JPH07138214A - Substituted amic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a new substituted amic acid derivative useful for treating and preventing hypercholesterolemia, hyperlipemia and arteriosclerosis, further fungal infection. CONSTITUTION:A compound of formula I [Ar and An<2> are an aryl or a heterocyclic aromatic group; A is a 3-8C straight-chain or an unsaturated aliphatic hydrocarbon group which may contain a substituent group (an alkyl, OH, an aryl, an aralkyl, etc.); Q is single bond, CO-O, O-CO, CH2CH2, CH=CH, OCH2, SCH2, etc.; R<1> to R<4> are H, a halogen, an alkyl, OH, an alkoxy, an aryl or a heterocyclic aromatic group which may contain a substituent group (a halogen, an alkyl or an alkoxy; R<5> to R<7> are H or an alkyl; R<8> is H, an alkyl, an alkenyl, an alkynyl or an aralkyl; with the proviso that in the case where Q is a single bond, a case in which groups of formula II and formula III are both 4-chlorophenyl is omitted] such as N-{(1RS,2RS)-2-(4-biphenyl)-3-4- chlorophenyl)-1-methylpropyl}carbamoylmethylsuccinic acid.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel substituted amic acid derivative, a process for producing the same, and its use. More specifically, the substituted amic acid derivative of the present invention has a squalene synthase inhibitory action, and thus hypercholesterolemia,
It is useful in the treatment and prevention of hyperlipidemia and arteriosclerosis. Further, the substituted amic acid derivative of the present invention has an antifungal action, and is useful as a therapeutic agent or preventive agent for fungal infections.

[0002]

2. Description of the Related Art In recent years, it has been pointed out that the incidence of arteriosclerosis and various coronary and cerebral arterial diseases associated with it increases with the aging of the population and changes in eating habits. Various factors are considered for the occurrence of this arteriosclerosis,
In particular, elevated blood cholesterol is one of the most important risk factors, and blood cholesterol lowering agents are known to be effective for the treatment and prevention of arteriosclerosis [AGENTS USED TO Treat Hyper Lipidemia, Drug Evaluated Sixth Edition (Agents Used to
Treat Hyperlipidemia, Drug
Evaluations 6th. editio
n), 903-926 (1986)].

The outline of cholesterol biosynthesis in vivo is as follows.

[0004]

[Chemical 50] Currently available lovastatin, pravastatin,
Simvastatin, etc. in the cholesterol biosynthesis system,
Hydroxymethylglutaryl CoA (hereinafter HMG-C
It is an extremely superior antihypercholesterolemic agent that specifically inhibits reductase and limits cholesterol biosynthesis. However, since these HMG-CoA reductase inhibitors inhibit relatively upstream of the cholesterol biosynthesis pathway, they have a drawback that they also inhibit the biosynthesis of ubiquinone, dolichol, isopentenyl t-RNA and the like necessary for the living body. .

On the other hand, squalene synthase is HMG-Co
It is an enzyme that is involved relatively downstream in the cholesterol biosynthesis system than A reductase, and by inhibiting the enzyme, a safe antihypercholesterolemic agent with fewer side effects can be expected.

[0006] Furthermore, if squalene synthase is inhibited in the biosynthesis system of sterol, which is an essential component of fungal cell membrane, to cause cell membrane damage and suppress the growth of fungi, it can be developed as an antifungal agent. Can be expected.

As compounds having a squalene synthase inhibitory action, compounds described in JP-A-4-279589, US Pat. No. 5,135,935, WO92 / 15579 and EP513760 are known. However, there are problems in using them as medicines.

Further, as a compound having a structure most similar to that of the compound of the present invention, Journal of Medicinal Chemistry (J. Med. Chem.), No. 10
Vol., P. 717 (1967), and the literature discloses that it has a cholesterol-lowering effect. However, the compound group described in the literature is characterized by having a maleamic acid structure, and further, the mechanism of action in the cholesterol-lowering action is different from the squalene synthase inhibitory action, and thus is completely different from the compound of the present invention. is there.

[0009]

DISCLOSURE OF THE INVENTION An object of the present invention is to have a squalene synthase inhibitory action, so that it has less side effects than conventional drugs and is safe and effective, hypercholesterolemia, hyperlipidemia and arteriosclerosis. The purpose of the present invention is to provide a therapeutic agent and a preventive agent for the disease. Still another object of the present invention is to provide a more useful antifungal agent than conventional antifungal agents by inhibiting squalene synthase in the fungal sterol biosynthesis system.

[0010]

DISCLOSURE OF THE INVENTION The present inventors have proposed the general formula [I]

[0011]

[Chemical 51] [In the formula,

[0012]

[Chemical 52] Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q is a single bond or- CO-O-, -O-CO-,-
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group or a hydroxyl group. , A lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ⁵ , R ⁶ and R ⁷ are The same or different, a hydrogen atom or a lower alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that Q is a single bond,

[0013]

[Chemical 53] Both of which are 4-chlorophenyl groups)] are useful in the treatment and prevention of hypercholesterolemia, hyperlipidemia and arteriosclerosis by having a squalene synthase inhibitory action. Furthermore, they have found that the compound has an antifungal action and are useful as a therapeutic agent and a preventive agent for fungal infections, and completed the present invention.

The present invention is directed to a compound represented by the general formula [I], a pharmaceutically acceptable salt or ester thereof, a process for producing the same and use thereof and an intermediate for producing the same, that is, the general formula [II '].

[0015]

[Chemical 54] [In the formula,

[0016]

[Chemical 55] Is

[0017]

[Chemical 56] (Wherein R ^1c and R ^2c are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group) or a naphthyl group;

[0018]

[Chemical 57] Is

[0019]

[Chemical 58] (Wherein R ^3b is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R ^4b is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, a lower alkyl group and a lower alkoxy group. Means an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of
A group represented by the formula (provided that when Q is a single bond, R ^4b is an aryl group or a heteroaromatic ring which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group) the means a group); Q is a single bond or -CO-O -, - O- CO -, - CH 2 CH 2 -, - C
_{H = CH -, - OCH 2} -, - SCH 2 -, - CH 2 O-
Or a group represented by —CH ₂ S—; R ^7a represents a lower alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group] And the general formula [III-b ¹ ].

[0020]

[Chemical 59] [Wherein, R ¹² and R ¹³ are the same or different and each represents a protective group for a carboxyl group] or a compound represented by the general formula [III-b ² ].

[0021]

[Chemical 60] [Wherein R ¹² and R ¹³ have the above-mentioned meanings].

The symbols and terms used in this specification will be described.

The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert. Examples thereof include a butyl group, a pentyl group and a hexyl group, and among them, a methyl group and an ethyl group are preferable.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and for example, a fluorine atom and a chlorine atom are preferable.

The lower alkoxy group has 1 to 6 carbon atoms.
Means an alkoxy group or an alkylenedioxy group of
Examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a tert-butoxy group, a methylenedioxy group, an ethylenedioxy group, and the like. Among them, a methoxy group, an ethoxy group, a methylenedioxy group and the like are preferable.

The aryl group means a phenyl group, a naphthyl group or an anthryl group, and a phenyl group or a naphthyl group is preferable.

The heteroaromatic ring group means a 5-membered or 6-membered monocyclic aromatic heterocycle containing 1 or 2 heteroatoms selected from the same or different from the group consisting of oxygen atom, nitrogen atom and sulfur atom. A condensed ring aromatic heterocyclic group in which a cyclic group or the monocyclic aromatic heterocyclic group is condensed with the aryl group, or the same or different monocyclic aromatic heterocyclic groups are condensed with each other, for example, Pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, oxazolyl group, isoxazolyl group, furyl group, thienyl group, thiazolyl group, isothiazolyl group, indolyl group, benzofuranyl group, benzothienyl group, benzimidazolyl group Group, benzoxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzisothi group Zoriru group, indazolyl group, a purinyl group, a quinolyl group, isoquinolyl group, a phthalazinyl group,
Examples thereof include a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, and a pteridinyl group. , Quinolyl group and the like are preferable.

The lower alkenyl group has 3 to 6 carbon atoms.
Means a linear or branched alkenyl group, and examples thereof include an allyl group, a 2-butenyl group, a 3-butenyl group, a 3-methyl-2-butenyl group, a 2-pentenyl group, and a 2-hexenyl group. Among them, an allyl group and a 2-butenyl group are preferable.

The lower alkynyl group has 3 to 6 carbon atoms.
A straight-chain or branched alkynyl group, for example, propargyl group, 2-butynyl group, 3-butynyl group, 2
Examples thereof include -pentynyl group and 4-methyl-2-pentynyl group, and among them, propargyl group and 2-butynyl group are preferable.

The aralkyl group means the halogen atom,
It means the above-mentioned lower alkyl group or lower alkenyl group, preferably lower alkyl group, which has the above aryl group optionally substituted by a lower alkyl group or a lower alkoxy group, for example, a benzyl group, a phenethyl group, 3-
Phenylpropyl group, 4-chlorobenzyl group, 3-chlorobenzyl group, 3,4-dimethylbenzyl group, 4-chlorophenethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1- (2-naphthyl) ethyl Group, 3- (4-
Chlorophenyl) propyl group, 3-phenyl-2-propenyl group, 3- (4-chlorophenyl) -2-propenyl group and the like, among which benzyl group, phenethyl group,
4-chlorobenzyl group, 3,4-dimethylbenzyl group,
2-naphthylmethyl group, 1- (2-naphthyl) ethyl group, 3-phenyl-2-propenyl group and the like are preferable,
Particularly, benzyl group, 2-naphthylmethyl group, 1- (2-naphthyl) ethyl group and the like are preferable.

Examples of the saturated aliphatic hydrocarbon group include a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group and an octamethylene group. For example, a trimethylene group, a tetramethylene group, a pentamethylene group and the like. Is preferred.

The unsaturated aliphatic hydrocarbon group means an unsaturated aliphatic hydrocarbon group having 1 or 2 or more, preferably 1 or 2 double bonds at any position on the carbon chain, for example, propenylene group. , 1-butenylene group, 2-butenylene group, 1,3-butadienylene group, 1-pentenylene group,
2-pentenylene group, 1,3-pentadienylene group,
1,4-pentadienylene group, 1-hexenylene group, 2
-Hexenylene group, 3-hexenylene group, 1,3-hexadienylene group, 1,4-hexadienylene group, 1,5
-Hexadienylene group, 1,3,5-hexatrienylene group, 1-heptenylene group, 2-heptenylene group, 3-
Heptenylene group, 1,3-heptadienylene group, 1,4
-Heptadienylene group, 1,5-heptadienylene group,
1,6-heptadienylene group, 1,3,5-heptatrienylene group, 1-octenylene group, 2-octenylene group, 3-octenylene group, 4-octenylene group, 1,3
-Octadienylene group, 1,4-octadienylene group,
1,5-octadienylene group, 1,6-octadienylene group, 1,7-octadienylene group, 2,4-octadienylene group, 2,5-octadienylene group, 2,6-octadienylene group, 3,5-octadienylene group, 1 ，
3,5-octatrienylene group, 2,4,6-octatrienylene group, 1,3,5,7-octatetraenylene group and the like are mentioned, and among them, propenylene group, 1-butenylene group, 1,3 -Butadienylene group, 1-pentenylene group and the like are preferable.

The salt of the compound of the general formula [I] means a conventional pharmaceutically acceptable salt, for example, a terminal carboxyl group or a saturated or a salt represented by A in the formula of the general formula [I]. Listed are salts of a base addition salt in the carboxyl group having a carboxyl group on the unsaturated aliphatic hydrocarbon group, or an acid addition salt on the basic heteroaromatic ring having a basic heteroaromatic ring. You can

Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; for example trimethylamine salt, triethylamine salt, dicyclohexylamine salt. , Organic amine salts such as ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, and N, N′-dibenzylethylenediamine salt.

Examples of the acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; for example, maleates, fumarates, tartrates, citrates and ascorbins. Acid salts, organic acid salts such as trifluoroacetic acid salts; and sulfonic acid salts such as methanesulfonic acid salts, isethionic acid salts, benzenesulfonic acid salts, and p-toluenesulfonic acid salts.

Examples of the ester of the compound represented by the general formula [I] include a terminal carboxyl group or a compound represented by the general formula [I]:
When a saturated or unsaturated aliphatic hydrocarbon group represented by A has a carboxyl group on the carboxyl group, it means a pharmaceutically acceptable conventional one, for example, methyl group, ethyl group, propyl group, isopropyl group. Group, butyl group, sec-butyl group, ester with lower alkyl group such as tert-butyl group, allyl group, ester with lower alkenyl group such as 2-butenyl group, acetoxymethyl group, pivaloyloxymethyl group, Ester with lower alkanoyloxy lower alkyl group such as 1-pivaloyloxyethyl group, 1- (ethoxycarbonyloxy)
An ester with a lower alkoxycarbonyloxy lower alkyl group such as an ethyl group or a 1- (cyclohexyloxycarbonyloxy) ethyl group, an ester with a carbamoyloxy lower alkyl group such as a carbamoyloxymethyl group,
Ester with phthalidyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group and the like (5
Examples thereof include an ester with a -substituted-2-oxo-1,3-dioxol-4-yl) methyl group.

Further, in the case where the terminal carboxyl group or the saturated or unsaturated aliphatic hydrocarbon group represented by A in the formula [I] has a carboxyl group, it is at the γ position or δ position of the carboxyl group. When a hydroxyl group is present,
An intramolecular ester, that is, a 5-membered or 6-membered lactone ring may be formed between the hydroxyl group and the carboxyl group.

Examples of the hydroxyl-protecting group include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group;
Eg tetrahydropyranyl group; eg benzyl group, p
Aralkyl groups such as -methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group; and acyl groups such as formyl group and acetyl group, and particularly methoxymethyl group. Group, tetrahydropyranyl group, trityl group, tert-
Butyldimethylsilyl group, acetyl group and the like are preferable.

Examples of the protective group for the carboxyl group include methyl group, ethyl group, propyl group, isopropyl group, t
lower alkyl groups such as ert-butyl group; for example, 2,2
Halo-substituted lower alkyl group such as 2-trichloroethyl group, 2,2,2-trifluoroethyl group; for example, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-pi Lower alkanoyloxyalkyl group such as baroyloxyethyl group; for example, 1- (methoxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, 1-
Lower alkoxycarbonyloxyalkyl group such as (isopropoxycarbonyloxy) ethyl group; for example, 2-propenyl group, 2-chloro-2-propenyl group, 3-methoxycarbonyl-2-propenyl group, 2-methyl-2-
Lower alkenyl groups such as propenyl group, 2-butenyl group, cinnamyl group; for example, benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, bis Aralkyl groups such as (p-methoxyphenyl) methyl group and trityl group; for example, (5-methyl-2-oxo-1,
(5-substituted-2-oxo-1,3-dioxol-4-yl) methyl group such as 3-dioxol-4-yl) methyl group; lower alkylsilyl group such as trimethylsilyl group and tert-butyldimethylsilyl group An indanyl group, a phthalidyl group, a methoxymethyl group and the like, and a methyl group, an ethyl group, a tert-butyl group, a 2-propenyl group, a benzyl group, a p-methoxybenzyl group, a benzhydryl group, a trityl group and the like are particularly preferable.

General formula [I-1]

[0041]

[Chemical formula 61] [In the formula,

[0042]

[Chemical formula 62] Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; and Q ¹ represents a single bond. R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or a halogen atom,
An aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkoxy group; R ⁵ , R ⁶ and R ⁷ are the same or different and each is a hydrogen atom or a lower atom; An alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that

[0043]

[Chemical formula 63] Both of which are 4-chlorophenyl groups)] and the general formula [I-2]

[0044]

[Chemical 64] [In the formula,

[0045]

[Chemical 65] Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q ² is —CO— O -, - O-CO - , - CH 2 CH 2
-, - CH = CH -, - OCH 2 -, - SCH 2 -, - C
H ₂ O-or -CH ₂ S- group represented by; R ^1a,
R ^2a , R ^3a and R ^4a are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group; R ⁵ , R ⁶ , R ⁷ and R ^8a are the same or different and a hydrogen atom. Or a lower alkyl group] is included in the compound represented by the general formula [I].

Among the compounds represented by the general formula [I], particularly the general formula [Ia]

[0047]

[Chemical formula 66] [In the formula,

[0048]

[Chemical formula 67] Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q is a single bond or- CO-O-, -O-CO-,-
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group or a hydroxyl group. , A lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ^7a is a lower alkyl group; ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that when Q is a single bond,

[0049]

[Chemical 68] A compound represented by both) is a 4-chlorophenyl group)]] is preferable.

The compound of the general formula [I] of the present invention is
Depending on the form of the substituent, stereoisomers such as optical isomers, diastereoisomers, and geometric isomers may exist, but the compound of the general formula [I] of the present invention contains all these stereoisomers and It also includes a mixture thereof. Above all,
The configuration is represented by the general formula [I-a ¹ ].

[0051]

[Chemical 69] [In the formula,

[0052]

[Chemical 70] A, Q, R < ¹ >, R ^{< 2} >, R ^{< 3} >, R ^{< 4} >, R ^<7a > and R ^{< 8} > have the above meanings] or a compound of the general formula [Ia
² ]

[0053]

[Chemical 71] [In the formula,

[0054]

[Chemical 72] A, Q, R ¹ , R ² , R ³ , R ⁴ , R ^7a and R ⁸ have the above-mentioned meanings], that is, the configuration on the carbon atoms at the 1′-position and the 2′-position. However, Q is a single bond or-
In the case of the group represented by CH ₂ CH ₂ — or —CH═CH—, the (1 ′S, 2 ′S) configuration or (1′R, 2′R)
A compound having a configuration is preferable, and Q is -CO-O-, -O.
_{-CO -, - OCH 2 -,} - SCH 2 -, - if the CH ₂ O- or -CH ₂ S- group represented by, (1'S, 2 '
A compound having the R) configuration or the (1′R, 2 ′S) configuration is preferable, and particularly a compound represented by the general formula [Ia ¹ ], that is, Q is a single bond or —CH ₂ CH ₂ —. Or-
In the case of a group represented by CH = CH-, (1'S, 2'S)
A compound having a configuration is preferable, and Q is -CO-O-, -O.
_{-CO -, - OCH 2 -,} - SCH 2 -, - if the CH ₂ O- or -CH ₂ S- group represented by, (1'S, 2 '
Compounds in the R) configuration are preferred. In addition, 1'here
The position and the 2 ′ position are the positions shown in the above general formula [Ia ¹ ] and general formula [Ia ² ].

When Q is a group represented by -CH = CH-, geometric isomers based on the group include E isomer (trans isomer) and Z isomer (cis isomer). , E isomer is more preferred.

A saturated straight chain having 3 to 8 carbon atoms which may have a substituent selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxyl group, an aryl group and an aralkyl group in A or The unsaturated aliphatic hydrocarbon group is an unsubstituted saturated aliphatic hydrocarbon group or the unsaturated aliphatic hydrocarbon group or the saturated aliphatic hydrocarbon group having a substituent at any substitutable position or the It means an unsaturated aliphatic hydrocarbon group, and the substituent is the same or different and is 1 or 2 or more, preferably 1 or more, from the group consisting of a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxyl group, an aryl group and an aralkyl group. Or two can be selected.

Q is a single bond or --CO--O--, --OC.
_{O -, - CH 2 CH 2} -, - CH = CH -, - OCH
_{2 -, - SCH 2 -,} - CH 2 O- or means a -CH ₂ S- group represented by, among others a single bond or -CO-
_{O -, - CH 2 CH 2} -, - CH = CH -, - OCH
₂ -, - SCH ₂ - or a group represented by -CH ₂ O-is suitable.

Further, the general formula [Ib]

[0059]

[Chemical formula 73] [In the formula,

[0060]

[Chemical 74] Are the same or different and each represents an aryl group or a heteroaromatic ring group; A ^a is-(CH ₂ ) _m -C (R ⁹ ) (R ¹⁰ )-(C
H _{2) n} - in (wherein, R ⁹ is a hydrogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group a; R ¹⁰ is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a carboxyl group; m is from 1 3 of an integer; n means an integer of 1 to 4) or - (CH _{2) q} -CH =
A group represented by CH- (wherein q represents an integer of 1 to 6); Q is a single bond or -CO-O-,
_{-O-CO -, - CH 2} CH 2 -, - CH = CH -, - O
_{CH 2 -, - SCH 2 -} , - CH 2 O- or -CH ₂ S
R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or a halogen atom,
An aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkoxy group; R ^7a is a lower alkyl group; R ⁸ is a hydrogen atom, a lower alkyl group, It means a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that when Q is a single bond,

[0061]

[Chemical 75] Is more preferably a 4-chlorophenyl group))] is more preferable.

R ⁹ is preferably a hydrogen atom or a hydroxyl group, and particularly preferably a hydrogen atom.

R ¹⁰ is preferably a lower alkyl group, a lower alkoxy group or a carboxyl group, particularly a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group,
A carboxyl group and the like are preferable.

It is preferred that m and n are the same or different and are 1 or 2, and it is preferred that q is 1 or 2.

In the formula [I],

[0066]

[Chemical 76] Are the same or different and represent an aryl group or a heteroaromatic ring group; R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, or It means an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, and when Q is a single bond,

[0067]

[Chemical 77] When both are 4-chlorophenyl groups, they are excluded from the present invention.

In the formula [I], R ¹ and R ² are the same or different,

[0069]

[Chemical 78] Can be substituted at any substitutable position on the aryl group or heteroaromatic ring group represented by, R ³ and R ⁴ are the same or different,

[0070]

[Chemical 79] It can be substituted at any substitutable position on the aryl group or heteroaromatic group represented by.

The aryl group or heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group in R ¹ , R ² , R ³ or R ⁴ is Means an unsubstituted aryl group or heteroaromatic ring group or an aryl group or heteroaromatic ring group having a substituent at any substitutable position, the substituent being a halogen atom, a lower alkyl group or a lower alkyl group. From the group consisting of alkoxy groups, the same or different, 1 or 2 or more, preferably 1 or 2 can be selected. Among them, unsubstituted phenyl group, naphthyl group, or heteroaromatic ring group such as pyridyl group, oxazolyl group, thienyl group; halogenated phenyl group such as chlorophenyl group, bromophenyl group, fluorophenyl group; methylphenyl group, ethylphenyl group , Lower alkylphenyl groups such as propylphenyl group and tert-butylphenyl group; methoxyphenyl group, ethoxyphenyl group, t
Lower alkoxyphenyl groups such as ert-butoxyphenyl group and methylenedioxyphenyl group are preferable, and especially phenyl group, naphthyl group, pyridyl group, oxazolyl group, thienyl group, chlorophenyl group, fluorophenyl group, methylphenyl group, methoxy group. A phenyl group and a methylenedioxyphenyl group are preferred.

In the compound represented by the general formula [I],
formula

[0073]

[Chemical 80] The group represented by

[0074]

[Chemical 81] (Here, R ^1b and R ^2b are the same or different and each have a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, a lower alkyl group and a lower alkoxy group. A group represented by an aryl group or a heteroaromatic ring group which may be present); for example, phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4- Methylphenyl group, 3,4-dichlorophenyl group, 4-methoxyphenyl group, 3-bromophenyl group, 3-biphenylyl group, 4
-Biphenylyl group, 4'-chloro-4-biphenylyl group, 2-fluoro-4-biphenylyl group, 6-fluoro-3-biphenylyl group, 3- (2-naphthyl) phenyl group, 3- (1-naphthyl) phenyl Group, 4- (2-naphthyl) phenyl group, 1-naphthyl group, 2-naphthyl group and the like are preferable, and among them,

[0075]

[Chemical formula 82] (Wherein R ^1c and R ^2c are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group) or a naphthyl group; for example, a phenyl group, a 2-chlorophenyl group, 3-
Chlorophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-methylphenyl group, 3,4-dichlorophenyl group, 4-methoxyphenyl group, 3-bromophenyl group, 1-naphthyl group, 2-naphthyl group, etc. Certain compounds are more preferable, and compounds having 3,4-dichlorophenyl group, 4-chlorophenyl group, 1-naphthyl group, 2-naphthyl group and the like are particularly preferable.

In the formula [I], the formula

[0077]

[Chemical 83] The group represented by

[0078]

[Chemical 84] (Wherein R ^3b is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R ^4b is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, a lower alkyl group and a lower alkoxy group. Means an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of
Compounds which are groups represented by are preferred, among which 4-biphenylyl group, phenyl group, 4-chlorophenyl group, 4
-Methylphenyl group, 4-bromophenyl group, 4-te
rt-butylphenyl group, 4-methoxyphenyl group, 3
-Chlorophenyl group, 2-naphthyl group, 4'-chloro-
4-biphenylyl group, 4- (3-thienyl) phenyl group, 4- (3-pyridyl) phenyl group, 3'-chloro-
4-biphenylyl group, 3,4-dichlorophenyl group,
3,4-difluorophenyl group, 3,4-dimethylphenyl group, 3-chloro-4-methylphenyl group, 4-chloro-3-methylphenyl group, 3,4-dimethoxyphenyl group, 3,4-methylenedi group Oxyphenyl group, 3-bromophenyl group, 4- (2-naphthyl) phenyl group, 2-
Fluoro-4-biphenylyl group, 4- (2-furyl) phenyl group, 3 ', 4'-methylenedioxy-4-biphenylyl group, 2'-fluoro-4-biphenylyl group, 2'
Compounds such as -methoxy-4-biphenylyl group and 4- (5-oxazolyl) phenyl group are preferred, and when Q is a single bond, 4-biphenylyl group, 2-naphthyl group, 4 '.
-Chloro-4-biphenylyl group, 4- (3-thienyl)
Phenyl group, 4- (3-pyridyl) phenyl group, 3'-
Chloro-4-biphenylyl group, 3,4-dichlorophenyl group, 4- (2-naphthyl) phenyl group, 2-fluoro-4-biphenylyl group, 4- (2-furyl) phenyl group, 3 ', 4'-methylene Dioxy-4-biphenylyl group, 2'-fluoro-4-biphenylyl group, 2'-methoxy-4-biphenylyl group, 4- (5-oxazolyl)
A compound having a phenyl group or the like is preferable.

In the formula [I], Q is -CO-
O -, - O-CO - , - CH 2 CH 2 -, - CH = CH
_{-, - OCH 2 -, -} SCH 2 -, - CH 2 O- or -
In the case of a group represented by CH ₂ S-, the formula

[0080]

[Chemical 85] The group represented by

[0081]

[Chemical 86] (Wherein R ^3b and R ^4c are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group), and a compound represented by the formula (2) -naphthyl group is preferable. , 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,4
Compounds such as -dimethylphenyl group, 3-chloro-4-methylphenyl group, 4-chloro-3-methylphenyl group, 3,4-dimethoxyphenyl group and 3,4-methylenedioxyphenyl group are preferred.

R ^1b and R ^3b on the naphthyl group can be substituted at any substitutable position on the naphthyl group.

In the formula [I], R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a lower alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, It means a lower alkynyl group or an aralkyl group.

As R ⁵ and R ⁶ , a hydrogen atom, a methyl group, an ethyl group and the like are preferable, and a hydrogen atom is particularly preferable.

As R ⁷ , a lower alkyl group is preferable, and among them, a methyl group, an ethyl group, a propyl group and the like are preferable, and a methyl group is particularly preferable.

R ⁸ is preferably a hydrogen atom, a lower alkyl group or an aralkyl group, and among them, a hydrogen atom, a methyl group, an ethyl group, a propyl group, a benzyl group, a 3,4-dimethylbenzyl group, a 4-chlorobenzyl group, 3 , 4-dichlorobenzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1- (2-naphthyl) ethyl group and the like are preferable, and further hydrogen atom, methyl group, ethyl group, benzyl group, 2- A naphthylmethyl group, a 1- (2-naphthyl) ethyl group and the like are preferable.

Particularly, R ⁸ is preferably a hydrogen atom or a lower alkyl group, and when Q is a single bond, R ⁸ is preferably an aralkyl group in addition to the hydrogen atom or the lower alkyl group.

Next, a method for producing the compound of the present invention will be described.

The compound of the present invention represented by the general formula [I] is
For example, it can be manufactured by the following method.

General formula [II]

[0091]

[Chemical 87] [In the formula,

[0092]

[Chemical 88] Are the same or different and represent an aryl group or a heteroaromatic ring group; Q is a single bond or -CO-O-, -O-CO-,-.
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ^1p , R ^2p , R ^3p and R ^4p are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, or a protective group; An optionally substituted hydroxyl group, a lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a lower alkyl group;
R ⁸ is a hydrogen atom, a lower alkyl group, a lower alkenyl group,
It means a lower alkynyl group or an aralkyl group (provided that when Q is a single bond,

[0093]

[Chemical 89] Both of which are 4-chlorophenyl groups)] and a compound of the general formula [III]

[0094]

[Chemical 90] [In the formula, A ^p is a lower alkyl group, a lower alkoxy group, an aryl group and an aralkyl group, and optionally has a substituent selected from the group consisting of a hydroxyl group and a carboxyl group and has 3 carbon atoms. To R 8 of a linear saturated or unsaturated aliphatic hydrocarbon group; R ¹¹ represents a hydrogen atom or a protective group of a carboxyl group], or a reactive derivative thereof.
General formula [IV]

[0095]

[Chemical Formula 91] [In the formula,

[0096]

[Chemical Formula 92] A ^p , Q, R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ , R ⁷ , R
⁸ and R ¹¹ have the above-mentioned meanings], and the compound represented by the general formula [I] can be obtained by removing the protecting group if necessary.

As the reactive derivative of the carboxylic acid represented by the general formula [III], for example, acid halide, mixed acid anhydride, active ester, active amide and the like are used.

When the carboxylic acid of the general formula [III] is used, the reaction is carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. Is preferably performed.

The reaction of the compound represented by the general formula [II] with the carboxylic acid represented by the general formula [III] or a reactive derivative thereof is carried out with respect to 1 mol of the compound represented by the general formula [II]. It is carried out using 1 mol to excess mol, preferably 1 to 5 mol, of the carboxylic acid [III] or its reactive derivative.

The reaction is usually carried out in an inert solvent, and examples of the inert solvent include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane and trichloroethylene; for example, ethyl ether, tetrahydrofuran, dioxane and the like. Ethers; aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; aprotic polar solvents such as dimethylformamide, acetonitrile, acetone, ethyl acetate, hexamethylphosphoric triamide, and mixed solvents thereof.

The reaction temperature is generally -70 ° C to the boiling point of the solvent used in the reaction, preferably -20 ° C to 100 ° C.

The reaction time is usually 5 minutes to 7 days, preferably 10 minutes to 24 hours.

The above reaction can also be carried out in the presence of a base in order to promote the reaction smoothly. In particular, the general formula [II
When an acid halide or a mixed acid anhydride is used as the reactive derivative of the carboxylic acid of [I], for example, an inorganic material such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc. It is preferably carried out in the presence of a base or an organic base such as triethylamine, N-ethyldiisopropylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline.

The amount of the base used is 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the reactive derivative of the carboxylic acid of the general formula [III].

The acid halide of the compound of general formula [III] can be obtained by reacting the carboxylic acid of general formula [III] with a halogenating agent according to a conventional method.
Examples of the halogenating agent include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, phosgene and the like.

The mixed acid anhydride of the compound of the general formula [III] can be obtained by subjecting the carboxylic acid of the general formula [III] to a conventional method, for example, an alkyl chlorocarbonate such as ethyl chlorocarbonate; an aliphatic carboxylic acid chloride such as acetyl chloride. It can be obtained by reacting with. Further, whether to form an intramolecular acid anhydride between the carboxy group at both ends, of general formula [III], when having a carboxyl group on the saturated or unsaturated aliphatic hydrocarbon group represented by A ^p An intramolecular acid anhydride can be formed between the carboxyl group and the carboxyl group involved in the reaction to form a reactive derivative of carboxylic acid.

The active ester of the compound of the general formula [III] can be obtained by using the carboxylic acid of the general formula [III] according to a conventional method, for example, N, N'-dicyclohexylcarbodiimide, 1-
In the presence of a condensing agent such as ethyl-3- (3-dimethylaminopropyl) carbodiimide, an N-hydroxy compound such as N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole; 4
-Nitrophenol, 2,4-dinitrophenol,
It can be obtained by reacting with a phenol compound such as 2,4,5-trichlorophenol or pentachlorophenol.

The active amide of the compound of the general formula [III] is obtained by using the carboxylic acid of the general formula [III] according to a conventional method, for example, 1,1′-carbonyldiimidazole, 1,1′-
It can be obtained by reacting with carbonylbis (2-methylimidazole) or the like.

In the formula [II],

[0110]

[Chemical formula 93] On the group represented by or in the formula [III], A ^p
When a hydroxyl group is present on the saturated or unsaturated aliphatic hydrocarbon group represented by or when a carboxyl group is present on the compound of the general formula [III], the reaction is carried out after appropriately protecting the hydroxyl group or the carboxyl group. It is preferable to remove the protecting group after the reaction.

After completion of the reaction, usual treatment can be carried out to obtain a crude product of the compound represented by the general formula [IV]. The compound represented by the general formula [IV] thus obtained is purified according to a conventional method, or if necessary, by appropriately combining the removal reactions of the protective groups of the hydroxyl group and the carboxyl group without purification. By carrying out, a compound of the general formula [I] can be produced.

The removal of the protecting group depends on its type,
Reference method [Protective Groups in
Organic Synthesis (Protective G
roups in Organic Synthesi
s), T.S. W. By TW Greene,
John Wiley & Sons (1981)
Reference] or a method analogous thereto, for example, solvolysis using an acid or a base, chemical reduction using a metal hydride complex or hydrogenation using a palladium-carbon catalyst, Raney nickel or the like.

The compound of the general formula [I] obtained by the above-mentioned method can be isolated and purified by column chromatography using silica gel, adsorption resin, etc., liquid chromatography, solvent extraction or recrystallization / reprecipitation. This can be achieved by performing conventional separation means alone or in appropriate combination.

The compound of the general formula [I] can be converted into a pharmaceutically acceptable salt or ester by a conventional method, and conversely, the salt or ester can be converted into a free carboxylic acid according to a conventional method. .

As the compound represented by the general formula [II] and the compound represented by the general formula [III], for example, commercially available products are used, or the method described in the literature [J. Med. Chem (J. Med. Chem. .), 10th
Volume 717 (1967); pp. 725; Journal of Chemical Society, Perkin Transaction I (J. Chem. Soc. Perkin).
I), 1978, p. 1636; Chemistry Letter (Chem. Lett.), P. 191 (1980).
Pp. 375 (1984); Journal of Chemical Society, Chemical Communication (J. Chem. Soc. Chem. Commu.
n. ), 1984, p.579; Journal of.
American Chemical Society (J. Am. C
hem. Soc. ), 104, 5716 (19
1982), etc.] or a method according to these methods, or the following methods or the methods described in Examples and Reference Examples. Manufacturing method A

[0116]

[Chemical 94] [In the formula,

[0117]

[Chemical 95] Q ¹ , R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ and R ⁶ have the above-mentioned meanings, X is a halogen atom; Y is a cyano group, a carboxyl group, a lower alkoxycarbonyl group, and a chloroformyl group. Or an N-methoxy-N-methylcarbamoyl group; Z is a leaving group selected from the group consisting of a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and a p-toluenesulfonyloxy group. R ^a represents a lower alkyl group] Production method A is a raw material for producing a compound represented by the general formula [I] in which Q is a single bond and R ⁷ is a lower alkyl group. A method for producing a compound, that is, a compound represented by the general formula [II-a].

According to this production method, the desired compound [II-
a] is obtained by reacting a nitrile or carboxylic acid derivative represented by the general formula 1 with an alkyllithium represented by the general formula 2 or an alkyl Grignard reagent (or an alkyl Gilman reagent) represented by the general formula 3. To produce a ketone body 4 , and then to react the ketone body 4 with an alkylating agent represented by the general formula 5 to produce an alkyl body 6 , and then to the alkyl body 6 with a reducing agent such as a metal hydride complex. Alcohol 7 is produced by the action of
7 , azodicarboxylic acid diethyl ester, triphenylphosphine and phthalimide (or hydrazoic acid), or methanesulfonyl chloride and triethylamine, followed by phthalimide (or sodium azide) in the presence of a base. To produce a phthalimide protected form (or azide form) of the amine form [II-a], and finally to act on hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group). Can be manufactured by.

The above reaction step will be specifically described below with reference to suitable reaction conditions and the like.

In the first step, the synthesis of ketone 4 is usually carried out by reacting 1 mol of starting compound 1 with alkyl lithium 2 or alkyl in an inert solvent such as tetrahydrofuran, ethyl ether or benzene which does not participate in the reaction. 1 mole to excessive mole of the 3 (alkyl Gilman reagent in the case of substituent Y is chloroformyl group or compound 1) Grignard reagent, preferably by 1 to 5 mol action, followed by hydrolysis under acidic conditions optionally Done by.

The reaction temperature is generally -80 ° C to the boiling point of the solvent used in the reaction, preferably -70 ° C to 50 ° C, and the reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. It's time.

When the substituent Y in the formula of the raw material compound 1 is a cyano group, it is necessary to carry out a hydrolysis reaction under acidic conditions after completion of the reaction. In this case, for example, hydrochloric acid or sulfuric acid is used. Alternatively, it is carried out in the presence of an acid such as p-toluenesulfonic acid, for example, in methanol, ethanol, tetrahydrofuran or a mixed solvent thereof with water. The reaction temperature is usually 0 ° C. to the boiling point of the solvent used in the reaction, and the reaction time is 30 minutes to 24 hours.

The step of converting the ketone body 4 obtained by the above reaction into the alkyl body 6 is carried out in the presence of a base in the absence of a solvent or in an inert solvent which does not adversely influence the reaction.
It can be carried out by reacting 4 with an alkylating agent represented by the general formula 5 in an equimolar to excess molar amount, preferably 1 to 2 molar amount.

Examples of the inert solvent include ethers such as ethyl ether, tetrahydrofuran and dioxane;
Aromatic hydrocarbons such as benzene, toluene, xylene;
Examples include aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide, and mixtures of the above solvents.

Examples of the base used in this reaction include alkali metal hydrides such as sodium hydride, lithium hydride and potassium hydride; lithium amides such as lithium amide, lithium diisopropylamide and lithium bistrimethylsilylamide; For example, alkyllithium such as methyllithium, butyllithium and tert-butyllithium; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; water such as sodium hydroxide, potassium hydroxide and lithium hydroxide. Examples thereof include alkali metal oxides.

The amount of the base used is usually 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the alkylating agent 5 as the raw material.

The reaction temperature is generally -100 ° C to the boiling point of the solvent used in the reaction, preferably -80 ° C to 100 ° C.
The reaction time is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

The reaction for reducing the compound 6 obtained in the above reaction to the alcohol 7 is usually carried out in an inert solvent which does not adversely influence the reaction, for example, sodium borohydride,
Catalytic reduction using a metal hydride complex such as diisobutylaluminum hydride, lithium aluminum hydride, or trisec-butyllithium borohydride (L-selectride ^™ ), or using a palladium-carbon catalyst, Raney nickel catalyst, etc. Etc.

When a metal hydride complex is used as the reducing agent, the amount of the reducing agent used is usually 1 mol to excess mol, preferably 1 to 5 mol, relative to 1 mol of the starting compound 6.
It is a mole.

The inert solvent used in this reaction can be appropriately selected depending on the kind of the reducing agent.

For example, when the reducing agent is sodium borohydride, alcohols such as methanol and ethanol; ethers such as dimethoxyethane, dioxane, tetrahydrofuran and diglyme; aprotic polar solvents such as dimethylformamide and dimethylacetamide. An inert solvent such as or the like, water, a mixed solvent thereof or the like is used, and alcohols such as methanol and ethanol are particularly preferable.

For example, when the reducing agent is diisobutylaluminum hydride, ethers such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran, diglyme; fats such as pentane, hexane, heptane, cyclohexane, etc. Group hydrocarbons; for example, aromatic hydrocarbons such as benzene and toluene; inert solvents such as methylene chloride and mixed solvents thereof, etc. are used, with toluene and methylene chloride being particularly preferable.

For example, when the reducing agent is lithium aluminum hydride or lithium trisec-butyl borohydride,
For example, dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane,
Ethers such as dioxane, tetrahydrofuran, diglyme; aliphatic hydrocarbons such as pentane, hexane, heptane, cyclohexane; inert solvents such as aromatic hydrocarbons such as benzene and toluene, or mixed solvents thereof are used. Especially, ethyl ether, tetrahydrofuran and the like are preferable.

When carrying out catalytic reduction, alcohols such as methanol and ethanol are preferable as the solvent.

The reaction conditions will vary depending on the stability of the ketone body 6 as a raw material, the susceptibility to the reduction reaction, the type of reducing agent and the type of solvent, but the reaction temperature is usually -8.
0 ° C to 100 ° C, preferably -70 ° C to 40 ° C,
The reaction time is generally 5 minutes to 2 days, preferably 30 minutes to 24 hours.

From the alcohol 7 to the desired amine [II
In the step of producing -a], various synthetic methods and reaction conditions for converting an alcohol to an amine, which are well known in synthetic organic chemistry, can be adopted. For example, azodicarboxylic acid diethyl ester, triphenylphosphine and phthalimide ( Or hydrazoic acid) or so-called Mitsunobu reaction, or sulfonylation with a sulfonylating agent such as methanesulfonyl chloride in the presence of a base such as triethylamine, and then phthalimide (or sodium azide) in the presence of a base Can be used, and then the resulting phthalimide body (or azide body) can be treated (or reduced) with hydrazine.

The above reaction is usually carried out in an inert solvent which does not participate in the reaction. Examples of the inert solvent in the Mitsunobu reaction include tetrahydrofuran, dimethoxyethane, benzene, toluene and the like, and sulfonylation. Later, in the reaction with phthalimide (or sodium azide), for example, methylene chloride, chloroform, tetrahydrofuran, benzene, ethyl acetate, dimethylformamide, etc., and in the next step of removing phthalimide with hydrazine, for example, methanol, ethanol, etc. When the metal hydride complex is used as the reducing agent in the reduction reaction of the azide, the ethers such as ethyl ether and tetrahydrofuran are used when the phosphine reduction is performed using triphenylphosphine and the like. Hydrous tetra Dorofuran etc., in the reduction by catalytic reduction, for example, methanol, alcohols such as ethanol and the like are preferable.

In the Mitsunobu reaction, for example, the amount of the reagent used is 1 mol of the alcohol compound 7 as a raw material, and 1 mol of diethyl azodicarboxylic acid, triphenylphosphine and phthalimide (or hydrazoic acid) are used. It is a mole to an excess mole, preferably 1 to 5 moles. In the reaction of reacting phthalimide (or sodium azide) after sulfonylation, 1 mole of alcohol 7 is treated with a sulfonylating agent such as methanesulfonyl chloride. 1 mol to excess mol, preferably 1 to 2 mol, and the base such as triethylamine used in this case is 1 mol to excess mol, preferably 1 to 2 mol, per 1 mol of the sulfonylating agent. In the reaction of phthalimide (or sodium azide) in the presence of the base, Against Le agent 1 mole, 1 mole to excessive mole, preferably 1 to 5 mol of phthalimide and a base or sodium azide, used. In this case, the base used together with phthalimide is preferably sodium carbonate, potassium carbonate or the like, and the sodium salt or potassium salt of phthalimide can be used as it is without using these bases. Next, in the reaction for removing the phthalimide group with hydrazine, the amount of hydrazine is 1 mol to an excess mol, preferably 1 to 10 mol, based on 1 mol of the phthalimide compound as a raw material compound. In the reduction reaction with phosphine, the reducing agent is 1 mol to excess mol, preferably 1 to 2 mol, relative to 1 mol of the azide compound as the raw material compound.

As the reaction conditions, in the case of the above Mitsunobu reaction,
The reaction temperature is generally -70 ° C to 100 ° C, preferably-
20 ° C to 50 ° C, and the reaction time is usually 5 minutes to 4
It is 8 hours, preferably 30 minutes to 24 hours. In the reaction for removing the phthalimide group with hydrazine, the reaction temperature is usually 0 ° C to the boiling point of the solvent used in the reaction, preferably room temperature to 100 ° C, and the reaction time is usually 5
Minutes to 48 hours, preferably 30 minutes to 24 hours. In the reaction of reducing the azide to convert it to the amine,
When a metal hydride complex is used as the reducing agent, the reaction temperature is generally -70 ° C to 150 ° C, preferably -20 ° C to
50 ° C., the reaction time is usually 5 minutes to 48 hours,
It is preferably 10 minutes to 10 hours, and when triphenylphosphine is used as the reducing agent, the reaction temperature is
Usually, it is from room temperature to the boiling point of the solvent used for the reaction, preferably from 30 ° C to 100 ° C, and the reaction time is usually 10
Minutes to 48 hours, preferably 30 minutes to 24 hours. In the case of reduction by catalytic reduction, the reaction temperature is usually 0 ° C to 100 ° C, preferably room temperature to 50 ° C,
The reaction time is usually 10 minutes to 48 hours, preferably 1
0 minutes to 24 hours.

In the present production method, the nitrile or carboxylic acid derivative represented by the general formula 1 is reacted with the alkylating agent represented by the general formula 5 to previously produce an alkyl compound, and then the alkyl compound is prepared. An alkyllithium represented by the general formula 2 or an alkyl Grignard reagent represented by the general formula 3 (or an alkyl Gilman reagent) is allowed to act on the body to give a compound represented by the general formula 6 . The reaction at this time can be carried out under the same conditions as in the above-mentioned production method A. Therefore, as the reaction conditions and the like, all the methods described in the above-mentioned production method A can be used as they are.

The compound represented by the general formula 1 or 5 may be a commercially available product, or may be produced by appropriately combining the methods described in the examples and reference examples or the known methods or their modifications as necessary. You can Manufacturing method B

[0142]

[Chemical 96] [In the formula,

[0143]

[Chemical 97] R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ , R ⁷ , R ⁸ , ^Ra and X have the above-mentioned meanings, and Boc means a tert-butoxycarbonyl group] Production Method B Is a production intermediate of an ester derivative in which Q is a group represented by —CO—O— in the formula [I], that is,
This is a method for producing a compound represented by the general formula [II-b].

According to this production method, the desired compound [II-
b] is obtained by first reacting a carboxylic acid represented by the general formula 8 or its reactive derivative with N, O-dimethylhydroxylamine to give an active amide 9 and the amide is represented by the general formula 10. A Grignard reagent is reacted to produce a ketone body 11 , and a reducing agent such as a metal hydride complex is allowed to act on the ketone body, or a Grignard reagent (or alkyllithium) represented by the general formula 12 is allowed to act on the alcohol. Isomer 13 or 14 is produced, then the carboxylic acid represented by the general formula 15 or its reactive derivative is allowed to act on the alcohol 13 or 14 to produce an ester, and finally tert which is a protecting group for amino group. It can be produced by removing the butoxycarbonyl group.

The above reaction step will be specifically described below with reference to suitable reaction conditions and the like.

The first step, the preparation of the active amide derivative 9 , is usually carried out in an inert solvent such as tetrahydrofuran, methylene chloride or dimethylformamide, which does not participate in the reaction, per 1 mol of the carboxylic acid 8 or its reactive derivative. It can be carried out by reacting a molar or excess molar amount of N, O-dimethylhydroxylamine or its hydrochloride. As the more specific reaction conditions of this reaction, the various conditions in the reaction between the compound represented by the general formula [II] and the carboxylic acid of the general formula [III] or the reactive derivative thereof can be applied as they are.

The process for producing the ketone body 11 from the active amide body 9 is usually carried out in the following general formula with respect to 1 mol of the active amide body 9 in an inert solvent which does not participate in the reaction such as ethyl ether, tetrahydrofuran and benzene. It can be carried out by reacting the Grignard reagent represented by 10 with 1 mol to excess mol, preferably 1 to 2 mol.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used in the reaction, preferably from -20 ° C to 40 ° C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 10 hours. It's time.

The step of reducing the ketone body 11 to the alcohol body 13 is carried out in an inert solvent which does not adversely influence the reaction.
For example, sodium borohydride, diisobutyl aluminum hydride, lithium aluminum hydride, tri sec
-Butyl lithium borohydride (L-selectri
de ^™ ), such as metal hydride complexes or, for example, palladium-
It can be carried out by catalytic reduction using a carbon catalyst or Raney nickel catalyst.

When a metal hydride complex is used as the reducing agent, the amount of the reducing agent used is usually 1 of the starting compound 11 .
1 mol to excess mol, preferably 1 to mol, relative to mol
It is 5 mol.

The inert solvent used in this reaction can be appropriately selected depending on the kind of the reducing agent.

For example, when the reducing agent is sodium borohydride, alcohols such as methanol and ethanol; ethers such as dimethoxyethane, dioxane, tetrahydrofuran and diglyme; aprotic polar solvents such as dimethylformamide and dimethylacetamide. An inert solvent such as or the like, water, a mixed solvent thereof or the like is used, and alcohols such as methanol and ethanol are particularly preferable.

For example, when the reducing agent is diisobutylaluminum hydride, ethers such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran, diglyme; fats such as pentane, hexane, heptane, cyclohexane, etc. Group hydrocarbons; for example, aromatic hydrocarbons such as benzene and toluene; inert solvents such as methylene chloride and chloroform, and mixed solvents thereof are used, and toluene and methylene chloride are particularly preferable.

For example, when the reducing agent is lithium aluminum hydride or lithium trisec-butyl borohydride,
For example, dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane,
Ethers such as dioxane, tetrahydrofuran, diglyme; aliphatic hydrocarbons such as pentane, hexane, heptane, cyclohexane; inert solvents such as aromatic hydrocarbons such as benzene and toluene, or mixed solvents thereof are used. Especially, ethyl ether, tetrahydrofuran and the like are preferable.

When carrying out catalytic reduction, alcohols such as methanol and ethanol are preferable as the solvent.

The reaction temperature and reaction time will vary depending on the stability of the ketone body 11 as a raw material, the susceptibility to the reduction reaction, the type of reducing agent and the type of solvent, etc., but the reaction temperature is usually -80. C. to 100.degree. C., preferably -70.degree. C. to 40.degree. C., and the reaction time is usually 5 minutes to 2 days, preferably 30 minutes to 24 hours.

The step of producing the alcohol body 14 from the ketone body 11 is usually represented by the general formula 12 with respect to 1 mol of the ketone body 11 in an inert solvent such as tetrahydrofuran, ethyl ether or benzene which does not participate in the reaction. 1 of the Grignard reagent (or alkyl lithium)
It can be carried out by reacting in a molar to excess molar amount, preferably 1 to 5 molar.

The reaction temperature is generally -80 ° C to the boiling point of the solvent used in the reaction, preferably -70 ° C to 50 ° C, and the reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. It's time.

[0159] step of producing a compound represented by the alcohol compound 13 or 14 in the general formula [II-b] is carboxylic acid or a reactive derivative thereof with respect to the alcohol compound 13 or 14, represented by the general formula 15 In an equimolar or excess molar amount, and then subjecting the resulting ester form to a deprotection reaction, that is, a de-tert-butoxycarbonyl group reaction.

Alcohol, the first step in this reaction
The step of reacting 13 or 14 with a carboxylic acid represented by the general formula 15 or a reactive derivative thereof to produce an ester is, for example, the above-mentioned compound represented by the general formula [II] and the general formula [III]. Can be carried out under the same conditions as the reaction with the carboxylic acid or its reactive derivative.

The deprotection reaction which is the next step is
Usually, it is carried out by reacting an acid such as trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid in a solvent that does not participate in the reaction or in the absence of the solvent.
For example, the ester obtained in the above reaction is directly
Alternatively, it is dissolved in an inert solvent such as methylene chloride or anisole, and an excess amount of an organic acid such as trifluoroacetic acid or formic acid is usually added at -20 ° C to 100 ° C, preferably 0 ° C.
~ Room temperature, 5 minutes to 48 hours, preferably 30 minutes to 2
4 hours or methanol, ethanol,
In the presence of a mineral acid or an organic acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, which is prepared to have a dilute concentration in tetrahydrofuran or a mixed solvent of them and water, usually 0 ° C or a solvent used for the reaction Boiling point, preferably 0 ° C to 100 ° C, for 5 minutes to 48 hours, preferably 30 minutes to 24 hours.

As the compound represented by the general formula 8 , 10 , 12 or 15 , a commercially available product may be used, or a method described in Examples / Reference Examples or a known method or a method analogous thereto may be appropriately combined. Can be manufactured by. Manufacturing method C

[0163]

[Chemical 98] [In the formula,

[0164]

[Chemical 99] R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ , R ^7a , R ^a , X and Z have the above-mentioned meanings, and E is a trityl group or te.
rt-butyldimethylsilyl group; Q ^a represents a phthalimido group or an azido group; Q ^b represents a methyl group, a phenyl group or a p-tolyl group] The production method C is represented by the formula [I]: Is -CH = CH-
The method is a process for producing an intermediate for producing a vinylene derivative which is a group represented by, that is, a compound represented by the general formula [II-c].

According to this production method, the desired compound [II-
c] is obtained by first reacting a β-keto acid derivative represented by the general formula 16 with an alkylating agent represented by the general formula 5 to produce an alkyl compound 17, and then converting the alkyl compound 17 to a metal hydride. after allowed to act a reducing agent such as a complex with an alcohol body to produce the resulting expressed only hydroxyl groups of primary alcohols body is selectively protected by the general formula 19 compounds, the compound 1
9 to diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide acid)
Or a sulfonylating agent represented by the general formula 20 is used to sulfonylate the secondary hydroxyl group, and then phthalimide (or sodium azide) is allowed to act in the presence of a base to give a phthalimide compound (or Azido body)
Manufactures, then after leaving the protective group of primary hydroxyl group is oxidized to produce aldehyde 21, after producing a vinylene derivative is reacted with Wittig reagent of the general formula 22 in the aldehyde 21 , And hydrazine to remove the phthalimide group (or reduce the azido group).

The above reaction steps will be specifically described below with reference to suitable reaction conditions.

[0167] The process for manufacturing the first alkyl body 17 from one β- ketoacid derivative 16 in step usually does not adversely affect the reaction in an inert solvent in the presence of a base, the β- keto acid derivative 16 The alkylating agent represented by the general formula 5 is 1 mol to excess mol, preferably 1 to 2 mol, per 1 mol.
It can be carried out by using a molar action.

Examples of the inert solvent include ethers such as ethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; aprotic substances such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide. Examples thereof include polar solvents, mixtures of the above solvents, and the like.

Examples of the base used in this reaction include alkali metal hydrides such as sodium hydride, lithium hydride, potassium hydride; lithium amide, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, etc. Alkali metal amides such as; alkyl lithium such as methyl lithium, butyl lithium, and tert-butyl lithium; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like.

The amount of the base used is usually 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the starting alkylating agent.

The reaction temperature is generally -100 ° C to the boiling point of the solvent used in the reaction, preferably -80 ° C to 100 ° C.
The reaction time is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

In the step of producing the compound represented by the general formula 19 from the alkyl compound 17 , the first reduction step is carried out in an inert solvent which does not adversely influence the reaction, such as sodium borohydride or lithium borohydride. , Diisobutylaluminum hydride, lithium aluminum hydride, trisec-butyllithium borohydride (Ls
This is achieved by reacting a metal hydride complex such as electride ^™ ). Regarding the conditions of this reduction reaction, the conditions for the case where compound 6 is reduced to a compound 7 using the metal hydride complex in the above production method A can be applied as it is. In addition, especially in this reaction, first, the compound 17
The ketone group of sodium borohydride or tri-sec
-After reduction with butyl lithium borohydride or the like, it is preferable to successively reduce the ester group with lithium borohydride, lithium aluminum hydride or the like, and the reaction conditions at this time are all the same as those in the above production method A. It can be used as is.

Next, in the step of producing the compound 19 by selectively protecting only the primary hydroxyl group of the alcohol obtained by the above reduction reaction, a trityl group or tert as a protecting group is used.
-Butyldimethylsilyl group is used, for example, in an inert solvent that does not adversely influence the reaction, in the presence of a base, in the presence of a base, 1 mol to an excess mol, preferably 1 mol.
It can be carried out by reacting ˜1.5 mol of trityl chloride or tert-butyldimethylchlorosilane.

Examples of the inert solvent include methylene chloride, tetrahydrofuran, dimethylformamide and the like, and examples of the base include triethylamine, 4-dimethylaminopyridine, imidazole and the like.

The reaction temperature is usually from -20 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to room temperature,
The reaction time is usually 10 minutes to 7 days, preferably 30 minutes.
Minutes to 24 hours.

From the compound represented by the general formula 19 to the general formula 2
Process for producing a compound represented by 1, initially Compound 1
9 to diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide acid)
Or a sulfonylation agent represented by the general formula 20 in the presence of a base such as triethylamine is reacted with phthalimide (or sodium azide) in the presence of a base. Thereby, the secondary hydroxyl group of the compound 19 is converted into a phthalimido group or an azido group, and then the primary hydroxyl group-protecting group represented by E in the formula is removed and then oxidized.

In the step of converting the secondary hydroxyl group into a phthalimide group (or azido group) which is the first step, compound 7 is phthalimidated (or azido) in the above production method A to give compound [II-a]. It can be carried out by the same method as in the step of producing a protected phthalimide (or azide), and therefore, the reaction conditions and the like can all be the same as those in production method A.

The step of removing the protective group for the primary hydroxyl group represented by E in the formula from the phthalimide derivative (or azide derivative) obtained in the above reaction is usually carried out in a solvent not participating in the reaction. Depending on the type, for example, when the protecting group is a trityl group, acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid,
By treating with an acid such as p-toluenesulfonic acid,
When the protective group is a tert-butyldimethylsilyl group, it can be treated with an acid as described above or with a fluoride salt such as tetrabutylammonium fluoride or potassium fluoride.

The reaction solvent varies depending on the type of various reactions and the stability of the compound, but when it is treated with an acid, for example, methylene chloride, methanol, ethanol, tetrahydrofuran or a mixed solvent thereof with water, and particularly an acid. When acetic acid, formic acid, trifluoroacetic acid or the like is used as the solvent, it is preferable to carry out the reaction using the acid itself or a mixture of the acid and water as a solvent, and further fluorinating tributylammonium fluoride or potassium fluoride. When a salt is used, for example, tetrahydrofuran, methylene chloride, dimethylformamide and the like are preferable.

In both the case of treating with an acid and the case of using a fluoride salt, the reaction temperature is usually from -20 ° C to the boiling point of the solvent used in the reaction, preferably from -20 ° C to 50 ° C, and the reaction time is Usually, it is 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

The step of oxidizing the primary alcohol derivative obtained above to the aldehyde derivative 21 is usually carried out in an inert solvent which does not participate in the reaction, as an oxidizing agent, for example, pyridinium chlorochromate, pyridinium dichromate, pyridine. Sulfur oxide complex salt or oxalyl chloride and dimethyl sulfoxide (so-called Swern oxidation condition) are used.

As the inert solvent, halogenated hydrocarbons such as methylene chloride and chloroform are usually preferable, and the amount of the oxidizing agent used is 1 alcohol of the starting material.
The amount is usually 1 mol to excess mol, preferably 1 to 2 mol per mol.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used in the reaction, preferably from -80 ° C when oxalyl chloride and dimethyl sulfoxide are used as oxidants.
0 ℃, when using other oxidizing agents, -20 ℃
~ Room temperature.

The reaction time depends on the type of oxidant
Usually 10 minutes to 48 hours, preferably 30 minutes to 24
It's time.

From the aldehyde 21 to the general formula [II-c]
Process for producing a compound represented by in the aldehyde 21
And a Wittig reagent represented by the general formula 22 are reacted to produce a vinylene derivative, which is then reacted with hydrazine to remove the phthalimido group (or reduce the azido group).

[0186] step of reacting Wittig reagents of the general formula 22 to aldehyde 21 initially is generally inert solvent which does not adversely influence the reaction, aldehyde form 2
To 1 of 1 mole, 1 mole to excessive mole, preferably be carried out by the action of 1-1.5 molar Wittig reagent 22.

This reaction is usually preferably carried out in the presence of a base or by treating Wittig reagent 22 with a base in advance.

Examples of the base include alkali metal hydrides such as sodium hydride, lithium hydride and potassium hydride; for example methyllithium, butyllithium and te.
alkyl lithium such as rt-butyl lithium; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide;
Examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.

The amount of the base used is usually 1 mol to excess mol, preferably 1 to 1.5 mol, per 1 mol of the Wittig reagent represented by the general formula 22 .

The reaction temperature is generally -100 ° C to the boiling point of the solvent used in the reaction, preferably -80 ° C to 50 ° C, and the reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 24. It's time.

Next, hydrazine is allowed to act on the vinylene derivative to remove the phthalimide group (or reduce the azide group).
Then, in the step of producing the compound represented by the general formula [II-c], the phthalimide protected body (or azide body) of the compound [II-a] obtained by converting the compound 7 in the above-mentioned production method A can be used. The phthalimide group can be removed (or the azido group can be reduced) in the same manner as in the step of producing compound [II-a]. Therefore, all reaction conditions and the like can be applied.

The compound represented by the general formula 16 or 22 may be a commercially available product, or may be produced by appropriately combining the methods described in the examples and reference examples or the known methods or their modifications according to need. You can Manufacturing method D

[0193]

[Chemical 100] [In the formula,

[0194]

[Chemical 101] R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ , R ⁷ , R ^a , Q ^a and Q ^b have the above-mentioned meanings, and Q ^c is a trityl group, a tetrahydropyranyl group or methoxymethyl. Group or tert-
A butyldimethylsilyl group; Q ^p means an oxygen atom or a sulfur atom] In the production method D, in the formula [I], Q is —O—CH ₂ —.
Or -S-CH ₂ - ether is a group represented by derivatives or manufacturing intermediates sulfide derivatives, i.e., namely a compound represented by the general formula [II-d].

According to this production method, the desired compound [II-
d] is a compound represented by the general formula 24 , which is produced by first reducing the ketone group of the compound represented by the general formula 17 to a hydroxyl group using a metal hydride complex or the like and then protecting the hydroxyl group. The ester group of the compound 24 is again reduced to a hydroxymethyl group using a metal hydride complex or the like, and the hydroxymethyl group is sulfonylated with a sulfonylating agent represented by the general formula 20 to produce a compound of the general formula 25 , The compound 25 has the general formula
After producing an ether or sulfide by reacting the compound represented by 26 , the hydroxyl-protecting group is removed to produce a compound represented by the general formula 31 , and the compound 27 is an azodicarboxylic acid diethyl ester. , Triphenylphosphine and phthalimide (or hydrazoic acid), or after sulfonylation with a sulfonylating agent represented by the general formula 20 , phthalimide (or sodium azide) is allowed to act in the presence of a base. It can be produced by producing a phthalimide body (or azide body), and finally reacting with hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the acid group).

The above reaction step will be specifically described below with reference to suitable reaction conditions.

The step of reducing the compound represented by the general formula 17 is usually carried out in an inert solvent which does not adversely influence the reaction,
For example, it can be carried out using a metal hydride complex such as sodium borohydride or sodium trisec-butyl sodium borohydride.

Regarding the reaction conditions and the like in this reduction reaction, the conditions and the like for the reduction reaction of compound 17 in the above-mentioned production method C can be used as they are.

The step of obtaining the compound 24 in which a hydroxyl group is protected from the reductant obtained in the above reaction is usually carried out in an inert solvent which does not adversely influence the reaction, in a tert-butyldimethylchlorosilane, trityl chloride, chlorodimethyl ether or 2, It can be performed using 3-dihydropyran or the like.

When a chloride such as trityl chloride, chlorodimethyl ether or tert-butyldimethylchlorosilane is used as a protecting reagent in the above reaction, the reaction conditions are usually such that the compound 17 in the above Production Method C is protected and then the hydroxyl group is protected. The conditions of the process can be used as they are. When 2,3-dihydropyran is used as a protective reagent, usually, in the presence of a catalyst such as p-toluenesulfonic acid or pyridinium p-toluenesulfonate, halogenated hydrocarbons such as methylene chloride and chloroform are usually used. It can be carried out in a solvent.

The amount of 2,3-dihydropyran used is usually preferably an excess amount with respect to the starting alcohol.

The reaction temperature is generally -80 ° C to the boiling point of the solvent used in the reaction, preferably -20 ° C to room temperature, and the reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. Is.

From the compound represented by the general formula 24 to the general formula 2
Process for producing a compound represented by the 5 first compound 24
The ester group of is reduced in an inert solvent which does not adversely influence the reaction, for example, by a metal hydride complex such as lithium aluminum hydride or lithium borohydride, and the hydroxyl group of the obtained alcohol is adversely affected. This is achieved by sulfonylation with a sulfonylating agent represented by the general formula 20 in the presence of a base in an inert solvent.

The above steps include the step of reducing the ester group of compound 17 in the above production method C, and compound 19
Can be carried out by the same method as the step of sulfonylating, and therefore, the same reaction conditions and the like can be applied.

[0205] to produce a compound represented by the general formula 27 from sulfonyloxy body 25, typically in an inert solvent which does not adversely influence the reaction, the presence of a base, in general formula 26 in sulfonyloxy 25 Table By reacting the compound described above with an ether derivative or a sulfide derivative, and treating the ether derivative or the sulfide derivative with an acid or a fluoride salt in an inert solvent that does not adversely influence the reaction. it can.

In the first step of etherification or sulfidation, an inert solvent such as methylene chloride, tetrahydrofuran, benzene or dimethylformamide is usually preferred, and a base such as sodium hydride or hydroxide is preferred. Sodium, potassium hydroxide, sodium carbonate, potassium carbonate and the like are preferable.

The amount of the reagent used is usually 1 mol to an excess mol, preferably 1 to 2 mol, of the compound represented by the general formula 26 per 1 mol of the sulfonyloxy derivative 25 , and the base is The amount is 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula 26 .

The reaction temperature is generally -80 ° C to the boiling point of the solvent used in the reaction, preferably -20 ° C to 100 ° C, and the reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. It's time.

From alcohol 27 to general formula [II-d]
In the step of producing the compound represented by, first, the alcohol 27 is treated with azodicarboxylic acid diethyl ester, triphenylphosphine and phthalimide (or hydrazoic acid), or in the presence of a base such as triethylamine, After sulfonylation with a sulfonylating agent represented by the formula 20, it is treated with phthalimide (or sodium azide) in the presence of a base to convert it to a phthalimide body (or azide body), and subsequently the obtained phthalimide body (or The azide compound) is usually treated with hydrazine (or a reducing agent) in an inert solvent that does not adversely influence the reaction.

The above reaction is a reaction of introducing a phthalimido group (or azido group) into the compound 7 or 19 in the above-mentioned production methods A and C, and a reaction of removing the phthalimido group (or reducing an azido group) as a final step. The same method can be used, and therefore, the same reaction conditions can be applied.

The compound represented by the general formula 26 may be a commercially available product, or can be produced by appropriately combining the methods described in the examples / reference examples or the known methods or their modifications according to need. . Manufacturing method E

[0212]

[Chemical 102] [In the formula,

[0213]

[Chemical 103] R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ , R ⁷ , R ^a , Q ^a ,
Q ^b and Z Production process E have the meanings given above, of general formula [I], Q is -CH ₂ CH ₂ -
And a method for producing an intermediate for producing an ethylene derivative in which R ⁶ is a hydrogen atom, that is, a compound represented by the general formula [II-e].

According to this production method, the desired compound [II-
e] firstly reacts a β-keto acid derivative represented by the general formula 17a with an alkylating agent represented by the general formula 28 to produce an alkyl derivative 29 , and subsequently, to form an ester group of the alkyl derivative. after hydrolysis, and decarboxylation to prepare the compound 30, after producing the alcohol compound 31 by reducing the compound 30 with a reducing agent such as the complex metal hydride, the resulting alcohol 31
With azodicarboxylic acid diethyl ester, triphenylphosphine and phthalimide (or hydrazoic acid), or with a sulfonylating agent represented by the general formula 20 to sulfonylate the hydroxyl group and then in the presence of a base. , Phthalimide (or sodium azide) is allowed to act to produce a phthalimide body (or azide body),
Finally, it can be produced by reacting with hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group).

The above reaction steps will be specifically described below with reference to suitable reaction conditions.

First step, β-keto acid derivative 17a
The step of producing the alkyl derivative 29 from the same can be carried out by the same method as the method of alkylating the β-keto acid derivative 16 with the alkylating agent 5 in the above-mentioned production method C. Therefore, the reaction conditions and the like are all the same. Conditions are available.

The step of hydrolyzing the alkylated compound 29 and subsequently decarboxylation is carried out in an inert solvent which does not adversely influence the reaction such as methanol, ethanol, propanol, tetrahydrofuran, dioxane and a mixed solvent thereof with water. , For example sodium hydroxide, potassium hydroxide,
Hydrolyze the ester group by acting an alkali metal hydroxide such as lithium hydroxide, sodium carbonate, potassium carbonate, or a base such as an alkali metal carbonate, and treat the obtained alkali metal salt of carboxylic acid with an acid. After forming the free carboxylic acid, it is preferably carried out by heating in a solvent such as benzene, toluene, methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide, acetic acid, etc. that does not adversely affect the reaction, preferably at 50 ° C to 100 ° C. it can. The reaction time required for decarboxylation at this time is usually 1 minute to 48 hours, preferably 10 minutes to 24 hours.

Next, the ketone body 30 obtained above is reduced with a reducing agent such as a metal hydride complex to give an alcohol body 31.
And then converting the obtained alcohol form into a phthalimide form (or azide form) and finally reacting with hydrazine (or a reducing agent) to produce the target compound [II-e]. process a, B, step of reducing the compound 6, 11 or 17 C and D to produce the alcohol compound, like compounds in process a, C and D 7, 19
Or 27 is phthalimidized (or azido),
The reaction can be carried out by the same method as the step of removing the phthalimide group (reducing the azido group) later, and therefore, the same reaction conditions can be applied.

The compound represented by the general formula 28 may be a commercially available product, or can be produced by appropriately combining the methods described in the examples and reference examples or the known methods or their modifications according to need. . Manufacturing method F

[0220]

[Chemical 104] [In the formula,

[0221]

[Chemical 105] Q, R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ , R ⁷ and R ⁸
Has the above meaning] Production method F is a synthetic method for producing an amine derivative [II] from a compound represented by the general formula 32 .

According to this production method, the desired amine compound [I
[I] causes an alcohol compound represented by the general formula 32 to act with a sulfonating agent such as methanesulfonyl chloride in the presence of a base, or a halogenating agent such as thionyl chloride or phosphorus tribromide. Then, after converting the hydroxyl group in the formula to a leaving group, the compound can be produced by subsequently reacting with an amine compound represented by the general formula 33 .

The reaction for introducing a leaving group is usually carried out, for example, with methylene chloride, chloroform, benzene, tetrahydrofuran,
In an inert solvent such as ethyl acetate, 1 mol to excess mol, preferably 1 to 2 mol, per 1 mol of alcohol 32.
It can be carried out by reacting with one mole of sulfonating agent and base or with 1 to excess moles, preferably 1 to 5 moles of halogenating agent.

The reaction temperature is generally -70 ° C to the boiling point of the solvent used in the reaction, preferably -20 ° C to 80 ° C, and the reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. It's time.

Next, the step of allowing the amine compound 33 to act on the compound obtained by introducing the leaving group after the introduction of the leaving group is usually
For example, in an inert solvent such as methylene chloride, chloroform, benzene, ethyl ether, or tetrahydrofuran, 1 mol to excess mol, preferably 1 to 50 mol, of amine compound 33 is used with respect to 1 mol of the starting compound having a leaving group. Can be done by

If necessary, this reaction can be carried out in the presence of a base other than the amine compound represented by the general formula 33 .

Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate, or triethylamine, N-ethyldiisopropylamine, pyridine, N, N-. Examples include organic bases such as dimethylaniline.

The amount of the base used is usually 1 mol to excess mol, preferably 1 to 5 with respect to 1 mol of the starting compound.
It is a mole.

The reaction temperature is usually from -50 ° C to 150 ° C,
It is preferably −20 ° C. to 100 ° C., and the reaction time is generally 5 minutes to 7 days, preferably 10 minutes to 24 hours.

The compound represented by the general formula 33 may be a commercially available product, or can be produced by appropriately combining the methods described in the examples and reference examples or the known methods or their modifications, if necessary. . Manufacturing method G

[0231]

[Chemical formula 106] [In the formula,

[0232]

[Chemical formula 107] Q, R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ , R ⁷ and R ⁸
Has the above meaning, R ^b is a hydroxyl group, a lower alkyl group,
A lower alkenyl group, a lower alkynyl group or an aralkyl group is meant.] Production method G is a synthetic method for producing an amine body [II] from a ketone body represented by the general formula 34 .

According to this production method, the desired compound [II]
Is usually, for example, methanol, ethanol, benzene,
Ethyl ether, in an inert solvent such as tetrahydrofuran, per mole of the starting carbonyl body 34, the general formula 3
It can be produced by reacting the compound represented by 5 with 1 mol to excess mol, preferably 1 to 2 mol to form an oxime or imine in advance, and then reducing this.

The reaction temperature in the process of forming the oxime and imine is usually 0 ° C. to the boiling point of the solvent used in the reaction, preferably room temperature to 100 ° C., and the reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 2
4 hours. After formation of the oxime and imine, the reaction solution is used as it is for the reduction reaction in the next step, or the reaction solution is distilled off, or the oxime form or imine form is isolated by a conventional separation means, and the subsequent reduction reaction is performed. Can be attached to.

As the reduction reaction, for example, a metal hydride complex such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or the like is used, or catalytic reduction using, for example, a palladium-carbon catalyst, a Raney nickel catalyst or the like. Can be done by.

When a metal hydride complex is used as the reducing agent, the amount of the reducing agent used is usually 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the imine.

In the reduction reaction, alcohols such as methanol and ethanol are appropriately used as a solvent depending on the kind of the reducing agent; for example, dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran, diglyme and the like. Ethers; aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; inert solvents such as aromatic hydrocarbons such as benzene and toluene; and mixed solvents thereof are used.

The reaction temperature is usually from 0 ° C to room temperature, and the reaction time is usually from 1 hour to 6 hours.

For the compound represented by the general formula 34 , a commercially available product may be used for the compound represented by the general formula 35 , or a known method or a method analogous thereto may be appropriately used. It can be manufactured by combining them. Manufacturing method H

[0240]

[Chemical 108] [In the formula,

[0241]

[Chemical 109] Q, R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ and R ⁷ have the above-mentioned meanings, and R ^c is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group. R ^d represents a hydrogen atom or a lower alkyl group; R ^e represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group.] Production method H is a substitution on the nitrogen atom in the general formula [I]. A method for producing a production intermediate for producing a compound of the present invention in which the group R ⁸ is a lower alkyl group, that is, a method for producing a compound represented by the general formula [II-g].

According to this production method, the desired compound [II-
g] is usually a compound represented by the general formula 36 with respect to 1 mol of the compound represented by the general formula [II-f] in an inert solvent such as methanol, ethanol, benzene, ethyl ether, or tetrahydrofuran. Can be produced by reacting 1 mol to an excess mol, preferably 1 to 2 mol, to form an imine in advance, and then reducing this.

The reaction temperature in the process of forming the imine is usually 0 ° C. to the boiling point of the solvent used in the reaction, preferably room temperature to 100 ° C., and the reaction time is usually 5
Minutes to 48 hours, preferably 30 minutes to 24 hours. After the imine is formed, the reaction solution can be used as it is for the reduction reaction in the next step, or the reaction solution can be distilled off or the imine derivative can be isolated by an ordinary separation means and then subjected to the subsequent reduction reaction.

As the reduction reaction, for example, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or the like metal hydride complex or the like is used, or, for example, catalytic reduction using a palladium-carbon catalyst, Raney nickel catalyst or the like. Can be done by.

When a metal hydride complex is used as the reducing agent, the amount of the reducing agent used is usually 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the imine.

In the reduction reaction, alcohols such as methanol and ethanol are appropriately used as solvents depending on the type of reducing agent; for example, dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran, diglyme and the like. Ethers; aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; inert solvents such as aromatic hydrocarbons such as benzene and toluene; and mixed solvents thereof are used.

The reaction temperature is usually from 0 ° C to room temperature, and the reaction time is usually from 1 hour to 6 hours.

The compound represented by the general formula 36 may be a commercially available product, or can be produced by appropriately combining the methods described in the examples and reference examples or the known methods or their modifications according to need. . Manufacturing method I

[0249]

[Chemical 110] [Wherein R ^f and R ^h are the same or different and represent a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group; R ⁱ and R ^j are the same or different and represent a protecting group for a carboxyl group; and R ^g is tert. -Butyl group, benzyl group,
Means a benzhydryl group or a trityl group] Production method I is a synthetic method for producing a carboxylic acid derivative represented by the general formula [III-a] among the compounds represented by the general formula [III]. .

According to this production method, the objective carboxylic acid derivative [III-a] is prepared by converting the ester derivative having the protecting group R ^g for the carboxyl group, which can be easily eliminated, represented by the general formula 29 into a base. In the presence of the above, a so-called Michael addition reaction of reacting a maleic acid derivative or a fumaric acid derivative represented by the general formula 30 with the resulting Michael adduct 3
From 1 , it can be produced by removing the protecting group R ^g for the carboxyl group under mild conditions.

The protecting group for the carboxyl group of R ⁱ and R ^j is preferably a lower alkyl group such as tert-butyl group or a benzhydryl group.

As the protecting group R ^g , for example, a tert-butyl group, a benzyl group, a benzhydryl group or a trityl group, which can be easily removed under mild conditions such as weak acidity or catalytic reduction, and Michael addition can be mentioned. Those which are stable under the reaction conditions are preferable.

The above Michael addition reaction is generally carried out in an inert solvent such as benzene, ethyl ether, tetrahydrofuran or the like in the presence of a base such as sodium hydride, butyllithium, lithium diisobutyramide or lithium bistrimethylsilylamide. The reaction can be carried out by reacting 1 mol of the compound represented by the formula 29 with 1 mol to an excess mol, preferably 1 to 2 mol of the compound represented by the formula 30 .

The amount of the base used is usually 1 mol to a slight excess mol, preferably 1 to 1.5 mol, relative to 1 mol of the compound represented by the general formula 30 .

The reaction temperature is usually from -100 ° C to 100 ° C.
C, preferably -80 C to room temperature, and the reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 10 hours.

The deprotecting group reaction from the compound represented by the general formula 31 to the desired carboxylic acid derivative [III-a] has different reaction conditions depending on the kind of the protecting group. In the case of a butyl group, a benzhydryl group or a trityl group, it is usually, for example, methylene chloride,
Anisole, tetrahydrofuran, methanol, in an inert solvent such as methanol or a mixed solvent thereof with water, or in the absence of a solvent, for example, using an acid such as acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, preferably -20
Examples include a method of treating at a temperature of 50 ° C to 50 ° C for 10 minutes to 24 hours.

For example, when the protecting group is a benzyl group, a benzhydryl group or a trityl group, it is usually in an inert solvent such as methanol, ethanol, water, acetic acid or the like or a mixed solvent thereof, such as a palladium-carbon catalyst or a Raney nickel catalyst. With catalyst, preferably 1 to 20 kg / c
1 under a hydrogen pressure of m ² preferably in the range of 0 ° C to 40 ° C.
Examples thereof include a method of catalytic reduction for 0 minutes to 24 hours.

In the compound represented by the general formula [III-a], the general formula [III-b ¹ ]

[0259]

[Chemical 111] Or the general formula [III-b ² ].

[0260]

[Chemical 112] [Wherein, R ¹² and R ¹³ are the same or different and each represents a protective group of a carboxyl group], and the optically active compound is represented by the general formula [III-b]

[0261]

[Chemical 113] [Wherein R ¹² and R ¹³ are the same or different and each represents a protective group for a carboxyl group], and a racemic compound of the compound represented by the following formula is reacted with cinchonidine or quinine to prepare a diastereoisomer mixture. Using the difference in solubility between the diastereoisomers, one of the diastereoisomers is separated, collected, and then decomposed with an acid.

The separation of the diastereoisomer mixture is carried out in an organic solvent such as carbon tetrachloride or isopropyl ether. Usually, the diastereoisomer mixture is dissolved in the organic solvent under heat and then gradually added. It can be carried out by cooling and utilizing the solubility difference between the diastereoisomers.

Furthermore, one of the diastereoisomers obtained above is treated with an acid such as hydrochloric acid to give a compound of the general formula [III-b ¹ ] or the general formula [I-b ¹ ].
II-b ^2] can be obtained an optically active compound represented by the.

The compound represented by the general formula 29 or 30 may be a commercially available product, or may be produced by appropriately combining the methods described in Examples and Reference Examples or known methods or methods analogous thereto as appropriate. You can

The compound of the general formula [I
I ']

[0266]

[Chemical 114] [In the formula,

[0267]

[Chemical 115] Is

[0268]

[Chemical formula 116] (Wherein R ^1c and R ^2c are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group) or a naphthyl group;

[0269]

[Chemical 117] Is

[0270]

[Chemical 118](Where R^3bIs hydrogen atom, halogen atom, lower
An alkyl group or a lower alkoxy group; R^4bIs hydrogen
Child, halogen atom, lower alkyl group, lower alkoxy
Group, or a halogen atom, a lower alkyl group and a lower alkyl group.
Having a substituent selected from the group consisting of lucoxy groups,
Means an aryl group or a heteroaromatic ring group)
A group represented by (provided that when Q is a single bond, R is^4bIs a halogen
Group, a lower alkyl group and a lower alkoxy group.
An aryl which may have a substituent selected from the group
Group or heteroaromatic group); Q is a single bond or
Is -CO-O-, -O-CO-, -CH₂CH₂-, -C
H = CH-, -OCH₂-, -SCH₂-, -CH₂O-
Or -CH₂A group represented by S-; R^7aIs lower al
Kill group; R⁸Is a hydrogen atom, a lower alkyl group, a lower alkyl
Means a alkenyl group, lower alkynyl group or aralkyl group
And a compound represented by the general formula [III-b ¹]

[0271]

[Chemical formula 119] [Wherein, R ¹² and R ¹³ are the same or different and each represents a protective group for a carboxyl group] or a compound represented by the general formula [III-b ² ].

[0272]

[Chemical 120] The compound represented by the formula [wherein R ¹² and R ¹³ have the above-mentioned meanings] is an important intermediate for producing the compound represented by the general formula [I], and is a novel compound not described in the literature. It is a compound.

The present invention also relates to a compound represented by the general formula [II ′] and a compound represented by the general formula [III-b ¹ ] or a compound represented by the general formula [III-b ² ].

In the compound represented by the general formula [II ′], the general formula [II′-1]

[0275]

[Chemical 121] [In the formula,

[0276]

[Chemical formula 122] Q, R ^7a and R ⁸ have the above meanings] or a compound represented by the general formula [II′-2]

[0277]

[Chemical 123] [In the formula,

[0278]

[Chemical formula 124] Q, R ^7a and R ⁸ have the above-mentioned meanings], and a compound represented by the general formula [II′-1] is particularly preferable.

In the formula [II '],

[0280]

[Chemical 125] Is

[0281]

[Chemical formula 126] (Wherein R ^1c and R ^2c are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group) or a naphthyl group, and specific examples include Phenyl group, 2
-Chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-methylphenyl group, 3,4-dichlorophenyl group, 4-methoxyphenyl group, 3-bromophenyl group, 1-naphthyl group,
A 2-naphthyl group, preferably a 3,4-dichlorophenyl group, a 4-chlorophenyl group, a 1-naphthyl group, a 2-naphthyl group and the like can be mentioned.

[0282]

[Chemical 127] Is

[0283]

[Chemical 128] (Wherein R ^3b is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R ^4b is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, a lower alkyl group and a lower alkoxy group. Means an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of
(Provided that when Q is a single bond, R ^4b is an aryl group or a heteroaromatic ring which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group) Means a group), and specific examples include 4-biphenylyl group, phenyl group, 4-
Chlorophenyl group, 4-methylphenyl group, 4-bromophenyl group, 4-tert-butylphenyl group, 4-methoxyphenyl group, 3-chlorophenyl group, 2-naphthyl group, 4'-chloro-4-biphenylyl group, 4 -(3-
Thienyl) phenyl group, 4- (3-pyridyl) phenyl group, 3'-chloro-4-biphenylyl group, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 3,
4-dimethylphenyl group, 3-chloro-4-methylphenyl group, 4-chloro-3-methylphenyl group, 3,4-
Dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 3-bromophenyl group, 4- (2-naphthyl)
Phenyl group, 2-fluoro-4-biphenylyl group, 4-
(2-furyl) phenyl group, 3 ', 4'-methylenedioxy-4-biphenylyl group, 2'-fluoro-4-biphenylyl group, 2'-methoxy-4-biphenylyl group, 4
Examples thereof include a-(5-oxazolyl) phenyl group. However, in the formula of the general formula [II ′], when Q is a single bond, for example, 4-biphenylyl group, 2-naphthyl group, 4′-chloro-4-biphenylyl group, 4- (3-thienyl) phenyl group, 4- (3-pyridyl) phenyl group, 3'-chloro-
4-biphenylyl group, 3,4-dichlorophenyl group, 4
-(2-naphthyl) phenyl group, 2-fluoro-4-biphenylyl group, 4- (2-furyl) phenyl group, 3 ',
4'-methylenedioxy-4-biphenylyl group, 2'-
Fluoro-4-biphenylyl group, 2'-methoxy-4-
Specific examples include a biphenylyl group and a 4- (5-oxazolyl) phenyl group.

General formula [III-b ¹ ] or general formula [I
II-b ² ], R ¹² and R ¹³ are the same or different and each represents a protective group for a carboxyl group, and for example, a lower alkyl group such as a tert-butyl group or a benzhydryl group is preferable. And a tert-butyl group and the like are particularly preferable.

To specifically demonstrate the usefulness of the compound of the present invention, the compound of the present invention having a squalene synthase activity of 5 was used.
The 0% inhibitory concentration (IC ₅₀ value) was determined. Squalene Synthase Inhibitory Action (1) Preparation of Microsome Fraction Journal of Biological Chemistry (J. Biol. Chem.), Vol. 267, Vol. 86
Microsome fractions were prepared from human hepatoma (Hep G2) cells by the method of Shechter et al. Described in Section 28 (1992).

That is, Hep G2 cells were treated with 0.3 M sucrose-1 mM DTT-1 mM EDTA-10 mMH.
Homogenize in the presence of epes buffer (pH 7.4) and various protease inhibitors, and perform 5 minutes at 2000 × g for 1 minute.
Centrifuged at 0000 xg for 15 minutes. The obtained supernatant was further centrifuged at 105,000 × g for 60 minutes to obtain a precipitate. This precipitate was suspended in the above buffer containing various protease inhibitors, and further centrifuged at 105,000 × g for 30 minutes to wash the precipitate. The washing operation was repeated 3 times. The finally obtained precipitate was used as a microsome fraction, suspended in the above buffer solution containing no various protease inhibitors, and used for measuring the enzyme activity. (2) Method for measuring squalene synthase activity The enzymatic reaction of squalene synthase is described in Journal of Biological Chemistry (J. Biol. Che.
m. ), Vol. 267, Item 8628 (1992), according to the method of Shechter et al.

Specifically, 50 μl of the reaction solution containing the microsome fraction prepared in (1) (microsome fraction 2-20
μg, 5 mM MgCl ₂ , 10 mM DTT, 2 mM
NADPH, 10 μM [ ³ H] farnesyl pyrophosphate, 100 mM phosphate buffer (pH 7.4)) was added with 1 μl of a dimethyl sulfoxide solution containing the compound of the present invention, and 3
A shaking reaction was performed at 7 ° C. for 20 minutes. Generated in the reaction solution
³ H- squalene and ^[3 H] farnesyl separation of pyrophosphate is Analytical Biochem (Ana
l. Biochem. ), 203, 310 (1
992) and the method of Tait et al. ³ H-
The radioactivity of squalene was measured with a liquid scintillation counter and used as the enzyme activity. Thus, the 50% inhibitory concentration (IC ₅₀ value) of the compound of the present invention on the squalene synthase activity was determined. The results are shown in the table below.

[0288]

[Table 1] From the above results, the compound of the present invention has an excellent squalene synthase inhibitory action, and is therefore useful in the treatment and / or prevention of hypercholesterolemia, hyperlipidemia and arteriosclerosis.

Furthermore, the compound of the present invention has a fungal squalene synthase inhibitory action and is therefore useful as an antifungal agent.

The compound of the general formula [I] of the present invention can be administered orally or parenterally, and by formulating into a form suitable for such administration, hypercholesterolemia, hyperlipidemia It can be provided as a therapeutic agent and a preventive agent or an antifungal agent for diseases such as infectious diseases and arteriosclerosis. In clinical use of the compound of the present invention, it is also possible to add a pharmaceutically acceptable additive in accordance with its administration form and administer it after various preparations. As the additive in that case, various additives usually used in the pharmaceutical field can be used, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn starch, micro. Crystallin wax,
White petrolatum, magnesium aluminometasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate , Light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin or hydroxypropyl cyclodextrin.

The dosage forms formulated as a mixture with these additives are, for example, tablets, capsules, granules,
Solid preparations such as powders or suppositories; or liquid preparations such as syrups, elixirs or injections; and in the case of antifungal agents, aerosols, eye drops, ointments, eye ointments, suspensions, emulsions, Creams, liniments, lotions and the like can be mentioned, which can be prepared according to the usual methods in the field of formulation. The liquid preparation may be dissolved or suspended in water or another suitable medium before use. Further, particularly in the case of an injection, it may be dissolved or suspended in physiological saline or glucose solution as necessary, and a buffering agent or a preservative may be added.

These preparations contain the compound of the present invention in an amount of 1.0 to 100% by weight, preferably 1.0 to 60% by weight, of the total drug.
It can be contained in the ratio of. These formulations may also contain other therapeutically effective compounds.

When the compound of the present invention is used as an antihyperlipidemic agent, antiarteriosclerotic agent or antihypercholesterolemic agent, the dose and frequency of administration are as follows:
Generally, in the case of oral administration, 0.01 to 20 mg / kg per day for an adult is divided into 1 to several doses per day, and parenteral In the case of administration, 0.001-2 mg / k
It is preferable to administer g in 1 to several divided doses.

When the compound of the present invention is used as an antifungal agent, the dose and frequency of administration vary depending on the sex of the patient, age, body weight, degree of symptoms, kind and range of desired therapeutic effect, etc. Generally, in the case of oral administration, 0.1 to 20 mg / kg is divided into 1 to several times per day for an adult, and in the case of parenteral administration, 0.01 to 2 mg / kg.
Is preferably administered in 1 to several divided doses.

[0295]

EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. Example 1 N-{(1RS, 2RS) -2- (4-biphenylyl)
-3- (4-chlorophenyl) -1-methylpropyl}
Preparation of carbamoylmethylsuccinic acid (1RS, 2RS) -2- (4-biphenylyl) -3-
(4-chlorophenyl) -1-methylpropylamine 1
00 mg, carboxymethyl succinic acid di-tert-butyl ester 78 mg and 4-dimethylaminopyridine 66 mg were dissolved in dichloromethane 3 ml, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 52 mg was added under ice-cooling stirring. And stirred overnight at room temperature. The reaction solution was poured into ice water, ethyl acetate was added for extraction,
1N hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution,
Then, it was washed successively with saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off and the residue was subjected to silica gel column chromatography (Wakogel ^TM C
-200, 10 g; hexane / ethyl acetate = 5/1) to obtain 126 mg (yield 77%) of a di-tert-butyl ester of the title compound.

126 mg of the ester obtained above was dissolved in 1 ml of dichloromethane, 1 ml of trifluoroacetic acid was added under stirring with ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 2 ml of toluene was added to the residue, and the mixture was concentrated under reduced pressure again. The obtained residue was treated with benzene to give 75 mg (yield 73%) of the title compound as a white crystalline powder, mp167.
˜169 ° C.

[0297]¹H-NMR (CDCl₃) Δ: 1.01
(3H, d, J = 6.6Hz), 2.47 (1H, d
t, J = 5.6 Hz, 15.1 Hz), 2.60-2.
95 (5H, m), 3.05-3.15 (1H, m),
3.20-3.30 (1H, m), 4.30-4.35
(1H, m), 6.92 (2H, d, J = 8.3H
z), 7.13 (2H, d, J = 8.3 Hz), 7.1
1 (2H, d, J = 7.5 Hz), 7.30-7.36
(1H, m), 7.43 (1H, t, J = 7.4H
z), 7.49 (2H, d, J = 8.0 Hz), 7.5
7 (2H, d, J = 7.4 Hz). (1RS, 2RS) -2 used as a raw material in the above reaction
-(4-biphenylyl) -3- (4-chlorophenyl)
Corresponding amination in place of -1-methylpropylamine
The same reaction as in Example 1 was carried out except that the compound was used.
Thus, the compounds of Examples 2 to 45 were obtained. Example 2N-{(1RS, 2RS) -1-methyl-2,3-diph
Phenylpropyl} carbamoylmethyl succinic acid ¹ H-NMR (CD₃OD) δ: 0.90 (3 / 2H,
d, J = 6.6 Hz), 0.91 (3 / 2H, d, J =
6.6 Hz), 2.41-2.88 (6H, m), 3.
11-3.30 (2H, m), 4.25 (1H, m),
6.88-7.25 (8H, m). Example 3N-{(1RS, 2RS) -2- (4-chloropheny
) -1-Methyl-3-phenylpropyl} carbamoy
Lumethylsuccinic acid ¹ H-NMR (CD₃OD) δ: 0.91 (3 / 2H,
d, J = 6.8 Hz), 0.92 (3 / 2H, d, J =
6.8 Hz), 2.40-2.95 (6H, m), 3.
08-3.29 (2H, m), 4.12-4.31 (1
H, m), 6.90-7.21 (9H, m). Example 4N-{(1RS, 2RS) -3- (4-chloropheny
) -1-Methyl-2-phenylpropyl} carbamoy
Lumethylsuccinic acid ¹ H-NMR (CD₃OD) δ: 0.89 (3 / 2H,
d, J = 6.6 Hz), 0.90 (3 / 2H, d, J =
6.6 Hz), 2.40-2.80 (6H, m), 3.
00-3.30 (2H, m), 4.20 (1H, m),
6.80-7.25 (9H, m). Example 5N-{(1RS, 2RS) -2- (4-chloropheny
) -1-Methyl-3- (4-methylphenyl) propy
Ru} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.96 (3H, d, J
= 6.9 Hz), 2.24 (3H, s), 2.43 (1
H, ddd, J = 1.7Hz, 4.8Hz, 15.0H
z), 2.59-2.69 (2H, m), 2.74-
2.86 (2H, m), 2.40-2.80 (6H,
m), 2.89-2.97 (1H, m), 3.03 (1
H, dd, J = 4.5 Hz, 12.9 Hz), 3.21
-3.25 (1H, m), 4.25-4.30 (1H,
m), 6.05-6.08 (1H, m), 6.85 (2
H, d, J = 7.6 Hz), 6.96 (2H, d, J =
8.3 Hz), 7.02 (2H, d, J = 8.3H
z), 7.22 (2H, d, J = 7.6 Hz). Example 6N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (4-Fluorophenyl) -1-methylpro
Pill} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.96 (3H, d, J
= 7.0 Hz), 2.40-2.55 (1H, m),
2.60-2.90 (5H, m), 3.07 (1H,
d, J = 11.4 Hz), 3.20-3.30 (1H,
m), 4.27 (1H, quint., J = 7.0H)
z), 6.78-6.90 (5H, m), 6.98 (2
H, d, J = 8.2 Hz), 7.21 (2H, d, J =
8.2 Hz). Example 7N-{(1RS, 2RS) -3- (4-biphenylyl)
-2- (4-chlorophenyl) -1-methylpropyl}
Carbamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.93 (3H, d, J
= 6.7 Hz), 2.33-2.47 (1H, m),
2.55-2.99 (5H, m), 3.01-3.13
(1H, m), 3.18-3.32 (1H, m), 4.
18-4.36 (1H, m), 6.12 (1H, b
r. ), 6.88-7.03 (4H, m), 7.12-
7.21 (2H, m), 7.22-7.30 (1H,
m), 7.31-7.42 (4H, m), 7.43-
7.52 (2H, m). Example 8N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (3-Chlorophenyl) -1-methylpropyi
Ru} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.96 (3H, d, J
= 6.4 Hz), 2.45 (1H, dd, J = 4.5H)
z, 15.5 Hz), 2.62-2.83 (4H,
m), 2.87-2.95 (1H, m), 3.06 (1
H, dd, J = 4.1 Hz, 13.3 Hz), 3.24
-3.31 (1H, m), 4.29 (1H, quin
t. , J = 2.6 Hz), 6.11 (1H, t, J =
9.5 Hz), 6.75-6.77 (1 H, m), 6.
96-6.99 (3H, m), 7.02-7.05 (2
H, m), 7.21 (2H, d, J = 7.8 Hz). Example 9N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (2-Chlorophenyl) -1-methylpropyi
Ru} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.97 (3 / 2H,
d, J = 6.6 Hz), 0.98 (3 / 2H, d, J =
6.6Hz), 2.50 (1H, dd, J = 5.0H
z, 15.5 Hz), 2.65-2.84 (4H,
m), 2.89-2.98 (1H, m), 3.26-
3.34 (2H, m), 4.32-4.40 (1H,
m), 6.08 (1H, br.), 6.68 (1H, d
t, J = 2.0 Hz, 7.9 Hz), 6.91-7.0
6 (2H, m), 6.97 (2H, d, J = 8.3H
z), 7.19 (2H, d, J = 8.3 Hz), 7.2
3-7.27 (1H, m). Example 10N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (4-Methoxyphenyl) -1-methylpro
Pill} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.86-0.92 (3
H, m), 2.40 (1H, dd, J = 4.2Hz, 1
5.5 Hz), 2.63-3.03 (6H, m), 3.
03-3.27 (1H, m), 3.70 (1H, s),
4.20-4.31 (1H, m), 5.93 (1H,
t, J = 7.8 Hz), 6.68 (2H, dd, J =
1.7 Hz, 8.5 Hz, 6.99 (2H, d, J =
8.1 Hz), 7.21 (2H, d, J = 8.1H
z). Example 11N-{(1RS, 2RS) -2- (4-chloropheny
Ru) -1-methyl-3- (1-naphthyl) propyl} ca
Lubamoylmethyl succinic acid ¹ H-NMR (CD₃OD) δ: 0.96 (3 / 2H,
d, J = 6.0 Hz), 0.97 (3 / 2H, d, J =
6.0 Hz), 2.48-2.83 (4H, m), 3.
06-3.12 (2H, m), 3.26-3.28 (1
H, m), 3.77 (1H, dd, J = 9.0 Hz, 1
4.5 Hz), 4.35-4.42 (1H, m), 6.
87 (1H, d, J = 7.5 Hz), 6.97 (2H,
d, J = 7.5 Hz), 7.11 (1H, d, J = 7.
5 Hz), 7.13 (2H, d, J = 6.0 Hz),
7.40-7.53 (2H, m), 7.58 (1H,
d, J = 8.5 Hz), 7.78 (1H, d, J = 8.
5 Hz), 8.09 (1H, d, J = 8.5 Hz). Example 12N-{(1RS, 2RS) -2- (4-chloropheny
L) -1-methyl-3- (2-naphthyl) propyl} ca
Lubamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.92 (3H, d, J
= 6.0 Hz), 2.20-2.45 (2H, m),
2.46-2.82 (2H, m), 2.83-3.08
(2H, m), 3.09-3.30 (2H, m), 4.
20-4.35 (2H, m), 4.50-5.50 (2
H, br. ), 6.25 (1H, br.), 6.92.
(2H, s), 7.08-7.20 (3H, m), 7.
34 (3H, s), 7.48-7.75 (3H, m). Example 13N-{(1RS, 2RS) -3- (4-chloropheny
) -1-methyl-2- (4-methylphenyl) propy
Ru} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.96 (3H, d, J
= 6.9 Hz), 2.29 (3H, s), 2.44 (1
H, dt, J = 5.0Hz, 15.0Hz), 2.50
-2.90 (5H, m), 2.98-3.09 (1H,
m), 3.19-3.29 (1H, m), 4.27 (1
H, dq, J = 3.3 Hz, 6.6 Hz), 6.89
(2H, d, J = 8.3 Hz), 6.94 (2H, d,
J = 8.1 Hz), 7.05 (2H, d, J = 8.1H)
z), 7.09 (2H, d, J = 8.3 Hz). Example 14N-{(1RS, 2RS) -2- (4-bromopheny
) -3- (4-Chlorophenyl) -1-methylpropyi
Ru} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.94 (2H, d, J
= 6.6 Hz), 2.47 (1H, dt, J = 5.6H)
z, 15.2 Hz), 2.62-2.82 (5H,
m), 3.07 (1H, dd, J = 3.0Hz, 10.
0Hz), 3.24 (1H, dt, J = 6.3Hz, 1
3.1 Hz), 4.25 (1H, q, J = 6.6H
z), 6.85 (2H, d, J = 8.3Hz), 6.9.
2 (2H, d, J = 8.0 Hz), 7.09 (2H,
d, J = 8.3 Hz), 7.36 (2H, d, J = 8.
0 Hz). Example 15N-{(1RS, 2RS) -2- (4-tert-butyl
Ruphenyl) -3- (4-chlorophenyl) -1-methyl
Lupropyl} carbamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.96 (3H, d, J
= 6.6 Hz), 1.28 (9 H, s), 2.45 (1
H, dt, J = 5.0 Hz, 14.9 Hz), 2.59
-2.89 (5H, m), 2.98-3.08 (1H,
m), 3.20-3.30 (1H, m), 4.25 (1
H, q, J = 6.6 Hz), 6.89 (2H, d, J =
8.3 Hz), 6.97 (2H, d, J = 8.3H)
z), 7.08 (2H, d, J = 7.4 Hz), 7.2
5 (2H, d, J = 8.1 Hz). Example 16N-{(1RS, 2RS) -3- (4-chloropheny
) -2- (4-Methoxyphenyl) -1-methylpro
Pill} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃+ CD₃OD) δ: 0.94
(3H, d, J = 6.6Hz), 2.45 (1H, d
t, J = 6.0 Hz, 15.0 Hz), 2.60-2.
80 (5H, m), 3.00-3.10 (1H, m),
3.20-3.28 (1H, m), 3.78 (3H,
s), 4.20-4.28 (1H, m), 6.78 (2
H, d, J = 8.5 Hz), 6.86 (2H, d, J =
8.2Hz), 6.96 (2H, d, J = 8.5H
z), 7.08 (2H, d, J = 8.2Hz). Example 17N-{(1RS, 2RS) -2- (3-chloropheni
) -3- (4-Chlorophenyl) -1-methylpropyi
Ru} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.99 (3H, d, J
= 6.5 Hz), 2.43 (1H, d, J = 5.2H
z), 2.67-2.90 (5H, m), 3.04 (1
H, dd, J = 3.9 Hz, 13.2 Hz), 3.25
-3.32 (1H, m), 4.30 (1H, q, J =
6.7 Hz), 5.94 (1H, br.), 6.86-
6.91 (3H, m), 7.06 (1H, s), 7.0
9-7.13 (2H, m), 7.18 (2H, d, J =
3.5 Hz). Example 18N-{(1RS, 2RS) -3- (4-chloropheny
Ru) -1-methyl-2- (1-naphthyl) propyl} ca
Lubamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.94 (3H, d, J
= 5.9 Hz), 2.31-2.35 (1H, m),
2.55-2.79 (3H, m), 2.99-3.03
(1H, m), 3.16-3.28 (2H, m), 4.
02-4.10 (1H, m), 4.40-4.45 (1
H, m), 6.20-6.30 (1H, m), 6.85.
(2H, d, J = 8.0 Hz), 6.87 (2H, d,
J = 7.7 Hz), 6.93 (2H, d, J = 7.7H)
z), 6.95 (2H, d, J = 8.0 Hz), 7.3
3-7.42 (4H, m), 7.65-7.68 (1
H, m), 7.73-7.76 (1H, m), 7.86
-7.89 (1H, m). Example 19N-{(1RS, 2RS) -3- (4-chloropheny
Ru) -1-methyl-2- (2-naphthyl) propyl} ca
Lubamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.98 (3H, d, J
= 6.6 Hz), 2.40-2.50 (1H, m),
2.56-2.86 (3H, m), 2.92-3.16
(3H, m), 3.24-3.36 (1H, m), 4.
39 (1H, dq, J = 7.1Hz, 14.1Hz),
6.10 (1H, br.), 6.86 (2H, br.
d, J = 8.0 Hz), 7.01 (1H, d, J = 8.
0 Hz), 7.03 (1H, d, J = 8.0 Hz),
7.23 (2H, br.d, J = 9.3Hz), 7.4
0-7.45 (3H, m), 7.68-7.79 (3
H, m). Example 20N-{(1RS, 2RS) -3- (4-chloropheny
) -2- (4-Hydroxyphenyl) -1-methyl group
Ropil} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.96 (3H, d, J
= 6.3 Hz), 2.44 (1H, dt, J = 4.8H)
z, 14.6 Hz), 2.60-2.86 (5H,
m), 2.96-3.06 (1H, m), 3.18-
3.28 (1H, m), 4.16-4.26 (1H,
m), 6.71 (2H, d, J = 8.0 Hz), 6.8
9 (4H, d, J = 8.4Hz), 7.08 (2H,
d, J = 7.1 Hz). Example 21N-{(1RS, 2RS) -2- (4'-chloro-4-
Biphenylyl) -3- (4-chlorophenyl) -1-me
Cylpropyl} carbamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.99 (3H, d, J
= 6.5 Hz), 2.47 (1H, dt, J = 6.1H)
z, 14.9 Hz), 2.60-3.14 (6H,
m), 3.20-3.30 (1H, m), 4.26-
4.35 (1H, m), 6.90 (2H, d, J = 8.
4Hz), 7.14-7.19 (4H, m), 7.39
(2H, d, J = 8.4 Hz), 7.45 (2H, d,
J = 7.3 Hz), 7.50 (2H, d, J = 8.8H)
z). Example 22N-[(1RS, 2RS) -3- (4-chloropheny
) -1-Methyl-2- {4- (3-thienyl) phenyl
Ru} propyl] carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.99 (3H, d, J
= 6.6 Hz), 2.43-2.88 (6H, m),
3.04-3.14 (1H, m), 3.20-3.30
(1H, m), 4.26-4.36 (1H, m), 6.
90 (2H, d, J = 8.3 Hz), 7.08 (2H,
d, J = 8.3 Hz), 7.09 (2H, d, J = 8.
3 Hz), 7.30-7.40 (2H, m), 7.44
(1H, t, J = 2.0Hz), 7.49 (2H, d,
J = 8.3 Hz). Example 23N-[(1RS, 2RS) -3- (4-chloropheny
) -1-Methyl-2- {4- (3-pyridyl) phenyl
Ru} propyl] carbamoylmethylsuccinic acid trifluoride
Roacetate ¹ H-NMR (CDCl₃) Δ: 1.02 (3H, d, J
= 6.9 Hz), 2.47 (1H, dt, J = 5.5H)
z, 15.4 Hz), 2.60-2.96 (3H,
m), 3.00-3.16 (2H, m), 3.18-
3.28 (1H, m), 4.28-4.38 (1H,
m), 6.93 (2H, d, J = 8.3 Hz), 6.9
4 (2H, d, J = 8.0 Hz), 7.09 (2H,
d, J = 8.5 Hz), 7.10 (2H, d, J = 8.
6Hz), 7.24 (2H, d, J = 7.4Hz),
7.52 (2H, d, J = 8.3Hz), 7.53 (2
H, d, J = 8.3 Hz), 7.68-7.74 (1
H, m), 8.224-8.30 (1H, m), 8.6
6 (1H, d, J = 4.9 Hz), 9.00 (1H,
d, J = 9.1 Hz). Example 24N-{(1RS, 2RS) -2- (3'-chloro-4-
Biphenylyl) -3- (4-chlorophenyl) -1-me
Cylpropyl} carbamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.99 (3H, d, J
= 6.5 Hz), 2.43-2.52 (1 H, m),
2.60-2.95 (5H, m), 3.08-3.13
(1H, m), 3.20-3.30 (1H, m), 6.
90 (2H, d, J = 8.3 Hz), 7.08-7.1
5 (4H, m), 7.29 (1H, dt, J = 1.7H
z, 7.5 Hz), 7.35 (1H, t, J = 7.5H)
z), 7.42-7.47 (3H, m), 7.55 (1
H, t, J = 1.7 Hz). Example 25N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (3,4-Dichlorophenyl) -1-methyl
Propyl} carbamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.93 (3H, d, J
= 6.5 Hz), 2.40-2.55 (1 H, m),
2.60-2.91 (5H, m), 2.98-3.10
(1H, m), 3.20-3.36 (1H, m), 4.
15-4.32 (1H, m), 6.51 (1H, b
r. ), 6.63-6.70 (1H, m), 6.94.
(2H, d, J = 8.2Hz), 7.05 (1H, b
r. t, J = 2.1 Hz), 7.10-7.16 (1
H, m), 7.20 (1H, d, J = 8.2 Hz). Example 26N-{(1RS, 2RS) -3- (4-chloropheny
) -2- (3,4-Dichlorophenyl) -1-methyl
Propyl} carbamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.95 (3H, d, J
= 6.4 Hz), 2.41-2.47 (1H, m),
2.59-2.78 (4H, m), 2.82-2.88
(1H, m), 3.00-3.07 (1H, m), 3.
23-3.31 (1H, m), 4.19-4.25 (1
H, m), 6.30-6.35 (1H, m), 6.85.
(3H, dd, J = 3.0Hz, 8.5Hz), 7.0
9 (2H, dd, J = 2.8Hz, 8.5Hz), 7.
14 (1H, s), 7.29 (1H, d, J = 8.3H
z). Example 27N-{(1RS, 2RS) -2- (3-bromopheny
) -3- (4-Chlorophenyl) -1-methylpropyi
Ru} carbamoylmethylsuccinic acid ¹ H-NMR (CD₃OD) δ: 0.91 (3 / 2H,
d, J = 6.6 Hz), 0.92 (3 / 2H, d, J =
6.6 Hz), 2.43-2.88 (6H, m), 3.
11-3.30 (2H, m), 4.20 (1H, m),
6.89 (2H, d, J = 8.1Hz), 7.02-
7.20 (4H, m), 7.24 (1H, br.),
7.30 (1H, br.d, J = 7.8Hz). Example 28N-{(1RS, 2RS) -2- (3-biphenylyl)
-3- (4-chlorophenyl) -1-methylpropyl}
Carbamoylmethyl succinic acid ¹ H-NMR (CD₃OD) δ: 0.95 (3 / 2H,
d, J = 9.9 Hz), 0.97 (3 / 2H, d, J =
9.9 Hz), 2.40-2.97 (6H, m), 3.
15-3.30 (2H, m), 4.30 (1H, m),
6.90 (2H, d, J = 12.6 Hz), 7.02-
7.10 (3H, m), 7.22-7.51 (8H,
m). Example 29N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (3,4-Difluorophenyl) -1-methyl
Lupropyl} carbamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.95 (3H, d, J
= 6.7 Hz), 2.43-2.50 (1H, m),
2.64-2.89 (5H, m), 3.02-3.07
(1H, m), 3.24-3.33 (1H, m), 4.
22-4.30 (1H, m), 6.19 (1H, m),
6.55-6.59 (1H, m), 6.74-7.80
(1H, m), 6.83-6.93 (1H, m), 6.
96 (2H, d, J = 8.3Hz), 7.21 (2H,
d, J = 8.3 Hz). Example 30N-{(1RS, 2RS) -2- (4-biphenylyl)
-3- (3,4-dichlorophenyl) -1-methylpro
Pill} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 1.02 (3H, d, J
= 6.6 Hz), 2.43-2.54 (1 H, m),
2.55-2.98 (5H, m), 3.01-3.11
(1H, m), 3.25-3.40 (1H, m), 4.
27-4.40 (1H, m), 6.13-6.28 (1
H, m), 6.70-6.79 (1H, m), 7.07.
-7.09 (3H, m), 7.14 (1H, dd, J =
3.3 Hz, 7.8 Hz), 7.32 (1 H, m),
7.40 (2H, m), 7.47 (2H, d, J = 7.
8 Hz), 7.54 (2H, m). Example 31N-[(1RS, 2RS) -2- (4-chloropheny
) -1-Methyl-3- {3- (3-thienyl) phenyl
Ru} propyl] carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 0.93 (3H, d, J
= 6.4 Hz), 2.35-2.40 (1H, m),
2.59-2.92 (5H, m), 3.05-3.09
(1H, m), 3.21-3.28 (1H, m), 4.
25-4.30 (1H, m), 6.16-6.19 (1
H, m), 6.81-6.85 (1H, m), 6.96.
(2H, d, J = 7.5 Hz), 7.11-7.15
(2H, m), 7.18 (2H, d, J = 7.5H
z), 7.20-7.24 (1H, m), 7.28-
7.32 (3H, m). Example 32N-{(1RS, 2RS) -2- (4-biphenylyl)
-1-Methyl-3- (2-naphthyl) propyl} carba
Moylmethyl succinic acid ¹ H-NMR (CDCl₃+ CD₃OD) δ: 1.03
(3H, d, J = 6.9 Hz), 2.40-2.50
(1H, m), 2.60-2.80 (3H, m), 3.
00-3.15 (2H, m), 3.20-3.35 (2
H, m), 4.30-4.40 (1H, m), 7.10
-7.80 (16H, m). Example 33N-[(1RS, 2RS) -3- (4-chloropheny
Ru) -1-methyl-2- {4- (2-naphthyl) pheny
Ru} propyl] carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 1.02 (3H, d, J
= 6.9 Hz), 2.46 (1 / 2H, t, J = 5.9)
Hz), 2.51 (1 / 2H, t, J = 5.9Hz),
2.60-2.84 (3H, m), 2.86-3.00
(2H, m), 3.06-3.18 (1H, m), 3.
21-3.32 (1H, m), 4.29-4.39 (1
H, m), 6.94 (2H, d, J = 8.6 Hz),
7.11 (2H, br.d, J = 8.2Hz), 7.1
7 (2H, d, J = 8.4Hz), 7.62 (2H,
d, J = 8.3 Hz), 7.45-7.54 (2H,
m), 7.72 (1H, dd, J = 1.6Hz, 8.5
Hz), 7.84-7.92 (3H, m), 8.20
(1H, d, J = 1.4 Hz). Example 34N-{(1RS, 2RS) -2- (4-biphenylyl)
-3- (4-chlorophenyl) -1-methylpropyl}
-N-methylcarbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃+ CD₃OD) δ: 0.90-
1.07 (3H, m), 2.60-3.00 (11H,
m), 4.15-4.25 and 5.00-5.
20 (total 1H, m), 6.63-6.71
(1H, m), 6.93-7.01 (1H, m), 7.
10-7.20 (3H, m), 7.30-7.65 (7
H, m). Example 35N-{(1RS, 2RS) -3- (4-chloropheny
) -2- (2-Fluoro-4-biphenylyl) -1-
Methylpropyl} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 1.01 (3 / 2H,
d, J = 6.5 Hz), 1.02 (3 / 2H, d, J =
6.5Hz), 2.45 (1 / 2H, t, J = 5.9H)
z), 2.50 (1 / 2H, t, J = 5.9Hz),
2.61-2.96 (5H, m), 3.00-3.18
(1H, m), 3.20-3.31 (1H, m), 4.
24-4.34 (1H, m), 6.86-6.95 (2
H, m), 6.93 (2H, d, J = 8.5 Hz),
7.11 (1H, d, J = 7.0Hz), 7.12 (1
H, d, J = 7.0 Hz), 7.29-7.38 (2
H, m), 7.39-7.46 (2H, m), 7.50.
-7.54 (2H, m). Example 36N-[(1RS, 2RS) -3- (4-chloropheny
Ru) -2- {4- (2-furyl) phenyl} -1-methy
Lupropyl] carbamoylmethyl succinic acid ¹ H-NMR (CDCl₃) Δ: 0.97 (3 / 2H,
d, J = 6.5 Hz), 0.98 (3 / 2H, d, J =
6.5 Hz), 2.43-2.90 (6H, m), 3.
20-3.30 (1H, m), 4.25-4.35 (1
H, m), 6.46 (1H, dd, J = 1.6Hz,
3.5Hz), 6.61 (1H, d, J = 3.5H
z), 6.88 (2H, d, J = 8.6 Hz), 7.0
5-7.10 (4H, m), 7.55 (2H, d, J =
8.3 Hz), 7.45 (1H, d, J = 1.6H
z). Example 37N-{(1RS, 2RS) -2- (4-chloropheny
) -1-Methyl-3- (4-pyridyl) propyl} ca
Luvamoylmethyl succinic acid trifluoroacetate ¹ H-NMR (CD₃OD) δ: 0.94 (3 / 2H,
d, J = 6.8 Hz), 0.97 (3 / 2H, d, J =
6.8 Hz), 2.40-2.80 (4H, m), 3.
00-3.30 (3H, m), 3.40-3.60 (1
H, m), 4.15-4.30 (1H, m), 7.13
(2H, dd, J = 1.3Hz, 8.6Hz), 7.2
5 (2H, d, J = 8.6 Hz), 7.50-7.60
(1H, m), 7.63 (2H, d, J = 6.4H
z), 8.53 (2H, d, J = 6.4 Hz). Example 38N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (5-Chloro-2-thienyl) -1-methyl
Propyl} carbamoylmethyl succinic acid ¹ H-NMR (CD₃OD) δ: 0.89 (3 / 2H,
d, J = 6.6 Hz), 0.91 (3 / 2H, d, J =
6.6 Hz), 2.40-3.05 (7H, m), 3.
20-3.30 (1H, m), 4.10-4.20 (1
H, m), 6.36 (1 / 2H, d, J = 3.6H)
z), 6.37 (1/2 H, d, J = 3.6 Hz),
6.56 (1 / 2H, d, J = 3.6Hz), 6.58
(1 / 2H, d, J = 3.6Hz), 7.12 (1H,
d, J = 8.7 Hz), 7.13 (1H, d, J = 8.
7 Hz), 7.27 (2H, d, J = 8.7 Hz). Example 39N-{(1RS, 2RS) -2- (4-chloropheny
) -1-Methyl-3- (8-quinolyl) propyl} ca
Luvamoylmethyl succinic acid trifluoroacetate ¹ H-NMR (CD₃OD) δ: 0.98 (3 / 2H,
d, J = 6.6 Hz), 1.00 (3 / 2H, d, J =
6.6 Hz), 2.45-2.82 (5H, m), 3.
30-3.70 (2H, m), 3.80-4.00 (1
H, m), 4.20-4.40 (1H, m), 6.95.
-7.20 (4H, m), 7.45-7.60 (2H,
m), 7.75-7.95 (2H, m), 8.65-
8.80 (1H, m), 9.03 (1H, dd, J =
1.7 Hz, 4.9 Hz). Example 40N-{(1RS, 2RS) -3- (7-benzo [b] chi
(Enyl) -2- (4-chlorophenyl) -1-methyl group
Ropil} carbamoylmethylsuccinic acid ¹ H-NMR (CD₃OD) δ: 0.95 (3H, d, J
= 6.8 Hz), 2.40-2.80 (4H, m),
3.00-3.50 (4H, m), 4.20-4.40
(1H, m), 6.79 (1H, t, J = 6.6H
z), 7.00-7.22 (5H, m), 7.29 (1
/ 2H, d, J = 5.5Hz, 7.30 (1 / 2H,
d, J = 5.5 Hz), 7.46 (1/2 H, d, J =
5.5Hz), 7.47 (1 / 2H, d, J = 5.5H)
z), 7.55 (1H, d, J = 8.0 Hz). Example 41N-{(1RS, 2RS) -3- (4-chloropheny
L) -1-methyl-2- (3 ′, 4′-methylenedioxy)
Ci-4-biphenylyl) propyl} carbamoylmethyl
Succinic acid ¹ H-NMR (CDCl₃) Δ: 0.99 (3 / 2H,
d, J = 6.9 Hz), 1.00 (3 / 2H, d, J =
6.9 Hz), 2.44 (1 / 2H, t, J = 6.1H
z), 2.49 (1/2 H, t, J = 6.9 Hz),
2.61-2.89 (6H, m), 3.04-3.30
(2H, m), 4.24-4.36 (1H, m), 5.
99 (2H, s), 6.85-6.88 (1H, m),
7.02-7.05 (2H, m), 6.91 (2H,
d, J = 8.6 Hz), 7.08-7.19 (4H,
m), 7.40 (2H, d, J = 8.6Hz). Example 42N-{(1RS, 2RS) -2- (5-benzo [b] chi
Enenyl) -3- (4-chlorophenyl) -1-methylpropyl
Ropil} carbamoylmethylsuccinic acid ¹ H-NMR (CD₃OD) δ: 0.90 (3 / 2H,
d, J = 6.7 Hz), 0.93 (3 / 2H, d, J =
6.7 Hz), 3.10-3.30 (2H, m), 4.
20-4.40 (1H, m), 6.84 (2H, d, J
= 8.4 Hz), 6.90-7.22 (4H, m),
7.25 (1 / 2H, d, J = 5.4Hz), 7.26
(1 / 2H, d, J = 5.4Hz), 7.48 (1H,
d, J = 5.4 Hz), 7.50 (1 H, s), 7.7
6 (1H, d, J = 8.3 Hz). Example 43N-{(1RS, 2RS) -3- (4-chloropheny
) -2- (2'-Fluoro-4-biphenylyl) -1
-Methylpropyl} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃+ CD₃OD) δ: 1.01
(3H, d, J = 6.5 Hz), 2.47 (1H, d
t, J = 6.0 Hz, 15.1 Hz), 2.61-2.
70 (2H, m), 2.77 (1H, dt, J = 6.8)
Hz, 17.2 Hz), 2.85-3.13 (3H,
m), 3.20-3.30 (1H, m), 4.26-
4.36 (1H, m), 6.93 (2H, d, J = 8.
3Hz), 7.11 (2H, d, J = 8.6Hz),
7.14 (2H, d, J = 8.1Hz), 7.18 (1
H, d, J = 8.0 Hz), 7.21 (1H, d, J =
7.6 Hz), 7.28-7.35 (1 H, m), 7.
40-7.46 (1H, m), 7.45 (2H, d, J
= 6.8 Hz). Example 44N-{(1RS, 2RS) -3- (4-chloropheny
) -2- (2'-methoxy-4-biphenylyl) -1
-Methylpropyl} carbamoylmethylsuccinic acid ¹ H-NMR (CDCl₃) Δ: 1.02 (3H, d, J
= 6.5 Hz), 2.45 (1H, dt, J = 5.9H)
z, 15.1 Hz), 2.59-2.71 (2H,
m), 2.76 (1H, dt, J = 7.4 Hz, 17.
1 Hz), 2.89-3.10 (3H, m), 3.81
(3H, s), 4.26-4.36 (1H, m), 6.
96 (2H, d, J = 8.2Hz), 7.01 (2H,
d, J = 7.3 Hz), 7.03 (1H, d, J = 6.
6 Hz), 7.11 (2H, d, J = 8.2 Hz),
7.29-7.34 (2H, m), 7.43 (2H,
d, J = 8.3 Hz). Example 45N-[(1RS, 2RS) -3- (3,4-dichlorofuran
Phenyl) -1-methyl-2- {4- (5-oxazoli
Lu) phenyl} propyl] carbamoylmethyl succinic acid ¹ H-NMR (CD₃OD) δ: 0.94 (3 / 2H.
d. J = 6.6 Hz), 0.95 (3 / 2H, d, J =
6.6 Hz), 2.40-3.00 (6H, m), 3.
10-3.30 (2H, m), 4.20-4.35 (1
H, m), 6.85 (1H, d, J = 8.3 Hz),
7.10-7.25 (4H, m), 7.45 (1H,
s), 7.62 (2H, d, J = 8.3Hz), 7.2
0 (1H, s). Example 46(2S)-and (2R) -2- [N-{(1S , 2
S ) -2- (4-Biphenylyl) -3- (4-chlorophenyl)
Phenyl) -1-methylpropyl} carbamoylmethyl]
Manufacture of succinic acid Obtained in Example 114 (1S , 2S ) -2- (4-bi
Phenylyl-3- (4-chlorophenyl) -1-methyl
Rupropylamine 112mg, carboxymethyl amber
170 mg of acid dibenzhydryl ester and 4-dime
41 mg of tylaminopyridine in 2 ml of dichloromethane
Dissolve and, under ice-cooling stirring, 1-ethyl-3- (3-dimme hydrochloride
Chillaminopropyl) carbodiimide 41mg
Stir overnight at room temperature. The reaction solution was filled with 5 g of silica gel.
Column, wash the column with ethyl acetate, and elute
The liquids were combined and dried under reduced pressure. Medium pressure liquid chromatograph of the residue
Luffy [Lobar column^TM, SizeB,
Lichroprep^TMSi60F (Merck)
Xane / ethyl acetate = 10/1]
Separation and purification of two types of products related to each other
Dibenzhydryl ester of each of the two compounds
92 mg (33% yield) of the stellate as the pre-eluting component,
77 mg (yield 28%) was obtained as a post-elution component.

Of the two dibenzhydryl ester compounds obtained above, 92 mg of the compound obtained as the preceding eluting component by medium pressure liquid chromatography treatment was dissolved in 1 ml of chloroform together with 20 mg of anisole, and stirred under ice-cooling. 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, and the residue was treated with benzene to give 49 mg (yield 89%) of the title compound whose absolute configuration at the 2-position of succinic acid was represented by S as white crystalline powder, mp 186-188 ° C. , [Α] ²⁰ _D = + 13
Obtained as 5.7 ° (c = 1.0, methanol).

[0299]¹H-NMR (CDCl₃+ CD₃OD)
δ: 0.99 (3H, d, J = 5.5Hz), 2.45
(1H, dd, J = 6.1Hz, 14.8Hz), 2.
58-2.79 (3H, m), 2.80-2.92 (2
H, m), 3.01-3.18 (1H, m), 3.20.
-3.32 (1H, m), 4.24-4.36 (1H,
m), 6.90 (2H, d, J = 8.2Hz), 7.0
9 (2H, d, J = 8.3 Hz), 7.12 (2H,
d, J = 8.0 Hz), 7.29-7.36 (1H,
m), 7.39-7.45 (2H, m), 7.47 (2
H, d, J = 8.3 Hz), 7.55-7.59 (2
H, m). Similarly, as the raw material dibenzhydryl ester,
Post-eluted components (7) in pressure liquid chromatography
7 mg) and carrying out a reaction similar to the above,
Title compound in which the absolute configuration at the 2-position of succinic acid is represented by R
39 mg (yield 85%) of white crystalline powder, mp191
~ 193 ° C, [α]²⁰ _D= + 129.3 ° (c = 0.
5, methanol). Example 47(2S) -2- [N-{(1S , 2S ) -2- (4-bi
Phenylyl) -3- (3,4-dichlorophenyl) -1
-Methylpropyl} carbamoylmethyl] succinic acid
Construction Obtained in Example 115 (1S , 2S ) -2- (4-bi
Phenylyl) -3- (3,4-dichlorophenyl) -1
-5.33 g of methylpropylamine, obtained in example 116
(2S) -carboxymethyl succinic acid di-ter
3.78 g of t-butyl ester and 4-dimethylamido
3.84 g of nopyridine dissolved in 75 ml of dichloromethane
Then, with stirring under ice-cooling, 1-ethyl-3- (3-dimethyl hydrochloride)
Aminopropyl) carbodiimide (3.01 g) is added to the chamber
Stir at temperature for 12 hours. Dilute reaction mixture with dichloromethane
After that, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and
Sequentially wash with saturated saline and dry with anhydrous magnesium sulfate.
Dried. After removing the desiccant, the solvent was distilled off under reduced pressure and the residue was removed.
After dissolving in 8 ml of dichloromethane, add 230 ml of hexane
In addition, the precipitate was collected by filtration to give the title compound di-t.
7.54 g of ert-butyl ester (yield 90%)
Obtained.

7.54 g of the ester obtained above was dissolved in 25 ml of dichloromethane, 50 ml of trifluoroacetic acid was added under stirring with ice cooling, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, 30 ml of toluene was added to the residue, and the concentration under reduced pressure was repeated again.
ml, dichloromethane 65 ml and hexane 290 m
Recrystallize from a mixed solvent of 1 to give 4.95 g of the title compound.
(79% yield) as white crystalline powder, mp 176-177
C, [α] ²⁰ _D = + 129 ° (c = 1.0, methanol).

[0301]¹H-NMR (CD₃OD) δ: 0.98
(3H, d, J = 6.5Hz), 2.54 (1H, d
d, J = 7.0 Hz, 15.5 Hz), 2.62 (1
H, dd, J = 5.8 Hz, 17.0 Hz), 2.69
(1H, dd, J = 7.0Hz, 15.5Hz) 2.7
4 (1H, dd, J = 7.5Hz, 17.0Hz),
2.78-2.92 (2H, m), 3.17 (1H, b
r. d, J = 9.9 Hz), 3.23-3.27 (1
H, m), 4.25 (1H, dq, J = 6.5 Hz,
9.0 Hz), 6.86 (1H, dd, J = 2.1H)
z, 8.4 Hz), 7.11 (1H, d, J = 2.1H
z), 7.15 (2H, d, J = 8.3 Hz), 7.2
1 (1H, d, J = 8.4HJz), 7.25-7.3
2 (1H, m), 7.36-7.42 (2H, m),
7.51 (2H, d, J = 8.3Hz), 7.54-
7.58 (2H, m). Used as a raw material in the above reaction (1S , 2S ) -2-
(4-biphenylyl) -3- (3,4-dichlorophenyl)
Lu) -1-methylpropylamine instead of the corresponding optics
Reaction similar to Example 47 except that an active amine compound is used.
By performing the above, the compounds of Examples 48 to 51 were obtained. Example 48(2S) -2- [N-{(1S , 2S ) -3- (3,4
-Dichlorophenyl) -2- (2-fluoro-4-bif
Phenylyl) -1-methylpropyl} carbamoylmethyi
Lu] succinic acid mp170-171 ° C¹ H-NMR (CD₃OD) δ: 0.99 (3H, d, J
= 6.9 Hz), 2.53 (1H, dd, J = 6.9H)
z, 15.6 Hz), 2.61 (1H, dd, J = 6.
0Hz, 17.1Hz), 2.69 (1H, dd, J =
6.9 Hz, 15.6 Hz) 2.74 (1H, dd, J
= 7.5 Hz, 17.1 Hz), 2.82 (1H, d
d, J = 11.7 Hz, 12.6 Hz), 3.12-
3.28 (1H, m), 4.23 (1H, dq, J =
6.9 Hz, 8.7 Hz), 6.91 (1H, dd, J
= 1.8 Hz, 8.1 Hz), 6.95 (1H, s),
6.99 (1H, s), 7.16 (1H, d, J = 1.
8Hz), 7.26 (1H, d, J = 7.8Hz),
7.29-7.43 (4H, m), 7.46-7.51
(2H, m). Example 49(2S) -2- [N-{(1S , 2S ) -2- (4-bi
Phenylyl) -3- (3,4-dichlorophenyl) -1
-Methylpropyl} -N-methylcarbamoylmethyl]
Succinic acid mp166.5-167.5 ° C¹ H-NMR (CD₃OD) δ: 0.92-1.04 (3
H, m), 2.64-3.12 (10H, m), 3.3.
9-3.41 (1H, m), 4.12-4.23, 5.
00-5.18 (total 1H, m), 6.62-
6.70 (1H, m), 6.93-7.02 (1H,
m), 7.09-7.19 (3H, m), 7.29-
7.38 (1H, m), 7.39-7.54 (4H,
m), 7.55-7.60 (2H, m). Example 50(2S) -2- [N-benzyl-N-{(1S , 2S )
-2- (2-Fluoro-4-biphenylyl) -3-
(3,4-Dichlorophenyl) -1-methylpropyl}
Carbamoylmethyl] succinic acid mp105-107 ° C¹ H-NMR (CDCl₃) Δ: 0.96-1.08 (3
H, m), 2.50-3.00 (6H, m), 3.12
-3.60 (2H, m), 4.17-4.20 (1H,
m), 4.51 (2H, s), 6.15 (1 / 4H, d
d, J = 1.5 Hz, 8.1 Hz), 6.27 (1/4)
H, d, J = 1.5 Hz), 6.61 (3/4 H, d
d, J = 1.5 Hz, 8.1 Hz), 6.76-6.9.
2 (11 / 4H, m), 7.02 (1 / 4H, d, J =
8.1 Hz), 7.14 (3 / 4H, d, J = 8.1H)
z), 7.24-7.45 (9H, m), 7.47-
7.53 (2H, m). Example 51(2S) -2- [N-{(1S , 2S ) -3- (3,4
-Dichlorophenyl) -2- (2-fluoro-4-bif
Phenylyl) -1-methylpropyl} -N-methylcarba
Moylmethyl] succinic acid mp165-166 ° C¹ H-NMR (CD₃OD) δ: 0.92-1.08 (3
H, m), 2.63-3.14 (7H, m), 2.85.
-2.95 (3H, m), 4.12-5.15 (1H,
m), 6.69-6.75 (1H, m), 6.90-
7.03 (3H, m), 7.20 (1H, d, J = 8.
4Hz), 7.30-7.48 (4H, m), 7.50
-7.57 (2H, m). Example 52(2S) -2- [N-{(1S , 2S , 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenyl} carbamoylmethyl] co
Manufacture of succinic acid Obtained in Example 124 (1S , 2S , 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenylamine 633 mg, Example
(2S) -Carboxymethylsuccinic acid obtained in 116
591 mg of di-tert-butyl ester and 4-di
250 mg of methylaminopyridine in dichloromethane 10
Dissolve in 1 ml of 1-ethyl-3- (3-dimethyl acetic acid hydrochloride.
Minopropyl) carbodiimide (393 mg) was added to room temperature.
It was stirred for 2 hours. After diluting the reaction solution with ethyl acetate,
Constant hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride
Wash sequentially with water and dry over anhydrous magnesium sulfate.
It was After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the residue was converted to silica.
Gel column chromatography (Wako gel^TMC-20
0.25 g; hexane / ethyl acetate = 5/1 → 3/1)
To give the title compound di-tert-butyl
920 mg of ester (yield 84%) was obtained.

920 mg of the ester obtained above was
Add to 8 ml of acid and stir at room temperature for 4 hours, then add formic acid under reduced pressure.
Distilled off. Treat the residue with a mixture of ethyl ether and hexane.
After that, the precipitate was collected by filtration, followed by chloroform / methanol.
Recrystallize from a mixture of hexane / hexane to give the title compound 400m
g (53% yield) as white crystalline powder, mp161-16
3 ° C, [α]²⁰ _D= + 86.6 ° (c = 1.0, methano
), Obtained as.

[0303]¹H-NMR (CDCl₃) Δ: 1.19
(3H, d, J = 6.8Hz), 2.45-2.75
(6H, m), 2.92-2.99 (1H, m), 3.
16-3.40 (1H, m), 3.99-4.04 (1
H, m), 6.16 (1H, dd, J = 8.5 Hz, 1
6.0 Hz), 6.31 (1H, d, J = 16.0H
z), 7.11 (1H, dd, J = 2.0 Hz, 8.5
Hz), 7.33 (1H, d, J = 7.9 Hz), 7.
37-7.44 (3H, m), 7.56 (1H, dd,
J = 1.5 Hz, 8.5 Hz), 7.63 (1H, b
r. d), 7.73-7.78 (3H, m). Used as a raw material in the above reaction (1S , 2S , 3E)-
2- (3,4-dichlorobenzyl) -1-methyl-4-
(2-naphthyl) -3-butenylamine and / or
(2S) -Carboxymethylsuccinic acid di-tert-bu
N-{(1S , 2S , 3E)-
2- (3,4-dichlorobenzyl) -1-methyl-4-
(2-Naphthyl) -3-butenyl} -N-methylamine
And / or 5- (tert-butoxycarbonyl)
Reaction similar to Example 52 except that -4-pentenoic acid was used.
The compounds of Examples 53 to 55 were obtained by carrying out. Example 53(2S) -2- [N-{(1S , 2S , 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenyl} -N-methylcarbamoy
Lumethyl] succinic acid ¹ H-NMR (CDCl₃) Δ: 1.15 (3H, d, J
= 6.5 Hz), 2.45-2.96 (7H, m),
2.86 (3H, s), 3.36-3.45 (1H,
m), 4.74-4.79 (1H, m), 5.99 (1
H, dd, J = 9.4 Hz, 16.0 Hz), 6.32
(1H, d, J = 16.0 Hz), 6.89-6.94
(1H, m), 7.19-7.20 (1H, m), 7.
24-7.28 (1H, m), 7.40-7.51 (3
H, m), 7.59-7.61 (1H, m), 7.74
-7.78 (3H, m). Example 54(2E) -5- [N-{(1S , 2S , 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenyl} carbamoyl] -2-pe
Acid ¹ H-NMR (CDCl₃) Δ: 1.18 (3H, d, J
= 6.9 Hz), 2.30 (2H, t, J = 7.2H)
z), 2.54-2.71 (4H, m), 2.78-
2.89 (1H, m), 4.10-4.23 (1H,
m), 5.45 (1H, d, J = 9.0 Hz), 5.8
5 (1H, d, J = 15.6Hz), 6.08 (1H,
dd, J = 9.0 Hz, 15.9 Hz), 6.39 (1
H, d, J = 15.6 Hz), 6.99 (1H, dd,
J = 2.1 Hz, 8.1 Hz), 7.03 (1H, d
t, J = 6.9 Hz, 15.6 Hz), 7.26 (1
H, s), 7.28 (1H, d, J = 8.4 Hz),
7.40-7.47 (2H, m), 7.51 (1H, d
d, J = 1.8 Hz, 8.4 Hz), 7.62 (1H,
s), 7.75-7.79 (3H, m). Example 55(2E) -5- [N-{(1S , 2S , 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenyl} -N-methylcarbamoy
L] -2-Pentenoic acid ¹ H-NMR (CDCl₃) Δ: 1.16, 1.26 (t
total 3H, d, J = 7.2 Hz), 2.40-
2.80 (7H, m), 2.85, 2.93 (tota
13H, s), 3.79-3.87, 4.78-4.
89 (total 1H, m), 5.90 (1H, d
t, J = 1.5 Hz, 15.6 Hz), 5.97-6.
07 (1H, m), 6.31 (1H, d, J = 15.6)
Hz), 6.89-6.95 (1H, m), 7.13
(1H, dt, J = 6.9Hz, 15.6Hz), 7.
19-7.21 (1H, m), 7.24-7.29 (1
H, m), 7.39-7.51 (3H, m), 7.5
9,7.61 (total 1H, s), 7.74-
7.81 (3H, m). Example 564- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -1-methyl-3- (2-naphthyl) propyl}
Production of carbamoyl] -3-methylbutanoic acid (1RS, 2RS) -2- (4-biphenylyl) -1-
Methyl-3- (2-naphthyl) propylamine hydrochloride 3
6 mg and 21 mg of 3-methylglutaric acid anhydride
Dissolve in 3 ml of loromethane and add 100 μl of triethylamine
1 was added, and the mixture was stirred overnight at room temperature. Pour the reaction solution into ice water
Gamma, add 1N hydrochloric acid to acidify, and then separate the organic layer.
It was The organic layer was dried over anhydrous sodium sulfate, and then the solvent was added.
The residue was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography.
ー (Wako gel^TMC-100, 10 g, dichloromethane
→ Attach to dichloromethane / methanol = 30/1)
To give 42 mg (96% yield) of the title compound as a white foam.
Obtained as a solid.

[0304]¹H-NMR (CDCl₃) Δ: 1.03-
1.14 (6H, m), 2.08-2.30 (2H,
m), 2.30-2.49 (3H, m), 3.10-
3.30 (3H, m), 4.39-4.52 (1H,
m), 5.46-5.53 (1H, m), 7.15-
7.29 (3H, m), 7.30-7.59 (10H,
m), 7.61-7.77 (3H, m). (1RS, 2RS) -2 used as a raw material in the above reaction
-(4-Biphenylyl) -1-methyl-3- (2-naphth
Cyl) propylamine and / or anhydrous 3-methyl group
Corresponding amine compound and / or instead of phthalic acid
The same reaction as in Example 56 was carried out except that an acid anhydride was used.
Thus, the compounds of Examples 57 to 65 were obtained. Example 574- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} carbamoyl] butanoic acid ¹ H-NMR (CDCl₃) Δ: 1.04 (3H, d, J
= 6.8 Hz), 2.01 (2H, m), 2.28 (2
H, t, J = 7.2 Hz), 2.47 (2H, t, J =
6.8 Hz), 2.96-3.09 (3H, m), 4.
39 (1H, m), 5.32 (1H, m), 6.82
(1H, br.d, J = 8.6Hz), 7.12-7.
22 (4H, m), 7.30-7.60 (7H, m). Example 584- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} carbamoyl] -3-methylbutanoic acid ¹ H-NMR (CDCl₃) Δ: 1.06-1.09 (6
H, m), 2.15-2.35 (2H, m), 2.35.
-2.52 (3H, m), 2.86-3.10 (3H,
m), 4.39 (1H, m), 5.51 (1H, br.
d, J = 9.4 Hz), 6.80 (1H, br.d, J
= 8.0 Hz), 7.10-7.22 (4H, m),
7.30-7.60 (7H, m). Example 594- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -1-methyl-3- (1-naphthyl) propyl}
Carbamoyl] -3-methylbutanoic acid ¹ H-NMR (CDCl₃+ CD₃OD) δ: 1.03-
1.13 (6H, m), 2.05-2.23 (2H,
m), 2.24-2.48 (3H, m), 3.11-
3.21 (1H, m), 3.68 (1H, br.d, J
= 14.1 Hz), 4.49-4.58 (1H, m),
7.00-7.07 (1H, m), 7.12-7.25
(2H, m), 7.32-7.37 (1H, m), 7.
39-7.60 (8H, m), 7.60-7.77 (1
H, m), 7.80-7.86 (1H, m), 8.02.
(1H, br.d, J = 8.1 Hz). Example 604- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} carbamoyl] -3,3-dimethylbutane
acid ¹ H-NMR (CDCl₃) Δ: 1.09 (3H, s),
1.09 (3H, d, J = 6.9Hz), 1.16 (3
H, s), 2.25 (1H, d, J = 13.8 Hz),
2.44 (1H, d, J = 12.3Hz), 2.50
(1H, d, J = 12.3 Hz), 2.89-3.10
(3H, m), 4.41 (1H, m), 5.98 (1
H, m), 6.79 (1H, dd, J = 1.8Hz,
8.4 Hz), 7.11 (1H, d, J = 1.8H
z), 7.14 (2H, d, J = 8.2 Hz), 7.2
0 (1H, d, J = 8.4 Hz), 7.36 (1H, b
r. d, J = 7.2 Hz), 7.44 (2H, m),
7.52 (2H, d, J = 8.2Hz), 7.57 (1
H, br. d, J = 7.2 Hz). Example 614- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} -N-methylcarbamoyl] -3-methyl
Butanoic acid ¹ H-NMR (CDCl₃) Δ: 0.90 to 1.07 (3
H, m), 1.14 (3H, d, J = 6.3Hz),
2.30-2.60 (6H, m), 2.60-2.96
(5H, m), 4.10-4.30 and 5.08
-5.28 (total 1H, m), 6.60-6.
70 (1H, m), 6.90-7.00 (1H, m),
7.07-7.20 (3H, m), 7.30-7.63
(7H, m). Example 623- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} carbamoylmethyl] pentanoic acid ¹ H-NMR (CDCl₃) Δ: 0.96 (3H, t, J
= 7.2 Hz), 1.03 (3H, d, J = 6.8H)
z), 1.42-1.48 (2H, m), 2.21-
2.39 (3H, m), 2.41-2.51 (2H,
m), 2.87-2.97 (2H, m), 3.06-
3.09 (1H, m), 4.36-4.41 (1H,
m), 5.69-5.72 (1H, m), 6.76-
6.81 (1H, m), 7.10 (1H, t, J = 2.
4 Hz), 7.13 (2H, d, J = 8.0 Hz),
7.18 (1H, dd, J = 2.0Hz, 8.4H
z), 7.33 (1H, t.J = 7.2Hz), 7.4.
3 (2H, t, J = 7.6Hz), 7.50 (2H,
d, J = 8.0 Hz), 7.57 (2H, d, J = 7.
2 Hz). Example 633- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} carbamoylmethyl] -4-methylpenta
Acid ¹ H-NMR (CDCl₃) Δ: 0.93 (6H, d, J
= 6.8 Hz), 1.03 (3H, d, J = 6.6H)
z), 1.70-1.88 (1H, m), 2.12
2.53 (5H, m), 2.82-3.11 (3H,
m), 4.28-4.48 (1H, m), 5.67 (1
H, br. d, J = 9.0 Hz), 6.79 (1H, d
t, J = 2.2 Hz, 8.4 Hz), 7.09-7.2
5 (4H, m), 7.30-7.60 (7H, m). Example 644- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} carbamoyl] -3-benzylbutanoic acid ¹ H-NMR (CDCl₃) Δ: 1.01 (3 / 2H,
d, J = 6.8 Hz), 1.04 (3 / 2H, d, J =
6.8 Hz), 2.17-2.35 (2H, m), 2.
53-2.80 (3H, m), 2.87-3.09 (3
H, m), 4.31-4.42 (1H, m), 5.40.
-5.49 (1H, m), 6.77 (1H, dd, J =
2.3 Hz, 8.3 Hz), 7.08-7.14 (3
H, m), 7.15-7.24 (4H, m), 7.26
-7.37 (3H, m), 7.39-7.46 (2H,
m), 7.49 (2H, d, J = 8.1Hz), 7.5
4-7.59 (2H, m). Example 654- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} carbamoyl] -3-hydroxy-3-me
Tilbutanoic acid ¹ H-NMR (CDCl₃) Δ: 1.05 (3H, d, J
= 6.6 Hz), 1.38 (3 / 2H, s), 1.40
(3 / 2H, s), 2.40 (1H, br.d, J = 1
5.0 Hz), 2.50-2.64 (3H, m), 2.
84-2.99 (2H, m), 3.00-3.12 (1
H, m), 4.32-4.45 (1H, m), 5.95.
-6.12 (1H, m), 6.77 (1H, br.d,
J = 8.0 Hz), 7.08-7.14 (3H, m),
7.18 (1H, d, J = 8.0 Hz), 7.33 (1
H, m), 7.42 (2H, br.t, J = 7.5H
z), 7.50 (2H, br.d, J = 7.8Hz),
7.56 (2H, br.d, J = 7.5Hz). Example 665- [N-{(1S , 2S ) -2- (4-biphenyli
) -3- (3,4-Dichlorophenyl) -1-methyl
Propyl} carbamoyl] pentanoic acid Obtained in Example 115 (1S , 2S ) -2- (4-bi
Phenylyl) -3- (3,4-dichlorophenyl) -1
-Methylpropylamine 24mg, monoethyl adipate
Luester 14 mg and 4-dimethylaminopyridine
Dissolve 10 mg in 2 ml of dichloromethane and stir on ice.
Underneath, 1-ethyl-3- (3-dimethylaminopropy!
) Add 15 mg of carbodiimide and stir at room temperature for 3 hours
did. Dilute the reaction mixture with ethyl ether and quench with 10%.
Acid solution, saturated sodium hydrogen carbonate solution, then saturated
Wash sequentially with brine, dry over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue
Graphography (Wakogel^TMC-200, 1g, hexane
/ Ethyl acetate = 2/1)
After dissolving 8 mg in 1 ml of methanol, 2N sodium hydroxide
0.5 ml of an aqueous lithium solution was added, and the mixture was stirred at room temperature overnight.
The reaction mixture was acidified with 1N hydrochloric acid and then with ethyl ether.
And water are added for liquid separation, and the organic layer is separated and washed with saturated brine.
It was purified and then dried over anhydrous magnesium sulfate. Desiccant
After separation by filtration, the solvent was distilled off, and the residue was mixed with isopropyl ether.
The title compound was treated with a mixture of ethyl ether.
16 mg (yield 49%) of white crystalline powder, mp12
3-124 ° C, [α]²⁰ _D= + 139 ° (c = 1.0,
Methanol).

[0305]¹H-NMR (CDCl₃) Δ: 1.03
(3H, d, J = 6.9Hz), 1.70 (4H,
m), 2.21 (2H, m), 2.41 (2H, m),
2.88-2.98 (3H, m), 4.36 (1H,
m), 5.33 (1H, d, J = 9.0Hz), 6.8
2 (1H, d, J = 1.8Hz, 8.3Hz), 7.3
4 (1H, m), 7.43 (2H, m), 7.51 (2
H, d, J = 8.3 Hz), 7.57 (2H, m). Used as a raw material in the above reaction (1S , 2S ) -2-
(4-biphenylyl) -3- (3,4-dichlorophenyl)
) -1-Methylpropylamine and adipic acid mono
Instead of ethyl ester, the corresponding amine compound
Substance and / or monoester derivative, and others
A similar reaction to that of Example 66 was performed to give Examples 67 to 7
1 compound was obtained. Example 678- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -3- (3,4-dichlorophenyl) -1-methyl
Lupropyl} carbamoyl] octanoic acid ¹ H-NMR (CDCl₃) Δ: 1.03 (3H, d, J
= 6.8 Hz), 1.34 (6 H, m), 1.63 (4
H, m), 2.17 (2H, t, J = 7.3 Hz),
2.34 (2H, t, J = 7.3Hz), 2.91-
3.09 (3H, m), 4.38 (1H, m), 5.2
3 (1H, d, J = 8.7 Hz), 6.82 (1H,
d, J = 2.0 Hz, 8.3 Hz), 7.12-7.1.
6 (3H, m), 7.19 (1H, d, J = 8.3H
z), 7.34 (1H, m), 7.43 (2H, m),
7.51 (2H, d, J = 8.4Hz), 7.58 (2
H, m). Example 685- [N-{(1S , 2S ) -3- (3,4-dichloro)
Phenyl) -2- (2-fluoro-4-biphenylyl)
-1-Methylpropyl} carbamoyl] pentanoic acid ¹ H-NMR (CDCl₃) Δ: 1.04 (3H, d, J
= 6.9 Hz), 1.69-1.71 (4H, m),
2.22 (2 H.t, J = 6.8 Hz), 2.41 (2
H, t, J = 6.3 Hz), 2.85-3.10 (3
H, m), 4.30-4.42 (1H, m), 5.47.
(1H, d, J = 8.8Hz), 6.83 (1H, d
d, J = 2.3 Hz, 8.4 Hz), 6.87-6.9.
4 (2H, m), 7.13 (1H, d, J = 2.3H
z), 7.22 (1H, d, J = 8.4 Hz), 7.3
2-7.39 (2H, m), 7.41-7.46 (2
H, m), 7.51-7.54 (2H, m). Example 69(E) -5- [N-{(1RS, 2RS)-
2- (4-biphenylyl) -3- (3,4-Dichlorophenyl) -1-methylpropyl}
Carbamoyl] -4-pentenoic acid ¹ H-NMR (CDCl₃) Δ: 1.04 (3H, d, J
= 6.8 Hz), 2.45-2.60 (4H, b
r. ), 2.90-3.15 (3H, m), 4.35-
4.55 (1H, m), 5.40-5.50 (1H,
m), 5.78 (1H, d, J = 15.2 Hz), 6.
80-6.95 (2H, m), 7.10-7.65 (1
1H, m). Example 70(E) -5- [N-{(1S , 2S ) -3- (3,4-
Dichlorophenyl) -2- (2-fluoro-4-biphe
Nilyl) -1-methylpropyl} carbamoyl] -2-
Pentenoic acid ¹ H-NMR (CDCl₃) Δ: 1.05 (3H, d, J
= 6.7 Hz), 2.34 (2H, t, J = 7.0H
z), 2.54-2.70 (2H, m), 2.84-
3.10 (3H, m), 4.30-4.45 (1H,
m), 5.20-5.33 (1H, m), 5.87 (1
H, d, J = 15.7 Hz), 6.58-7.60 (1
2H, m). Example 715- [N-{(1RS, 2RS) -2- (4-biphenyl
Ryl) -1-methyl-3- (2-naphthyl) propyl}
Carbamoyl] pentanoic acid ¹ H-NMR (CDCl₃) Δ: 1.06 (3H, d, J
= 6.9 Hz), 1.64-1.66 (4H, m),
2.13 (2H, t, J = 6.7Hz), 3.10-
3.28 (3H, m), 4.37-4.49 (1H,
m), 5.29 (1H, d, J = 9.3 Hz), 7.1
8-7.22 (3H, m), 7.28-7.43 (5
H, m), 7.48-7.57 (5H, m), 7.64
-7.74 (3H, m). Example 72(2E) -5- [N-{(1S , 2S , 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenyl} carbamoyl] -3-me
Production of chill-2-pentenoic acid Obtained in Example 124 (1S , 2S , 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenylamine hydrochloride 2.06 g,
(E) -5- (allyloxycarbohydrate obtained in Reference Example 6)
1.20 g of nyl) -4-methyl-4-pentenoic acid and
4-Dimethylaminopyridine 1.12 g methylene chloride
Dissolve in 100 ml, and under ice-cooling stirring, 1-ethyl-3 hydrochloride.
-(3-Dimethylaminopropyl) carbodiimide 1.
20 g was added and the mixture was stirred at room temperature for 12 hours. Reduce the reaction pressure
After concentration, add ethyl acetate and 1N hydrochloric acid to the residue for liquid separation.
After separating the organic layer, a saturated aqueous solution of sodium hydrogencarbonate and
And washed with saturated saline. Extract the extract with anhydrous magnesium sulfate
After drying with um, the solvent was distilled off under reduced pressure, and the residue was methylene chloride.
-Treat with a mixture of hexane to give the allyl ester of the title compound.
2.28 g (yield 82%) of the tel compound was used as white crystalline powder.
I got it.

2.28 g of the ester obtained above was dissolved in 50 ml of tetrahydrofuran, and 0.91 of dimedone was added.
g and 0.49 g of tetrakis (triphenylphosphine) palladium were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, methylene chloride and water were added to the residue for liquid separation, and the organic layer was separated and dried over anhydrous magnesium sulfate.
After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel ^™ C-200,
After purification with methylene chloride / methanol = 100/1 → 50/1) and recrystallization from a mixed solution of methylene chloride-hexane, 1.26 g (yield 59%) of the title compound was obtained as a white crystalline powder, mp 146-148 ° C. , [Α] ²⁰ _D = + 63.8
(C = 1.0, chloroform).

[0307]¹H-NMR (CDCl₃) Δ: 1.20
(3H, d, J = 6.9 Hz), 2.18 (3H,
s), 2.33 (2H, t, J = 7.5Hz), 2.5
3 (2H, m), 2.57-2.74 (2H, m),
2.83 (1H, m), 4.18 (1H, m), 5.3
9 (1H, d, J = 9.0 Hz), 5.70 (1H, b
r. ), 6.09 (1H, dd, J = 9.0Hz, 1
5.3 Hz), 6.39 (1H, d, J = 15.3H)
z), 7.00 (1H, dd, J = 2.4 Hz, 8.4)
Hz), 7.25-7.30 (2H, m), 7.40-
7.49 (2H, m), 7.51 (1H, dd, J =
1.5 Hz, 8.4 Hz), 7.63 (1H, b
r. ), 7.75-7.81 (3H, m). Example 73(3R ) -4- [N-{(1S , 2S ) -2- (4-bi
Phenylyl) -3- (3,4-dichlorophenyl) -1
-Methylpropyl} carbamoyl] -3-methylbutane
Acid production Obtained in Example 115 (1S , 2S ) -2- (4-bi
Phenylyl) -3- (3,4-dichlorophenyl) -1
-Methylpropylamine 1.40 g, (R )-(+)-
0.61 g of 3-methylglutaric acid methyl ester and
0.47 g of 4-dimethylaminopyridine was added to dichlorometa
Dissolved in 100 ml of water and stirred under ice-cooling with 1-ethyl-hydrochloride.
3- (3-dimethylaminopropyl) carbodiimide
0.73 g was added and the mixture was stirred at room temperature for 4 hours. 1 reaction mixture
Normal hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated food
Wash sequentially with brine and dry over anhydrous magnesium sulfate.
It was After removing the desiccant, the solvent was distilled off under reduced pressure and the residue was converted to silica.
Gel column chromatography (Wako gel^TMC-10
0,200g; Hexane / ethyl acetate = 2/1)
Thus, 1.81 g of the methyl ester of the title compound was obtained.
(Yield 93%) was obtained.

1.81 g of the ester obtained above was dissolved in 50 ml of acetic acid, 35 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour.
Stir for 5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue for extraction, the organic layer was separated, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel ^™ C-200, 200 g; dichloromethane / methanol = 10/1) and then recrystallized from water-containing methanol. 1.18 g of the title compound (yield 6
7%) as colorless needles, mp 133-134.5 ° C.,
[Α] ²⁰ _D = + 153 ° (c = 1.0, methanol),
Got as.

[0309]¹H-NMR (CDCl₃) Δ: 1.04
(3H, d, J = 6.3 Hz), 1.09 (3H, d,
J = 6.3 Hz), 2.17-2.35 (2H, m),
2.35-2.54 (3H, m), 2.88-3.09
(3H, m), 4.30-4.39 (1H, m), 5.
50-5.60 (1H, m), 6.79 (1H, dd,
J = 2.1 Hz, 8.4 Hz), 7.11 (1H, d,
J = 2.1 Hz), 7.13 (2H, d, J = 8.1H
z), 7.19 (1H, d, J = 8.4 Hz), 7.3
3 (1H, tt, J = 1.5Hz, 6.8Hz), 7.
43 (2H, m), 7.51 (2H, d, J = 8.1H
z), 7.57 (2H, br.d, J = 6.9 Hz). Used as a raw material in the above reaction (1S , 2S ) -2-
(4-biphenylyl) -3- (3,4-dichlorophenyl)
) -1-methylpropylamine instead of (1S , 2
S ) -2- (2-Fluoro-4-biphenylyl) -3-
(3,4-dichlorophenyl) -1-methylpropyla
Min or (1S, 2S, 3E) -2- (3,4-diglyco)
Lolobenzyl) -1-methyl-4- (2-naphthyl)-
The same reaction as in Example 73 was carried out except that 3-butenylamine was used.
By reacting the compounds of Examples 74 and 75
Obtained. Example 74(3R) -4- [N-{(1S , 2S ) -3- (3,4
-Dichlorophenyl) -2- (2-fluoro-4-bif
Phenylyl) -1-methylpropyl} carbamoyl] -3
-Methylbutanoic acid ¹ H-NMR (CDCl₃) Δ: 1.05 (3H, d, J
= 6.5 Hz), 1.09 (H, d, J = 6.3H)
z), 2.20 (1H, dd, J = 6.9 Hz, 13.
2Hz), 2.30 (1H, dd, J = 6.3Hz, 1
4.1 Hz), 2.32-2.50 (3H, m), 2.
84-3.00 (2H, m), 3.06 (1H, dd,
J = 3.9 Hz, 12.6 Hz), 4.37 (1H,
q, J = 6.5 Hz), 5.60 (1H, d, J = 6.
8Hz), 6.81 (1H, dd, J = 2.1Hz,
8.1 Hz), 6.85-6.93 (2H, m), 7.
12 (1H, d, J = 2.0 Hz), 7.15-7.2
5 (2H, m), 7.31-7.46 (3H, m),
7.51-7.54 (2H, m). Example 75(3R) -4- [N-{(1S , 2S , 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenyl} carbamoyl] -3-me
Tilbutanoic acid mp146-147 ° C¹ H-NMR (CDCl₃) Δ: 1.04 (3H, d, J
= 6.3 Hz), 1.19 (3H, d, J = 6.9H)
z), 2.11-2.30 (3H, m), 2.35-
2.47 (2H, m), 2.57-2.68 (2H,
m), 2.94 (1H, d, J = 10.2Hz), 4.
03 (1H, quint., J = 6.6 Hz), 6.1
5 (1H, dd, J = 8.4Hz, 15.3Hz),
6.30 (1H, d, J = 15.3Hz), 7.10
(1H, d, J = 8.1 Hz), 7.31-7.44
(4H, m), 7.55 (1H, d, J = 8.7H
z), 7.62 (1H, s), 7.73-7.78 (3
H, m). Example 76(3R^*)-And (3S^*) -4- [N-{(1S , 2
S ) -2- (4-Biphenylyl) -3- (3,4-dichloro)
Lorophenyl) -1-methylpropyl} carbamoyl]
Preparation of 3-methoxybutanoic acid 324 mg of 3-methoxyglutaric acid was added to 3 ml of acetic anhydride.
It was dissolved, heated at 90 ° C. for 2 hours, and then dried under reduced pressure. The residue
Dissolve in 10 ml of dichloromethane, (1S , 2S ) -2
-(4-Biphenylyl) -3- (3,4-dichlorophen)
(Nil) -1-methylpropylamine (214 mg) and trie
Cylamine (150 μl) was added, and the mixture was stirred at room temperature for 5 hours.
Add 5 ml of 0.1N sodium hydroxide to the reaction mixture and add
After stirring at temperature for 1 hour, 1N hydrochloric acid was added to acidify. Existence
The machine layer was separated, washed with saturated saline solution, and then washed with anhydrous magnesium sulfate.
Dried with um. After removing the desiccant, the solvent was distilled off under reduced pressure.
And dissolve the residue in 15 ml of acetone,
310 mg of zomethane was added, and the mixture was stirred at room temperature overnight. solvent
Was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column.
W (Wakogel^TMC-100, 50 g; hexane / vinegar
After crude purification with ethyl acetate = 2/1), medium pressure liquid chromatograph
Fee [Lobar column^TM, SizeB, L
icroprep^TMSi60F (Merck);
Sun / Ethyl acetate = 5/2]
Pre-dissolve each benzhydryl ester of the two compounds
49 mg as a source component and 121 as a post-elution component
mg was obtained.

Pre-eluted component benzhydrid obtained above
The luster compound was treated with the same method as in Example 46 above.
Butanoic acid by deprotection with fluoroacetic acid
For the sake of convenience, the absolute position of the 3rd place is R^*Title compound displayed by
27 mg (yield 9.1%) and also the post-eluted components
Similarly, by deprotection, the absolute configuration of butanoic acid 3-position
Is S^*72 mg (24% yield) of the title compound
Were obtained as white crystalline powders, respectively. (3R^*) -Body¹ H-NMR (CDCl₃) Δ: 1.03 (3H, d, J
= 6.9 Hz), 2.52 (1H, d, J = 14.7H)
z), 2.54 (1H, d, J = 14.7Hz), 2.
64 (1H, dd, J = 4.0Hz, 14.7Hz),
2.72 (1H, dd, J = 4.6Hz, 14.7H
z), 2.86-2.97 (2H, m), 3.09 (1
H, m), 3.36 (3H, s), 4.05 (1H,
m), 4.39 (1H, m), 6.12 (1H, br.
d, J = 9.3 Hz), 6.78 (1H, dd, J =
2.1 Hz, 8.4 Hz), 7.10 (1H, d, J =
2.1 Hz), 7.13 (2H, d, J = 8.4H)
z), 7.18 (1H, d, J = 8.4 Hz), 7.3
3 (1 H, br.t, J = 8.4 Hz), 7.43 (2
H, m), 7.50 (2H, d, J = 8.4 Hz),
7.56 (2H, m). (3S^*) -Body¹ H-NMR (CDCl₃) Δ: 1.04 (3H, d, J
= 6.9 Hz), 2.54 (1H, dd, J = 8.1H)
z, 14.7 Hz), 2.55-2.65 (2H,
m), 2.77 (1H, dd, J = 4.8 Hz, 14.
7 Hz), 2.85-2.94 (2H, m), 3.10
(1H, m), 3.38 (3H, s), 4.01 (1
H, m), 4.39 (1H, m), 6.08 (1H,
m), 6.76 (1H, dd, J = 2.1Hz, 8.0
Hz), 7.10 (1H, d, J = 2.1 Hz), 7.
13 (2H, d, J = 8.1Hz), 7.18 (1H,
d, J = 8.0 Hz), 7.34 (1H, br.t, J
= 7.2 Hz), 7.43 (2H, m), 7.51 (2
H, d, J = 8.1 Hz), 7.57 (2H, br.
d, J = 7.2 Hz). 3-methoxyglutaric acid used as a raw material in the above reaction
And / or (1S , 2S ) -2- (4-biphenyli
) -3- (3,4-Dichlorophenyl) -1-methyl
Instead of propylamine, 3-phenylglutaric acid and
(1RS, 2RS) -2- (4-biphenylyl) -3
-(3,4-Dichlorophenyl) -1-methylpropyl
Amine or (1S, 2S, 3E) -2- (3,4-di
Chlorobenzyl) -1-methyl-4- (2-naphthyl)
-3-butenylamine was used, and otherwise the same as in Example 76.
By carrying out the reaction, the compounds of Examples 77 and 78
Got Example 77(3R^*)-And (3S^*) -4- [N-{(1S , 2
S , 3E) -2- (3,4-Dichlorobenzyl) -1-
Methyl-4- (2-naphthyl) -3-butenyl} carba
Moyl] -3-methoxybutanoic acid (3R^*) -Body¹ H-NMR (CDCl₃) Δ: 1.20 (3H, d, J
= 6.9 Hz), 2.45-2.75 (6H, m),
2.78-2.90 (1H, m), 3.28 (3H,
s), 3.95 (1H, m), 4.18 (1H, m),
6.08 (1H, dd, J = 9.0Hz, 15.6H
z), 6.38 (1H, d, J = 15.6Hz), 6.
99 (1H, dd, J = 2.1Hz, 8.4Hz),
7.25-7.30 (2H, m), 7.40-7.53
(3H, m), 7.62 (1H, br.), 7.73-
7.81 (3H, m). (3S^*) -Body¹ H-NMR (CDCl₃) Δ: 1.21 (3H, d, J
= 6.9 Hz), 2.45-2.75 (6H, m),
2.83 (1H, m), 3.29 (3H, s), 3.9
6 (1H, m), 4.18 (1H, m), 6.09 (1
H, dd, J = 9.0 Hz, 15.6 Hz), 6.31
(1H, br.d, J = 8.4 Hz), 6.40 (1
H, d, J = 15.6 Hz), 7.00 (1H, dd,
J = 2.1 Hz, 8.4 Hz), 7.27-7.31
(2H, m), 7.40-7.54 (3H, m), 7.
63 (1H, br.), 7.74-7.82 (3H,
m). Example 78(3R ^* )-4- [N-{(1RS, 2RS) -2-
(4-biphenylyl) -3- (3,4-dichlorophenyl)
) -1-Methylpropyl} carbamoyl] -3-phen
Nilbutanoic acid ¹ H-NMR (CDCl₃) Δ: 0.73 (3H, d, J
= 6.8 Hz), 2.50 (1H, br.dd, J = 1)
1.2 Hz, 14.0 Hz), 2.65-2.95 (6
H, m), 3.65 (1H, m), 4.20 (1H,
m), 5.13 (1H, br.d, J = 9.0 Hz),
6.70 (1H, dd, J = 2.0Hz, 8.2H
z), 6.97-7.04 (3H, m), 7.14-
7.50 (10H, m), 7.51-7.60 (3H,
m).(3S ^* )-4- [N-{(1RS, 2RS) -2-
(4-biphenylyl) -3- (3,4-dichlorophenyl)
) -1-Methylpropyl} carbamoyl] -3-phen
Nilbutanoic acid ¹ H-NMR (CDCl₃) Δ: 0.88 (3H, d, J
= 6.8 Hz), 2.49 (1H, dd, J = 9.0H)
z, 13.8 Hz), 2.40-2.80 (6H,
m), 3.70 (1H, m), 4.25 (1H, m),
5.18 (1H, br.d, J = 8.8Hz), 6.6
3 (1H, dd, J = 2.0Hz, 8.2Hz), 6.
86-6.95 (3H, m), 7.14 (1H.d.J.
= 8.2 Hz), 7.14-7.48 (10H, m),
7.52-7.59 (3H, m). Example 79(4S) -4- [N-{(1RS, 2RS) -2- (4
-Biphenylyl) -3- (3,4-dichlorophenyl)
-1-Methylpropyl} carbamoyl] -4-hydroxy
Production of sodium cibutanoate (1RS, 2RS) -2- (4-biphenylyl) -3-
(3,4-dichlorophenyl) -1-methylpropyla
Min 18.5 mg, (S)-(+)-5-oxo-2-
Tetrahydrofuran carboxylic acid 9.8 mg and 1-hi
Droxybenzotriazole 10.1 mg was added to dichlorometh
Dissolve in 1 ml of tan, and add 1-ethyl-3- (3-dimme hydrochloride
14.4 mg of tylaminopropyl) carbodiimide was added.
The mixture was stirred at room temperature for 2 hours. Dilute reaction mixture with ethyl acetate
After that, wash with 1N hydrochloric acid and saturated saline solution successively,
Dried with magnesium acid. After filtering the desiccant, solvent
Was distilled off under reduced pressure, and the residue was subjected to medium pressure liquid chromatography [L
obar column^TM, SizeA, Lichro
prep^TMSi60F (Merck); Hexane / acetic acid
Ethyl = 1/1] to give the lactone of the title compound.
Body: (2S) -N-{(1RS, 2RS) -2- (4-
Biphenylyl) -3- (3,4-dichlorophenyl)-
1-methylpropyl} -5-oxotetrahydrofuran
2-Carboxamide (19 mg, yield 79%) was obtained.

15 mg of the lactone obtained above was dissolved in a mixed solution of 0.5 ml of tetrahydrofuran and 0.5 ml of methanol, 34 μl of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction solution was dried under reduced pressure to give the title compound (16 mg) as a white glassy solid.

[0312]¹H-NMR (CDCl₃) Δ: 0.99
(3 / 2H, d, J = 6.6Hz), 1.00 (3/2
H, d, J = 6.6 Hz), 1.88-2.05 (1
H, m), 2.05-2.20 (1H, m), 2.36
-2.47 (2H, m), 2.75-2.88 (1H,
m), 2.92-3.03 (1H, m), 3.12-
3.21 (1H, m), 4.07-4.17 (1H,
m), 4.23-4.36 (1H, m), 6.84-
6.92 (1H, m), 7.10-7.60 (11H,
m). Example 80(3R, 5S) -5- [N-{(1S , 2S , 3E)-
2- (3,4-dichlorobenzyl) -1-methyl-4-
(2-Naphthyl) -3-butenyl} carbamoyl]-
Production of 3,5-dihydroxypentanoic acid sodium salt (3R, 5S) -5-methoxycarbonyl-3,5-O
-Isopropylidene-3,5-dihydroxypentanoic acid
1.0 g of tert-butyl ester was added to tetrahydrofuran.
Dissolved in 10 ml of 1N sodium hydroxide solution
3.5 ml was added and the mixture was stirred at room temperature for 1 hour. Depressurize the solvent
After evaporation, the residue was dissolved in methylene chloride and 1N hydrochloric acid was added.
After adjusting the pH to 3.5, the organic layer was separated. Extract
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
The residue was dissolved in 20 ml of methylene chloride and stirred with ice cooling.
Under stirring, (1S , 2S , 3E) -2- (3,4-dichloro
Benzyl) -1-methyl-4- (2-naphthyl) -3-
Butenylamine hydrochloride 1.41 g, 4-dimethylamino
Pyridine 0.89 g and hydrochloric acid 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide 0.73 g
In addition, the mixture was stirred at room temperature for 15 hours. Water and methyl chloride in the reaction mixture
After adding ren to separate the organic layer, the organic layer is collected and dried over anhydrous sodium sulfate.
Dried with um. After removing the desiccant by filtration, the solvent is distilled off under reduced pressure.
Silica gel column chromatography (waco
Gel^TMC-200, 100 g; hexane / ethyl acetate
= 3/1 → 2/1) and purified (3R, 5S) -5-
[N-{(1S , 2S , 3E) -2- (3,4-dichloro)
Robenzyl) -1-methyl-4- (2-naphthyl) -3
-Butenyl} carbamoyl] -3,5-O-isopropylate
Ridene-3,5-dihydroxypentanoic acid tert-bu
1.66 g (76% yield) of chill ester was obtained.

Isopropylidene derivative 1.6 obtained above
5 g of 1N hydrochloric acid 4 ml and tetrahydrofuran 18 ml
The resulting mixture was dissolved in the above mixture and stirred at room temperature for 18 hours, and then tetrahydrofuran was distilled off under reduced pressure. Ethyl acetate was added to the residual liquid for liquid separation, and the organic layer was separated and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was mixed with 1 ml of 1N aqueous sodium hydroxide solution and 2 ml of methanol.
It was dissolved in 0 ml of the mixed solution and stirred at room temperature for 1 hour. Methanol was distilled off from the reaction solution under reduced pressure, and 1N hydrochloric acid (5 m) was added to the residual solution.
1 was added to acidify, and ethyl acetate was added for extraction. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give 1.36 g (yield 97%) of the free acid of the title compound. .

1.32 g of the carboxylic acid obtained above was added as a salt.
Dissolve in 15 ml of methylene chloride,
0.37 g of gin and 1-ethyl-3- (3-dimethyl chloride)
Add 0.57 g of tylaminopropyl) carbodiimide
And stirred at room temperature for 4 hours. 30 ml of 1N hydrochloric acid in the reaction solution
And methylene chloride (30 ml) are added for liquid separation, and the organic layer is collected.
Then, it was dried with anhydrous magnesium sulfate. Filter desiccant
After separation, the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography.
Matography (Wakogel^TMC-200,100g;
Purified with ethyl acetate / hexane = 3/1 → ethyl acetate)
After manufacturing, recrystallize from a mixed solution of chloroform-hexane.
By, (4R, 6S) -6- [N-{(1S , 2
S , 3E) -2- (3,4-Dichlorobenzyl) -1-
Methyl-4- (2-naphthyl) -3-butenyl} carba
Moyl] -4-hydroxy-3,4,5,6-tetrahi
Doro-2H-pyran-2-one 0.83 g (yield 65
%) As white crystalline powder, mp 192-193 ° C.
Obtained.

100 mg of the lactone derivative obtained above was added to 1
2 ml of normal sodium hydroxide aqueous solution and 4 ml of methanol
Dissolve in a mixed solution of, and stir at room temperature for 1 hour, then add 1 m of water to the reaction solution.
l was added and the deposited precipitate was collected by filtration. The crystals were washed with ethyl ether and hexane and dried to give 41m of the title compound.
g (43% yield) as white crystalline powder, mp 210-21
_{^{2 ℃, [α] 20 D}} = + 91.1 ° (c = 1.06, methanol) was obtained as a.

[0316]¹H-NMR (CD₃OD) δ: 1.21
(3H, d, J = 6.6Hz), 1.74-1.84
(1H, m), 1.93-2.01 (1H, m), 2.
30 (1H, dd, J = 8.1Hz, 15.3Hz),
2.42 (1H, dd, J = 4.8Hz, 15.3H
z), 2.57-2.71 (2H, m), 2.96 (1
H, q, J = 9.3 Hz), 4.04 (1H, quin
t. , J = 6.6 Hz), 4.14-4.21 (1H,
m), 4.23 (1H, dd, J = 3.9Hz, 9.0)
Hz), 6.15 (1H, dd, J = 8.7Hz, 1
5.9 Hz), 6.34 (1H, d, J = 15.9H)
z), 7.11 (1H, dd, J = 1.8Hz, 8.1
Hz), 7.33 (1H, d, J = 8.1 Hz), 7.
35-7.44 (3H, m), 7.56 (1H, dd,
J = 1.5 Hz, 8.7 Hz), 7.63 (1H,
s), 7.72-7.78 (3H, m). Used as a raw material in the above reaction (1S , 2S , 3E)-
2- (3,4-dichlorobenzyl) -1-methyl-4-
Instead of (2-naphthyl) -3-butenylamine (1
S , 2S ) -3- (3,4-Dichlorophenyl) -2-
(2-Fluoro-4-biphenylyl) -1-methylpro
The same reaction as in Example 80 is carried out except that pyramine is used.
Thus, the compound of Example 81 was obtained. Example 81(3R, 5S) -5- [N-{(1S , 2S ) -3-
(3,4-dichlorophenyl) -2- (2-fluoro-
4-biphenylyl) -1-methylpropyl} carbamoy
] -3,5-Dihydroxypentanoic acid sodium salt ¹ H-NMR (CD₃OD) δ: 1.01 (3H, d, J
= 6.9 Hz), 1.82 (1H, ddd, J = 7.6)
Hz, 8.5 Hz, 14.3 Hz), 2.00 (1H,
ddd, J = 3.9Hz, 5.1Hz, 14.3H
z), 2.33 (1H, dd, J = 7.6 Hz, 15.
0Hz), 2.45 (1H, dd, J = 4.9Hz, 1
5.0Hz), 2.80 (1H, dd, J = 11.3H
z, 13.3 Hz), 2.97-3.05 (1H,
m), 3.18 (1H, dd, J = 3.8Hz, 13.
3 Hz), 4.17-4.34 (3H, m), 6.91
(1H, dd, J = 2.0Hz, 8.4Hz), 6.9
5-7.01 (2H, m), 7.15 (1H, d, J =
2.0 Hz), 7.25 (1H, d, J = 8.4H
z), 7.30-7.44 (4H, m), 7.47-
7.52 (2H, m). Example 825- [N-{(1R , 2R ) -2- (4-biphenyli
) -3- (3,4-Dichlorophenyl) -1-methyl
Propyl} carbamoyl] -2,3,4,5-tetrahi
Droxypentanoic acid sodium salt and 5- [N-
{(1S , 2S ) -2- (4-Biphenylyl) -3-
(3,4-Dichlorophenyl) -1-methylpropyl}
Carbamoyl] -2,3,4,5-tetrahydroxype
Production of sodium tantanate 2,3: 4,5-di-O-isopropylidene-2,3
4,5-Tetrahydroxyadipic acid diethyl ester
34.6 mg of a mixture of 1 ml of ethanol and 0.2 ml of water
And 0.1 ml of 1N aqueous sodium hydroxide solution
In addition, it was left overnight at room temperature. The reaction mixture was dried under reduced pressure and the residue
Was dissolved in 2 ml of dimethylformamide, and (1RS, 2
RS) -2- (4-biphenylyl) -3- (3,4-di
Chlorophenyl) -1-methylpropylamine 37 m
g, 1-hydroxybenzotriazole 15 mg and
Hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl)
Add 21 mg carbodiimide and stir for 2 hours at room temperature
It was The reaction mixture was diluted with ethyl acetate, washed with water, and dried with anhydrous sulfuric acid.
Dried with magnesium acid. After separating the desiccant by filtration, the solvent
Was distilled off under reduced pressure, and the residue was subjected to medium pressure liquid chromatography [L
obarcolumn^TM, SizeA, Lichrop
rep^TMSi60F (Merck); Hexane / acetic acid
Chill = 5/1 → 2/1] and purified (2R, 3S, 4
S, 5R) -5- [N-{(1RS, 2RS) -2-
(4-biphenylyl) -3- (3,4-dichlorophenyl)
L) -1-methylpropyl} carbamoyl] -2,3:
4,5-di-O-isopropylidene-2,3,4,5-
39 mg of dihydroxypentanoic acid ethyl ester (yield
58%).

Di-O-isopropylidene obtained above
Dissolve 39 mg of body in 2 ml of ethanol, and add 1N hydroxylation.
Add 70 μl of sodium aqueous solution and leave it at room temperature overnight.
It was The reaction mixture was evaporated to dryness under reduced pressure, and 0.75 ml of acetic acid and water were added to the residue.
A mixed solution of 0.25 ml was added and heated at 90 ° C. for 3 hours.
The reaction solution was dried under reduced pressure and the residue was subjected to silica gel column chromatography.
Graphography (Wakogel^TMC-200,5g; Ethyl acetate
5- [2- [N-{(1R , 2R ) −
2- (4-biphenylyl) -3- (3,4-dichlorophenyl)
Phenyl) -1-methylpropyl} carbamoyl] -1-
Hydroxyethyl] -3,4-dihydroxytetrahydr
Rofuran-2-one 5 mg (16% yield) and 5- [2-
[N-{(1S , 2S ) -2- (4-Biphenylyl)-
3- (3,4-dichlorophenyl) -1-methylpropyi
Ru} carbamoyl] -1-hydroxyethyl] -3,4
-Dihydroxytetrahydrofuran-2-one 4 mg
(Yield 13%) was obtained.

5 mg of (1R, 2R) -form obtained above
Was dissolved in 1 ml of methanol, 11 μl of 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was dried under reduced pressure to give the title compound as a (1R, 2R) -form as a white powder.

¹ H-NMR (CD ₃ OD) δ: 1.02
(3H, d, J = 6.5 Hz), 2.85 (1H, d
d, J = 11.1 Hz, 13.2 Hz), 2.95-
3.05 (1H, m), 3.21 (1H, dd, J =
3.6 Hz, 13.2 Hz), 3.97 (1 H, dd,
J = 1.2 Hz, 9.9 Hz), 4.01 (1H, d
d, J = 0.9 Hz, 9.9 Hz), 4.21 (1H,
d, J = 1.2 Hz), 4.26-4.38 (1H,
m), 4.46 (1H, d, J = 0.9 Hz), 6.8
8 (1H, dd, J = 1.8Hz, 8.4Hz), 7.
13-7.25 (4H, m), 7.26-7.33 (1
H, m), 7.36-7.44 (2H, m), 7.50.
-7.60 (4H, m). By using the (1S, 2S) -form lactone as a raw material and carrying out the same reaction as above, (1S, 2S)-
The body of the title compound is obtained.

¹ H-NMR (CD ₃ OD) δ: 0.99
(3H, d, J = 7.0 Hz), 2.71-2.94
(2H, m), 3.33-3.40 (1H, m), 3.
98 (1H, dd, J = 1.2Hz, 9.9Hz),
4.03 (1H, dd, J = 1.2Hz, 9.9H
z), 4.22 (1H, d, J = 1.2 Hz), 4.3
0-4.42 (1H, m), 4.45 (1H, d, J =
1.2Hz), 6.83 (1H, dd, J = 1.8H
z, 8.1 Hz), 7.10-7.23 (4H, m),
7.26-7.33 (1H, m), 7.36-7.44
(2H, m), 7.49-7.61 (4H, m). Example 83 N-{(1RS, 2RS) -3- (4-biphenylyl)
-2- (4-chlorophenyl) -1-methylpropyl}
-N- (2-naphthylmethyl) carbamoylmethylcoha
Production of humic acid N-{(1RS, 2RS) -3- (4-biphenylyl)
-2- (4-chlorophenyl) -1-methylpropyl}
2-Naphthylmethylamine (46.5 mg) and N-ethyldiisopropylamine (35 μl) were added to dichloromethane 1
It was dissolved in ml, 31 mg of chloroformylmethylsuccinic anhydride was added under ice-cooling stirring, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in a mixed solution of 1 ml of tetrahydrofuran and 0.5 ml of water, 42 mg of lithium hydroxide (monohydrate) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl ether and saturated brine. The organic layer was separated and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography [K
ieselgel ^™ 60F ₂₅₄ , Art 5744 (manufactured by Merck); dichloromethane / methanol = 8/1] to give 40.1 mg of the title compound (yield 67%).
Was obtained as a white powder.

¹ H-NMR (CDCl ₃ + CD ₃ OD)
δ: 0.83-0.95 (3H, m), 2.45-3.
40 (8H, m), 4.25-4.93 (3H, m),
6.85-7.85 (20H, m). N-{(1RS, 2R used as a raw material in the above reaction
S) -3- (4-biphenylyl) -2- (4-chlorophenyl) -1-methylpropyl} -2-naphthylmethylamine in place of the corresponding naphthylamine derivative,
The same reaction as in Example 83 was carried out otherwise to obtain the compounds of Examples 84 to 90. Example 84 N-{(1RS, 2RS) -3- (3-biphenylyl)
-2- (4-chlorophenyl) -1-methylpropyl}
-N- (2-naphthylmethyl) carbamoylmethylcoha
Citric acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 0.83-
1.00 (3H, m), 2.25-3.50 (8H,
m), 4.25-5.00 (3H, m), 6.30-
7.90 (20H, m). Example 85 N-{(1RS, 2RS) -3- (4'-chloro-4-
Biphenylyl) -2- (4-chlorophenyl) -1-me
Cylpropyl} -N- (2-naphthylmethyl) carbamo
Ilmethylsuccinic acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 0.85-
1.00 (3H, m), 2.45-3.50 (8H,
m), 4.25-4.95 (3H, m), 6.35-
7.90 (19H, m). Example 86 N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (2-Fluoro-4-biphenylyl) -1-
Methylpropyl} -N- (2-naphthylmethyl) carba
Moylmethyl succinic acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 0.85-
1.00 (3H, m), 2.45-3.40 (8H,
m), 4.25-4.85 (3H, m), 6.05-
7.90 (19H, m). Example 87 N-{(1RS, 2RS) -2- (4-chloropheny
) -3- (6-Fluoro-3-biphenylyl) -1-
Methylpropyl} -N- (2-naphthylmethyl) carba
Moylmethyl succinic acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 0.85-
1.0 (3H, m), 2.45-3.45 (8H,
m), 4.28-4.88 (3H, m), 6.05-
7.88 (19H, m). Example 88 N-[(1RS, 2RS) -2- (4-chlorophenyl)
Ru) -1-methyl-3- {3- (2-naphthyl) pheny
Ru} propyl] -N- (2-naphthylmethyl) carbamo
Ilmethylsuccinic acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 0.80-
1.02 (3H, m), 2.40-3.40 (8H,
m), 4.35-5.00 (3H, m), 6.30-
7.90 (22H, m). Example 89 N-{(1RS, 2RS) -3- (4-biphenylyl)
-2- (3,4-dichlorophenyl) -1-methylpro
Pill} -N- (2-naphthylmethyl) carbamoylmethy
Rusuccinic acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 0.95 /
1.02 (3H, each of d, J = 6.5Hz
/6.2Hz), 2.54-3.23 (8H, m),
4.56-4.86 (2H, m), 4.3-4.4 /
5.0-5.4 (1H, m), 6.41-7.89 (1
9H, m). Example 90 N-{(1RS, 2RS) -3- (4-biphenylyl)
-2- (2-naphthyl) -1-methylpropyl} -N-
(2- Naphthylmethyl ) carbamoylmethyl succinic acid ¹ H-NMR (CDCl ₃ ) δ: 0.87-1.04 (3
H, m), 2.59-3.45 (8H, m), 4.55
-4.94 (2H, m), 6.44-7.92 (22
H, m). Example 91 N-{(1RS, 2SR) -3- (3,4-dichlorofuran
Phenyl) -1-methyl-2- (2-naphthoyloxy)
Production of propyl} carbamoylmethylsuccinic acid (1RS, 2SR) -3- (3,4-dichlorophenyl) -1-methyl-2- (2-naphthoyloxy) propylamine 16.2 mg, carboxymethylsuccinic acid di-tert Butyl ester (18.2 mg) and 4-dimethylaminopyridine (7.0 mg) were added to methylene chloride (10 ml).
12.3 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added with stirring under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue for extraction, and the organic layer was washed successively with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and silica gel thin layer chromatography [Kieselgel ^™ 60F was used.
₂₅₄ , Art5744 (manufactured by Merck); hexane / ethyl acetate = 2/1] to give the di-
14.0 mg of tert-butyl ester (51% yield)
Got

14.0 mg of the ester compound obtained above was dissolved in 3 ml of methylene chloride, and trifluoroacetic acid 0.5
ml was added and the mixture was stirred at room temperature for 5 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was treated with hexane to obtain 12.1 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.23
(3H, d, J = 6.6 Hz), 2.35-2.46
(1H, m), 2.59-2.71 (3H, m), 2.
89-3.00 (2H, m), 3.15-3.26 (1
H, m), 4.20-4.35 (1H, m), 5.30.
-5.41 (1H, m), 6.88-7.00 (1H,
m), 7.01-7.08 (1H, m), 7.21-
7.26 (1H, m), 7.33 (1H, br.),
7.48-7.60 (2H, m), 7.77-7.92
(4H, m), 8.45 (1H, s). Example 92 (2S) -2- [N-{(1S, 2R) -3- (3,4)
-Dichlorophenyl) -1-methyl-2- (2-naphtho
Iloxy) propyl} carbamoylmethyl] succinic acid
(1S, 2R) -3- (3,4) obtained in Production Example 122 of
1.35 g of -dichlorophenyl) -1-methyl-2- (2-naphthoyloxy) propylamine and Example 1
1.11 g of (2S) -carboxymethyl succinic acid di-tert-butyl ester obtained in 16 was dissolved in 20 ml of methylene chloride, and 1-ethyl-3-hydrochloride was stirred under ice cooling.
(3-Dimethylaminopropyl) carbodiimide 0.8
1 g and 4-dimethylaminopyridine 0.51 g were added, and the mixture was stirred at room temperature for 3 hours. Water and methylene chloride were added to the reaction solution for extraction, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [Wakogel ^™ C-200, 100 g; hexane /
Ethyl acetate = 3/1 → 2/1] to obtain 1.87 g (yield 71%) of di-tert-butyl ester of the title compound.

1.84 g of the ester obtained above was dissolved in 20 ml of methylene chloride, and 2 ml of trifluoroacetic acid was dissolved.
Was added and the mixture was stirred overnight at room temperature. The reaction solution was dried under reduced pressure, and the residue was recrystallized from a mixed solution of 15 ml of methanol, 30 ml of chloroform and 100 ml of hexane,
1.15 g (yield 75%) of the title compound as white needle crystals,
mp 181-182 ° C.

[0325]¹H-NMR (CD₃OD) δ: 1.31
(3H, d, J = 7.2 Hz), 2.43 (1H, d
d, J = 7.5 Hz, 14.7 Hz), 2.56-2.
72 (3H, m), 2.99 (1H, dd, J = 9.0)
Hz, 14.1 Hz), 3.07 (1H, dd, J =
4.5Hz, 14.1Hz), 3.20 (1H, qui
nt. , J = 6.6 Hz), 4.24-4.33 (1
H, m), 5.45 (1H, quint., J = 4.5)
Hz), 7.20 (1H, dd, J = 2.4 Hz, 8.
4Hz), 7.32 (1H, d, J = 8.4Hz),
7.48 (1H, d, J = 1.8Hz), 7.53-
7.64 (2H, m), 7.89-8.01 (4H,
m), 8.22 (1H, d, J = 8.7 Hz), 8.5
4 (1H, s). (1S, 2R) -3- used as a raw material in the above reaction
(3,4-dichlorophenyl) -1-methyl-2- (2
-Naphthoyloxy) propylamine instead of
The same reaction as in Example 92 was carried out except that the amine derivative was used.
By carrying out, compounds of Examples 93 to 95 were obtained. Example 93(2S) -2- [N-{(1S, 2R) -3- (3,4
-Dichlorophenyl) -1-methyl-2- (2-naphtho
Iloxy) propyl} -N-methylcarbamoylmethy
Lu] succinic acid mp71-74 ° C¹ H-NMR (CD₃OD) δ: 1.29, 1.38 (t
total 3H, each d, J = 6.6 Hz, 6.
9Hz), 2.50-3.10 (6H, m), 2.8
3,2.94 (total 1H, s), 3.24-
3.35 (1H, m), 4.25-4.32, 4.72
-4.82 (total 1H, m), 5.50-5.
60 (1H, m), 7.18, 7.22 (total
1H, each dd, J = 2.0Hz, 8.1Hz /
1.8 Hz, 8.4 Hz), 7.44, 7.48 (to
tal 1H, each d, J = 2.0 Hz, 1.8
Hz), 7.54-7.68 (2H, m), 7.90-
8.06 (4H, m), 8.56, 8.61 (tota
11H, br. ). Example 94(2S) -2- [N-{(1S, 2R) -2- (4-q
Lolo-3-methylbenzoyloxy) -3- (3,4-
Dichlorophenyl) -1-methylpropyl} carbamoy
Lumethyl] succinic acid mp172-173 ° C¹ H-NMR (CD₃OD) δ: 1.23 (3H, d, J
= 6.6 Hz), 2.41 (3H, s), 2.41 (1
H, dd, J = 7.5 Hz, 14.4 Hz), 2.53
-2.69 (3H, m), 2.93 (1H, dd, J =
9.6Hz, 14.1Hz), 3.03 (1H, dd,
J = 3.6 Hz, 14.1 Hz), 3.16-3.20.
(1H, m), 4.24 (1H, dq, J = 4.5H
z, 6.9 Hz), 5.36 (1H, dt, J = 4.5)
Hz, 9.3 Hz), 7.17 (1H, d, J = 5.7)
Hz), 7.74 (1H, dd, J = 1.8Hz, 8.
4 Hz), 7.84 (1H, d, J = 1.8 Hz). Example 95(2S) -2- [N-{(1S, 2R) -3- (3,4
-Dichlorophenyl) -1-methyl-2- (2-quinoli
Carbonyloxy) propyl} carbamoylmethyl]
Succinic acid mp111-114 ° C¹ H-NMR (CD₃OD) δ: 1.35 (3H, d, J
= 6.6 Hz), 2.45-2.72 (4H, m),
3.01-3.21 (3H, m), 4.45 (1H,
m), 5.50 (1H, m), 7.27 (1H, dd,
J = 1.8 Hz, 7.2 Hz), 7.36 (1H, d,
J = 7.2 Hz), 7.54 (1H, d, J = 1.8H
z), 7.92 (1H, m), 8.09 (1H, m),
8.24 (1H, br.d, J = 7.8Hz), 8.3
4 (1H, d, J = 8.4 Hz), 8.39 (1H, b
r. d, J = 8.4 Hz), 8.98 (1H, br.
d, J = 8.4 Hz). Example 96(3R ) -4-{(1S, 2R) -3- (3,4-dichloro)
Lolophenyl) -1-methyl-2- (2-naphthoyl)
Xyl) propylcarbamoyl} -3-methylbutanoic acid
Manufacturing (1S, 2R) -3- (3,4-dichlorophenyl)-
1-methyl-2- (2-naphthoyloxy) propyla
Min 233mg and methyl (R) -3-methylglutarate
103 mg of the ester was dissolved in 15 ml of methylene chloride,
Under ice-cooling stirring, 1-ethyl-3- (3-dimethylamido hydrochloride)
Nopropyl) carbodiimide 127 mg and 4-dime
Add 60 mg of tylaminopyridine and stir overnight at room temperature.
It was Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was separated.
After washing with saturated saline, drying with anhydrous magnesium sulfate
did. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the residue
Kagel column chromatography [Wako gel^TMC-2
00, 40 g; hexane / ethyl acetate = 2/1 → 1 /
1] to give the methyl ester of the title compound 2
69 mg (yield 85%) was obtained.

63 mg of the methyl ester obtained above
Was added to a mixed solution of 2.5 ml of concentrated hydrochloric acid and 5 ml of acetic acid, and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction solution to separate the layers, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography [Kie.
50 mg (yield 80%) of the title compound was obtained as a white crystalline powder, mp 122-128 ° C. by subjecting it to selgel ^™ 60F ₂₅₄ , Art 5744 (manufactured by Merck); methylene chloride / methanol = 9/1].

¹ H-NMR (CDCl ₃ + CD ₃ OD)
δ: 1.05 (3H, d, J = 6.3Hz), 1.30
(3H, d, J = 6.9 Hz), 2.13-2.30
(2H, m), 2.30-2.46 (3H, m), 2.
98 (1H, dd, J = 5.6Hz, 14.4Hz),
3.06 (1H, dd, J = 8.4Hz, 14.4H
z), 4.30-4.40 (1H, m), 5.35-
5.43 (1H, m), 6.21 (1H, br.d, J
= 8.4 Hz), 7.13 (1H, dd, J = 1.8H)
z, 8.1 Hz), 7.31 (1H, d, J = 8.1H)
z), 7.39 (1H, d, J = 1.8 Hz), 7.5
3-7.65 (2H, m), 7.86-7.92 (2
H, m), 7.93-7.99 (2H, m), 8.52
(1H, s). Example 97 (3S) -4-{(1S, 2R) -3- (3,4-di)
Lolophenyl) -1-methyl-2- (2-naphthoyl)
Xyl) propylcarbamoyl} -3-methylbutanoic acid
(1S, 2R) -3- (3,4-dichlorophenyl) -1-methyl-2- (2-naphthoyloxy) as a raw material for production
Propylamine and (S) -3-methylglutarate ter
t-Butyl ester [(R) -3-methylglutarate methyl ester was treated with tert-butanol, 1-ethyl-3- (3-dimethylaminoethylpropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine to give te.
After rt-butyl esterification, the resulting diester was prepared by partial hydrolysis in a 25% aqueous methanol solution of 0.5N sodium hydroxide] to carry out the same reaction as in Example 96. Tert of the title compound
-Butyl ester was obtained.

103 mg of the ester obtained above was dissolved in 5 ml of methylene chloride, and 0.5 ml of trifluoroacetic acid was dissolved.
1 was added and the mixture was stirred overnight at room temperature. The reaction solution was dried under reduced pressure,
The residue was subjected to silica gel thin layer chromatography [Kiese].
lgel ^™ 60F ₂₅₄ , Art 5744 (manufactured by Merck); chloroform / methanol = 9/1] to obtain 65 mg (yield 70%) of the title compound as a white crystalline powder, mp 170-172 ° C.

¹ H-NMR (CDCl ₃ ) δ: 1.03
(3H, d, J = 6.3 Hz), 1.29 (3H, d,
J = 6.9 Hz), 2.10 (1H, dd, J = 7.0)
Hz, 14.0 Hz), 2.21-2.46 (3H,
m), 2.95-3.05 (2H, m), 4.24-
4.40 (1H, m), 5.30-5.40 (1H,
m), 7.12 (1H, dd, J = 2.0 Hz, 8.1
Hz), 7.29 (1H, d, J = 8.1 Hz), 7.
38 (1H, d, J = 2.0 Hz), 7.53 to 7.6
4 (2H, m), 7.84-8.00 (4H, m),
8.51 (1H, br.). In place of (S) -3-methylglutaric acid used as a raw material in the above reaction, adipic acid mono-tert-butyl ester or (E) -5-tert-butoxycarbonyl-4-pentenoic acid was used, and the other examples were used. The compound of Examples 98 and 99 was obtained by performing the same reaction as that of 97. Example 98 5-{(1S, 2R) -3- (3,4-dichlorophenyl)
) -1-Methyl-2- (2-naphthoyloxy) pro
Pyrcarbamoyl } pentanoic acid mp 73-75 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, d, J
= 6.6 Hz), 1.58-1.76 (4H, m),
2.15-2.24 (2H, m), 2.29-2.40
(2H, m), 2.92-3.12 (2H, m), 4.
30-4.40 (1H, m), 5.32-5.42 (1
H, m), 6.06 (1H, br.d, J = 8.2H
z), 7.13 (1H, dd, J = 2.0 Hz, 8.2)
Hz), 7.30 (1H, d, J = 8.2 Hz), 7.
39 (1H, d, J = 2.0 Hz), 7.52-7.6.
6 (2H, m), 7.85-8.01 (4H, m),
8.52 (1H, br.). Example 99 (2E) -5-{(1S, 2R) -3- (3,4-di)
Lolophenyl) -1-methyl-2- (2-naphthoyl)
Xy ) Propylcarbamoyl } -2-pentenoic acid mp 72-75 ° C. ¹ H-NMR (CD ₃ OD) δ: 1.28 (3H, d, J
= 6.9 Hz), 2.31 (2H, t, J = 7.5H)
z), 2.57 (2H, q, J = 6.9Hz), 2.9
7 (1H, dd, J = 5.4Hz, 14.7Hz),
3.06 (1H, dd, J = 8.4Hz, 14.1H
z), 4.32-4.37 (1H, m), 5.35-
5.41 (1H, m), 5.85 (1H, d, J = 1
5.6 Hz), 6.00 (1H, d, J = 8.4H
z), 7.03 (1H, dt, J = 6.6 Hz, 15.
6 Hz), 7.12 (1H, dd, J = 1.8 Hz,
8.4 Hz), 7.31 (1H, d, J = 8.4H
z), 7.39 (1H, d, J = 1.8 Hz), 7.5
4-7.64 (2H, m), 7.89 (2H, d, J =
8.7 Hz), 7.95-7.99 (2H, m), 8.
52 (1H, s). Example 100 4-{(1S, 2R) -3- (3,4-dichlorophenyl)
) -1-Methyl-2- (2-naphthoyloxy) pro
Preparation of pyrcarbamoyl} -3- methoxybutanoic acid 162 mg of 3-methoxyglutaric acid was dissolved in 3 ml of acetone to prepare N, N′-dicyclohexylcarbodiimide 2
06 mg was added, and the mixture was stirred at room temperature for 2 hours. The precipitate formed in the reaction solution was filtered off, the solvent was distilled off under reduced pressure, the residue was dissolved in 5 ml of methylene chloride, and the mixture was stirred under cooling with water (1S, 2R) -3.
-(3,4-Dichlorophenyl) -1-methyl-2-
(2-naphthoyloxy) propylamine hydrochloride 106
mg and triethylamine 209 μl were added, and the mixture was cooled to 1 on ice.
Stir for hours. 1N Hydrochloric acid and methylene chloride were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography [Kieselgel ^™ 60F ₂₅₄ , Art 5744.
(Manufactured by Merck); methylene chloride / methanol = 10 /
1] to give 31 mg of the title compound as a white powder.

¹ H-NMR (CD ₃ OD) δ: 1.31
(3H, d, J = 6.9 Hz), 2.42-2.69
(4H, m), 2.94-3.10 (2H, m), 3.
26 (3 / 2H, s), 3.27 (3 / 2H, s),
3.91-3.99 (1H, m), 4.32-4.41
(1H, m), 5.38-5.45 (1H, m), 6.
57-6.74 (1H, m), 7.12 (1H, dd,
J = 2.1 Hz, 8.1 Hz), 7.30 (1H, d,
J = 8.1 Hz), 7.38 (1H, d, J = 1.8H)
z), 7.53-7.64 (2H, m), 7.88 (2
H, d, J = 8.4 Hz), 7.95-7.99 (2
H, m), 8.52 (1H, s). Example 101 4-{(1S, 2R) -3- (3,4-dichlorophenyl)
) -1-Methyl-2- (2-naphthoyloxy) pro
Preparation of pyrcarbamoyl} -3-hydroxybutanoic acid (1S, 2R) -3- (3,4-dichlorophenyl)-
129 mg of 1-methyl-2- (2-naphthoyloxy) propylamine hydrochloride and 120 μl of triethylamine were dissolved in 15 ml of methylene chloride, and 3- (t
82 mg of glutaric anhydride was added, and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid and methylene chloride were added to the reaction solution for extraction, and the organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was mixed with 10 ml of tetrahydrofuran and 1
It was dissolved in a mixed solution of 5 ml of normal hydrochloric acid and left overnight at room temperature.
Water and ethyl acetate were added to the reaction solution for extraction, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography [Kieselgel ^™ 6
0F _254, Art5744 (manufactured by Merck); by subjecting the chloroform / methanol = 6/1] to give the title compound 112mg (71% yield) as a white powder.

¹ H-NMR (CD ₃ OD) δ: 1.30
(3H, d, J = 6.9 Hz), 2.47-12.58
(4H, m), 3.01 (1H, dd, J = 9.0H
z, 14.1 Hz), 3.09 (1H, dd, J = 4.
4 Hz, 14.1 Hz), 4.26-4.35 (1H,
m), 4.35-4.37 (1H, m), 5.39-
5.48 (1H, m), 7.20 (1H, dd, J =
1.8 Hz, 8.1 Hz), 7.31 (1H, d, J =
8.1 Hz), 7.47 (1H, d, J = 1.8H
z), 7.53-7.64 (2H, m), 7.89-
8.03 (4H, m), 8.55 (1H, br.). Example 102 N-{(1RS, 2RS, 3E) -2- (3,4-di)
Lolobenzyl) -1-methyl-4- (2-naphthyl)-
Preparation of 3-butenyl} carbamoylmethylsuccinic acid (1RS, 2RS, 3E) -2- (3,4-dichlorobenzyl) -1-methyl-4- (2-naphthyl) -3-butenylamine 28 mg and N-ethyldiisopropyl 13 μl of amine was dissolved in 1 ml of tetrahydrofuran, and this solution was stirred under ice-cooling and chloroformylmethyl succinic anhydride 1
6 mg of tetrahydrofuran solution (1 ml) was added dropwise and the mixture was stirred for 2 hours under ice cooling. The reaction mixture was extracted by adding 5% aqueous oxalic acid solution and ethyl ether, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [Wakogel ^™ C-200, 3
g; chloroform → chloroform / methanol = 10 /
1] to give 20 mg of the title compound (yield: 58
%) As a white powder.

¹ H-NMR (CDCl ₃ + CD ₃ OD)
δ: 1.15 (3H, d, J = 6.9Hz), 2.32
-2.42 (1H, m), 2.55-2.80 (6H,
m), 3.19-3.27 (1H, m), 4.02-
4.15 (1H, m), 6.02 (1H, dd, J =
7.7 Hz, 15.8 Hz), 6.15-6.25 (1
H, m), 6.34 (1H, d, J = 15.8 Hz),
6.94 (1H, dd, J = 2.1Hz, 8.5H
z), 7.26 (2H, s), 7.36-7.45 (2
H, m), 7.48 (1H, d, J = 8.6 Hz),
7.59 (1H, s), 7.72-7.77 (3H,
m). Used as a raw material in the above reaction (1RS, 2RS, 3
E) -2- (3,4-Dichlorobenzyl) -1-methyl-4- (2-naphthyl) -3-butenylamine was replaced with the corresponding amine compound, and otherwise the same reaction as in Example 102 was carried out. By carrying out, compounds of Examples 103 to 106 were obtained. Example 103 N-{(1RS, 2RS, 3E) -4- (2-benzo
[B] Furanyl) -2- (3,4-dichlorobenzyl)
-1-Methyl-3-butenyl} carbamoylmethylcoha
Citric acid ¹ H-NMR (CD ₃ OD) δ: 1.10-1.25 (3
H, m), 2.40-3.10 (7H, m), 3.15.
-3.30 (1H, m), 6.10-6.35 (2H,
m), 6.52 (1H, s), 7.05 to 7.52 (7
H, m). Example 104 N-[(1RS, 2RS, 3E) -2- (3,4-di)
Lolobenzyl) -1-methyl-4- {3- (3-thieni)
Lu) phenyl} -3-butenyl] carbamoylmethylco
Succinic acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.10-
1.20 (3H, m), 2.30-2.80 (7H,
m), 3.10-3.30 (1H, m), 4.00-
4.20 (1H, m), 5.94 (1H, dd, J =
8.1 Hz, 15.2 Hz), 6.16-6.23 (1
H, br. ), 6.22 (1H, d, J = 15.2H)
z), 6.91-6.98 (2H, m), 7.21-
7.24 (2H, m), 7.30-7.46 (6H,
m). Example 105 N-{(1RS, 2RS, 3E) -2- (3,4-di)
Lorobenzyl) -1-methyl-4- (1-naphthyl)-
3-Butenyl} carbamoylmethyl succinic acid ¹ H-NM
R (CDCl ₃ + CD ₃ OD) δ: 1.15-1.18
(3H, m), 2.30-2.95 (7H, m), 4.
05-4.21 (1H, m), 6.09 (1H, dd,
J = 8.0 Hz, 16.1 Hz), 7.10 (2H,
d, J = 8.4 Hz), 7.19 (2H, d, J = 7.
1 Hz), 7.38-7.50 (2H, m), 7.51
(1H, d, J = 8.2Hz), 7.62 (1H,
s), 7.70-7.83 (3H, m). Example 106 N-{(1RS, 2RS, 3E) -2- (4-chlorobe
Benzyl) -4- (4-chlorophenyl) -1-methyl-
3-butenyl} carbamoylmethyl succinic acid ¹ H-NMR (CD ₃ OD) δ: 1.13 (3 / 2H,
d, J = 6.8 Hz), 1.15 (3 / 2H, d, J =
6.8 Hz), 2.37-2.75 (1H, m), 2.
85-2.90 (1H, m), 3.18-3.27 (1
H, m), 3.92-4.03 (1H, m), 5.95.
-6.15 (2H, m), 7.09-7.30 (8H,
m). Example 107 N-{(1RS, 2SR) -2- (3,4-dichlorobenzene
Benzyl) -1-methyl-3- (2-naphthoxy) propyi
Preparation of ru} carbamoylmethylsuccinic acid 33 mg of N-{(1RS, 2SR) -2- (3,4-dichlorobenzyl) -1-methyl-3- (2-naphthoxy) propyl} phthalimide was dissolved in 3 ml of ethanol, 0.1 ml of hydrazine monohydrate was added, and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methylene chloride, the insoluble material was filtered off, and the filtrate was again dried under reduced pressure to dryness. The residue was dissolved in methylene chloride (3 ml) and carboxymethyl succinic acid di-tert-butyl ester (33 mg), 4-dimethylaminopyridine (14 mg) and hydrochloric acid 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide 2
2 mg was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [Wakogel ^™ C-200, 5 g; hexane / ethyl acetate = 5.
1/1 → 3/1] to give the title compound
52 mg (yield 93%) of the rt-butyl ester compound was obtained as a colorless oil.

52 mg of the ester thus obtained was dissolved in 1 ml of methylene chloride, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, toluene was added to the residue and the mixture was dried under reduced pressure again, and the obtained product was treated with a mixed solution of methylene chloride and hexane.
31 mg (72% yield) of the title compound was obtained as a white powder.

¹ H-NMR (CDCl ₃ + CD ₃ OD)
δ: 1.24 (3H, d, J = 6.8Hz), 2.20
-2.30 (1H, m), 2.47 (1H, dd, J =
5.9 Hz, 14.9 Hz), 2.59-2.87 (5
H, m), 3.18-3.28 (1H, m), 3.92.
-4.02 (2H, m), 4.21-4.31 (1H,
m), 7.02 (1H, d, J = 2.5 Hz), 7.0
6 (1H, dd, J = 2.0Hz, 8.3Hz), 7.
11 (1H, dd, J = 2.3Hz, 9.0Hz),
7.31-7.36 (3H, m), 7.43 (1H, d
t, J = 1.0 Hz, 8.0 Hz), 7.68 (1H,
d, J = 8.0 Hz), 7.74 (1H, d, J = 8.
8 Hz), 7.76 (1H, d, J = 7.5 Hz). N-{(1RS, 2S used as a raw material in the above reaction
R) -2- (3,4-Dichlorobenzyl) -1-methyl-3- (2-naphthoxy) propyl} phthalimide was used in place of the corresponding phthalimide derivative, otherwise Example 1
By carrying out the same reaction as in Example 07,
11 compounds were obtained. Example 108 N-{(1RS, 2SR) -2- (4-chlorobenze
) -3- (4-Chlorophenoxy) -1-methylpro
Pyr} carbamoylmethyl succinic acid ¹ H-NMR (CD ₃ OD) δ: 1.20 (3 H, d, J
= 6.9 Hz), 2.08-2.17 (1H, m),
2.38-2.52 (2H, m), 2.53-2.75
(4H, m), 2.82-2.93 (1H, m), 3.
15-3.25 (1H, m), 3.78 (1H, br.
dd, J = 5.0 Hz, 9.6 Hz), 3.85 (1
H, br. dd, J = 4.2 Hz, 9.6 Hz), 4.
13-5.03 (1H, m), 6.82 (2H, br.
d, J = 9.3 Hz), 7.15-7.24 (6H,
m). Example 109 N-{(1RS, 2SR) -2- (3,4-dichlorobenzene
Benzyl) -1-methyl-3- (2-naphthylthio) pro
Pyr} carbamoylmethyl succinic acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.19
(3H, d, J = 6.8Hz), 1.98-2.08
(1H, m), 2.43 (1H, dt, J = 6.0H
z, 15.2 Hz), 2.58-2.80 (5H,
m), 2.93 (2H, d, J = 6.3 Hz), 3.1
4-3.24 (1H, m), 4.27-4.37 (1
H, m), 6.98 (1H, dd, J = 2.0 Hz,
8.0 Hz), 7.23-7.31 (3H, m), 7.
40-7.50 (3H, m), 7.61 (1H, br.
d, J = 8.0 Hz), 7.68 (1H, br.d, J
= 9.0 Hz), 7.77 (1H, br.d, J = 9.
0 Hz). Example 110 N-{(1RS, 2RS) -2- (4-chlorobenze
) -4- (4-Chlorophenyl) -1-methylbuty
Ru} carbamoylmethylsuccinic acid ¹ H-NMR (CD ₃ OD) δ: 1.08 (3 / 2H,
d, J = 6.6 Hz), 1.15 (3 / 2H, d, J =
6.6 Hz), 1.31-1.90 (3H, m), 2.
20-2.83 (8H, m), 3.10-3.40 (1
H, m), 6.95-7.40 (8H, m). Example 111 N-{(1RS, 2SR) -3- (3,4-dichlorofuran
Phenyl) -1-methyl-2- (2-naphthylmethyloxy)
Ci) Propyl} carbamoylmethyl succinic acid ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.17
(3H, d, J = 6.3Hz), 1.75 (1 / 2H,
m), 1.93 (1 / 2H, m), 2.27-2.50
(2H, m), 2.58-2.85 (3H, m), 2.
94-3.09 (1H, m), 3.61-3.70 (1
H, m), 3.98-4.09 (1H, m), 4.30.
(1H, br.d, J = 12.3 Hz), 4.54-
4.52 (1H, m), 5.78-5.87 (1H,
m), 7.03-7.08 (1H, br.dd, J =
1.8 Hz, 8.1 Hz), 7.27-7.36 (3
H, m), 7.45-7.52 (2H, m), 7.58.
(1H, br.), 7.76-7.84 (3H, m). Example 112 4-{(1RS, 2RS, 3E) -2- (3,4-di)
Lolobenzyl) -1-methyl-4- (2-naphthyl)-
Preparation of 3-butenylcarbamoyl} -3-methylbutanoic acid
Concrete (1RS, 2RS, 3E) -2- (the 3,4-dichlorobenzyl) -1-methyl-4- (2-naphthyl) -3-butenylamine 20mg was dissolved in methylene chloride 1 ml,
3-Methyl glutaric anhydride (10 mg) and triethylamine (4 μl) were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium carbonate solution and methylene chloride were added to the reaction solution, the mixture was stirred for 30 minutes, the organic layer was separated, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [Wakogel ^™ C-200, 2 g;
Chloroform / methanol = 20/1] to give the title compound (16 mg, yield 74%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.36
(3H, d, J = 6.0 Hz), 1.20 (3H, d,
J = 6.8 Hz), 2.12-2.45 (5H, m),
2.61-2.78 (2H, m), 2.83 (1H,
t, J = 8.5 Hz), 4.11-4.22 (1H,
m), 5.70 (1H, br.d, J = 7.8Hz),
6.09 (1H, dd, J = 9.1Hz, 15.3H
z), 6.99 (1H, dd, J = 1.9Hz, 8.5
Hz), 7.28 (2H, s), 7.50 (1H, d
d, J = 1.9 Hz, 8.5 Hz), 7.61 (1H,
s), 7.76-7.79 (3H, m). Example 113 5-{(1RS, 2RS, 3E) -2- (3,4-di)
Lolobenzyl) -1-methyl-4- (2-naphthyl)-
Preparation of 3-butenylcarbamoyl } pentanoic acid (1RS, 2RS, 3E) -2- (3,4-dichlorobenzyl) -1-methyl-4- (2-naphthyl) -3-butenylamine 30 mg in methylene chloride 1 ml. Dissolve
Adipic acid monoethyl ester 18 mg, 4-dimethylaminopyridine 12 mg and hydrochloric acid 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide 19m
g was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was dissolved in 1 ml of methanol, 0.5 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, extracted with ethyl ether and 1N hydrochloric acid, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography [Kieselgel ^™ 60F ₂₅₄ , Art 5744.
(Merck): chloroform / methanol = 10 /
1] to give 21 mg of the title compound (yield 51
%) As a colorless oil.

[0336]¹H-NMR (CDCl₃) Δ: 1.14
(3H, d, J = 6.5Hz), 1.50-1.70
(4H, br.), 2.05-2.20 (2H, b.
r. ), 2.20-2.35 (2H, br.), 2.6.
4 (2H, t, J = 9.9Hz), 2.83-2.90
(1H, m), 3.70-4.50 (1H, br.),
4.05-4.17 (1H, m), 5.90-6.00
(1H, br.), 6.05 (1H, dd, J = 8.8
Hz, 15.7 Hz), 7.05 (2H, d, J = 5.
9Hz), 7.16 (2H, d, J = 8.3Hz),
7.36-7.42 (2H, m), 7.46 (1H,
d, J = 9.4 Hz), 7.55 (1 H, s), 7.6
8-7.80 (3H, m). Example 114(1RS, 2RS) -2- (4-biphenylyl) -3-
Of (4-chlorophenyl) -1-methylpropylamine
Manufacturing and its optical resolution (1) Production of 1- (4-biphenylyl) -2-propanone
10.5 g of 4-biphenylylacetic acid was added to 50 m of thionyl chloride.
It was dissolved in 1 liter and heated at 80 ° C for 3 hours, and then an excess of thionyl chloride was added.
The solvent was distilled off under reduced pressure. Benzene is added to the residue and the solvent is added again.
After distilling off and repeating this operation again, the resulting acid chloride
The product was dissolved in 100 ml of ethyl ether. Separately,
Suspension of 23.7 g of cuprous oxide in 50 ml of ethyl ether
Then, with stirring under ice cooling, 1.5M methyllithium ethyl acetate
166 ml of tellurium solution was added to obtain a homogeneous solution.
In an ethyl ether solution of the acid chloride obtained in the above reaction
Under a nitrogen atmosphere at -70 ° C with cooling and stirring.
It was After completion of dropping, the mixture was stirred at the same temperature for 1 hour and then meta
Excess copper-lithium reagent was decomposed by adding a nol. reaction
Insoluble formed by adding ethyl ether and 2N hydrochloric acid to the liquid
After separating the substances, the liquid was separated and the organic layer was washed with saturated saline.
Then, it was dried with anhydrous magnesium sulfate. Filter desiccant
After separation, the solvent was distilled off under reduced pressure to give the title compound 9.
93 g (yield 96%) was obtained as a colorless oil. (2) 3- (4-biphenylyl) -4- (4-chlorophenyl)
Preparation of 1- (4-biphenylyl) -2-propanone 9.93
g, 4-chlorobenzyl chloride 8.4 g and hydroxylation
Mix 2.1 g of sodium and stir at 80-90 ° C.
Heat on oil bath for 5 hours. After allowing the reaction solution to cool to room temperature,
After adding chill ether and water and separating the organic layer, anhydrous sodium sulfate was added.
Dried with gnesium. After removing the desiccant by filtration, reduce the solvent
By distilling off under pressure and recrystallizing the residue from hexane,
Colorless needle-like crystals of 8.42 g (yield 53%) of the title compound,
mp107-108.5 ° C. (3) (2RS, 3SR) -3- (4-biphenylyl)
Preparation of 4- (4-chlorophenyl) -2-propanol
3- (4-biphenylyl) -4- (4-chlorophenyl)
Ru) -2-butanone 8.42 g of tetrahydrofuran 3
It was dissolved in 0 ml and cooled at −78 ° C. under stirring for 3 seconds.
Butyl lithium borohydride (L-selectride^TM)
30 ml of 1M tetrahydrofuran solution of
Stirred for 30 minutes. 2N sodium hydroxide in the reaction solution
Add 50 ml of aqueous solution and stir at room temperature for 1 hour, then stir on ice.
Then, add 20 ml of 30% hydrogen peroxide solution and stir for another hour.
I stirred. Extract the product by adding ethyl ether and extract
The solution was washed with saturated saline and then washed with anhydrous magnesium sulfate.
Dried. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the residue was removed.
Medium pressure liquid chromatography (hexane / ethyl acetate =
15/1 to 10/1) to give the title compound
7.36 g (yield 87%) was obtained as a colorless oil. (4) N-{(1RS, 2RS) -2- (4-bipheni
Ryl) -3- (4-chlorophenyl) -1-methylpro
Preparation of Pyr} phthalimide (2RS, 3SR) -3- (4-biphenylyl) -4-
(4-chlorophenyl) -2-propanol 7.36
g, triphenylphosphine 11.5 g and phthali
Dissolve 6.5 g of amide in 100 ml of tetrahydrofuran
Then, under ice-cooling stirring, the azodicarboxylic acid diet prepared separately was prepared.
Tetrahydrofuran solution of 7.66 g of luster 20 m
1 was added and the mixture was stirred overnight at room temperature. After concentrating the reaction solution under reduced pressure,
Ethyl ether and water are added to the residue for extraction, and the organic layer is saturated.
After washing with Japanese salt water, drying over anhydrous magnesium sulfate
It was After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was treated with methanol.
After treatment with alcohol, the precipitate is filtered off to give the title compound
3.08 g (30% yield) of white crystalline powder, mp14
2 to 144 ° C. (5) (1RS, 2RS) -2- (4-biphenylyl)
-3- (4-chlorophenyl) -1-methylpropyl
Preparation of Min Hydrochloride N-{(1RS, 2RS) -2- (4-biphenylyl)
-3- (4-chlorophenyl) -1-methylpropyl}
Suspended 3.08 g of phthalimide in ethanol and added hydra
1 ml of gin monohydrate was added and the mixture was heated under reflux for 4 hours. reaction
After allowing the liquid to cool, the insoluble material is filtered off, and the filtrate is concentrated under reduced pressure and the residue
Is treated with hydrogen chloride methanol to give the title compound.
2.44 g (yield 99%) of white needle crystals, mp24
3 to 249 ° C. (6) (1S , 2S )-And (1R , 2R ) -2-
(4-Biphenylyl) -3- (4-chlorophenyl)-
Preparation of 1-methylpropylamine (1RS, 2RS) -2- (4-biphenylyl) -3-
(4-chlorophenyl) -1-methylpropylamine salt
2.20 g of acid salt were mixed with 50 ml of ethyl ether under ice cooling.
Add to a mixture with 20 ml of normal sodium hydroxide solution,
After shaking well, the organic layer was separated. Organic layer with water and saturated food
Wash with brine, dry over anhydrous magnesium sulfate, and then use as solvent.
Was dried under reduced pressure. The residual free base was treated with D-(+)-diben
20 ml of methanol with 2.22 g of zoyl tartaric acid
Dissolve, add seed crystals and let stand overnight at room temperature. Precipitated crystals
By filtering, washing with ethanol, and drying,
(1S , 2S ) -Form of the title compound D-(+)-diben
Zoyl tartrate 342 mg, [α]²⁰ _D= + 161.7
(C = 1.5, methanol) was obtained.

The dibenzoyl tartrate salt obtained above was converted to
20 ml of ethyl ether and 2N sodium hydroxide under ice cooling
Dissolve in 10 ml of um aqueous solution, collect the organic layer, and
By post-processing, (1S , 2S ) -Compound title
162 mg (yield 8.2%), [α]²⁰ _D= + 207
(C = 1.5, methanol) as a colorless oil
It was

Similarly, (1S , 2S ) -Body D-(+)
− Combine the filtrate and wash after filtering dibenzoyl tartrate.
And dry under reduced pressure, then add ethyl ether and 2N to the residue.
Post-treatment by adding sodium hydroxide aqueous solution in the usual way
Gives 1.4 g of the free base, a mixture of enantiomers
Obtained. This base was dissolved in 20 ml of methanol and L-
2.22 g of (-)-dibenzoyltartaric acid and seed crystals were added.
In addition, the same division as above was performed, and the above obtained (1
S , 2S ) -Of the title compound in an enantiomeric relationship with
(1R , 2R ) -L-(-)-dibenzoyltartaric acid
300 mg salt, [α]²⁰ _D= -152.4 ° (c = 2
Methanol). The tartrate salt with ethyl ether
Dissolve in a mixture with 2N sodium hydroxide aqueous solution
By post-processing with (1R , 2R ) -Body title
Compound 132 mg (yield 6.7%), [α]²⁰ _D= -1
85.2 ° (c = 1.5, methanol), colorless oil
Got as.

4-Biphenylyl acetic acid used in the above reaction
And / or instead of 4-chlorobenzyl chloride,
Corresponding phenylacetic acid derivative and / or ha
The same as in Example 114 except that a benzylated benzyl derivative was used.
By carrying out such a reaction, (1RS, 2RS) -1-
Methyl-2,3-diphenylpropylamine, (1R
S, 2RS) -2- (4-Chlorophenyl) -1-methyl
Lu-3-phenylpropylamine, (1RS, 2RS)
-3- (4-chlorophenyl) -1-methyl-2-phen
Nylpropylamine, (1RS, 2RS) -2- (4-
Chlorophenyl) -1-methyl-3- (4-methylphene)
Nyl) propylamine, (1RS, 2RS) -2- (4
-Chlorophenyl) -3- (4-fluorophenyl)-
1-methylpropylamine, (1RS, 2RS) -3-
(4-biphenylyl) -2- (4-chlorophenyl)-
1-methylpropylamine, (1RS, 2RS) -3-
(3-chlorophenyl) -2- (4-chlorophenyl)
-1-Methylpropylamine, (1RS, 2RS) -3
-(2-chlorophenyl) -2- (4-chlorophenyl
) -1-methylpropylamine, (1RS, 2RS)
-2- (4-chlorophenyl) -3- (4-methoxyphenyl)
Phenyl) -1-methylpropylamine, (1RS, 2R
S) -2- (4-Chlorophenyl) -1-methyl-3-
(1-naphthyl) propylamine, (1RS, 2RS)
-2- (4-chlorophenyl) -1-methyl-3- (2
-Naphthyl) propylamine, (1RS, 2RS) -3
-(4-chlorophenyl) -1-methyl-2- (4-me
(Cylphenyl) propylamine, (1RS, 2RS)-
2- (4-bromophenyl) -3- (4-chlorophenyl
) -1-methylpropylamine, (1RS, 2RS)
-3- (4-chlorophenyl) -1-methyl-2- (4
-Tert-butylphenyl) propylamine, (1R
S, 2RS) -3- (4-chlorophenyl) -2- (4
-Methoxyphenyl) -1-methylpropylamine,
(1RS, 2RS) -2- (3-chlorophenyl) -3
-(4-Chlorophenyl) -1-methylpropylami
, (1RS, 2RS) -3- (4-chlorophenyl)
-1-methyl-2- (1-naphthyl) propylamine,
(1RS, 2RS) -3- (4-chlorophenyl) -1
-Methyl-2- (2-naphthyl) propylamine, (1
RS, 2RS) -3- (4-chlorophenyl) -2-
(4-hydroxyphenyl) -1-methylpropylami
, (1RS, 2RS) -2- (4-chlorophenyl)
-3- (3,4-dichlorophenyl) -1-methylpro
Pyramine, (1RS, 2RS) -3- (4-chlorophyl)
Phenyl) -2- (3,4-dichlorophenyl) -1-me
Cylpropylamine, (1RS, 2RS) -2- (3-
Bromophenyl) -3- (4-chlorophenyl) -1-
Methylpropylamine, (1RS, 2RS) -2- (4
-Chlorophenyl) -3- (3,4-difluorophenyl)
) -1-methylpropylamine, (1RS, 2RS)
-2- (4-biphenylyl) -3- (3,4-dichloro)
Phenyl) -1-methylpropylamine, (1RS, 2
RS) -2- (4-chlorophenyl) -1-methyl-3
-[3- (3-thienyl) phenyl] propylamine,
(1RS, 2RS) -2- (4-biphenylyl) -1-
Methyl-3- (2-naphthyl) propylamine, (1R
S, 2RS) -2- (4-Chlorophenyl) -1-methyl
Lu-3- (4-pyridyl) propylamine, (1RS,
2RS) -2- (4-chlorophenyl) -3- (5-ku)
Loro-2-thienyl) -1-methylpropylamine,
(1RS, 2RS) -2- (4-chlorophenyl) -1
-Methyl-3- (8-quinolyl) propylamine, (1
RS, 2RS) -3- (7-benzo [b] thienyl)-
2- (4-chlorophenyl) -1-methylpropylami
, (1RS, 2RS) -2- (5-benzo [b] thie
Nyl) -3- (4-chlorophenyl) -1-methylpro
Pyramine, (1RS, 2RS) -2- (4-chlorophyl)
Phenyl) -3- (2-fluoro-4-biphenylyl)-
1-methylpropylamine, (1RS, 2RS) -3-
(4-biphenylyl) -2- (3,4-dichlorophenyl)
) -1-methylpropylamine and (1RS, 2R
S) -3- (4-Biphenylyl) -1-methyl-2-
(2-naphthyl) propylamine was obtained. Example 115(1S , 2S ) -2- (4-Biphenylyl) -3-
(3,4-dichlorophenyl) -1-methylpropyla
Manufacture of min Obtained by the same production method as in Example 114, (1RS,
2RS) -2- (4-biphenylyl) -3- (3,4-
Dichlorophenyl) -1-methylpropylamine 2.4
Dissolve 4 g in 15 ml of methanol, and add L-(+)-tartar
Acid solution of 0.99 g, in methanol (15 ml) and seeds
Add crystals and leave at room temperature overnight. The precipitated crystals are collected by filtration and
Reconstitute twice with 30 ml of tanol and 15 ml of methanol
By repeating the crystal, (1S , 2S ) -Body title
Compound L-(+)-tartrate 360 mg, [α]²⁰ _D=
+ 150.3 ° (c = 1.5, methanol) was obtained.

The tartrate salt obtained above was treated by a conventional method to give 238 mg of the free title compound (yield 9.8%),
[Α] ²⁰ _D = + 188 ° (c = 1.5, methanol) was obtained as a colorless oil. Example 116 Carboxymethyl succinate di-tert-butyl ester
And its optical resolution 13.1 ml of a 1.5 M solution of lithium diisopropylamide in cyclohexane was dissolved in 10 ml of tetrahydrofuran, and a solution of 2.96 g of benzyl acetate in tetrahydrofuran (10 ml) was added under stirring with cooling at -70 ° C. The mixture was stirred at the same temperature for 30 minutes. Then, a solution of 2.96 g of tert-butyl ester of maleic acid in tetrahydrofuran (10
ml) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. 20 ml of water and 50 ml of ethyl ether were added to the reaction solution for extraction, the organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of dioxane, 0.4 g of 10% palladium-carbon catalyst was added, and the mixture was stirred at room temperature under normal pressure for 2 minutes.
It was catalytically reduced for 0 hours. After filtering off the catalyst, the solvent was distilled off under reduced pressure, the residue was treated with hexane, and the resulting precipitate was filtered off,
By drying, 3.02 g of the title compound (yield 85
%) As a white crystalline powder, mp 55-57 ° C.

12.97 g of the di-tert-butyl ester obtained above and 13.24 g of cinchonidine were heated and dissolved in 1 L of carbon tetrachloride, and seed crystals were added to the solution at room temperature for 24 hours.
Left for hours. The crystals were collected by filtration, again dissolved in 1 L of carbon tetrachloride with heat, seed crystals were added, and the mixture was allowed to stand at room temperature for 24 hours. This operation was repeated twice more to give cinchonidine salt of the (S) -form title compound. 66 g (yield 25%), [α]
²⁰ _D = −62.7 ° (c = 1.0, chloroform) was obtained.

The cinchonidine salt obtained above was dissolved in a mixed solution of ethyl ether and 1N hydrochloric acid under ice-cooling, and the organic layer was separated and post-treated by a conventional method (S).
-Form of the title compound, [α] ²⁰ _D = + 4.44 ° (c =
0.92, chloroform) was obtained as a colorless oil.

The other enantiomer-rich fraction obtained in the above optical resolution operation was converted to a free acid, and the same operation was performed in isopropyl ether using quinine to obtain the enantiomer. The (R) -form of the title compound was obtained. Example 117 (1RS, 2RS) -3- (4-chlorophenyl) -1
-Methyl-2- [4- (3-thienyl) phenyl] pro
Preparation of pyramine N-{( 1RS , 2RS) -2- (4-bromophenyl) -3- (4-chlorophenyl) -1-methylpropyl} phthalimide [synthesized by a method similar to that in Example 114] 113 mg toluene 3 ml Was dissolved in water, 99 mg of tributyl (3-thienyl) tin and 14 mg of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was heated under reflux for 3 hours under a light-shielded and nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, 2 ml of a 5% potassium fluoride aqueous solution was added and the mixture was stirred for 30 minutes, the insoluble matter was filtered off, and ethyl acetate and water were added to the filtered solution for liquid separation. The organic layer was separated, washed with saturated brine and dried over colorless magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 100).
/ →→ 30/1), N-[(1RS,
2RS) -3- (4-chlorophenyl) -1-methyl-
83 mg of 2- {4- (3-thienyl) phenyl} propyl] phthalimide was obtained.

The cross-coupling product obtained above was suspended in 4 ml of ethanol to give hydrazine monohydrate (0.1%).
1 ml was added and the mixture was heated under reflux for 5 hours. The reaction mixture was dried under reduced pressure, the residue was dissolved in 10 ml of dichloromethane, the insoluble matter was filtered off, and the solvent was dried under reduced pressure to give the title compound (56 mg, yield 68%) as a colorless oil.

N-{(1RS, 2R used in the above reaction
S) -2- (4-Bromophenyl) -3- (4-chlorophenyl) -1-methylpropyl} phthalimide and / or tributyl (3-thienyl) tin instead of the corresponding phenyl bromide derivative and / or By using an aromatic stannane derivative and carrying out the same reaction as in Example 117 except otherwise, (1RS, 2RS) -2- (4 ′) is obtained.
-Chloro-4-biphenylyl) -3- (4-chlorophenyl) -1-methylpropylamine, (1RS, 2R
S) -3- (4-chlorophenyl) -1-methyl-2-
{4- (3-pyridyl) phenyl} propylamine,
(1RS, 2RS) -2- (3′-chloro-4-biphenylyl) -3- (4-chlorophenyl) -1-methylpropylamine, (1RS, 2RS) -2- (3-biphenylyl) -3- ( 4-chlorophenyl) -1-methylpropylamine, (1RS, 2RS) -3- (4-chlorophenyl) -1-methyl-2- {4- (2-naphthyl)
Phenyl} propylamine, (1RS, 2RS) -3-
(4-chlorophenyl) -2- {4- (2-furyl) phenyl} -1-methylpropylamine, (1RS, 2R
S) -3- (4-chlorophenyl) -1-methyl-2-
(3 ', 4'-methylenedioxy-4-biphenylyl)
Propylamine, (1RS, 2RS) -3- (3-biphenylyl) -2- (4-chlorophenyl) -1-methylpropylamine, (1RS, 2RS) -3- (4′-chloro-4-biphenylyl)- 2- (4-chlorophenyl) -1-methylpropylamine, (1RS, 2RS)
-2- (4-chlorophenyl) -3- (6-fluoro-
3-biphenylyl) -1-methylpropylamine and (1RS, 2RS) -2- (4-chlorophenyl) -1
-Methyl-3- [3- (2-naphthyl) phenyl] propylamine was obtained. Example 118 (1RS, 2RS) -3- (4-chlorophenyl) -2
-(2'-Fluoro-4-biphenylyl) -1-methyl
Production of propylamine (1RS, 2SR) -2- (4-bromophenyl) -3
0.70 g of-(4-chlorophenyl) -1-methylpropanol was dissolved in 7 ml of dimethylformamide, and t
0.34 g of ert-butyldimethylchlorosilane and 0.18 g of imidazole were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, ethyl ether was added for extraction, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane) to give [(2
RS, 3SR) -3- (4-bromophenyl) -2-
(Tert-Butyldimethylsilyloxy) -4- (4
0.70 g (yield 75%) of -chlorophenyl) butane was obtained as a colorless oil.

0.35 g of the silyloxy derivative obtained above
Was dissolved in 4 ml of ethyl ether and stirred under a nitrogen atmosphere.
1.64 of n-butyllithium while cooling to -78 ° C
0.5 ml of M hexane solution was added dropwise. The temperature of the reaction solution was raised to 0 ° C, 0.22 ml of tri-n-butylchlorosilane was added, and the mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 30 minutes. The reaction mixture was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane) to give (2RS, 3SR) -3- (4-tributylstannylphenyl) -2- (tert-. Butyldimethylsilyloxy) -4- (4-chlorophenyl) butane 0.
39 g (yield 76%) was obtained as a colorless oil.

133 mg of the stannane derivative obtained above
Was dissolved in 3 ml of toluene, 42 mg of o-bromofluorobenzene and 12 mg of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was heated under reflux for 2 hours under a nitrogen atmosphere. The reaction solution was allowed to cool to room temperature, 1.5 ml of a saturated aqueous potassium fluoride solution was added, and the mixture was stirred for 30 minutes. The insoluble material was filtered off, and ethyl acetate and water were added to the filtrate for extraction. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 50/1) to give (2RS, 3SR) -2- (tert-butyldimethylsilyloxy). ) -4- (4-Chlorophenyl) -2
-(2'-Fluoro-4-biphenylyl) butane 75 m
g (80% yield) was obtained as a colorless oil.

75 mg of the biphenyl compound obtained above was dissolved in 2 ml of tetrahydrofuran and fluorinated tetra-n-
0.60 ml of a 1.0 M tetrahydrofuran solution of butylammonium was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, ethyl acetate was added for extraction, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 10/1) to give (2RS, 3S
R) -4- (4-chlorophenyl) -3- (2′-fluoro-4-biphenylyl) -2-propanol 58 mg
Was obtained as a colorless oil.

The compound obtained above was treated with triphenylphosphine, phthalimide and diethyl azodicarboxylic acid in the same manner as in Example 114, and then:
Removal of the phthalimido group with hydrazine gave the title compound as a colorless oil.

By replacing o-bromofluorobenzene used in the above reaction with o-bromoanisole and carrying out the same reaction as in Example 118, except that (1RS, 2
RS) -3- (4-Chlorophenyl) -2- (2'-methoxy-4-biphenylyl) -1-methylpropylamine was obtained. Example 119 (1RS, 2RS) -3- (3,4-dichlorophenyl)
) -1-methyl-2- {3- (5-oxazolyl) fur
Preparation of 60% oily sodium hydride (0.15 g) was dissolved in a mixture of dimethylformamide (1.5 ml) and benzene (1.5 ml), and 4-dimethoxymethylphenylacetone (0.72 g) and dimethylformamide (2 ml) were stirred under ice-cooling. / Benzene 2 ml solution was added dropwise and stirred at the same temperature for 15 minutes. To this solution, a solution of 3,4-dichlorobenzyl chloride (0.65 ml) in dimethylformamide (2 ml) / benzene (2 ml) was added dropwise under ice-cooling stirring, and the mixture was stirred at the same temperature for 40 minutes, and 3% aqueous citric acid solution and ethyl ether were added. The layers were separated. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to medium pressure liquid chromatography [Lobar column ^™ , s].
size B, Lichroprep ^™ Si60F (Merck); hexane / ethyl acetate = 10/1 → 6 /
1] to give 0.64 g (yield 46%) of 4- (3,4-dichlorophenyl) -3- (4-dimethoxymethylphenyl) -2-butanone as a colorless oil.

The compound obtained above was reduced using L-Selectride ^™ in the same manner as in Example 114, and then:
Treated with a mixture of 0.5 ml of 1N hydrochloric acid and 2 ml of tetrahydrofuran to give (2RS, 3SR) -4- (3,4-dichlorophenyl) -3- (4-formylphenyl) -2.
-Propanol was obtained as a colorless oil.

0.28 g of the formyl compound obtained above was dissolved in 5 ml of methanol, and 0.17 g of p-toluenesulfonylmethyl isocyanide and 0.12 g of potassium carbonate were dissolved.
Was added and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and water, the organic layer was separated, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1) to give (2RS, 3SR) -4- (3,4-dichlorophenyl). -3- {4- (5-oxazolyl) phenyl}-
0.20 g of 2-propanol (yield 62%) was obtained as a colorless oil.

The compound obtained above was treated with triphenylphosphine, phthalimide and diethyl azodicarboxylic acid in the same manner as in Example 114, and then:
Removal of the phthalimido group with hydrazine gave the title compound as a colorless oil. Example 120 (1RS, 2RS) -N- {2- (4-biphenylyl)
-3- (3,4-dichlorophenyl) -1-methylpro
Preparation of pill} methylamine 3- (4-biphenylyl) -4- (3,4-dichlorophenyl) -2-butanone (738 mg) in methanol (20 m)
dissolved in a mixed solution of 1 and 4 ml of tetrahydrofuran, and 40%
4 ml of a methylamine methanol solution was added and the mixture was left at room temperature overnight. The reaction mixture was dried under reduced pressure and the residue was added with methanol 15
After dissolving in ml, 57 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was again dried under reduced pressure, the residue was dissolved in a mixed solution of ethyl ether and water, the organic layer was separated, washed with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel ^TM C
-300,80 g; dichloromethane / methanol = 50
1/1 → 25/1) and silica gel thin layer chromatography [Kieselgel ^™ 60F ₂₅₄ , Art574].
4 (manufactured by Merck); dichloromethane / methanol = 20
/ 1] to give 97 mg of the title compound (yield 1
3%) as a colorless oil.

3- (4-biphenylyl) used in the above reaction
) -4- (3,4-Dichlorophenyl) -2-butano
In place of 3- (4-biphenylyl) -4- (4-
Example 12 using lorophenyl) -2-butanone
By performing the same reaction as 0, (1RS, 2RS)
-N- {2- (4-biphenylyl) -3- (4-chloro)
Phenyl) -1-methylpropyl} methylamine is obtained.
It was Example 121(1S , 2S ) -N- {2- (4-biphenylyl) -3
-(3,4-Dichlorophenyl) -1-methylpropyi
Production of ru} methylamine hydrochloride Obtained in Example 114 (1S , 2S ) -2- (4-bi
Phenylyl) -3- (3,4-dichlorophenyl) -1
-Methylpropylamine 0.82g in dichloromethane 2
It was dissolved in ml and stirred under ice-cooling with trifluoroacetic anhydride.
5 ml was added and the mixture was stirred at room temperature for 3 hours. Dry the reaction mixture under reduced pressure
Solidify, dissolve the residue in 5 ml of dimethylformamide, and
1.5 ml of methyl iodide and 60% oily water under cold stirring
0.15 g of sodium nitrite was added and stirred at room temperature for 2 hours.
It was Add water and ethyl ether to the reaction mixture and extract.
The layer was washed with saturated saline and then dried over anhydrous magnesium sulfate.
Dried. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the residue was removed.
Dissolved in 15 ml of tetrahydrofuran and 3 ml of methanol
Then, add 4N sodium hydroxide and stir at room temperature for 12 hours.
I stirred. Water and ethyl ether were added to the reaction solution for extraction,
The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate.
Drier. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
Mix the residue with hydrogen chloride-methanol and ethyl ether
By treatment with 0.65 g of the title compound (yield 7
0%) as colorless crystalline powder, mp 248-249 ° C,
[Α]²⁰ _D= + 155 ° (c = 1.0, methanol),
Got as.

Used in the above reaction (1S , 2S ) -2-
(4-biphenylyl) -3- (3,4-dichlorophenyl)
Ru) -1-methylpropylamine or methyl iodide
Instead, (1S , 2S ) -3- (3,4-dichlorophen)
Nil) -2- (2-fluoro-4-biphenylyl) -1
-Methylpropylamine or benzyl chloride, other
By performing the same reaction as in Example 121, (1
S , 2S ) -N- {3- (3,4-dichlorophenyl)
-2- (2-Fluoro-4-biphenylyl) -1-methyi
Lupropyl} methylamine and (1S , 2S ) -N-
Benzyl-2- (4-biphenylyl) -3- (3,4-
Dichlorophenyl) -1-methylpropylamine was obtained.
It was Example 122(1S, 2R) -3- (3,4-dichlorophenyl)-
1-methyl-2- (2-naphthoyloxy) propyla
Production of min and its hydrochloride 4 g of magnesium (cut) in 40 ml of ethyl ether
In addition, after adding a few drops of dibromoethane, under ice-cooled stirring,
3,4-dichlorobenzyl chloride 29.3 g ethyl
Add ether solution (100 ml) dropwise over 2 hours
It was After the dropping, the mixture was stirred under ice cooling for 1 hour, and then N- (te
rt-Butoxycarbonyl) -L-alanine N-methyl
-N-Methoxycarboxamide [Journal of Me
Digital Chemistry (J. Med. Che
m. ), 33, 11-13 (1990)].
11.6 g of tetrahydrofuran solution (300 ml)
The mixture was added over 1 hour, and the mixture was stirred at the same temperature for 1 hour. Anti
Saturated ammonium chloride aqueous solution 10 was added to the solution under stirring with ice cooling.
0 ml was added, the organic layer was separated, washed with saturated saline,
It was dried over anhydrous magnesium sulfate. Filter off the desiccant
After that, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
Topography [hexane / ethyl acetate = 10/1 → 4 /
1] to give (S) -N- (tert-butene)
Xycarbonyl) -3- (3,4-dichlorophenyl)
-1-methyl-2-oxopropylamine 15.7g
(Yield 95%) was obtained.

15.7 g of the ketone body obtained above was dissolved in 300 ml of methanol, 1.8 g of sodium borohydride was added under stirring with ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with water, methanol was distilled off under reduced pressure, and ethyl acetate was added to the residual solution for extraction. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue is methylene chloride 3
It was dissolved in a mixed liquid of 00 ml and 30 ml of dimethylformamide, and under stirring with ice cooling, 8.9 g of 2-naphthoic acid, 6.3 g of 4-dimethylaminopyridine and 1-ethyl-3-hydrochloride.
(3-Dimethylaminopropyl) carbodiimide 10.
0 g was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine,
It was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane / ethyl acetate = 10/1 → 5 /
[1S, 2R) -N- (ter
t-butoxycarbonyl) -3- (3,4-dichlorophenyl) -1-methyl-2- (2-naphthoyloxy)
14.2 g (yield 62%) of propylamine was obtained.

N- (ter of the above-obtained title compound was obtained.
t-butoxycarbonyl) form 5 g dioxane 30 ml
20 ml of a 4N hydrogen chloride-dioxane solution was added, and the mixture was left at room temperature for 2 days. The precipitated crystals were collected by filtration, washed with ethyl ether, and dried to give 4.1 g (yield 93%) of the hydrochloride of the title compound as a white crystalline powder, mp.
Obtained as 194-196 ° C.

The hydrochloride obtained above was added to a mixed solution of methylene chloride and 0.5N aqueous sodium hydroxide solution with stirring. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain the free base of the title compound.

The N- (te
rt-butoxycarbonyl) -L-alanine N-methyl-N-methoxycarboxamide or 2-naphthoic acid instead of N- (tert-butoxycarbonyl) -D, L-alanine N-methyl-N-methoxycarboxamide or 4-chloro-3-methylbenzoic acid or quinaldic acid was used and the same reaction as in Example 122 was carried out otherwise to give (1RS, 2SR) -3- (3,4-dichlorophenyl) -1-methyl-2-. (2-naphthoyloxy) propylamine, (1S, 2R) -2- (4-chloro-3-methylbenzoyloxy) -3- (3,4-
Dichlorophenyl) -1-methylpropylamine and (1S, 2R) -3- (3,4-dichlorophenyl)-
1-Methyl-2- (2-quinolinecarbonyloxy) propylamine was obtained. Example 123 (1RS, 2RS, 3E) -2- (3,4-dichlorobe
Benzyl) -1-methyl-4- (2-naphthyl) -3-bu
Preparation of tenylamine 2- (3,4-dichlorobenzyl) acetoacetic acid tert
-Butyl ester [3,4-dichlorobenzyl chloride and acetoacetic acid tert-butyl ester, tert-
Produced by treatment with potassium tert-butoxide in butanol] 10.5 g was dissolved in 100 ml of tetrahydrofuran and hydrogenated tri-sec- under cooling and stirring at -70 ° C.
1M tetrahydrofuran solution of lithium butylboron 4
5 ml was added and the mixture was stirred at the same temperature for 1 hour. Water 2 in the reaction solution
0 ml and 15 ml of 3N aqueous sodium hydroxide solution were added, and the mixture was cooled and stirred at -20 ° C with 30% hydrogen peroxide water 15 m.
1 was added dropwise and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction solution, the organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane / ethyl acetate = 10/1 → 5/1] to give (2RS, 3RS) -2- (3,3). 4-dichlorobenzyl) -3-hydroxybutanoic acid tert-
3.79 g (33% yield) of butyl ester were obtained.

3.0 g of the alcohol compound obtained above was dissolved in a mixed solution of 30 ml of ethyl ether and 30 ml of tetrahydrofuran, and lithium borohydride 1.
2 g was added and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane / ethyl acetate = 10/1],
2.1 g of (2RS, 3RS) -2- (3,4-dichlorobenzyl) -1,3-butanediol (90% yield)
Got

1.66 g of the diol compound obtained above was dissolved in 10 ml of methylene chloride, and tert- was added with stirring under ice cooling.
1.10 g of butyldimethylchlorosilane, 1.0 ml of triethylamine and 0.4 ml of 4-dimethylaminopyridine.
04 g was added and the mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness under reduced pressure, water and 5% citric acid aqueous solution were added to the residue for extraction, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane → hexane / ethyl acetate = 10/1],
(2RS, 3RS) -3- (3,4-dichlorobenzyl) -4- (tert-butyldimethylsilyloxy)
2-butanol 1.50 g (yield 62%) was obtained.

1.49 g of the silyloxy derivative obtained above
Was dissolved in 10 ml of tetrahydrofuran, 1.21 g of phthalimide, 2.15 g of triphenylphosphine and 1.43 g of azodicarboxylic acid diethyl ester were added, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane / ethyl acetate = 30/1 → 20/1] to give N-
{(1RS, 2SR) -2- (3,4-dichlorobenzyl) -3- (tert-butyldimethylsilyloxy)
1.07 g (yield 53%) of -1-methylpropyl} phthalimide was obtained.

1.07 g of the phthalimide derivative obtained above
Was dissolved in 15 ml of tetrahydrofuran, and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added.2.
6 ml was added and the mixture was stirred at room temperature overnight. The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in a mixed solution of water and ethyl ether, the organic layer was separated and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the residue was collected by medium pressure liquid chromatography [hexane / ethyl acetate = 4/1 → 2.
/]], N-{(1RS, 2SR)-
2- (3,4-dichlorobenzyl) -3-hydroxy-
1-methylpropyl} phthalimide 0.39 g (yield 4
7%).

0.26 g of the alcohol obtained above was dissolved in 4 ml of methylene chloride, 0.44 g of pyridinium chlorochromate was added under stirring with ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl ether, the insoluble material was filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to preparative medium pressure liquid chromatography [hexane / ethyl acetate = 5/1 → 3/1]. , N-{(1RS, 2SR) -3-
0.13 g of (3,4-dichlorophenyl) -2-formyl-1-methylpropyl} phthalimide (yield 73%)
Got

340 mg of (2-naphthylmethyl) triphenylphosphonium chloride and 24 mg of 60% oily sodium hydride were added to 4 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 3 times.
After stirring for 0 minutes, a tetrahydrofuran solution (1 ml) containing 144 mg of the formyl compound obtained above was added, and the mixture was further stirred at room temperature for 2 hours. Add ethyl ether and water to the reaction mixture,
The organic layer was separated, washed with saturated saline and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane → hexane / ethyl acetate = 10/1] to give N-{(1RS, 2RS, 3E) -2-
(3,4-dichlorobenzyl) -1-methyl-4- (2
-Naphthyl) -3-butenyl} phthalimide 150 mg
(Yield 75%) was obtained.

150 mg of the butenyl compound obtained above was dissolved in 2 ml of ethanol to give 190 m of hydrazine monohydrate.
g was added and the mixture was heated under reflux for 2 hours. After drying the reaction mixture under reduced pressure,
The residue was dissolved in methylene chloride, the insoluble material was filtered off, and the solvent was distilled off again under reduced pressure. The residue was subjected to silica gel column chromatography [chloroform → chloroform / methanol = 10/1] to give 76 mg of the title compound.
(Yield 68%) was obtained as a colorless oil.

2- (3, used as a raw material in the above reaction
4- (dichlorobenzyl) acetoacetic acid tert-butyl ester and / or (2-naphthylmethyl) triphenylphosphonium chloride instead of 2- (4-chlorobenzyl) acetoacetic acid tert-butyl ester and / or the corresponding phosphonium derivative, respectively. By performing the same reaction as in Example 123 except that (1R
S, 2RS, 3E) -4- (2-Benzo [b] furanyl) -2- (3,4-dichlorobenzyl) -1-methyl-3-butenylamine, (1RS, 2RS, 3E) -2
-(3,4-Dichlorobenzyl) -1-methyl-4-
{3- (3-thienyl) phenyl} -3-butenylamine, (1RS, 2RS, 3E) -2- (3,4-dichlorobenzyl) -1-methyl-4- (1-naphthyl) -3
-Butenylamine and (1RS, 2RS, 3E) -2
-(4-Chlorobenzyl) -4- (4-chlorophenyl) -1-methyl-3-butenylamine was obtained. Example 124 (1S, 2S, 3E) -2- (3,4-dichlorobenzyl
) -1-Methyl-4- (2-naphthyl) -3-butenyl
Preparation of luamine (R)-(-)-3-hydroxybutyric acid methyl ester 9.45 g was dissolved in tetrahydrofuran 200 ml,
After cooling and stirring at −70 ° C. and adding 112 ml of a 1.5M cyclohexane solution of lithium diisopropylamide,
The temperature was raised to -25 ° C. To this liquid, while maintaining -25 ° C under stirring, 3,4-dichlorobenzyl bromide 21.
1 g of hexamethylphosphoric triamide (35 m
l) The solution was added dropwise, and the temperature was raised to room temperature after the addition. A saturated aqueous ammonium chloride solution was added to the reaction solution under ice-cooling stirring, the temperature was raised to room temperature, and ethyl ether and water were added to separate the layers. After separating the organic layer, the organic layer was post-treated as usual, and the product was purified by silica gel column chromatography [hexane / ethyl acetate = 4/1] to obtain (2R, 3R) -2-
10.6 g (yield 48%) of (3,4-dichlorobenzyl) -3-hydroxybutyric acid methyl ester was obtained.

10.6 g of the benzyl compound obtained above was dissolved in 100 ml of dimethylformamide, and the mixture was stirred under ice-cooling.
Imidazole (3.9 g) and tert-butyldimethylchlorosilane (6.9 g) were added, and the mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution to make it basic, and then ethyl ether and water were added to separate the layers. After separating the organic layer, the organic layer was post-treated as usual, and the product was subjected to silica gel column chromatography [hexane / ethyl acetate = 50 /
1] and then (2R, 3R) -3- (tert-butyldimethylsilyloxy) -2- (3,4-dichlorobenzyl) butyric acid methyl ester 12.6 g (yield 84
%) Was obtained.

12.6 g of the silyloxy derivative obtained above
Was dissolved in 100 ml of toluene, 79 ml of a 1.02M toluene solution of diisobutylaluminum hydride was added under cooling at -78 ° C, and the mixture was stirred at the same temperature for 45 minutes. A saturated ammonium chloride aqueous solution was added to the reaction solution under cooling and stirring at -70 ° C, the temperature was raised to room temperature, and 1N hydrochloric acid and ethyl acetate were added for extraction. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was dissolved in 70 ml of methylene chloride, 13.9 g of pyridinium chlorochromate was added, and the mixture was stirred at room temperature for 2 hours. Ethyl ether was added to the reaction solution for dilution, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [hexane / ethyl acetate = 50/1], (2R, 3R) -3-
(Tert-Butyldimethylsilyloxy) -2-
(3,4-dichlorobenzyl) butyraldehyde 8.1
5 g (yield 70%) was obtained.

2-Naphthylmethyltriphenylphosphonium bromide (14.7 g) was dissolved in tetrahydrofuran (80 ml), 60% oily sodium hydride (1.27 g) was added, and the mixture was stirred at room temperature for 30 minutes. To this liquid, tetrahydrofuran (20 m) of 8.15 g of the aldehyde obtained above was added.
l) The solution was added, and the mixture was stirred for 1 hour at room temperature, and then water and ethyl acetate were added for extraction. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was treated with tetrahydrofuran 6
After dissolving in 0 ml, tributylammonium fluoride 1M
45 ml of a tetrahydrofuran solution was added and stirred at room temperature for 3 hours. Ethyl acetate and water were added to the reaction solution for extraction, the organic layer was separated and post-treated in the usual way, and the product was subjected to silica gel column chromatography [hexane / ethyl acetate = 1.
0/1 → 7/1] and purified (2R, 3S) -3-
(3,4-dichlorobenzyl) -5- (2-naphthyl)
-4-Penten-2-ol 6.43 g (yield 77%)
Got

6.43 g of the alcohol compound obtained above and 6.81 g of triphenylphosphine were dissolved in 80 ml of tetrahydrofuran, and under stirring with ice cooling, 4.14 ml of diethyl azodicarboxylic acid ester was added, followed by 7.15 g of azide diphenylphosphoric acid. Tetrahydrofuran (20 ml) solution was sequentially added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate = 50/1] to obtain (3S,
6.50 g of 4S) -4-azido-3- (3,4-dichlorobenzyl) -1- (2-naphthyl) -1-pentene
(Yield 95%) was obtained.

6.50 g of the azide compound obtained above was dissolved in a mixed solution of 100 ml of tetrahydrofuran and 10 ml of water, 4.30 g of triphenylphosphine was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure, ethanol was added to the residue, and the residue was evaporated to dryness again under reduced pressure.
After dissolving in 0 ml, (-)-dibenzoyl-L-tartaric acid monohydrate (6.17 g) was added and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration, washed with ethyl ether and dried to give 10.35 g (yield 87%) of the title compound (-)-dibenzoyltartrate.

The (-)-dibenzoyl tartrate salt obtained above was added to a mixed solution of ethyl ether and water, and 1N aqueous sodium hydroxide solution was added dropwise to the mixture under ice-cooling stirring to make it basic. Was treated as usual to give the title compound as a colorless oil.

Similarly, the title compound of the free base obtained above was treated with hydrogen chloride-methanol and recrystallized from a mixed solution of methylene chloride-ethyl ether to give the hydrochloride of the title compound as a white crystalline powder. can get. Example 125 (1RS, 2RS) -3- (3,4-dichlorophenyl)
) -2- (2-Fluoro-4-biphenylyl) -1-
Production of methylpropylamine and its optical resolution 150 g of 4-bromo-2-fluorobiphenyl, 89.6 g of acetic acid isopropenyl ester, 258 ml of tributyltin methoxide and 4.7 g of palladium chloride-tri (o-phenyl) phosphine complex were added to 300 ml of toluene.
In addition, the mixture was heated and stirred at 80 ° C. for 2 hours under a nitrogen atmosphere.
The reaction solution was allowed to cool to room temperature, 1 L of ethyl acetate and 500 ml of a saturated potassium fluoride aqueous solution were added, and the mixture was stirred well, the insoluble material was filtered off, and the organic layer was separated. The obtained organic layer was post-treated as usual and the product was treated with hexane to give 1- (2-
Fluoro-4-biphenylyl) -2-propanone 106
g (yield 78%) was obtained.

45.1 g of the ketone body obtained above, 3,
4-Dichlorobenzyl chloride (50.3 g) and sodium hydroxide (15.8 g) were mixed, and the mixture was heated with stirring at 100 ° C for 6 hours. The reaction solution was allowed to cool to room temperature, extracted by adding ethyl acetate and water, the organic layer was post-treated as usual, and the product was purified by silica gel column chromatography [hexane / ethyl acetate = 50/1]. , 4- (3,4-dichlorophenyl) -3- (2-fluoro-4-biphenylyl)
-2-Butanone 65.0 g (yield 85%) was obtained.

63.0 g of the 3,4-dichlorobenzyl compound obtained above was dissolved in 630 ml of tetrahydrofuran, and the mixture was cooled and stirred at -78 ° C. under stirring with 1 M of trisec-butyl lithium borohydride (L-Selectride ^™ ). 200 ml of a tetrahydrofuran solution was added and stirred at the same temperature for 1 hour. To the reaction solution was added 3N aqueous sodium hydroxide solution, and the mixture was stirred for 30 minutes under ice cooling, then 30% hydrogen peroxide water 90m
1 was added and the mixture was further stirred for 3 hours. Ethyl acetate 1 in the reaction solution
L was added and liquid-separated, and the organic layer was separated and post-treated in the usual manner to give (2RS, 3SR) -4- (3,4-dichlorophenyl) -3- (2-fluoro-4-biphenylyl). -2
-Butanol 60.1 g (yield 95%) was obtained.

60.1 g of the alcohol obtained above was dissolved in 420 ml of ethyl acetate, and 13.2 ml of methanesulfonyl chloride and 25.6 of triethylamine were stirred under ice-cooling.
ml was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution, the solvent was distilled off under reduced pressure,
The residue was dissolved in 210 ml of dimethylformamide, 50 g of sodium azide was added, and the mixture was heated with stirring at 100 ° C. for 1 hour. Ethyl ether and water were added to the reaction solution for partitioning, the organic layer was separated and washed with saturated saline, and then the solvent was distilled off under reduced pressure. The residue is tetrahydrofuran 400 ml and water 40
Dissolve in a mixed solution of ml, and add triphenylphosphine 60.3
g was added and the mixture was heated with stirring at 80 ° C. for 8 hours. The reaction mixture was dried under reduced pressure, ethanol was added to the residue, and the mixture was dried again under reduced pressure. The obtained residue was dissolved in a mixed solution of 200 ml of methanol and 200 ml of isopropyl ether, and then L-(+)-tartaric acid 2
3.1 g was added and left overnight at room temperature. The precipitated crystals were collected by filtration, washed with isopropyl ether and dried to give the title compound L-(+)-tartrate 51.8 g (yield 62.5).
%) Was obtained.

L-(+)-of the title compound obtained above
Dissolve 50.8 g of tartrate in 920 ml of hot methanol
Then, seed crystals were added and the mixture was allowed to stand at room temperature for 3 days. The precipitated crystals are filtered
After taking it up and dissolving it again in 680 ml of hot methanol, seed crystals were collected.
In addition, it was left to stand at room temperature for 2 days. The precipitated crystals are collected by filtration and a small amount of
After washing with methanol and drying, (1S , 2S ) -Body
13.0 g of the L-(+)-tartrate salt of the title compound (yield 2
6%) as white crystals, [α]²⁰ _D= + 136 ° (c = 0.
75, methanol).

Similarly (1S , 2S ) -Body L-(+)-
After filtering the tartrate salt, combine the filtrate and washings and dry under reduced pressure.
After that, it is a mixture of enantiomers treated with a base in a conventional manner.
The free base of the title compound is obtained, which base is D-(-)-
By applying the same optical resolution as above using tartaric acid,
Obtained above (1S , 2S ) − Relationship between body and enantiomer
In charge (1R , 2R ) -D-(-) of the title compound
-Tartrate, [α]²⁰ _D= -134 ° (c = 0.75,
Methanol).

Racemic and optically active titles obtained above
By treating the tartrate salt of the compound with a base as usual.
, (1RS, 2RS) -body, (1S , 2S ) -Body
[Α]²⁰ _D= + 192 ° (c = 0.5, methanol)
And (1R , 2R ) -Body [α]²⁰ _D= -191 ° (c =
The title compound free amine (0.5, methanol) was obtained.

By replacing 4-bromo-2-fluorobiphenyl used as a starting material in the above reaction with 4-bromobiphenyl and carrying out the same reaction as in Example 125 except that,
(1RS, 2RS) -2- (4-biphenylyl) -3-
(3,4-Dichlorophenyl) -1-methylpropylamine was obtained. Reference Example 1 Carboxymethylsuccinic acid dibenzhydryl ester
1.5M cyclohexane solution 5.7ml of manufacturing lithium diisopropylamide, acetic acid trityl 2.6g and maleic acid benzhydryl ester 3.2g employed, Example 1
The reaction product obtained by carrying out the Michael addition reaction in the same manner as in 16 was dissolved in a mixed solution of 20 ml of acetic acid and 5 ml of water, left overnight at room temperature, and then dried under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol = 10).
0/1 → 10/1) to give the title compound 1.
05 g (yield 29%) of white crystalline powder, mp105-
Obtained as 106 ° C. Reference Example 2 N-{(1RS, 2RS) -3- (4-biphenylyl)
-2- (4-chlorophenyl) -1-methylpropyl}
Preparation of 2-naphthylmethylamine (1RS, 2RS) -3- (4-biphenylyl) -2-
(4-chlorophenyl) -1-methylpropylamine 3
2 mg was melt | dissolved in methanol 1 ml, 2-naphthaldehyde 22 mg was added, and it stirred at room temperature for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, the residue was redissolved in 1 ml of methanol again, 6.7 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 30 minutes. Water and ethyl ether were added to the reaction solution for extraction, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure,
The residue was subjected to silica gel thin layer chromatography (hexane /
Ethyl acetate = 5/1) to give the title compound 4
6 mg was obtained as a colorless oil.

(1RS, 2RS) -used in the above reaction
By using the corresponding amine compound in place of 3- (4-biphenylyl) -2- (4-chlorophenyl) -1-methylpropylamine and carrying out the same reaction as in Reference Example 2 otherwise, N-{(1RS , 2RS) -3- (3-Biphenylyl) -2- (4-chlorophenyl) -1-methylpropyl} -2-naphthylmethylamine, N-{(1R
S, 2RS) -3- (4′-chloro-4-biphenylyl) -2- (4-chlorophenyl) -1-methylpropyl} -2-naphthylmethylamine, N-{(1RS, 2
RS) -2- (4-chlorophenyl) -3- (2-fluoro-4-biphenylyl) -1-methylpropyl} -2
-Naphthylmethylamine, N-{(1RS, 2RS)-
2- (4-chlorophenyl) -3- (6-fluoro-3
-Biphenylyl) -1-methylpropyl} -2-naphthylmethylamine, N-[(1RS, 2RS) -2- (4
-Chlorophenyl) -1-methyl-3- {3- (2-naphthyl) phenyl} propyl] -2-naphthylmethylamine, N-{(1RS, 2RS) -3- (4-biphenylyl) -2- (3 , 4-Dichlorophenyl) -1-methylpropyl} -2-naphthylmethylamine and N-
{(1RS, 2RS) -3- (4-biphenylyl) -1
-Methyl-2- (2-naphthyl) propyl} -2-naphthylmethylamine was obtained. Reference Example 3 N-{(1RS, 2SR) -2- (3,4-dichlorobenzene)
Benzyl) -1-methyl-3- (2-naphthoxy) propyi
Preparation of ru} phthalimide (2RS, 3RS) -2-obtained in Example 123
(3,4-Dichlorobenzyl) -3-hydroxybutanoic acid tert-butyl ester (1.14 g) was dissolved in dimethylformamide (10 ml), and tert-butyldimethylchlorosilane (0.65 g) and imidazole (0.37 g) were added under ice-cooling stirring. Stir at room temperature for 6 hours. The reaction mixture was diluted with ethyl ether, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was dissolved in 10 ml of toluene, and a 1 M toluene solution of diisobutylaluminum hydride was added under cooling with stirring at -78 ° C, followed by stirring at the same temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution under cooling and stirring at -78 ° C, the temperature was raised to room temperature, and 1N hydrochloric acid and ethyl acetate were added to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. By subjecting the residue to silica gel column chromatography, 0.99 g (yield 76%) of (2RS, 3RS) -2- (3,4-dichlorobenzyl) -3- (tert-butyldimethylsilyloxy) butanol was obtained. It was

200 mg of the alcohol derivative obtained above was dissolved in 5 ml of ethyl acetate, 55 μl of methanesulfonyl chloride and 120 μl of triethylamine were added under ice-cooling stirring, and the mixture was stirred at the same temperature for 30 minutes. The deposited precipitate was filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was treated with dimethylformamide 5
Dissolved in ml. Separately, 87 mg of 2-naphthol was dissolved in 5 ml of dimethylformamide, 24 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. A dimethylformamide solution of the mesyl derivative obtained above was added to this solution with stirring, and 91 mg of potassium iodide was further added, followed by stirring at room temperature for 3 days. Pour the reaction solution into water,
After extraction by adding ethyl ether, the ether extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give (2
RS, 3RS) -2- (3,4-dichlorobenzyl)-
3- (tert-butyldimethylsilyloxy) -1-
77 mg (yield 29%) of (2-naphthoxy) butane was obtained.

77 mg of the naphthoxy compound obtained above was dissolved in 3 ml of tetrahydrofuran, and 0.5 ml of a 1 M tetrahydrofuran solution of tetrabutylammonium fluoride was dissolved.
Was added and the mixture was stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction solution, the organic layer was separated, washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain (2RS, 3RS)-
60 mg of 3- (3,4-dichlorobenzyl) -4- (2-naphthoxy) -2-butanol was obtained (yield 100%).

60 mg of the alcohol compound obtained above was dissolved in 3 ml of tetrahydrofuran to give 31 m of phthalimide.
g, triphenylphosphine 55 mg, and azodicarboxylic acid diethyl ester 30 μl were added, and the mixture was stirred at room temperature overnight. The reaction mixture was dried under reduced pressure and the residue was treated with methanol to give the title compound (45 mg, yield 56%) as a white crystalline powder.

Used as a raw material in the above reaction (2RS,
3RS) -1- (3,4-dichlorobenzyl) -3-hydroxybutanoic acid tert-butyl ester and / or 2-naphthol, respectively (2RS, 3R
S) -1- (4-chlorobenzyl) -3-hydroxybutanoic acid tert-butyl ester and / or 4-chlorophenol or 2-naphthalenethiol was used, and otherwise the same reaction as in Reference Example 3 was carried out to obtain N. -{(1R
S, 2SR) -2- (4-chlorobenzyl) -3- (4
-Chlorophenoxy) -1-methylpropyl} phthalimide and N-{(1RS, 2SR) -2- (3,4-
Dichlorobenzyl) -1-methyl-3- (2-naphthylthio) propyl} phthalimide was obtained. Reference Example 4 N- {2- (4-chlorobenzyl) -4- (4-chloro)
Preparation of phenyl) -1-methylbutyl} phthalimide 2- {2- (4-chlorophenyl) ethyl} -3-oxobutanoic acid tert-butyl ester 1.94 g te
Dissolved in 10 ml of rt-butanol, 1.17 g of p-chlorobenzyl chloride and potassium tert-butoxide of 0.17 g.
90 g was added and the mixture was heated under reflux for 1 hour. Ethyl ether and water were added to the reaction solution to separate it, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was subjected to preparative medium pressure liquid chromatography [hexane / ethyl acetate = 9/1] to give 2- (4-chlorobenzyl) -2- {. 2-
1.43 g (yield 52%) of (4-chlorophenyl) ethyl} -3-oxobutanoic acid tert-butyl ester was obtained.

4-Chlorobenzyl Form 1.
43 g was dissolved in 15 ml of methylene chloride, 2.6 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was dried under reduced pressure, and the residue was dissolved in 5 ml of toluene.
After heating at ℃ for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of ethanol, 63 mg of sodium borohydride was added under ice-cooling stirring, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl ether and water were added to the residue for extraction, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was dissolved in 2 ml of tetrahydrofuran, 96 mg of phthalimide, 173 mg of triphenylphosphine and 104 μl of azodicarboxylic acid diethyl ester were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution to separate the layers, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane / ethyl acetate = 19/1 → 4/1] to give the title compound (mixture of two diastereomers). ) 78 mg (yield 52%) was obtained as a white powder. Reference Example 5 N- {3- (3,4-dichlorophenyl) -1-methyl
Of 2- (naphthylmethoxy) propyl} phthalimide
2.45 g of manufactured magnesium (cutting) was added to 10 parts of ethyl ether.
In addition to 0 ml, a few drops of 1,2-dibromoethane were added to activate magnesium, and then 19.2 g of an ethyl ether solution of 3,4-dichlorobenzyl chloride (100 g, under ice-cooling stirring).
(ml) was added dropwise over 3 hours. 2- (tert-butyldimethylsilyloxy) propionaldehyde [produced by silylating 2-hydroxypropionic acid ethyl ester with tert-butyldimethylchlorosilane and then reducing with diisobutylaluminum hydride] under stirring with ice cooling. 6.11 g of ethyl ether solution (50 m
l) was added dropwise over 30 minutes, the mixture was stirred at the same temperature for 1 hour, saturated aqueous ammonium chloride solution was added, and the mixture was further stirred at room temperature for 1 hour.
Stir for 0 minutes. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give 3- (tert-butyldimethylsilyloxy) -1- (3,4-dichlorophenyl) -2-butanol 3 0.82 g (yield 33%)
Got

2.32 g of the alcohol obtained above was dissolved in a mixed solution of 100 ml of tetrahydrofuran and 20 ml of dimethylformamide, 0.34 g of 60% oily sodium hydride was added under ice-cooling stirring, and the mixture was stirred at the same temperature for 30 minutes. , 2-naphthylmethyl bromide (1.47 g) was added, and the mixture was stirred at room temperature for 20 hours. Ethyl ether and water were added to the reaction solution to separate it, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane → hexane / ethyl acetate = 50/1] for crude purification, and then 100 ml of tetrahydrofuran and 1M of tetrabutylammonium fluoride. The mixture was added to a mixed solution of 8 ml of a tetrahydrofuran solution and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue for extraction, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane / ethyl acetate = 20/1 → 5/1] to give 4- (3,4-dichlorophenyl) -3. 0.46 g of-(2-naphthylmethoxy) -2-butanol (yield 1
8%).

The alcohol compound obtained above was dissolved in methylene chloride, and phthalimide, triphenylphosphine and diethyl azodicarboxylic acid were used to carry out the same reaction as in Reference Example 4 above to obtain the title compound as a white powder. It was Reference Example 6 (E) -5-allyloxycarbonyl-4-methyl-4
-Preparation of pentenoic acid 34.4 g of triethyl phosphonoacetate was added to 200 parts of ethanol.
It was dissolved in ml, 170 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 4 hours. Ethanol was distilled off from the reaction solution under reduced pressure, the residual solution was washed with ethyl ether, acidified by adding concentrated hydrochloric acid, and then extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give 29.2 g of diethylphosphonoacetic acid.

Diethylphosphonoacetic acid 2 obtained above
9.2 g was dissolved in 350 ml of methylene chloride, and under stirring with ice cooling, 17.8 g of allyl alcohol, 1.92 g of 4-dimethylaminopyridine and 1-ethyl-3- (3-hydrochloride).
Dimethylaminopropyl) carbodiimide (29.0 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to remove diethylphosphonoacetic acid allyl ester 2
8.9 g was obtained.

Allyl ester derivative 28.9 obtained above
g was dissolved in 250 ml of tetrahydrofuran, and under stirring with ice cooling, 5.5 g of 60% oily sodium hydride was added to 30 g.
After stirring for a minute, levulinic acid benzhydryl ester [synthesized by reacting levulinic acid with diphenyldiazomethane in acetone] 31.9 g of tetrahydrofuran solution (15
0 ml) was added and the mixture was stirred at room temperature for 13 hours. The reaction solution was neutralized with acetic acid, the solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue for extraction. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (hexane / ethyl acetate = 13/1) to give 14.4 g of the benzhydryl ester of the title compound.
(Yield 35%) was obtained.

The benzhydryl ester derivative (7.61 g) obtained above was added to formic acid (35 ml), the mixture was stirred at room temperature for 4 hours, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol = 20/1).
The title compound (3.85 g, yield 93%) was obtained as a colorless oil. Reference Example 7 (3R, 5S) -5-methoxycarbonyl-3,5-O
-Isopropylidene-3,5-dihydroxypentanoic acid
Production of tert-butyl ester Malonic acid tert-butyl ester (132 g) was dissolved in tetrahydrofuran (1.5 L), and magnesium chloride (49.2 g) and triethylamine (134 ml) were added under ice-cooling stirring, followed by stirring at room temperature for 3 hours. Separately, to this solution, 2,2-dimethyl-1,3-dioxolan-4-one-5-ylacetic acid [tetrahedron letter (Tetrahedron
Letter, 28, 1685 (1987).
Year))] 60.0 g with 1,1'-carbonyldiimidazole 64.2 g in tetrahydrofuran 500 m
1 and 100 ml of dimethylformamide,
The liquid stirred at room temperature for 2 hours was added, and the mixture was stirred at room temperature overnight. The insoluble material was filtered off, the filtrate was evaporated to dryness under reduced pressure, the residue was dissolved in a mixture of ethyl ether and water, and 1N hydrochloric acid was added to adjust the pH.
Adjusted to 3-4. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. After dissolving the residue in ethyl acetate, activated alumina 30
The solution was passed through a 0 g column, and the passed solution was dried under reduced pressure to give 4-
72.4 g (yield 77%) of (2,2-dimethyl-1,3-dioxolan-4-one-5-yl) -3-oxobutyric acid tert-butyl ester was obtained.

62.4 g of the β-ketobutyric acid derivative obtained above
Was dissolved in 500 ml of methanol, 460 ml of 0.5N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 15 minutes. After adjusting the pH to 3 to 4 by adding 1N hydrochloric acid to the reaction solution, ethyl acetate was added and the mixture was extracted twice. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is ethyl ether 30
Dissolve in 0 ml, add ethyl ether solution of diazomethane (appropriate amount) and stir at room temperature for 30 minutes, evaporate the solvent under reduced pressure to give (5S) -5-methoxycarbonyl-5-hydroxy-3-oxopentanoic acid tert. -Butyl ester 38.2 g (yield 78%) was obtained.

19.7 g of the diester obtained above was dissolved in 300 ml of tetrahydrofuran, 128 ml of a 1M tetrahydrofuran solution of triethylborane was added, and the mixture was stirred at room temperature for 30 minutes. Cool the reaction to -70 ° C,
With stirring, 63 ml of methanol and 6.05 g of sodium borohydride were added, and the mixture was stirred at -50 ° C to -40 ° C for 1 hr. Under the same cooling and stirring, 30 ml of 30% hydrogen peroxide solution was added, and the mixture was stirred at room temperature for 1 hour and then 1N hydrochloric acid was added to adjust the pH to 3
Adjusted to. Ethyl acetate was added to the reaction solution for extraction, the extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and then passed through a column of 50 g of silica gel. The passing liquids were combined and the solvent was distilled off under reduced pressure.
After dissolving in 200 ml of 2-dimethoxypropane, 0.24 g of p-toluenesulfonic acid was added and the mixture was allowed to stand at room temperature for 24 hours. Pyridine (2 ml) was added to the reaction solution and the mixture was dried under reduced pressure. The residue was purified by column chromatography (hexane → hexane / ethyl acetate = 4/1) on activated alumina (200 g) and treated with hexane to give the title compound (8.0 g). Yield 3
3%) as a white crystalline powder.

[0395]

Industrial Applicability The compound of the present invention is a novel compound which has not been described in the literature and has an excellent squalene synthase inhibitory action, and therefore is useful in the treatment and prevention of hypercholesterolemia, hyperlipidemia and arteriosclerosis. Is. Furthermore, the compound of the present invention has an antifungal action and is useful as a therapeutic agent or preventive agent for various diseases caused by fungal infection.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/38 9454-4C 31/44 9454-4C 31/47 9454-4C C07C 69/34 9279- 4H 231/02 233/13 233/18 233/25 233/27 233/47 235/06 235/08 235/12 235/28 323/41 7419-4H C07D 213/40 215/12 263/32 307/52 317/58 333/20 333/28 333/58 (72) Inventor Zenichi Iwasawa, Okubo, Tsukuba City, Ibaraki Prefecture, 3rd, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd. (72) Morihiro Mitsuya, 3rd, Okubo, Tsukuba, Ibaraki Prefecture In-house pharmaceutical company Tsukuba Research Institute (72) Inventor Yoshiaki Iida No.3 Okubo Tsukuba City, Ibaraki Prefecture Manyu Pharmaceutical Company Limited Tsukuba Research Institute (72) Inventor Katsumasa Nonoshita No.3 Okubo Tsukuba City, Ibaraki Prefecture Tsukuba Manyu Pharmaceutical Co., Ltd. Institute (72) Inventor Yasushi Nagata 3 Okubo, Tsukuba City, Ibaraki Prefecture Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd.

Claims (22)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q is a single bond or- CO-O-, -O-CO-,-
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group or a hydroxyl group. , A lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ⁵ , R ⁶ and R ⁷ are The same or different, a hydrogen atom or a lower alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that when Q is a single bond, Both of which are 4-chlorophenyl groups)], a pharmaceutically acceptable salt or ester thereof. 2. A compound represented by the general formula [I-1]: [Wherein Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; and Q ¹ represents a single bond. R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or a halogen atom,
An aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkoxy group; R ⁵ , R ⁶ and R ⁷ are the same or different and each is a hydrogen atom or a lower atom; An alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that Both of which are 4-chlorophenyl groups)]]. 3. A compound represented by the general formula [I-2]: [In the formula, Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q ² is —CO— O -, - O-CO - , - CH 2 CH 2
-, - CH = CH -, - OCH 2 -, - SCH 2 -, - C
H ₂ O-or -CH ₂ S- group represented by; R ^1a,
R ^2a , R ^3a and R ^4a are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group; R ⁵ , R ⁶ , R ⁷ and R ^8a are the same or different and a hydrogen atom. Or a lower alkyl group], The compound according to claim 1. 4. A compound represented by the general formula [Ia]: [In the formula, Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q is a single bond or- CO-O-, -O-CO-,-
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group. , A lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ^7a is a lower alkyl group; ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that when Q is a single bond, Both of which are 4-chlorophenyl groups)]]. 5. A compound represented by the general formula [Ia ¹ ] [In the formula, Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q is a single bond or- CO-O-, -O-CO-,-
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group. , A lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ^7a is a lower alkyl group; ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that when Q is a single bond, Both of which are 4-chlorophenyl groups)] or a compound represented by the general formula [Ia ² ] [Wherein A, Q, R ¹ , R ² , R ³ , R ⁴ , R ^7a and R ⁸ have the above-mentioned meanings]. 6. A compound represented by the general formula [Ib]: [In the formula, Are the same or different and each represents an aryl group or a heteroaromatic ring group; A ^a is-(CH ₂ ) _m -C (R ⁹ ) (R ¹⁰ )-(C
H _{2) n} - in (wherein, R ⁹ is a hydrogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group a; R ¹⁰ is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a carboxyl group; m is from 1 3 of an integer; n means an integer of 1 to 4) or - (CH _{2) q} -CH =
A group represented by CH- (wherein q represents an integer of 1 to 6); Q is a single bond or -CO-O-,
_{-O-CO -, - CH 2} CH 2 -, - CH = CH -, - O
_{CH 2 -, - SCH 2 -} , - CH 2 O- or -CH ₂ S
R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or a halogen atom,
An aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkoxy group; R ^7a is a lower alkyl group; R ⁸ is a hydrogen atom, a lower alkyl group, It means a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that when Q is a single bond, Are both 4-chlorophenyl groups)]]. 7. The compound according to claim 6, wherein R ⁹ is a hydrogen atom or a hydroxyl group. 8. The compound according to claim 6, wherein R ¹⁰ is a lower alkyl group, a lower alkoxy group or a carboxyl group. 9. The compound according to claim 6, wherein m and n are the same or different and are 1 or 2. 10. The compound according to claim 6, wherein q is 1 or 2. 11. The formula: The group represented by is (Here, R ^1b and R ^2b are the same or different and each have a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, a lower alkyl group and a lower alkoxy group. The compound according to claim 1, which is a group represented by an aryl group or a heteroaromatic ring group which may be present. 12. The formula: The group represented by is The compound according to claim 11, wherein R ^1c and R ^2c are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, or a naphthyl group. 13. The formula: The group represented by is (Wherein R ^3b is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R ^4b is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, a lower alkyl group and a lower alkoxy group. Means an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of
The compound according to claim 1, which is a group represented by: 14. Q is --CO--O--, --O--CO--, --C.
_{H 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SCH 2
In the case of a group represented by —, —CH ₂ O— or —CH ₂ S—, the formula: The group represented by is The compound according to claim 1, wherein R ^3b and R ^4c are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. 15. The compound according to claim 1, wherein R ⁸ is a hydrogen atom, a lower alkyl group or an aralkyl group. 16. The compound according to claim 1, wherein R ⁸ is a hydrogen atom or a lower alkyl group. 17. The compound according to claim 1, wherein when Q is a single bond, R ⁸ is an aralkyl group. 18. A compound represented by the general formula [II]: [Wherein Are the same or different and represent an aryl group or a heteroaromatic ring group; Q is a single bond or -CO-O-, -O-CO-,-.
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ^1p , R ^2p , R ^3p and R ^4p are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, or a protective group; An optionally substituted hydroxyl group, a lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a lower alkyl group;
R ⁸ is a hydrogen atom, a lower alkyl group, a lower alkenyl group,
Means a lower alkynyl group or an aralkyl group (provided that when Q is a single bond, Both of which are 4-chlorophenyl groups)] and a compound of the general formula [III] [In the formula, A ^p is a lower alkyl group, a lower alkoxy group, an aryl group and an aralkyl group, and optionally has a substituent selected from the group consisting of a hydroxyl group and a carboxyl group and has 3 carbon atoms. To R 8 of a linear saturated or unsaturated aliphatic hydrocarbon group; R ¹¹ represents a hydrogen atom or a protective group of a carboxyl group], or a reactive derivative thereof.
General formula [IV] [In the formula, A ^p , Q, R ^1p , R ^2p , R ^3p , R ^4p , R ⁵ , R ⁶ , R ⁷ , R
⁸ and R ¹¹ have the above-mentioned meanings], and a protective group is optionally removed.
General formula [I] [In the formula, Q, R ⁵ , R ⁶ , R ⁷ and R ⁸ have the above meanings, and A is a substituent selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxyl group, an aryl group and an aralkyl group. C 3 -C may have to a linear saturated or unsaturated aliphatic hydrocarbon group having 8; R ^1,
R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom,
A halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group. (However, when Q is a single bond, Wherein both are 4-chlorophenyl groups)], a method for producing a pharmaceutically acceptable salt or ester thereof. 19. A compound represented by the general formula [II ′]: [Wherein Is (Wherein R ^1c and R ^2c are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group) or a naphthyl group; Is (Wherein R ^3b is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R ^4b is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, a lower alkyl group and a lower alkoxy group. Means an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of
A group represented by the formula (provided that when Q is a single bond, R ^4b is an aryl group or a heteroaromatic ring which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group) the means a group); Q is a single bond or -CO-O -, - O- CO -, - CH 2 CH 2 -, - C
_{H = CH -, - OCH 2} -, - SCH 2 -, - CH 2 O-
Or a group represented by —CH ₂ S—; R ^7a represents a lower alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group] . 20. The general formula [III-b ¹ ] [Wherein R ¹² and R ¹³ are the same or different and each represents a protecting group for a carboxyl group] or a compound represented by the general formula [III-b ² ] A compound represented by the formula: wherein R ¹² and R ¹³ have the above-mentioned meanings. 21. A compound represented by the general formula [I]: [In the formula, Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q is a single bond or- CO-O-, -O-CO-,-
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group. , A lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ⁵ , R ⁶ and R ⁷ are The same or different, a hydrogen atom or a lower alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that when Q is a single bond, Both of which are 4-chlorophenyl groups)], and the treatment of hypercholesterolemia, hyperlipidemia or arteriosclerosis, which comprises a pharmaceutically acceptable salt or ester thereof as an active ingredient, and / or Preventive agent. 22. The general formula [I]: [Wherein Are the same or different and are an aryl group or a heteroaromatic ring group; A is a lower alkyl group, a hydroxyl group, a lower alkoxy group,
A straight-chain saturated or unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, which may have a substituent selected from the group consisting of a carboxyl group, an aryl group and an aralkyl group; Q is a single bond or- CO-O-, -O-CO-,-
_{CH 2 CH 2 -, - CH} = CH -, - OCH 2 -, - SC
A group represented by H ₂ —, —CH ₂ O— or —CH ₂ S—; R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group. , A lower alkoxy group, or an aryl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R ⁵ , R ⁶ and R ⁷ are The same or different, a hydrogen atom or a lower alkyl group; R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group (provided that when Q is a single bond, Both of which are 4-chlorophenyl groups)], and a therapeutic and / or prophylactic agent for fungal infections comprising a pharmaceutically acceptable salt or ester thereof as an active ingredient.