluoroacetic acid, e.g.
When the ratio of trifluoroacetic acid is from 100: 1 to 0: 100,
It is preferably carried out in a 10: 1 to 1: 1 mixed solution.
You. The reaction temperature is usually from -78 ° C to the solvent used for the reaction.
Up to the boiling point, preferably from -20C to 50C,
The time is usually 10 minutes to 5 days, preferably 1 hour to 2 days
4 hours.

When R ⁶ is a tert-butyldimethylsilyl group, it can be easily removed with tetrabutylammonium fluoride. Tetrahydrofuran,
In an inert solvent such as benzene or diethyl ether, tetrabutylammonium fluoride is usually used in an amount of 1 mol to excess mol, preferably 1 to 1 mol, relative to 1 mol of compound (4).
The reaction is carried out in an amount of 3 mol, if necessary, in the presence of 1 mol to an excess of acetic acid, preferably 1 to 3 mol. The reaction temperature is usually from -78 ° C to the boiling point of the solvent used in the reaction,
The reaction temperature is preferably from -20 ° C to 30 ° C, and the reaction time is generally from 10 minutes to 5 days, preferably from 0.5 hours to 24 hours. Further, in Q ³ in the reaction formula (A), the functional group may be protected by a protecting group in some cases, and the method for removing the protecting group can be performed according to the method described in the above-mentioned literature. .

A specific method for producing the compound (1) from the compound (5) will be described below.

When R ¹ and R ² are both hydrogen atoms in the compound (1), the compound (5) can be produced by reacting pivaloyloxymethyl iodide with the compound (5) in the presence of a base. In an inert solvent such as acetonitrile or N, N-dimethylformamide, pivaloyloxymethyl iodide is used in an amount of 1 to 5 mol, preferably 1.1 to 2 mol, based on 1 mol of compound (5), and triethylamine as a base. , Potassium carbonate, 1,8-diazabicyclo [5.
4.0] -7-undecene, sodium hydride and the like can be used in an amount of 1 to excess mol, preferably 1 to 2 mol, based on pivaloyloxymethyl iodide.
The reaction temperature is usually from -78 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 80 ° C, and the reaction time is generally from 10 minutes to 5 days, preferably from 1 hour to 24 hours.

In the case where both R ¹ and R ² in the compound (1) are alkyl groups, for example, a methyl group, 2,2-dimethoxypropane is added to the compound (5) if necessary in the presence of a catalytic amount of an acid. , Can be manufactured by acting. Benzene, toluene, tetrahydrofuran,
In a solvent such as diethyl ether or dioxane, 1 to 2 moles, preferably 2 to 5 moles of 2,2-dimethoxypropane is used per mole of compound (5), and benzenesulfonic acid and p- Toluenesulfonic acid, D-10-camphorsulfonic acid, sulfuric acid and the like can be used in an amount of 0.01 to 0.5 mol based on 1 mol of compound (5). The reaction temperature is usually from 0 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 12 ° C.
0 ° C., and the reaction time is usually about 1 to 24 hours, preferably about 2 hours.

In the compound (1), when R ¹ and R ² are the same oxygen atom and form a carbonyl group,
The compound (5) can be produced by allowing a carbonylating agent such as diphosgene, carbonyldiimidazole, diethyl carbonate, diphenyl carbonate or the like to act in the presence of a base. In a solvent such as benzene, toluene, tetrahydrofuran, diethyl ether, dioxane, methylene chloride, and acetonitrile, the carbonylating agent is used in an amount of 1 to an excess mole, preferably 1 to 10 moles, preferably 1 to 10 moles, based on 1 mole of the compound (5). The reaction can be performed using pyridine, triethylamine, 4-dimethylaminopyridine, or the like. The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from 0 ° C. to 120 ° C., and the reaction time is generally from 1 to 48 hours, preferably from about 2 to 24 hours.

The above compound (4) can also be produced according to the following reaction formula (B). [Reaction formula (B)]

[0048]

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[In the formula, Q ^3a represents a carboxyl group or a cyano group which may be esterified, and R ⁷ represents a carboxylic acid ester group. R ⁵ , R ⁶ , A ¹ , A ² , A ³ ,
Q ¹ , Q ² , Q ³ , a ¹ and a ² are the same as described above. ]

The method for producing compound (4a) from compound (2) and compound (3a) is the same as the method for producing compound (4) from compound (2) and compound (3).

The method for producing the compound (4) by converting Q ^3a of the compound (4a) to Q ³ is specifically described below.

When Q ³ in the compound (4) is a heterocyclic group having a hydrogen atom capable of being deprotonated, for example, a tetrazolyl group, the carboxylic acid compound (4a-2) or the compound (4a-3) having a cyano group may be used. It can be manufactured using.

As a method using the carboxylic acid compound (4a-2), for example, a method of converting a carboxyl group to an amide group and then leading to a tetrazolyl group can be mentioned. To convert a carboxyl group to an amide group, for example, 3-aminopropionitrile and a carboxylic acid compound (4a
-2). For the condensation reaction, a method similar to the method for producing the compound (4) from the compound (2) and the compound (3) can be used. As a method for converting this amide group into a tetrazolyl group, for example, a method described in a literature (JV Duncia)
Et al., Journal of O, Nick Chemistry,
56, 2395-2400, 1991; W. Thomas, Synthesis. 767 pages, 199
3 years). That is, there can be mentioned, for example, a method in which trimethylsilyl azide or sodium azide is allowed to act on an amide group to form a 1- (2-cyanoethyl) -1H-tetrazolyl group, followed by treatment with a base to lead to a tetrazolyl group. In a method using trimethylsilyl azide, in an inert solvent such as tetrahydrofuran, benzene, diethyl ether, methylene chloride, or acetonitrile, with respect to 1 mol of the compound having an amide group, trimethylsilyl azide and triphenylphosphine and diethyl azodicarboxylate as a condensing agent are used. Usually, it is carried out using 1 mol to excess mol, preferably 1 to 3 mol. The reaction temperature is usually from -78 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 50 ° C.
The reaction time is generally 5 hours to 7 days, preferably 5 hours to 48 hours. Further, the method using sodium azide is a method of using sodium azide and trifluoromethanesulfonic acid per mole of a compound having an amide group in an inert solvent such as tetrahydrofuran, benzene, diethyl ether, methylene chloride, or acetonitrile,
Usually 1 mole to excess mole, preferably 1 to 3
This is done using moles. The reaction temperature is usually from -78 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 50 ° C.
° C, and the reaction time is usually 5 hours to 3 days, preferably 5 hours to 24 hours. Further, the method of treating the 1- (2-cyanoethyl) -1H-tetrazolyl group with a base can be carried out in a solvent such as acetonitrile, methylene chloride, N, N-dimethylformamide, tetrahydrofuran, methanol, ethanol, water or a mixed solvent thereof. And 1,8-diazabicyclo [5.4.0] -7-undecene as a base, sodium hydroxide, potassium carbonate, triethylamine, etc., based on 1 mol of the compound having a 1- (2-cyanoethyl) -1H-tetrazolyl group. 1 to an excess, preferably 1 to 5 mol. The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from 10 ° C. to 50 ° C.
To 10 hours, preferably 1 to 5 hours.

As a method for using the compound (4a-3) having a cyano group, the compound (4a-
A method of reacting 3) with trimethylsilyl azide or sodium azide or the like can be cited. In the case of the method using trimethylsilyl azide, trimethylsilyl azide is usually used in an inert solvent such as benzene, hexane, toluene, or xylene per 1 mol of the cyano group-containing compound (4a-3), usually 1 mol to excess mol, preferably 1 mol. , And usually 0.01 mol to an excess mol, preferably 0.05 to 1 mol of dibutyltin (IV) oxide.
This is done using moles. The reaction temperature is usually from 0 ° C to the boiling point of the solvent used in the reaction, preferably from 50 ° C to 150 ° C.
° C, and the reaction time is usually from 10 hours to 48 hours, preferably from 15 hours to 30 hours. When sodium azide is used, the reaction is carried out by allowing sodium azide to act in an inert solvent such as N, N-dimethylformamide in the presence of a Lewis acid such as aluminum chloride, ammonium chloride or pyridinium chloride. it can. It is usually 1 mol to an excess mol, preferably 1 to 3 mol, per 1 mol of the compound (4a-3) having a cyano group. The reaction temperature is usually from 50 ° C to the boiling point of the solvent used in the reaction, preferably from 80 ° C to 150 ° C,
The reaction time is generally 10 to 48 hours, preferably 15 hours.
From 30 hours to 30 hours.

In the case where Q ³ in the compound (4) is a heterocyclic group having a hydrogen atom capable of being deprotonated, for example, a 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl group, a carboxylic acid compound ( 4a-2). For example, it can be produced by converting a carboxyl group to hydrazide and then carbonylating it. The method for converting a carboxyl group to hydrazide is carried out, for example, by using hydrazine hydrate instead of compound (3) in the method for producing compound (4) from compound (2) and compound (3). . To carbonylate the obtained hydrazide, carbonyldiimidazole, phosgene or the like is used as a carbonylating agent, and diethyl ether, tetrahydrofuran, dioxane, methylene chloride, ethyl acetate or the like is used as a solvent,
If necessary, the reaction is carried out in the presence of a base such as triethylamine. The carbonylating agent is added to 1 mole of the hydrazide.
A mole to excess mole, preferably 1 to 3 mole, is used.
The reaction temperature is usually from -30 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 50 ° C, and the reaction time is generally from 1 hour to 48 hours, preferably from 5 hours to 24 hours.

In the case where Q ³ in the compound (4) is a heterocyclic group having a hydrogen atom capable of being deprotonated, for example, a 2,5-dihydro-5-oxo-1,2,4-thiadiazolyl group has a cyano group. It can be produced using compound (4a-3). For example, it can be produced by reacting a compound having a cyano group (4a-3) with hydroxylamine to give a hydroxyamidine compound, and further reacting the obtained hydroxyamidine compound with thiocarbonyldiimidazole to effect cyclization. it can. To convert a compound having a cyano group into a hydroxyamidine compound, in the presence of a base such as triethylamine, sodium hydrogen carbonate, or potassium carbonate, methanol, ethanol,
In a solvent such as propanol, N, N-dimethylformamide, acetonitrile, or dimethylsulfoxide, the reaction is usually carried out using 1 to excess mol, preferably 2 to 5 mol of hydroxylamine hydrochloride with respect to 1 mol of the compound having a cyano group. Can be. Reaction temperature is from 30 ° C to 150
° C, preferably 50 ° C to 100 ° C, and the reaction time is 1-2.
4 hours, preferably 5 to 10 hours. To cyclize the obtained hydroxyamidine compound, tetrahydrofuran, dioxane, in a solvent such as diethyl ether,
The thiocarbonyldiimidazole is usually used in an amount of 1 mol to excess mol, preferably 1 to 3 mol, and allowed to act at 0 to 50 ° C. for about 0.5 hour, and further in a solvent such as tetrahydrofuran, dioxane, diethyl ether, or the like. The reaction can be carried out by using a boron trifluoride diethyl ether complex in an amount of usually 1 mol to an excess, preferably 3 to 10 mol, at 0 to 50 ° C. for 1 to 48 hours.

When Q ³ in the compound (4) is an acylcarbamoyl group, for example, an N- (methylsulfonyl) carbamoyl group, the compound can be produced using a carboxylic acid compound (4a-2). For example, a carboxylic acid compound (4
a-2) and a method of condensing methanesulfonamide. This condensation reaction is carried out, for example, by using methanesulfonamide instead of compound (3) in the method for producing compound (4) from compound (2) and compound (3), and further comprising carboxylic acid compound (4a -2) In a solvent such as tetrahydrofuran, dioxane or diethyl ether, the carboxyl group is activated with carbonyldiimidazole or the like and then in the presence of a base such as 1,8-diazabicyclo [5.4.0] -7-undecene. This is performed by reacting methanesulfonamide. The carbonyldiimidazole is used in an amount of 1 to excess mol, preferably 2 to 3 mol, per 1 mol of the carboxylic acid compound (4a-2). Reaction temperature is from 0 ° C to 150
° C, preferably 10 ° C to 100 ° C, and the reaction time is 1-2.
4 hours, preferably 2 to 6 hours. The methanesulfonamide is used in an amount of 1 to excess mole, preferably 2 to 3 mole. The reaction temperature is -20 ° C to 100 ° C, preferably 10 ° C to 50 ° C, and the reaction time is 10 minutes to 10 days,
Preferably it is 1 to 24 hours.

The method of removing the ester group of the carboxylic acid ester group in producing the carboxylic acid compound (4a-2) from the compound (4a-1) differs depending on the type of the ester group, but is described in the literature. [Protective Groups in Organic Synthesis]
ganic Synthesis), 2nd edition, T.M. W.
Green, T.W. G. FIG. M. By John Wiley, by PGM Wuts
& Sons (1991)] or a method analogous thereto. For example, the removal is performed by hydrolysis using an acid or a base, hydrogenation in the presence of a palladium-carbon catalyst, Raney nickel, or the like, or a method in the presence of trifluoroacetic acid. Hereinafter, the present invention will be specifically described with reference to Reference Examples, Examples, and Test Examples, but the present invention should not be limited to these.

[0059]

Reference Example Reference Example 1 (1) 5- (2-naphthyl) pentyl bromide

[0060]

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5- (2-Naphthyl) -1-pentanol (15.0 g) was dissolved in acetonitrile (150 ml), and pyridine (9.04 ml) and dibromotriphenylphosphorane (38.4 g) were cooled with ice water. Was added and stirred for 1 hour. The mixture was diluted with ethyl acetate, and the insoluble solid was removed by filtration.
The filtrate was concentrated under reduced pressure, ethyl acetate was added again, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 5% ethyl acetate-hexane) to give the title compound (19.2 g) as a pale-yellow oil.

MS (EI) m / z: 276, 278 (M
⁺ ). ¹ H-NMR (CDCl ₃ ) δ: 1.46-1.54 (2
H, m), 1.69-1.76 (2H, m), 1.86.
-1.93 (2H, m), 2.78 (2H, t, J =
7.6 Hz), 3.39 (2H, t, J = 6.8H)
z), 7.31 (1H, dd, J = 8.3, 1.5H
z), 7.38-7.46 (2H, m), 7.60 (1
H, s), 7.75-7.80 (3H, m). (2) Benzyl 3-[[5- (2-naphthyl) pentyl] amino] propionate

[0063]

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Glycine benzyl ester p-toluenesulfonate (75.0 g) was mixed with diethyl ether (500 ml) and a 1N aqueous potassium carbonate solution (300 m).
1) The mixture was added to the mixture and stirred for 30 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain glycine benzyl ester (17 g).
This was dissolved in acetonitrile (250 ml), and the above-mentioned (1) 5- (2-naphthyl) pentyl bromide (6.5 g) and potassium carbonate (4.9 g) were added, followed by heating under reflux for 3 days. After cooling, the insoluble solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (4
The residue was purified by elution with 0-50% ethyl acetate-hexane to give the title compound (4.28 g) as a colorless oil.

MS (EI) m / z: 375 (M ⁺ ). ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.55 (4
H, m), 1.67-1.74 (2H, m), 2.54
-2.60 (4H, m), 2.76 (2H, t, J =
7.8 Hz), 2.88 (2H, t, J = 6.6H)
z), 5.11 (2H, s), 7.29-7.45 (8
H, m), 7.59 (1H, s), 7.74-7.80.
(3H, m).

Reference Example 2 (2R, 3R) -3- [N- [2- (benzyloxycarbonyl) ethyl] -N- [5- (2-naphthyl) pentyl] carbamoyl] -2-tert-butyldimethylsilyl Tert-Butyl oxy-3- [5- (3,4-dimethylphenyl) pentyloxy] propionate

[0067]

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(2R, 3R) -3-tert-butoxycarbonyl-3-tert-butyldimethylsilyloxy-2- [5- (3,4-dimethylphenyl) pentyloxy] propionic acid (WO 98/2938) Gazette, compound of Example 31- (5)) (0.87 g),
The compound of Reference Example 1- (2) (0.66 g), 1-hydroxybenzotriazole (0.27 g) and triethylamine (0.32 ml) were dissolved in methylene chloride (30 ml). 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.44
g) was added and the mixture was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 15% ethyl acetate-hexane) to give the title compound (1.37 g) as a colorless oil.

MS (FAB +) m / z: 852 (M +
H) ⁺ . ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 0.
050, 0.058 (total 3H, seac
h), 0.089, 0.100 (total 3H, s
each), 0.88, 0.89 (total 9
H, seach), 1.23-1.36 (4H,
m), 1.42, 1.43 (total 9H, sea
ch), 1.50-1.75 (8H, m), 2.20,
2.21 (total 3H, search), 2.4
5-2.52 (2H, m), 2.60-2.68 (2
H, m), 2.70-2.79 (2H, m), 3.12
-3.30 (1.2H, m), 3.37-3.70
(4.4H, m), 4.02-4.12 (0.4H,
m), 4.28, 4.34 (total 1H, de)
ach, J = 6.8 / 5.8 Hz), 4.42, 4.4
6 (total 1H, deach, J = 6.8 /
5.8 Hz), 5.09, 5.11 (total 2
H, seach), 6.86 (1H, d, J = 7.3).
Hz), 6.90 (1H, s), 7.01 (1H, d
d, J = 7.3, 2, 9 Hz), 7.25-7.35
(6H, m), 7.38-7.45 (2H, m), 7.
58 (1H, s), 7.74-7.79 (3H, m).

Reference Example 3 3- [N-[(2R, 3R) -3-tert-butoxycarbonyl-3-tert-butyldimethylsilyloxy-2- [5- (3,4-dimethylphenyl) pentyloxy] Propionyl] -N- [5- (2-naphthyl) pentyl] amino] propionic acid

[0071]

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The compound of Reference Example 2 (1.35 g) was dissolved in ethyl acetate (30 ml), 10% palladium / carbon (0.10 g) was added, and the mixture was stirred under a hydrogen atmosphere for 25 hours. After filtering off palladium / carbon and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give the title compound (1.17).
g) was obtained as a pale yellow oil.

MS (FAB +) m / z: 784 (M + N
a) ⁺ . ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 0.
050, 0.063 (total 3H, seac
h), 0.090, 0.105 (total 3H, s
each), 0.88, 0.89 (total 9
H, seach), 1.23-1.48 (13H,
m), 1.50-1.80 (8H, m), 2.20 (6
H, s), 2.50 (2H, t, J = 7.6 Hz),
2.60-2.68 (2H, m), 2.72-2.80
(2H, m), 3.17-3.31 (1.4H, m),
3.38-3.70 (4.3H, m), 3.98-4.
07 (0.3H, m), 4.29, 4.36 (tota
11H, deach, J = 6.3 / 6.3 Hz),
4.41, 4.47 (total 1H, deac)
h, J = 6.3 / 6.3 Hz), 6.86 (1H, d,
J = 7.6 Hz), 6.91 (1H, s), 7.00
(1H, d, J = 7.6 Hz), 7.30 (1H, d,
J = 7.3 Hz), 7.39-7.45 (2H, m),
7.58 (1H, s), 7.73-7.79 (3H,
m).

Reference Example 4 N- [3- [N-[(2R, 3R) -3-tert-
Butoxycarbonyl-3-tert-butyldimethylsilyloxy-2- [5- (3,4-dimethylphenyl) pentyloxy] propionyl] -N- [5- (2
-Naphthyl) pentyl] amino] propionyl] methanesulfonamide

[0075]

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To a solution of the compound of Reference Example 3 (1.0 g) in tetrahydrofuran (15 ml) was added 1,1'-carbonylbis-1H-imidazole (0.425 g).
Stirred at 4.5 ° C. for 4.5 hours. After cooling, methanesulfonamide (0.312 g), 1,8-diazabicyclo [5.
4.0] -7-undecene (0.41 ml).
Stir for 5 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed with 1 N hydrochloric acid and saturated saline. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 50-70% ethyl acetate-hexane) to give the title compound (0.
92 g) were obtained as a colorless oil.

MS (FAB +) m / z: 861 (M + N
a) ⁺ , 839 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 0.
06 (3H, s), 0.09 (3H, s), 0.89
(9H, s), 1.25-1.45 (4H, m), 1.
48 (9H, s), 1.51-1.70 (6H, m),
1.70-1.80 (2H, m), 2.23 (6H,
s), 2.52 (2H, t, J = 7.6 Hz), 2.5
3-2.65 (2H, m), 2.79 (2H, t, J =
7.5 Hz), 3.21-3.32 (1H, m),
26 (3H, s), 3.41-3.59 (4H, m),
3.63-3.74 (1H, m), 4.24 (0.9
H, d, J = 6.9 Hz), 4.33 (0.1 H, d,
J = 5.7 Hz), 4.41 (0.9H, d, J = 6.
9Hz), 4.55 (0.1H, d, J = 5.7H)
z), 6.88 (1H, broad d, J = 7.6H)
z), 6.93 (1H, broads), 7.02
(1H, broad d, J = 7.6 Hz), 7.31
(1H, d, J = 8.3 Hz), 7.38-7.48
(2H, m), 7.60 (1H, s), 7.76 (1
H, d, J = 7.8 Hz), 7.74-7.83 (2
H, m).

Reference Example 5 N- [3- [N-[(2R, 3R) -3-tert-
Butoxycarbonyl-2- [5- (3,4-dimethylphenyl) pentyloxy] -3-hydroxypropionyl] -N- [5- (2-naphthyl) pentyl] amino] propionyl] methanesulfonamide

[0079]

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To a solution of the compound of Reference Example 4 (106 mg) in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1 M solution in tetrahydrofuran,
2.1 ml) and acetic acid (0.45 ml) were added and stirred for 5 days. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with 2N acid and saturated saline, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to give the title compound (62 mg) as a colorless oil.

MS (FAB +) m / z: 747 (M + N
a) ⁺ . ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 1.
22-1.67 (10H, m), 1.44 (9H,
s), 1.70-1.80 (2H, m), 2.209
(3H, s), 2.214 (3H, s), 2.50 (2
H, t, J = 7.8 Hz), 2.53-2.56 (1
H, m), 2.67-2.78 (1H, m), 2.77
(2H, t, J = 7.6 Hz), 3.24 (3H,
s), 3.35-3.80 (6H, m), 4.33 (1
H, d, J = 2.6 Hz), 4.41 (1H, d, J =
2.6 Hz), 6.87 (1H, broad d, J =
7.6 Hz), 6.91 (1H, broads),
7.01 (1H, broad d, J = 7.6 Hz),
7.30 (1H, d, J = 8.5 Hz), 7.38-
7.47 (2H, m), 7.58 (1H, s), 7.7
3-7.80 (3H, m).

Reference Example 6 (2R, 3R) -3- [5- (3,4-dimethylphenyl) pentyloxy] -2-hydroxy-3- [N-
[2- [N- (methylsulfonyl) carbamoyl] ethyl] -N- [5- (2-naphthyl) pentyl] carbamoyl] propionic acid

[0083]

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To a solution of the compound of Reference Example 5 (61 mg) in methylene chloride (2 ml) was added trifluoroacetic acid (0.5 ml).
Was added and stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to give the title compound (61 mg) as a colorless oil.

MS (FAB +) m / z: 669 (M +
H) ⁺ . HR-MS (FAB +) C 36 H 49 N 2 O 8 theoretical value as S m / z: 669.3210 [( M + H) +]. Experimental value m / z: 669.3221 [(M + H) ⁺ ]. ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 1.
25-1.42 (4H, m), 1.43-1.82 (8
H, m), 2.166 (3H, s), 2.172 (3
H, s), 2.47 (2H, t, J = 7.7 Hz),
2.47-2.73 (2H, m), 2.73-2.82
(2H, m), 3.18 (0.9H, s), 3.21
(2.1H, s), 3.36-3.58 (4.6H,
m), 3.63-3.77 (1.2H, m), 3.87
-3.98 (0.2H, m), 4.35-4.42 (1
H, m), 4.47 (0.8H, d, J = 4.2H
z), 4.58 (0.2 H, d, J = 2.6 Hz),
6.80-6.68 (3H, m), 7.31 (1H, b
load d, J = 6.9 Hz), 7.34-7.43
(2H, m), 7.59 (1H, s), 7.71-7.
79 (3H, m).

Reference Example 7 3-[[5- (2-naphthyl) pentyl] amino] propionitrile

[0087]

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The title compound was obtained as an oil by treating in the same manner as in Reference Example 1- (2), except that 3-aminopropionitrile was used instead of glycine benzyl ester.

MS (FAB +) m / z: 279 (M + N
a) ⁺ , 267 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.43 (2
H, m), 1.49-1.56 (2H, m), 1.68.
-1.76 (2H, m), 2.47 (2H, t, J =
6.8 Hz), 2.61 ((2H, t, J = 7.1H)
z), 2.77 (2H, t, J = 7.6 Hz), 2.8
9 (2H, t, J = 6.8 Hz), 7.32 (1H, d
d, J = 8.5, 1.7 Hz), 7.38-7.46
(2H, m), 7.60 (1H, s), 7.75-7.
80 (3H, m).

Reference Example 8 (1) Benzyl (2R, 3R) -2- [5- (3,4-dimethylphenyl) pentyloxy] -3-ethoxycarbonyl-3-hydroxypropionate

[0091]

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(2R, 3R) -3-tert-butoxycarbonyl-2- [5- (3,4-dimethylphenyl)
Pentyloxy] -3-hydroxypropionate (International Publication WO98 / 2938, Example 31-
(3)) To a solution of (3.05 g) in methylene chloride (15 ml) was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 3 hours. The residue was dissolved in methylene chloride, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in toluene and distilled off under reduced pressure. To a solution of this residue in diethyl ether (50 ml) were added triphenylphosphine (2.04 g) and ethanol (0.79 ml).
Diethyl azodicarboxylate (1.22 ml) under ice water cooling
Was added dropwise over 5 minutes. After stirring at room temperature for 1 hour, the mixture was diluted with hexane and stirred for 1.5 hours. The insoluble solid was separated by filtration and washed with hexane. The filtrate and the washings were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 20% ethyl acetate-hexane) to give the title compound (2.
43 g) as a colorless oil.

MS (EI) m / z: 442 (M ⁺ ). ¹ H-NMR (CDCl ₃ ) δ: 1.24 to 1.40 (5
H, m), 1.50-1.62 (4H, m), 2.21
(3H, s), 2.23 (3H, s), 2.50 (2
H, t, J = 7.8 Hz), 3.07 (1H, d.J =
8.8 Hz), 3.29 (1 H, dt, J = 9.3,
6.8 Hz), 3.77 (1H, dt, J = 8.8,
6.3 Hz), 4.23 (1H, q, J = 7.0H)
z), 4.24 (1H, q, J = 7.2 Hz), 4.2
8 (1H, d, J = 2.4 Hz), 4.59 (1H, d
d, J = 8.8, 2.4 Hz), 5.22 (1H, d,
J = 12.2 Hz), 5.26 (1H, d, J = 12.
2Hz), 6.88 (1H, d, J = 7.3Hz),
6.92 (1H, s), 7.02 (1H, d, J = 7.
3Hz), 7.32-7.37 (5H, m).

(2) (2R, 3R) -3-tert-
Benzyl dimethylsilyloxy-2- [5- (3,4-dimethylphenyl) pentyloxy] -3-ethoxycarbonylpropionate benzyl

Embedded image

The compound of the above (1) (2.43 g) was treated with N,
Imidazole (0.75 g) and tert-butylchlorodimethylsilane (1.50 g) were added to a N-dimethylformamide (40 ml) solution, and the mixture was stirred at room temperature for 23.5 hours. The mixture was diluted with ethyl acetate, washed sequentially with water, saturated saline, and water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 6% ethyl acetate-hexane) to give the title compound (2.68 g) as a colorless oil.

MS (FAB +) m / z: 557 (M +
H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 0.017 (3H,
s), 0.107 (3H, s), 0.87 (9H,
s), 1.25 (3H, t, J = 7.3 Hz), 1.2
5-1.34 (2H, m), 1.50-1.60 (4
H, m), 2.21 (3H, s), 2.23 (3H,
s), 2.49 (2H, t, J = 7.8 Hz), 3.3
1-3.37 (1H, m), 3.66-3.71 (1
H, m), 4.15 (2H, q, J = 7.3 Hz),
4.28 (1H, d, J = 3.9 Hz), 4.65 (1
H, d, J = 3.9 Hz), 5.11 (1H, d, J =
12.2 Hz), 5.23 (1H, d, J = 12.2H)
z), 6.88 (1H, d, J = 7.6 Hz), 6.7
1 (1H, s), 7.02 (1H, d, J = 7.6H)
z), 7.32-7.36 (5H, m).

(3) (2R, 3R) -3-tert-butyldimethylsilyloxy-2- [5- (3,4-dimethylphenyl) pentyloxy] -3-ethoxycarbonylpropionic acid

[0098]

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A 10% palladium / carbon (0.3%) solution was added to a solution of the compound (2) (2.38 g) in ethyl acetate (40 ml).
1 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. The palladium / carbon was removed by filtration and concentrated to dryness under reduced pressure to obtain the title compound (2.08 g) as a colorless oil.

MS (FAB +) m / z: 467 (M +
H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 0.045 (3H,
s), 0.120 (3H, s), 0.89 (9H,
s), 1.18-1.33 (5H, m), 1.49-
1.60 (4H, m), 2.21 (3H, s), 2.2
3 (3H, s), 2.52 (2H, t, J = 7.6H
z), 3.31-3.50 (1H, m), 3.60-
3.73 (1H, m), 4.18-4.24 (2H,
m), 4.33 (1H, d, J = 2.9 Hz), 4.6
4 (1H, d, J = 2.9 Hz), 6.88 (1H,
d, J = 7.6 Hz), 6.72 (1H, s), 7.0
2 (1H, d, J = 7.6 Hz).

(4) (2R, 3R) -2-tert-butyldimethylsilyloxy-3- [N- (2-cyanoethyl) -N- [5- (2-naphthyl) pentyl] carbamoyl] -3- [ Ethyl 5- (3,4-dimethylphenyl) pentyloxy] propionate

[0102]

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To a solution of the compound of the above (3) (1.02 g) in methylene chloride (7 ml) was added the compound of Reference Example 7 (0.64 g).
g), diisopropylethylamine (0.68 ml) and benzotriazolyloxy-tris [pyrrolidino] -phosphonium hexafluorophosphate (1.25)
g) was added and the mixture was stirred at room temperature for 75 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
After washing with an aqueous solution of sodium hydrogencarbonate and saturated saline, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 25% ethyl acetate-hexane) to give the title compound (1.
10 g) were obtained as a colorless oil.

MS (FAB +) m / z: 737 (M + N
a) ⁺ , 715 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 0.
043, 0.063 (total 3H, seac
h), 0.095 (3H, s), 0.88, 0.89
(Total 9H, search), 1.25 (3
H, t, J = 7.1 Hz), 1.25-1.42 (4
H, m), 1.52-1.78 (8H, m), 2.2
1, 2.22 (total 6H, search),
2.48-2.54 (2H, m), 2.57-2.68
(2H, m), 2.75-2.80 (2H, m), 3.
24-3.32 (1H, m), 3.39-3.56 (1
3 / 3H, m), 3.69-3.76 (2 / 3H.m).
m), 4.09-4.22 (2H, m), 4.33 (2
/ 3H, d, J = 6.6 Hz), 4.39 (1 / 3H,
d, J = 5.1 Hz), 4.54 (2 / 3H, d, J =
6.6 Hz), 4.60 (1 / 3H, d, J = 5.1H)
z), 6.86-6.92 (2H, m), 7.00-
7.03 (1H, m), 7.29-7.30 (1H,
m), 7.39-7.46 (2H, m), 7.59 (1
H, s), 7.74-7.80 (3H, m).

(5) (2R, 3R) -3- [N- (2-
Ethyl cyanoethyl) -N- [5- (2-naphthyl) pentyl] carbamoyl] -3- [5- (3,4-dimethylphenyl) pentyloxy] -2-hydroxypropionate

[0106]

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The compound of the above (4) (11.65 g) was treated in the same manner as in Reference Example 5 to give the title compound (10.
0g) as a colorless oil.

¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 1.23-1.41 (7H, m), 1.50-
1.81 (8H, m), 2.21 (3H, s), 2.2
2 (3H, s), 2.48-2.53 (2H, m),
2.55-2.81 (4H, m), 3.27-3.33
(2H, m), 3.42-3.50 (2H, m), 3.
58-3.65 (2H, m), 4.21-4.38 (2
H, m), 4.43 (2H, s), 6.87 (1H,
d, J = 7.2 Hz), 6.92 (1H, s), 7.0
2 (1H, d, J = 7.2 Hz), 7.30 (1H,
d, J = 7.3 Hz), 7.41-7.46 (2H,
m), 7.59 (1H, s), 7.75-7.80 (3
H, m).

(6) (2R, 3R) -3- [5- (3,
4-dimethylphenyl) pentyloxy] -2-hydroxy-3- [N- [5- (2-naphthyl) pentyl]-
N- [2- [1 (and 3) -triphenylmethyl-1
H (or 3H) -tetrazol-5-yl] ethyl] carbamoyl] ethyl propionate

[0110]

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The compound of the above (5) (9.40 g) containing N,
Sodium azide (2.16 g) and ammonium chloride (1.7) were added to an N-dimethylformamide (150 ml) solution.
8 g) and stirred at 100 ° C. for 16 hours. Sodium azide (2.4 g) and ammonium chloride (2.0 g)
g) was added and the mixture was further stirred at 100 ° C. for 22 hours. After cooling, the mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. N, N-dimethylformamide of this residue (15
0 ml) solution in triphenylmethyl chloride (8.7).
2g) and triethylamine (8.7 ml) were added, and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed with diluted hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate-hexane = 1: 2 to 2: 3
Purification gave the title compound (7.1 g) as a colorless oil.

MS (FAB +) m / z: 908 (M + N
a) ⁺ . ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 1.
20-1.34 (7H, m), 1.42-1.61 (6
H, m), 1.65-1.71 (2H, m), 2.20
(3H, s), 2.21 (3H, s), 2.43-2.
49 (2H, m), 2.72-2.77 (2H, m),
3.15-3.26 (3H, m), 3.30-3.42
(1H, m), 3.48-3.57 (1.5H, m),
3.62-3.70 (1H, m), 3.74-3.80
(0.5H, m), 3.89-3.92 (1H, m),
4.18-4.23 (2H, m), 4.33-4.36
(0.5H, m), 4.39-4.42 (1H, m),
4.46-4.48 (0.5H, m), 6.83-6.
91 (2H, m), 6.99 (1H, d, J = 8.3H
z), 7.05-7.10 (6H, m), 7.25-
7.34 (10H, m), 7.38-7.44 (2H,
m), 7.56 (1H, s), 7.72-7.78 (3
H, m).

(7) (2R, 3R) -3- [5- (3,
4-dimethylphenyl) pentyloxy] -2-hydroxy-3- [N- [5- (2-naphthyl) pentyl]-
N- [2- [1 (and 3) -triphenylmethyl-1
H (or 3H) -tetrazol-5-yl] ethyl] carbamoyl] propionic acid

[0114]

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To a solution of the compound (6) (1.0 g) in ethanol (40 ml) was added a 1N aqueous sodium hydroxide solution (1.2 ml), and the mixture was stirred at room temperature for 3.5 hours. The mixture was concentrated under reduced pressure, diluted hydrochloric acid (2 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give the title compound (0.9%).
2g) was obtained as a colorless oil. MS (FAB +) m / z: 880 (M + Na) ^<+> .

(8) 5- [2- [N-[(R) -2-]
[5- (3,4-dimethylphenyl) pentyloxy]
-2-[(R) -1,3-dioxolan-4-one-5
-Yl] acetyl] -N- [5- (2-naphthyl) pentyl] amino] ethyl] -1 (and 3) -triphenylmethyl-1H (or 3H) -tetrazole

[0117]

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The title compound (0.16 g) was obtained by treating the compound of the above (7) (0.30 g) in the same manner as in Example 1.
g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 1.
19-1.35 (4H, m), 1.42-1.74 (8
H, m), 2.20 (6H, s), 2.43-2.50
(2H, m), 2.75 (2H, t, J = 7.6H
z), 3.06-3.10 (1H, m), 3.10-
3.33 (3.5H, m), 3.45-3.54 (2
H, m), 3.75-3.83 (0.5H, m), 3.
90-4.05 (1H, m), 4.22 (0.5H,
s), 4.36 (0.5H, s), 4.44 (1H,
s), 5.17 (0.5H, s), 5.29 (1H,
s), 5.47 (0.5H, s), 6.82-6.91.
(2H, m), 6.99-7.01 (1H, m), 7.
04-7.10 (6H, m), 7.25-7.43 (1
2H, m), 7.57 (1H, s), 7.72-7.7.
8 (3H, m).

Reference Example 9 O-benzyl-N- [5- (2-naphthyl) pentyl]
Hydroxylamine

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The title compound was obtained as a colorless oil by treating in the same manner as in Reference Example 1- (2) except that O-benzylhydroxylamine hydrochloride was used instead of glycine benzyl ester p-toluenesulfonate.

MS (FAB +) m / z: 320 (M +
H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.43 (2
H, m), 1.52-1.59 (2H, m), 1.67.
-1.75 (2H, m), 2.71-2.78 (2H,
m), 2.92 (2H, t, J = 7.3 Hz), 4.6
9 (2H, s), 5.52 (1H, s), 7.26-
7.34 (6H, m), 7.38-7.45 (2H,
m), 7.59 (1H, s), 7.74-7.80 (3
H, m).

Reference Example 10 (1) (2R, 3R) -3- [N-benzyloxy-N
-[5- (2-naphthyl) pentyl] carbamoyl]-
Tert-Butyl 3- [5- (3,4-dimethylphenyl) pentyloxy] -2-hydroxypropionate

[0123]

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(2R, 3R) -3-tert-butoxycarbonyl-3-tert-butyldimethylsilyloxy-2- [5- (3,4-dimethylphenyl) pentyloxy] propionic acid (WO 98/2938) Publication, Compound (2.17 g) of Reference Example 9 and diisopropylethylamine (1.9) were added to a solution of 3.01 g of the compound of Example 31- (5) (3.05 g) in methylene chloride (15 ml).
ml) and benzotriazolyloxy-tris [pyrrolidino] -phosphonium hexafluorophosphate (
3.21 g) and stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with 1N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 10% ethyl acetate-hexane).
(2R, 3R) -3- [N-benzyloxy-N- [5
-(2-naphthyl) pentyl] carbamoyl] -2-t
tert-butyldimethylsilyloxy-3- [5-
Tert-Butyl (3,4-dimethylphenyl) pentyloxy] propionate and O-benzyl-N- [5-
A mixture of (2-naphthyl) pentyl] hydroxylamine (4.76 g) was obtained.

This mixture was treated with tetrahydrofuran (60 m
l) and cooled under ice-water cooling with tetrabutylammonium
Fluoride (1M tetrahydrofuran solution, 5.5m
l) was added and stirred for 85 minutes. The solvent is distilled off under reduced pressure,
The residue was dissolved in ethyl acetate, washed successively with 1 N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 30% ethyl acetate-hexane) to give the title compound (3.
31 g) was obtained as a colorless oil.

MS (FAB +) m / Z: 704 (M + N
a) ⁺ , 682 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.23-1.60 (1
7H, m), 1.67-1.78 (4H, m), 2.2
1 (3H, s), 2.22 (3H, s), 2.49 (2
H, t, J = 7.7 Hz), 2.73-2.83 (3
H, m), 2.97 (1H, d, J = 8.8 Hz),
3.30-3.47 (2H, m), 3.99-4.12
(1H, m), 4.24 (1H, d, J = 2.0H
z), 4.47 (1H, dd, J = 8, 8, 2.0H
z), 4.76 (1H, d, J = 10.9 Hz), 4.
83 (1H, d, J = 10.9 Hz), 6.88 (1
H, d, J = 7.7 Hz), 6.92 (1H, s),
7.02 (1H, d, J = 7.7 Hz), 7.29−
7.43 (8H, m), 7.58 (1H, s), 7, 7
3-7.79 (3H, m).

(2) (2R, 3R) -3- [N-benzyloxy-N- [5- (2-naphthyl) pentyl] carbamoyl] -3- [5- (3,4-dimethylphenyl)
Pentyloxy] -2-hydroxypropionic acid

[0128]

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To a solution of the compound (1) (21.5 g) in methylene chloride (210 ml) was added trifluoroacetic acid (30 ml).
ml) and stirred for 12 hours. After concentration under reduced pressure, the residue was dissolved in methylene chloride, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from a small amount of ethyl acetate and hexane to give the title compound (11.85 g) as colorless crystals.

Melting point 89-90 ° C MS (FAB +) m / Z: 648 (M + Na) ⁺ , 62
6 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.30 (2
H, m), 1.32-1.55 (6H, m), 1.65.
-1.75 (4H, m), 2.20 (3H, s), 2.
21 (3H, s), 2.47 (2H, t, J = 7.7H
z), 2.74 (2H, t, J = 7.6 Hz), 2.9
3-3.01 (1H, m), 3.31-3.37 (1
H, m), 3.52-3.60 (1H, m), 3.81
-3.88 (1H, m), 4.31 (1H, d, J =
2.2Hz), 4.52 (1H, d, J = 2.2H)
z), 4.75-4.86 (2H, m), 6.87 (1
H, d, J = 7.6 Hz), 6.91 (1H, s),
7.01 (1H, d, J = 7.6 Hz), 7.27 −
7.44 (8H, m), 7. 56 (1H, s), 7.
72-7.78 (3H, m). Elemental analysis: as C ₃₉ H ₄₇ NO ₆ Theoretical: C, 74.85; H, 7.57; N, 2.24 Experimental: C, 74.69; H, 7.61; N, 2.23

(3) (R) -N- [5- (2-naphthyl) pentyl] -2- [5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -4-oxo −
1,3-dioxolan-5-yl] benzyl acetohydroxamate

[0132]

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The title compound was obtained as a pale yellow oil by treating the compound of Reference Example 10- (2) in the same manner as in Example 1. MS (ESI) m / z: 638 (M + H) ^<+> . ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.80 (1
2H, m), 2.21 (3H, s), 2.23 (3H,
s), 2.50 (2H, t, J = 7.8 Hz), 2.7
6 (2H, t, J = 7.8 Hz), 2.73-2.88
(1H, m), 3.30-3.45 (2H, m), 4.
03-4.14 (1H, m), 4.23 (1H, d, J
= 1.2 Hz), 4.58 (1H, broad s),
4.75 (1H, d, J = 11.0 Hz), 4.82
(1H, d, J = 11.0 Hz), 5.30 (1H, b
load s), 5.52 (1H, s), 6.86-
7.03 (3H, m), 7.25-7.49 (8H,
m), 7.57 (1H, s), 7.70-7.85 (3
H, m).

Reference Example 11 (1) (2R, 3R) -2-tert-butyldimethylsilyloxy-3- [5- (3,4-dimethylphenyl) pentyloxy] -3- [N- [5- ( 2-naphthyl) pentyl] carbamoyl] propionic acid tert
-Butyl

[0135]

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In Reference Example 2, 5- (2-naphthyl) pentylamine was used instead of the compound of Reference Example 1- (2).
The title compound was obtained as a colorless oil by treating in the same manner except for using the hydrochloride (WO98 / 2938, Reference Example 5). MS (FAB +) m / Z: 690 (M + H) ^<+> . ¹ H-NMR (CDCl ₃ ) δ: 0.00 (3H, s),
0.099 (3H, s), 0.87 (9H, s), 1.
22-1.58 (19H, m), 1.68-1.75
(2H, m), 2.20 (3H, s), 2.21 (3
H, s), 2.50 (2H, t, J = 7.8 Hz),
2.76 (2H, t, J = 7.6 Hz), 3.01-
3.09 (1H, m), 3.38 (2H, t, J = 6.
8Hz), 3.41-3.49 (1H, m), 4.12
(1H, d, J = 2.4 Hz), 4.52 (1H, d,
J = 2.4 Hz), 6.60 (1 H, t, J = 5.6 H)
z), 6.87 (1H, d, J = 7.6 Hz), 6.9
1 (1H, s), 7.01 (1H, d, J = 7.6H)
z), 7.30 (1H, dd, J = 8.3, 2.0H
z), 7.37-7.45 (2H, m), 7.58 (1
H, s), 7.73-7.79 (3H, m).

(2) (2R, 3R) -3- [5- (3,
4-dimethylphenyl) pentyloxy] -2-hydroxy-3- [N- [5- (2-naphthyl) pentyl]
Carbamoyl] tert-butyl propionate

[0138]

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The compound of the above (1) was treated in the same manner as in Reference Example 5 to give the title compound as a colorless oil. MS (FAB +) m / z: 598 (M + Na) ^<+> , 57
6 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.25 to 1.45 (4
H, m), 1.45-1.65 (15H, m), 1.6.
9-1.76 (2H, m), 2.20 (3H, s),
2.21 (3H, s), 2.51 (2H, t, J = 7.
8Hz), 2.76 (2H, t, J = 7.5Hz),
2.00 (1H, d, J = 6.8 Hz), 3.22-
3.45 (4H, m), 4.04 (1H, d, J = 2.
0 Hz), 4.42 (1H, dd, J = 6.8, 2.0
Hz), 6.50 (1H, broad), 6.87 (1
H, d, J = 7.8 Hz), 6.92 (1H, s),
7.02 (1H, d, J = 7.8 Hz), 7.30 (1
H, dd, J = 8.3, 1.5 Hz), 7.37-7.
44 (2H, m), 7.58 (1H, s), 7.73-
7.79 (3H, m).

(3) (2R, 3R) -3- [5- (3,
4-dimethylphenyl) pentyloxy] -2-hydroxy-3- [N- [5- (2-naphthyl) pentyl]
Carbamoyl] tert-butyl propionate

[0141]

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The compound of the above (2) was treated in the same manner as in Reference Example 6 to give the title compound as a pale-yellow oil. MS (FAB +) m / z: 542 (M + Na) ^<+> , 52
0 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.23-1.40 (4
H, m), 1.48-1.59 (6H, m), 1.69.
-1.75 (2H, m), 2.20 (3H, s), 2.
22 (3H, s), 2.51 (2H, t, J = 7.6H)
z), 2.76 (2H, t, J = 7.6 Hz), 3.2
6-3.34 (2H, m), 3.41-3.54 (2
H, m), 4.14 (1H, d, J = 1.4 Hz),
4.54 (1H, d, J = 3.2 Hz), 6.88 (1
H, d, J = 7.3 Hz), 6.92 (1H, s),
7.02 (1H, d, J = 7.3 Hz), 7.29 (1
H, dd, J = 8.3, 1.5 Hz), 7.38-7.
45 (2H, m), 7.57 (1H, s), 7.73-
7.79 (3H, m).

[0143]

EXAMPLES Example 1 N- [3- [N-[(R) -2- [5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -4-
Oxo-1,3-dioxolan-5-yl] acetyl]
-N- [5- (2-naphthyl) pentyl] amino] propionyl] methanesulfonamide

[0144]

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To a solution of the compound of Reference Example 6 (2.42 g) in acetonitrile (35 ml) was added pivaloyloxymethyl iodide (1.31 g) and triethylamine (0.81 m).
l) was added and the mixture was stirred at room temperature for 4 days. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 5% methanol-methylene chloride) to give the title compound (0.88 g).
Was obtained as a pale yellow oil.

MS (FAB +) m / z: 681 (M +
H) ⁺ . HR-MS (FAB +) C 37 H 48 N 2 O 8 theoretical value as S m / z: 681.3210 [( M + H) +]. Experimental value m / z: 681.3239 [(M + H) ⁺ ]. ¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 1.
30-1.40 (4H, m), 1.48-1.67 (6
H, m), 1.70-1.77 (2H, m), 2.20
(3H, s), 2.21 (3H, s), 2.50 (2
H, t, J = 7.7 Hz), 2.55-2.68 (2
H, m), 2.78 (2H, t, J = 7.4 Hz),
3.20 (3H, s), 3.27-3.42 (2H,
m), 3.49-3.59 (3H, m), 3.65-
3.70 (1H, m), 4.44 (1H, d, J = 2.
9Hz), 4.56 (1H, d, J = 2.9Hz),
5.45 (1H, s), 5.52 (1H, s), 6.8
7 (1H, d, J = 7.6 Hz), 6.92 (1H,
s), 7.01 (1H, d, J = 7.6 Hz), 7.2
9 (1H, dd, J = 8.3, 1.2 Hz), 7.41
-7.44 (2H, m), 7.58 (1H, s), 7.
74-7.80 (3H, m).

Example 2 5- [2- [N-[(R) -2- [5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -4-
Oxo-1,3-dioxolan-5-yl] acetyl]
-N- [5- (2-naphthyl) pentyl] amino] ethyl] -1H-tetrazole

[0148]

Embedded image

The compound of Reference Example 8- (8) (0.162)
g) in ethanol (5 ml)
l) was added and the mixture was heated under reflux for 5 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 2-5% methanol-methylene chloride) to give the title compound (0.056 g) as a pale-yellow oil.

MS (FAB +) m / z: 650 (M + N
a) ⁺ , 628 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.30 (2
H, m), 1.32-1.41 (2H, m), 1.45.
−1.56 (4H, m), 1.59-1.68 (2H,
m), 1.73-1.80 (2H, m), 2.19 (3
H, s), 2.20 (3H, s), 2.46 (2H,
t, J = 7.7 Hz), 2.78 (2H, t, J = 7.
5Hz), 3.22-3.41 (5H, m), 3.47
-3.52 (1H, m), 3.63-3.70 (1H,
m), 3.86-3.93 (1H, m), 4.34 (1
H, d, J = 2.2 Hz), 4.48 (1H, d, J =
2.2 Hz), 5.38 (1H, s), 5.52 (1
H, s), 6.85 (1H, d, J = 7.6 Hz),
6.90 (1H, s), 6.99 (1H, d, J = 7.
6 Hz), 7.29 (1H, dd, J = 8.6, 1.5)
Hz), 7.39-7.45 (2H, m), 7.58
(1H, s), 7.58-7.79 (3H, m).

Example 3 (R) -N- [5- (2-naphthyl) pentyl] -2-
[5- (3,4-dimethylphenyl) pentyloxy]
-2-[(R) -4-oxo-1,3-dioxolane-
5-yl] acetohydroxamic acid

[0152]

Embedded image

The compound of Reference Example 10- (3) (1.85)
To a solution of g) in ethanol (10 ml) was added palladium hydroxide / carbon (containing 20% as palladium, 0.1 g), and the mixture was stirred under a hydrogen atmosphere for 2 days. Palladium hydroxide / carbon was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 3: 2), and further purified by high performance liquid column chromatography (Sensyu Pak ODS-5).
Purification with 251-SH, acetonitrile-0.1% trifluoroacetic acid = 9: 1) gave the title compound (0.47
5g) was obtained as a pale yellow oil.

MS (FAB +) m / z: 570 (M +
Na) ⁺ , 548 (M + H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.83 (1
2H, m), 2.21 (3H, s), 2.22 (3H,
s), 2.51 (2H, t, J = 7.8 Hz), 2.7
7 (2H, t, J = 7.8 Hz), 3.23-3.95
(5H, m), 4.55 (1H, broad s),
4.67 (1H, broads), 5.39-5.6
0 (2H, m), 5.58 (1H, s), 6.85-
7.07 (3H, m), 7.25-7.49 (3H,
m), 7.59 (1H, s), 7.71-7.83 (3
H, m).

Example 4 (R) -N-methyl-N- [5- (2-naphthyl) pentyl] -2- [5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -4-oxo-1,3-
Dioxolan-5-yl] acetamide

[0156]

Embedded image

(2R, 3R) -3- [5- (3,4-dimethylphenyl) pentyloxy] -2-hydroxy-
3- [N-methyl-N- [5- (2-naphthyl) pentyl] carbamoyl] pyrropionic acid (International Publication WO98 /
No. 2938, compound of Example 31- (8)) was treated in the same manner as in Example 1 to give the title compound as a colorless oil.

MS (ESI) m / z: 546 (M + H)
⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.81 (1
2H, m), 2.21 (3H, s), 2.22 (3H,
s), 2.48-2.57 (2H, m), 2.73-
2.83 (2H, m), 2.93 (3H, s), 3.
08 (3H, s), 3.30-3.69 (4H,
m), 4.43-4.55 (2H, m), 5.41-
5.46 (1H, m), 5.54 (1H, broad)
s), 6.86-7.06 (3H, m), 7.25-
7.50 (3H, m), 7.59 (1H, s), 7.7
2-7.83 (3H, m).

Example 5 (R) -N- [5- (2-naphthyl) pentyl] -2
-[5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -2,2-dimethyl-4-oxo-
1,3-dioxolan-5-yl] acetamide

[0160]

Embedded image

Compound of Reference Example 11- (3) (1.0 g)
2,2-dimethoxypropane (0.24 g) was added to a benzene solution (20 ml), and the mixture was heated under reflux for 150 minutes.
After cooling to room temperature, the reaction solution was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 10: 1) to give the title compound (0.95 g) as a colorless oil.

MS (FAB +) m / z: 560 (M +
H) ⁺ . ¹ H-NMR (CDCl ₃ ) δ: 1.25 to 1.43 (4
H, m), 1.49-1.62 (12H, m), 1.7.
0-1.77 (2H, m), 2.21 (3H, s),
2.22 (3H, s), 2.52 (2H, t, J = 7.
7 Hz), 2.77 (2H, t, J = 7.6 Hz),
3.22-3.38 (2H, m), 3.47 (2H,
t, J = 6.5 Hz), 4.05 (1H, d, J = 1.
7 Hz), 4.87 (1H, d, J = 1.7 Hz),
6.55 (1H, broad), 6.88 (1H, d,
J = 7.6 Hz), 6.93 (1H, s), 7.02
(1H, d, J = 7.6 Hz), 7.30 (1H, d
d, J = 8.3, 1.7 Hz), 7.38-7.46
(2H, m), 7.58 (1H, s), 7.74-7.
79 (3H, m).

Example 6 (R) -N-methyl-N- [5- (2-naphthyl) pentyl] -2- [5- (3,4-dimethylphenyl) pentyloxy] -2-[(R) -2,4-dioxo-
1,3-dioxolan-5-yl] acetamide

[0164]

Embedded image

(2R, 3R) -3- [5- (3,4-dimethylphenyl) pentyloxy] -2-hydroxy-
3- [N-methyl-N- [5- (2-naphthyl) pentyl] carbamoyl] pyrropionic acid (International Publication WO98 /
No. 2938, compound of Example 31- (8)) (83
mg) in methylene chloride (5 ml).
2 mg) was added. Pyridine (0.020m
l) was added and the mixture was stirred for 1 hour. Diphosgene (1
60 mg), and the mixture was heated under reflux for 16 hours. The reaction solution was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (eluted with ethyl acetate-hexane = 1: 2) to give the title compound (26 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ , rotamer mixture) δ: 1.26-1.38 (3H, m), 1.50-
1.63 (7H, m), 1.71-1.76 (2H,
m), 2.21 (3H, s), 2.22 (3H, s),
2.51 (2H, t, J = 7.2 Hz), 2.77 (2
H, t, J = 7.2 Hz), 2.92 (1.2H,
s), 3.12 (1.8H, s), 3.23-3.60.
(4H, m), 4.38 (0.6H, d, J = 2.0H
z), 4.43 (0.4H, broad s), 4.7
2 (0.4H, broads), 4.73 (0.6
H, broads), 6.88 (1H, d, J = 8.
0 Hz), 6.92 (1H, s), 7.00 (1H,
d, J = 7.6 Hz), 7.30 (1H, broad)
d, J = 8.4 Hz), 7.40-7.46 (2H,
m), 7.59 (1H, s), 7.74-7.80 (3
H, m).

[0167]

[Test Examples] The squalene synthase inhibitory activity and the cholesterol synthesis inhibitory activity of rat hepatocytes of the dioxolane derivative or a salt thereof of the present invention were confirmed by the following methods.

[0168] 1. Squalene synthase inhibitory activity (1) Preparation of enzyme source As an enzyme source for measuring squalene synthase inhibitory activity, a microsomal fraction prepared from human hepatoma-derived HepG2 cell line was used. For the preparation of the microsomal fraction,
Journal of Biological Chemistry (J
ownal of Biological Chem
The method of Schechter et al., described in J. Istry, Vol. 267, pp. 8628-8635 (1992) was used. That is, first, HepG2 cells were placed in 0.
3M sucrose, 1mM dithiothreitol (DT
T) 1 mM sodium ethylenediaminetetraacetate (ED
TA) and 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPE) adjusted to pH 7.4 by adding various protease inhibitors.
S) Homogenized in the presence of buffer and centrifuged at 2,000 × g for 5 minutes, 10,000 × g for 15 minutes. Phenylmethanesulfonyl fluoride (PMSF), leupeptin, and aprotinin were used as protease inhibitors at final concentrations of 1 mM, 10 μM, and 5 μM, respectively.
/ Ml. Next, the supernatant after centrifugation was further centrifuged at 105,000 × g for 60 minutes, and the obtained precipitate was subjected to 20 mM phosphate buffer (pH 7) containing 1 mM DTT, 1 mM EDTA, and the above protease inhibitor. The operation of suspending the suspension in .4) and centrifuging at 105,000 × g for 30 minutes was repeated twice to wash. The sediment is washed with 2 mM containing 1 mM DTT and 1 mM EDTA.
The suspension was suspended in 0 mM phosphate buffer (pH 7.4), centrifuged in the same manner, and the finally obtained precipitate was used as a microsomal fraction for enzyme activity measurement.

(2) Measurement of Squalene Synthase Inhibitory Activity The measurement of squalene synthase activity was also carried out in the Journal of Biological Chemistry.
Biological Chemistry) Magazine, No. 2
67, 8628-8635 (1992), according to the method of Schechter et al. That is, first, water or dimethyl sulfoxide (DM
SO) was dissolved in 5 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH), 5 mM
mM 3-[(3-cholamidopropyl) dimethylammonio] propanesulfonic acid (CHAPS), 10 mM
Potassium fluoride, 10 mM magnesium chloride, 10 m
M DTT, 1 μM / ml NB-598 (squalene epoxidase inhibitor, Journal of Biological Chemistry, Vol. 265, 18075-180
78, 1990), 50 mM HEPES buffer (pH 7.4), 0.01-0.1 μM HepG2 cell microsomal fraction, and 5 μM [ ³ H] farnesyl pyrophosphate in an enzyme reaction solution (50 μl in total volume). The reaction was carried out at 37 ° C. for 20 minutes (37 ° C. in advance).
[ ^3]
H] Farnesyl pyrophosphate was added to initiate the enzymatic reaction). 1 M EDTA (pH 9.2) was added to this enzyme reaction solution.
Was added to stop the enzyme reaction, and 5 μl of a 0.5% squalene-ethanol solution was further added. From here 4
A 0 μl portion was spotted on a plastic sheet for thin layer chromatography, developed with 5% toluene-95% hexane, dried, and then placed in iodine vapor to develop a color, thereby identifying a squalene band. This was cut out with scissors, placed in a vial, 10 ml of Aquasol-2 (New England Nuclear Research Products, USA) was added, and the radioactivity was measured with a liquid scintillation counter. The squalene synthase inhibitory activity was represented by a concentration (IC ₅₀ , molar concentration) that inhibited radioactivity incorporated by squalene by 50%.

[0170] 2. Cholesterol synthesis inhibitory activity in rat hepatocytes (1) Preparation of rat hepatocytes Hepatocytes were isolated and prepared from rat liver using an in situ collagenase perfusion method. That is, first, a 6-week-old male SD rat was anesthetized by intraperitoneal administration of a 50 mg / ml sodium pentobarbital solution. . From the cannula, first 2% albumin, 0.5 mM ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA) and 10 mM
Divalent calcium ion containing HEPES and divalent magnesium ion-free Hank's buffer (pH 7.2)
Perfusion (flow rate: 0.5 ml / sec). Next, 0.0
5% collagenase, 4 mM calcium chloride, and 10
Hanks' buffer (pH 7.
Switch to 5) and continue perfusion for another 15-20 minutes.
After confirming that the collagenase was sufficiently digested by collagenase, the liver tissue was placed in a petri dish, 30 ml of Dulbecco's modified Eagle (DME) medium was added, and the cells were dispersed by pipetting. The tissue was removed. This cell suspension is collected at 600 rpm for 1 hour.
After centrifugation for 30 minutes and adding 30 ml of DME medium to the precipitate to disperse the cells, the cells were centrifuged again at 600 rpm for 1 minute. After repeating this washing operation by centrifugation a total of three times, the obtained hepatocyte suspension was suspended in a DME medium containing 10% poor lipoprotein serum (LPDS), and the cell count was placed on a commercially available collagen-coated 6-well plate. Was seeded at 1 × 10 ⁶ cells / well and cultured overnight in a CO ₂ incubator (5% CO ₂ , 37 ° C.).

(2) Measurement of Cholesterol Synthesis Inhibitory Activity Using the hepatocytes prepared by the above method, the incorporation of [ ¹⁴ C] acetic acid radioactivity into cholesterol was measured, and the cholesterol synthesis inhibitory activity of the test drug was evaluated. That is, first, a culture solution of hepatocytes was added to 25 mM HE containing a test agent.
The medium was replaced with a PES-10% LPDS-DME medium (pH 7.4) and cultured for 1 hour in a CO ₂ incubator. Next, sodium [ ¹⁴ C] acetate was added to a final concentration of
After further culturing for 1 hour in a CO ₂ incubator, the culture supernatant was removed, washed three times with phosphate buffered saline (pH 7.2), and 1 ml of 0.1N
Dissolved in NaOH. Part of this cell lysate (10μ
l), the protein was determined by the Lowry method, and the remainder was 2 ml of ethanol and 0.5 ml of 50% KOH.
Was added and subjected to a saponification treatment at 75 ° C. for 1 hour. For the saponified sample, 50,000 dp was used as an internal standard.
m of [ ³ H] cholesterol, and add 4.5 m under ice-cooling.
l of petroleum ether was added and stirred vigorously to extract the unsaponifiable lipid. This petroleum ether layer was transferred to another test tube, dried under a stream of nitrogen, dissolved in 50 μl of dichloromethane-methanol (2: 1) containing 10 mg / ml cholesterol, and spotted on a thin-layer chromatography plastic sheet. And the toluene-ethyl acetate (3:
Expanded in 1). After the developed thin-layer chromatography sheet was dried, it was placed in iodine vapor to develop color, and a cholesterol band was identified. Cut this out with scissors, put it in a scintillation vial,
And add ¹⁴ ml with a liquid scintillation counter.
C and ³ H radioactivity was measured. The cholesterol synthesis inhibitory activity of the test drug was calculated according to the following procedure. That is, first, the difference in the extraction rate due to petroleum ether was corrected by the following equation using the measurement result of the radioactivity of [ ³ H] cholesterol added as an internal standard.

[ ¹⁴ C] Incorporation of acetic acid radioactivity into cholesterol (dpm) = ( ¹⁴ C radioactivity measurement result (dp
m) x 50,000 (dpm)) ³ H radioactivity measurement result (dpm)

Next, from this value, the ¹⁴ C radioactivity uptake value per unit protein amount (unit: dpm / mg protein) was determined using the result of measuring the protein concentration of the cell lysate. The cholesterol synthesis inhibitory activity of the test drug was represented by the concentration (IC ₅₀ , molar concentration) that inhibited this radioactivity uptake value by 50%.

[0174] 3. Experimental results I of the compound of Example 3 measured by the method described in 1 above
C ₅₀ was 1.3nM. Further, the compound of the example measured by the method shown in the above 2 and the following compound, namely, (2S) -2- [N-｛(1S, 2R) -3- (3,4)
-Dichlorophenyl) -1-methyl-2- (2-naphthoyloxy) propyl {carbamoylmethyl] succinic acid (compound A) (described in JP-A-7-138214) and N-[(3R, 5S) -7- Chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl] aminoacetic acid (compound B) (European Patent 5
Table 1 shows the cholesterol synthesis inhibitory action of rat hepatic cells on the basis of 67026).

[0175]

[Table 1]

As described above, it was confirmed that the dioxolane derivative of the present invention or a salt thereof exhibited excellent squalene synthase inhibitory activity and cholesterol synthesis inhibitory activity. In addition, as a result of an oral administration test in hamsters and the like, the compounds of Examples 1 to 3 showed a better hepatic cholesterol synthesis inhibitory action and lower blood cholesterol action than the conventional compounds.

[0177]

The dioxolane derivative or its salt of the present invention has a potent squalene synthase inhibitory activity and is useful as a medicament for preventing and / or treating hypercholesterolemia, hyperlipidemia and arteriosclerosis. It is.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/06 A61P 3/06 9/10 9/10 43/00 111 43/00 111 C07D 405/12 C07D 405/12 413/12 413/12 417/12 417/12 (72) Inventor Kenjiro Yamamoto 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo F-term in Daiichi Pharmaceutical Co., Ltd. Tokyo Research Center 4C063 AA01 BB09 CC81 DD47 DD58 DD67 EE01 4C086 AA01 AA02 AA03 BC60 BC62 BC71 BC86 GA02 GA07 GA09 GA10 MA01 MA04 NA14 ZA45 ZC20 ZC33

Claims (11)

[Claims] 1. The following formula (1) [In the formula, A ¹ and A ² are the same or different and each represent a divalent hydrocarbon group having 4 to 7 carbon atoms which may have a substituent; A ³ represents a single bond or a carbon atom which may have a substituent. A ¹ and a ² are the same or different and represent a single bond, —O— or —N (A ⁴ ) —;
(Where A ⁴ represents a hydrogen atom, a hydroxyl group or a hydrocarbon group which may have a substituent); and Q ¹ and Q ²
Represents a cyclic hydrocarbon group which may have the same or different substituent, or a heteroaromatic group which may have the substituent; Q ³ represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, 1 to 6 alkoxyl groups, cyano groups, heterocyclic groups which may have a substituent, heterocyclic groups having a hydrogen atom which can be deprotonated, carbamoyl groups which may have a substituent, and may have a substituent An acylcarbamoyl group or a carboxyl group which may be esterified; R ¹ and R ² are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, or R ¹ , R ² and It may form a carbonyl group with the carbon atom to which it is attached, or may form a 3-7 membered aliphatic ring. And a salt thereof. 2. The dioxolane derivative and the salt thereof according to claim 1, wherein in the formula (1), Q ³ is a heterocyclic group having a hydrogen atom that can be deprotonated. 3. The dioxolane derivative and the salt thereof according to claim 1, wherein in the formula (1), Q ³ is an acylcarbamoyl group which may have a substituent. 4. In the formula (1), Q ³ is a tetrazolyl group,
2,3-dihydro-2-oxo-1,3,4-oxadiazolyl group or 2,5-dihydro-5-oxo-1,
The dioxolane derivative according to claim 1, which is a 2,4-thiadiazolyl group, and a salt thereof. 5. The dioxolane derivative and the salt thereof according to claim 1, wherein in the formula (1), Q ³ is an N- (methylsulfonyl) carbamoyl group. 6. The dioxolane derivative and the salt thereof according to claim 1, wherein in the formula (1), Q ³ is a hydroxyl group. 7. The dioxolane derivative and a salt thereof according to claim 1, wherein in formula (1), a ¹ and a ² are both a single bond. 8. The compound according to claim 1, wherein in formula (1), A ¹ and A ² are both divalent hydrocarbon groups having 5 carbon atoms.
9. The dioxolane derivative and the salt thereof according to item 1. 9. The dioxolane derivative according to claim 1, wherein in formula (1), A ³ is a single bond and Q ³ is a hydroxyl group. 10. A medicament containing the dioxolane derivative or a salt thereof according to any one of claims 1 to 9. 11. Prevention and / or prevention of hypercholesterolemia, hyperlipidemia or arteriosclerosis containing the dioxolane derivative or a salt thereof according to any one of claims 1 to 10.
Or therapeutic drugs.