JPH08337569A - Analgesic active substance - Google Patents

Abstract

PURPOSE: To obtain a new compound having strong analgesic action comparable to morphine. CONSTITUTION: This substance is a compound expressed by formula I (X is single bond, methylene, etc.; Y is phenyl or a naphthyl; R<1> and R<2> are each methyl, benzyl, etc.; Q is CH2 CH2 , CONH, CH2 CO, etc.; (n) is 0-5; W is a substituted 1-piperidinyl, etc.), e.g. N-(2-chloroacetyl)-L-3-(2-naphthyl)alanine N-benzyl-N-methylamide. The compound of formula I can be produced by condensing a compound of formula II (Z is an amino-protecting group), deprotecting the condensation product, reacting with a compound of formula III in the presence of a base and reacting the reaction product with an amine compound. It is useful as an active component of an analgesic for the prevention and treatment of bronchial asthma, pain, vomition, depression, anxiety, migraine, chronic bronchitis, allergic dermatitis, allergic rhinitis, inflammatory bowel disease, arthritis, insanity, allergy, hypertension, etc. The administration rate is 10-500mg/day.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound useful as an analgesic active substance.

[0002]

2. Description of the Related Art European Patent Publication No. 443132 A1 discloses prolylnaphthylalanine amides having tachykinin receptor antagonistic activity, for example, FK-888 [trans-4-hydroxy-1. -((1
-Methyl-1H-indol-3-yl) carbonyl-L-prolyl-N-methyl-3- (2-naphthalenyl) -N- (phenylmethyl) -L-alaninamide] is specifically taught. The publication does not mention the analgesic effect of the compounds mentioned above.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to provide a compound having a strong analgesic action and useful as an active ingredient of an analgesic. As a result of diligent efforts to solve such problems, the present inventor has found that the caboxamide derivative represented by the following formula has a strong analgesic action comparable to that of morphine, and completed the present invention. That is, the present invention provides the following formula:

[0004]

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[Wherein X represents a single bond or represents a methylene group, a sulfur atom, or an oxygen atom; Y represents a substituted or unsubstituted aryl group or heteroaryl group; R ¹ and R ² are Each independently represent a lower alkyl group, an aralkyl group, a cycloalkyl group, or a substituted or unsubstituted aryl group or heteroaryl group, or R ¹
And R ² together represent a substituted or unsubstituted cyclic amino group with the nitrogen atom which they replace; Q is -CH
₂ CH _2- , -CH ₂ CO-, -COCH _2- , -CH ₂ NR ^3- , -NR ³ CH _2- , -CONR ³
A group selected from the group consisting of-, and -NR ³ CO- (R ³ represents a hydrogen atom, a lower alkyl group, or a lower alkoxycarbonyl group); n represents an integer of 0 to 5; W represents a substituent And a heterocycloalkyl group having].

In a preferred embodiment of the present invention, X is a single bond, methylene, or sulfur atom; Y is a naphthyl group, a substituted or unsubstituted phenyl group, a thienyl group, an indolyl group, or a thiazolyl group; R ¹ And R ² are each independently a hydrogen atom (but not simultaneously representing a hydrogen atom), a lower alkyl group, a substituted or unsubstituted benzyl group, a benzhydryl group, a 4- to 8-membered cycloalkyl group, 1,2-diphenyl. An ethyl group or an adamantyl group, -NR ¹ R ² is a 1,2,3,4-tetrahydroisoquinolinyl group or a 1-morpholino group; n is 0, 1, 2, or 3 ; Q is -CH ₂ CH _2- , -COCH _2- , -CH ₂ NH-, and -CONH
A compound selected from the group consisting of; wherein W is a 1-piperidinyl group having a substituent, a 1-piperazinyl group having a substituent, or a 1-pyrrolidinyl group having a substituent.

In a further preferred embodiment, X is a single bond,
A methylene or sulfur atom; Y is a 1-naphthyl group;
2-naphthyl group, phenyl group, parahydroxyphenyl group, 2-thienyl group, 4-thiazolyl group, indolyl group, 3,
4-dichlorophenyl group or 3-indolyl group; R ¹
And R ² are each independently a hydrogen atom (not simultaneously representing a hydrogen atom), methyl group, benzyl group, benzhydryl group, tert-butyl group, cyclohexyl group, 2-methoxybenzyl group, 1,2-diphenylethyl group. A 3,5-ditrifluoromethylbenzyl group, or an adamantyl group,
-NR ¹ R ² is a 1,2,3,4-tetrahydroisoquinolinyl group or
A 1-morpholino group; n is 0, 1, 2, or 3;
Q is a group selected from the group consisting of -CH ₂ CH _2- , -COCH _2- , -CH ₂ NH-, and -CONH-; W is 4-acetylamino-4
-Phenyl-1-piperidinyl group; 4-acetyl-4-phenyl-1-piperidinyl group; 4-carbamoyl-1-piperazinyl group; 4-acetyl-1-piperazinyl group; 4-oxo-1-piperidinyl group; 4- Hydroxy-4-phenyl-1-piperidinyl group; 4-hydroxy-1-piperidinyl group; 3-acetylamino-1-pyrrolidinyl group; 1-phenyl-1,3,8-triaza-4-oxospiro [4,5] Decan-8-yl group; the above compound is a 4- (2-oxo-1-pyrrolidinyl) -1-piperidinyl group; and X is a single bond, methylene (-CH ₂ ), or a sulfur atom; Y is 2-naphthyl group, 1-naphthyl group, phenyl group, 3,4-dichlorophenyl group; R ¹ is a methyl group, and R ² is a benzyl group, or -NR ¹ R ² is
1,2,3,4-tetrahydroisoquinolinyl group; n is
1; Q is -CONH- or -CH ₂ CH _2- ; W is 4-acetylamino-4-phenyl-1-piperidinyl group, 4-acetyl-1-piperazinyl group, or 4-acetyl-4 -Phenyl-1
-Provided is a compound as above which is a piperidinyl group.

In the above general formula, when X represents a single bond, Q and a carbon atom substituted by a carboxamide group
It is shown that the substituted or unsubstituted aryl group or heteroaryl group represented by Y 3 is directly bonded. In the compound of the present invention, X is preferably a single bond, a methylene group (-CH _2- ), or a sulfur atom, more preferably X is a single bond or a methylene group, and X is a single bond. Is particularly preferable.

Y represents an aryl group or a heteroaryl group, preferably an aryl group or a heteroaryl group having a 5- to 10-membered ring, and more specifically, a substituted or unsubstituted phenyl group as Y 1 or a substituted or unsubstituted An aryl group having a 5- to 10-membered ring such as a substituted naphthyl group; or pyridine, furan, thiophene, thiazole,
A heteroaryl group having a substituted or unsubstituted 5- to 10-membered ring containing one or more heteroatoms such as indole or imidazole can be used.
The above aryl group or heteroaryl group may have, for example, 1 or 2 or more, preferably 1 to 3 substituents. Examples of such a substituent include, for example, a lower alkyl group, a lower alkoxy group, fluorine, chlorine, bromine, a halogen atom which is an iodine atom, a halogenated lower alkyl group such as a trifluoromethyl group, a hydroxyl group, a carboxy group,
Examples thereof include a lower alkoxycarbonyl group, a cyano group, a nitro group, a lower alkyl-substituted or unsubstituted amino group, and a methylenedioxy group. More specifically,
As such an aryl group, a substituted or unsubstituted 2-
Naphthyl group or 1-naphthyl group, unsubstituted phenyl group,
A 3,4-dichlorophenyl group, a parahydroxyphenyl group or the like can be used. Further, a thienyl group, a thiazolyl group, an indolyl group, an imidazolyl group, a pyridinyl group, a heteroaryl group such as a furyl group can be used, but these heteroaryl groups may be substituted or unsubstituted, and at any position. May be bound to X. Of these, 2-naphthyl group, 1-naphthyl group,
Alternatively, a 3,4-dichlorophenyl group is preferable, a 2-naphthyl group or a 1-naphthyl group is more preferable, and a 2-naphthyl group is particularly preferable.

R ¹ and R ² are each independently a hydrogen atom,
A lower alkyl group, an aralkyl group, a cycloalkyl group, or a substituted or unsubstituted aryl group or heteroaryl group is shown, but both do not show a hydrogen atom at the same time.
In the present specification, the lower alkyl group refers to a linear or branched alkyl group having about 1 to 6 carbon atoms, and more specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. , S-butyl, tert-butyl,
n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl,
4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1, 3-dimethylbutyl, 2,3-dimethylbutyl, or 2-
Ethyl butyl or the like can be used. Of these, a methyl group or an ethyl group is preferable, and a methyl group is more preferable.

As the aralkyl group represented by R ¹ and R ² , an aryl lower alkyl group can be preferably used. As the aryl group and lower alkyl group, for example, those exemplified above can be used, and more specifically, a substituted or unsubstituted phenyl group as the aryl group and a methyl group or an ethyl group as the lower alkyl group are preferable. More specifically, the aralkyl group is an unsubstituted benzyl group, a 2-methoxybenzyl group or 3,5-
A substituted benzyl group such as a bistrifluoromethylbenzyl group, a benzhydryl group, and a 1,2-diphenylethyl group can be used. Examples of the cycloalkyl group represented by R ¹ and R ² include a cyclopropyl group, a cyclobutyl group,
In addition to cyclopentyl group, cyclohexyl group and adamantyl group, substituted cycloalkyl groups (methylcyclopropyl group, dimethylcyclopropyl group, etc.) in which these cycloalkyl groups are substituted with lower alkyl groups such as 1 or 2 or more methyl groups and ethyl groups , 2-methylcyclobutyl group, etc.) can be used.

As the substituted or unsubstituted aryl group or heteroaryl group represented by R ¹ and R ² , those described above can be used, preferably a phenyl group, a 1-naphthyl group, a 2-naphthyl group, A thienyl group, a furyl group, or the like can be used. Further, R ¹ and R ² may be taken together to form a substituted or unsubstituted cyclic amino group together with the nitrogen atom with which they are substituted. For example, -NR ¹ R ²
A 1,2,3,4-tetrahydroisoquinolinyl group, a morpholino group or a 2,3-dihydro-isoindolyl group may be formed.

Q is -CH ₂ CH _2- , -CH ₂ CO-, -COCH _2- , -CH ₂ N
R ^3- , -NR ³ CH _2- , -CONR ^3- , and -NR ³ CO- each represent a group selected from the group consisting of, and R ³ represents a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group. In the present specification, the lower alkoxy group refers to a straight or branched alkoxy group having about 1 to 6 carbon atoms. More specifically,
Examples of the lower alkoxy group of the lower alkoxycarbonyl group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methoxybutoxy, neopentoxy, 1 -Ethoxypropyl, n-hexoxy, isohexoxy, 4-methoxypentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy,
1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, or the like can be used. Of these, R ³
Is preferably a hydrogen atom or a methyl group. n is
It represents an integer of 0 to 5, preferably 0 to 3, more preferably 1 or 2, and particularly preferably 1. When n is 0,
The above Q and W (heterocycloalkyl group having a substituent) are directly bonded via a single bond.

The heterocycloalkyl group having a substituent represented by W is one or more heteroatoms, preferably 1
Or a cycloalkyl group containing 2 or more nitrogen atoms, more preferably 1 or 2 nitrogen atoms, which is 1 on the ring.
Alternatively, it is not particularly limited as long as it has two or more arbitrary substituents. As the heterocycloalkyl ring, for example, a 3- to 8-membered ring, preferably a 4- to 6-membered ring, particularly preferably a 6-membered ring can be used, and more specifically, azetidine, pyrrolidine, pyrroline, imidazolidine, piperidine. , Piperazine, morpholine, or thiomorpholine, preferably piperidine, pyrrolidine, piperazine, or azetidine, particularly preferably piperidine or piperazine can be used. These heterocycloalkyl rings are preferably represented by a heteroatom contained in the cycloalkyl ring, preferably a nitrogen atom.
It can be bonded to a methylene group represented by (CH ₂ ) _n -Q (or Q when n is 0).

The substituent on the heterocycloalkyl ring of the heterocycloalkyl group is not particularly limited, but as an example, a lower alkyl group such as a methyl group, a lower alkanoyl group such as an acetyl group, an acetylamino group or the like. Lower alkanoylamino group, halogenated lower alkyl group such as trifluoromethyl group, cycloalkyl group such as cyclohexyl group, lower alkoxycarbonyl group such as carbonyl group and ethoxycarbonyl group, carboxyl group, hydroxyl group, halogen atom, amino group, carbamoyl Group, a substituted or unsubstituted aryl group such as a phenyl group, and the like. These groups may be further substituted with, for example, one kind or two or more kinds of the substituents exemplified above, In addition, 1 when the hetero atom can be included Others may have two or more any heteroatom. Further, as the substituent substituting on the heterocycloalkyl ring, a heterocycloalkyl ring and a spiro cycloalkyl ring may be used. In such a case, the cycloalkyl ring to be spiro may contain one or more hetero atoms, preferably 1 or 2 nitrogen atoms, and the ring may have, for example, the substituents exemplified above. You may have 1 type (s) or 2 or more types.

Specific examples of the heterocycloalkyl group having a substituent are shown below, but W is not limited thereto. Of these, 4-acetylamino-4-
Phenylpiperidine, 4-acetyl-4-phenylpiperidine, 4-carbamoylpiperazine, 4-acetylpiperazine and the like can be preferably used.

[0017]

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Among the compounds of the present invention, compounds wherein X is a single bond, methylene (-CH ₂ ) or sulfur atom; Y is 1-naphthyl group, 2-naphthyl group, phenyl group, parahydroxyphenyl group, 2 -A compound that is a thienyl group, a 4-thiazolyl group, or a 3,4-dichlorophenyl group; R ¹ and R ² are each independently a hydrogen atom (not simultaneously representing a hydrogen atom), a methyl group, a benzyl group, a benzhydryl group, tert-butyl group, cyclohexyl group, 2-methoxybenzyl group, 1,2-diphenylethyl group, 3,5-bistrifluoromethylbenzyl group, or adamantyl group, or -NR ¹ R ² is 1,2,3 ,Four
A compound which is a tetrahydroisoquinolinyl group or a 1-morpholino group; a compound in which n is 0, 1, 2, or 3; Q is
-CH ₂ CH _2- , -COCH _2- , -CH ₂ NH-, and -CONH-: W is 4-acetylamino-4-phenyl-1-piperidinyl group; 4-acetyl-4-phenyl- 1-piperidinyl group;
4-carbamoyl-1-piperazinyl group; 4-acetyl-1-piperazinyl group; 4-oxo-1-piperidinyl group; 4-hydroxy-4-phenyl-1-piperidinyl group; 4-hydroxy-1
-Piperidinyl group; 3-acetylamino-1-pyrrolidinyl group; 1-phenyl-1,3,8-triaza-4-oxospiro [4,
5] Decan-8-yl group; 4- (2-oxo-1-pyrrolidinyl)
A compound which is a -1-piperidinyl group is a preferred compound of the present invention.

Of these, compounds in which X is a single bond, methylene (--CH ₂ ), or sulfur atom; Y is a 2-naphthyl group, a 1-naphthyl group, a phenyl group or a 3,4-dichlorophenyl group. A compound; R ¹ is a methyl group and R ² is a benzyl group, or -NR ¹ R ² is a 1,2,3,4-tetrahydroisoquinolinyl group; n is 1 a compound; Q is -CO-NH- or -CH ₂ -CH ₂ -, compound; W is 4-
Acetylamino-4-phenyl-1-piperidinyl group, 4-acetyl-1-piperazinyl group, 4-acetyl-4-phenyl-1
Compounds that are piperidinyl groups are more preferred compounds.

Particularly preferred compounds among the compounds of the present invention are specifically illustrated below, but the scope of the present invention is not limited to the following. Also, in the following examples,
Although many preferable compounds of the present invention are specifically shown including the following compounds, the scope of the present invention is not limited to these compounds.

[0021]

[Chemical 4]

[0022]

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In the above compound of the present invention, the carbon atom substituted by Q and X is an asymmetric carbon atom, and
The groups represented by Y, R ¹ , R ² , and / or W may optionally have one or more asymmetric carbons. Therefore, the compound of the present invention may have optical isomers based on these asymmetric carbons, or may have diastereoisomers based on two or more optical isomers.
It goes without saying that all such isomers are included in the scope of the present invention. Further, any mixture or racemate of these optically active isomers, or any mixture of diastereoisomers is also included in the scope of the present invention.

Further, the compound of the present invention can form an acid addition salt or a base addition salt depending on the kind of the substituent.
Examples of such salts include hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodides, nitrates, perchlorates, sulfates, and phosphates. Inorganic acid salts such as carbonates; lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, aryl sulfonates such as benzene sulfonate, p-toluene sulfonate , Fumarate, succinate, citrate, tartrate, oxalate,
Mention may be made of organic acid salts such as maleic acid salts and acid addition salts which are organic acids such as amino acid salts such as glutamate and aspartate. Examples of the base addition salt include metal salts such as sodium salt, potassium salt, lithium salt and calcium salt, ammonium salt, and base addition salts such as organic amine compound salts such as monomethylamine and triethylamine. Furthermore, the compounds of the present invention may exist as any hydrate or solvate of the free compound or salt thereof.

According to another aspect of the present invention, there is provided a method for producing the above compound. The production methods of the respective schemes shown below are all included in the scope of the present invention, while the production methods of the present invention are limited to specific details such as reaction reagents and reaction conditions described in the following schemes. There is no.

Some of the compounds included in the compound of the present invention have an amino acid residue portion, and can be produced, for example, from an amino acid derivative as a raw material according to the following scheme.

[0027]

[Chemical 6]

In the above scheme, X represents a single bond or a methylene group, R ¹ , R ² , n, and Y are as defined above, Z is an amino-group protecting group, and hal is a halogen atom. Show. The amino-protecting group of the compound represented by (1) acts as a protecting group in step (a) of the above scheme,
There is no particular limitation as long as it can be easily deprotected according to (b), and any one may be used. Such a protecting group can be appropriately selected by those skilled in the art, and examples thereof include Boc (t-butoxycarbonyl group), Z (benzyloxycarbonyl group), Bn (benzyl group), Fmoc (fluorenylmethyloxycarbonyl group). Protecting groups such as can be preferably used. For introducing Boc, for example, Boc ₂ O may be reacted in the presence of triethylamine, and for introducing Z, BnOCOCl may be reacted in the presence of a base. Step (a) is a condensation reaction of an amine compound (HNR ¹ R ² ) and a carboxyl group, and is performed using a condensing agent well known to those skilled in the art,
Alternatively, it may be carried out by an active esterification method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method or the like which can be used by those skilled in the art. After the condensation, the protecting group Z is removed according to the step (b), and the reaction conditions in this step can be appropriately selected by those skilled in the art depending on the type and property of the protecting group used. For example,
When Boc is used as the protecting group, it can be easily deprotected by acid treatment with hydrochloric acid or trifluoroacetic acid, and when a benzyl group is used as the protecting group, an appropriate hydrogenation catalyst is used. It can be easily deprotected by hydrogenolysis.

In step (c), hal- (CH ₂ ) _n- CO-X (hal and
X independently represents a halogen atom, preferably hal is a bromine atom, X is a chlorine atom, and n is preferably 1 or 2
And more preferably 1) is reacted with the compound (3), preferably in the presence of a base. The compound (5) of the present invention can be produced by reacting the obtained compound (4) with an amine compound (WH: W is as described above). In addition, as shown in the following scheme (the symbols in the scheme are the same as above), the compound (3) is preferably treated with an acrylic acid halide in the presence of a base (such as a tertiary amine) and the step (e). And then the compound obtained according to step (f)
The compound (5 ′) of the present invention can also be produced by Michael addition of the amine compound (WH) to (6), preferably in the presence of a base. In addition, according to step (g) of the following scheme, n is Compound (7) of 0 can be prepared.

[0030]

[Chemical 7]

Further, according to the following scheme, the compound
It is also possible to produce the compound of the present invention from (3) (in the scheme, V represents a hydroxyl-protecting group, and other symbols are the same as above).

[0032]

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In step (h), it is preferably represented by VO- (CH ₂ ) _n -hal (hal represents a halogen atom, preferably a chlorine atom or a bromine atom) in the presence of a base (such as sodium hydrogen carbonate). To a compound (3) above,
Thereafter, the hydroxyl-protecting group represented by V is removed according to step (i). As the hydroxyl-protecting group, any group may be used as long as it can protect the hydroxyl group in the reaction of step (h) and can be easily deprotected in the subsequent step (i), and examples thereof include a tetrahydropyranyl group ( It is preferred to use protecting groups such as THP). When THP is used as a protecting group, compound (9) can be easily obtained by acid treatment in step (i). Then step (j)
The compound (10) with the amino group protected according to the above is subjected to the oxidation reaction of step (k) to be converted into the aldehyde derivative (11). Process (k)
As the reagent for the oxidation reaction of, for example, (Cl ₃ CO) ₂ C = O, DM
A combination of S0 and triethylamine or a combination of oxalic acid dichloride, DMSO and triethylamine can be used. Then, the amino compound (WH) is reacted (reductive amination) with the compound (11) in the presence of a reducing agent (for example, sodium cyanoborohydrate (NaB (CN) H ₃ ), etc.) to give the compound (12). Then, the amino group is deprotected according to the step (b) to produce the compound (13) of the present invention. Process as a protecting group for amino group
The amino group can be protected in the oxidation reaction of (k) and the reductive amination reaction of step (l), and the subsequent step (b)
There is no particular limitation as long as it can be easily deprotected by, for example, a protecting group such as Boc or Z can be preferably used, and the introduction or deprotection can be performed by, for example, the method described above. can do.

Some of the compounds included in the compound of the present invention have a saturated fatty acid amide moiety, and can be produced, for example, from a carboxylic acid derivative as a raw material according to the following scheme (in the scheme, L Represents a leaving group,
T represents a protected aldehyde group, and other symbols are the same as above).

[0035]

[Chemical 9]

Step (a) is a step of condensing an amine compound, and can be carried out by substantially the same steps as those described in the method for producing an amino acid derivative above. Then, the condensate (15) is reacted with an alkylating agent represented by VO- (CH ₂ ) _n -L according to the step (m) to produce an alkylated compound (16), and this compound is dehydroxylated. Protection process
The compound (19) of the present invention can be obtained by subjecting to (i), the oxidation step (k), and the reductive amination step (l). A halogen atom or a sulfonate group can be used as the leaving group L, and the steps (i), (k), and
And (l) may be performed by substantially the same method as described for the amino acid derivative above.

Further, the above compound (15) is converted into an alkylating agent T
After reacting with-(CH ₂ ) _n-1 -L, the compound (18) is produced by deprotecting the protecting group of the aldehyde group according to step (o), and then subjecting to step (l). Can also be used to produce the compound (19) of the present invention. Examples of the protected aldehyde group (T) include an acetal-protected aldehyde group such as (-OCH ₂ CH ₂ O-) CH- and (CH ₃ O) ₂ CH-, and R ⁶ O-CH = CH-
(R ⁶ represents a substituent such as a lower alkyl group), a protected aldehyde group can be used, and for deprotection in step (o), for example, hydrochloric acid, sulfuric acid, paratoluenesulfonic acid or the like is used. The acid treatment may be performed. Further, the compound (17)
The hydroxyl group of is converted to a leaving group according to the step (p), or the compound (15) is alkylated by the step (m) using an alkylating agent L- (CH ₂ ) _n -L to give the compound (17 ' ),
Further, the compound (19) of the present invention can also be produced by reacting with the amine compound (WH) according to the step (d). In the step (p) of converting a hydroxyl group to a leaving group, when converting to a compound having a sulfonate as the leaving group L, mesyl chloride (MsCl) or mesyl chloride is preferably used in the presence of a base (such as triethylamine or pyridine). It may be reacted with an acid anhydride (Ms ₂ O), and when converting to a compound having a halogen atom as the leaving group L, for example, a halogenating agent such as phosphorus pentachloride or phosphorus tribromide may be used. .

Further, by using the compound (14) as a starting material, the compound (19) of the present invention can be produced according to the following scheme (in the scheme, R is a lower alkyl group, preferably a methyl group or an ethyl group). , And other symbols are as above). That is, the compound (14) is esterified by reacting it with a lower alcohol, preferably methanol, under heating in the presence of an acid such as sulfuric acid, preferably at reflux temperature, and the obtained ester form (21) is subjected to step (m) according to step (m). V
-O- (CH ₂ ) _n -L is reacted with an alkylating agent represented by to produce an alkylated compound (22), and this compound is further deprotected with a hydroxyl group (i), an oxidation step (k) , And reductive amination step (l) to produce compound (25). Each of these steps may be performed by substantially the same method as described above. Then, according to step (s), the compound (25)
A compound (26) is subjected to a hydrolysis reaction with a base (for example, sodium hydroxide), and the resulting compound (26) is condensed with an amine compound (HNR ¹ R ² ) according to step (a) to produce a compound (19). You can

[0039]

[Chemical 10]

Further, the compound (20) was prepared using the malonic acid diester derivative as a starting material in the following scheme (in the scheme,
R independently represents a lower alkyl group, preferably independently a methyl group or an ethyl group, more preferably both represent an ethyl group, and other symbols are as described above), and the deacetal step (according to the above scheme) ( It is also possible to convert to compound (19) via o) and reductive amination step (l). The compound (20) is obtained by reacting the compound (49) with the alkylating agent T- (CH ₂ ) _n-1 -L according to the step (m), and the obtained compound (50) is present in the presence of a salt according to the step (n). Below (eg DM
It is deesterified by heat treatment in SO (using lithium chloride) and converted to the compound (51), and then the hydrolysis step (S) and the condensation step (a) with the amine compound (HNR ¹ R ² ). Can be manufactured through. Step (m) in this scheme,
The steps (s) and (a), and the deacetal step (o) and the reductive amination step (l) may be carried out by substantially the same methods as described above.

[0041]

[Chemical 11]

Furthermore, according to the following scheme (the symbols in the scheme are as described above), the compound (32) of the present invention can be produced using the compound (27) as a starting material. That is, from the compound (27) to the amine compound (H
NR ¹ R ² ) and the resulting compound (28) is subjected to the step (m ′)
To react with an alkylating agent Y-CH ₂ -L (L represents a leaving group, preferably a sulfonyl group or a halogen atom) to convert it into compound (29). As the hydroxyl group-protecting group for the compound (27), any group can be used as long as it can protect the hydroxyl group in the condensation step (a) and the alkylation step (m ′) and can be easily deprotected according to the step (i). Although it may be used, it is preferable to use, for example, a tertiary butyldimethylsilyl group. In this case, tetrabutylammonium fluoride (B
u ₄ NF) or hydrofluoric acid or hydrochloric acid can be used for easy deprotection. Obtained compound (3
0) is subjected to an oxidation step (k) and a reductive amination step (l), or is subjected to a conversion step (p) of converting a hydroxyl group into a leaving group, and then an amino compound (WH) is obtained according to step (d). By reacting, the compound (32) of the present invention can be produced.

[0043]

[Chemical 12]

The condensing agent used in the condensation step (for example, the step (a)) in the above reaction scheme will be described more specifically. For example, N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBT). ), N-
Hydroxy-5-norbornene-2,3-dicarboximide
N-hydroxy derivatives such as (HONB); Disulfide compounds such as 2,2'-dipyridyl disulfide; N, N '
-Succinic acid compounds such as disuccinimidyl carbonate; N, N'-bis (2-oxo-3-oxazolidinyl)
Phosphinic chloride compounds such as phosphinic chloride; N, N'-disuccinimidyl oxalate (DSO), N, N'-diphthalimido oxalate (DPO)
, N, N'-bis (norbornenylsuccinimidyl) oxalate (BNO), 1,1'-bis (benzotriazolyl)
Oxalate (BBTO), 1,1'-bis (6-chlorobenzotriazolyl) oxalate (BCTO), 1,1'-bis (6-trifluoromethylbenzotriazolyl) oxalate (BTBO)
Oxalate derivatives such as; triarylphosphines such as triphenylphosphine, diethyl azodicarboxylate-di-lower alkyl azodicarboxylates such as triphenylphosphine; N-ethyl-5-phenylisoxazolium-3'- N-lower alkyl-5 such as sulfonate
-Arylisoxazolium-3'-sulfonates;
Like N ', N'-dicyclohexylcarbodiimide (DCC)
N ', N'-dicycloalkylcarbodiimides, 1-ethyl-3
Carbodiimide derivatives such as-(3-dimethylaminopropyl) carbodiimide (WSC); Diheteroaryl diselenides such as di-2-pyridyl diselenide; Arylsulfonyl triazolides such as p-nitrobenzenesulfonyl triazolide 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; diarylphosphoryl azides such as diphenylphosphoryl azide (DPPA); 1,1′-oxalyldiimidazole , N, N′-carbonyldiimidazole derivatives such as imidazole can be used. Although the reaction temperature and the reaction time are not particularly limited, for example, 0 to
It is preferable to carry out the reaction at a reaction temperature of about 50 ° C. for about 5 minutes to 16 hours. In carrying out the condensation reaction, a catalytic amount of 4- (N, N-dimethylamino) pyridine, 4-pyrrolidinopyridine or the like can be used, and in order to carry out the reaction effectively, benzyltriethylammonium chloride is used. , Quaternary ammonium salts such as tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and the like may be added.

The active ester method may be used for the condensation reaction such as step (a). In this reaction, for example, a carboxylic acid is reacted with an active esterifying agent to give an active ester which is a reactive derivative. After production, it is carried out by reacting with an amino compound. Both reactions are preferably carried out in an inert solvent, and examples of the solvent to be used include methylene chloride, halogenated hydrocarbons such as chloroform, ethers, ethers such as tetrahydrofuran, dimethylformamide, Examples thereof include amides such as dimethylacetamide and nitriles such as acetonitrile. Examples of the active esterifying agent used include N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-
An N-hydroxy compound such as 2,3-dicarboximide or a disulfide compound such as dipyridyl disulfide can be mentioned, and the active esterification reaction is preferably carried out in the presence of the above condensing agent. The reaction temperature is about -10 ° C to 100 ° C in the active esterification reaction, it is around room temperature in the reaction between the active ester compound and the amine compound, and the time required for the reaction is about 30 minutes to 80 hours for both reactions. . In addition, the condensation reaction such as the step (a) may be carried out by a mixed acid anhydride method or an acid halide method described below.

The step of forming an amide with an acid halide (eg, step (c)) is carried out by reacting a carboxylic acid with a reactive derivative such as an acid halide such as acid chloride or acid bromide.
Suitably, it can be carried out by converting to an acid chloride and then reacting with a compound having an amino group. Conversion from a carboxylic acid to an acid halide may be carried out by a method known per se, but it is necessary to use a halogenating agent (for example, phosphorus pentachloride, thionyl chloride, oxalyl chloride, etc.) at about room temperature and
It may be treated for 5 minutes to 5 hours to be converted into a corresponding acid halide. For example, in the case of producing acid chloride, a method of reacting a carboxylic acid with oxalyl chloride in methylene chloride is preferable. This reaction may be performed at room temperature for about 2 hours, for example. The reaction between the obtained acid halide and the compound having an amino group is preferably carried out in an inert solvent such as methylene chloride in the presence of a base under ice cooling for about 30 minutes.

When the carboxy group is converted to an ester (for example, step (r)), it is not particularly limited, for example, in a solvent (as long as it does not inhibit the reaction and dissolves the starting material to some extent). , Preferably the same alcohol as the reagent; aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, Halogenated hydrocarbons such as dichlorobenzene; ethyl formate, ethyl acetate,
Esters such as propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide,
N, N-dimethylacetamide, N-methyl-2-pyrrolidone,
Examples thereof include amides such as N-methylpyrrolidinone and hexamethylphosphorotriamide, and preferably the same alcohol as the reagent. ), In the presence of an acid catalyst (not particularly limited as long as it is used as an acid catalyst in a normal reaction, preferably, hydrochloric acid, chlorobromic acid,
Inorganic acids such as sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid,
Bronsted acids such as organic acids such as oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or Lewis acids such as boron trichloride, boron trifluoride, boron tribromide, or acidic An ion exchange resin can be mentioned. ), Corresponding lower alcohols such as methanol, ethanol, propanol, butanol and 0 ° C.
The reaction may be performed at -100 ° C (preferably 20 ° C-60 ° C) for 1 hour to 24 hours.

Further, in the above reaction, the removal of the lower alkyl ester group which is a protective group for the carboxyl group (for example, step (s)) can be carried out by treating with an acid or a base. The acid or base is not particularly limited as long as it does not affect the other parts of the compound, but for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or the like can be used as the acid. As the base, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, concentrated ammonia-methanol solution and the like can be used. When performing hydrolysis with a base, a base that does not cause isomerization should be selected. The solvent used is not particularly limited as long as it is used in a usual hydrolysis reaction and does not inhibit the reaction, but water, methanol, ethanol, alcohols such as n-propanol, tetrahydrofuran or dioxane is preferable. A mixed solvent of an organic solvent such as ethers and water can be used. The reaction temperature and the reaction time vary depending on the starting materials, the solvent, the reagents to be used and the like and are not particularly limited, but in order to suppress side reactions, it is usually carried out at 0 to 150 ° C. for about 1 to 10 hours.

Needless to say, the reaction conditions, reagents and the like in the reactions of the above steps can be appropriately changed. The reaction in each step can be carried out in an inert solvent or in the absence of a solvent, depending on the nature of the reaction and the type of reagent. When a solvent is used, it is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligrolein, and petroleum ether; benzene, toluene, xylene. Aromatic hydrocarbons such as; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, halogenated hydrocarbons such as dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol,
n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,
Alcohols such as octanol, cyclohexanol, methyl cellosolve; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; Nitro compounds such as nitroethane, nitrobenzene; Nitriles such as acetonitrile, isobutyronitrile Amides; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane The kind etc. can be used.

By referring to the above description, or in addition to the detailed description of the examples, or by making appropriate modifications and alterations to those methods, those skilled in the art will appreciate the compounds of the present invention. Can be easily manufactured. After the completion of the reaction, the compound of the present invention can be collected from the reaction mixture according to a conventional method, for example, by distilling off the solvent from the reaction mixture or pouring the reaction mixture into water and extracting with a water-insoluble organic solvent. Then, the solvent can be distilled off from the extract. Further, if necessary, it can be further purified by means well known to those skilled in the art, such as recrystallization, reprecipitation or chromatography.

The compound of the present invention has a potent analgesic activity comparable to that of morphine, and a drug containing the compound of the present invention as an active ingredient is useful as an analgesic agent for mammals including humans. Therefore, according to still another aspect of the present invention, there is provided an analgesic containing one or more of the above compounds as an active ingredient, and the medicament of the present invention is useful for preventing or treating pain. Further, the above-mentioned medicament containing the compound of the present invention as an active ingredient is, for example, bronchial asthma, pain, vomiting,
Depression, anxiety, migraine, chronic bronchitis, allergic dermatitis, allergic rhinitis, inflammatory bowel disease, arthritis, carcinoid, Huntington's disease, acute idiopathic polyneuritis,
It is expected to be useful for the prevention and treatment of diseases of mammals including humans such as urinary incontinence or colitis, and also for the prevention and treatment of diseases such as mental illness, hypersensitivity, or hypertension.

As the active ingredient of the medicament of the present invention, in addition to the above compounds in a free form, physiologically and pharmaceutically acceptable acid addition salts or base addition salts can be used.
The medicament of the present invention can be administered to mammals including human as a pharmaceutical composition in an oral dosage form or a pharmaceutical composition in a parenteral dosage form, preferably an oral dosage form. The pharmaceutical composition for oral administration includes tablets, capsules, powders, granules, fine granules, solutions, suspensions, pills,
Examples include troches, sublingual agents, syrups, and the like, and examples of pharmaceutical compositions for parenteral administration include injections, drops, ointments, patches, nasal drops, ear drops, suppositories, etc. You can Formulations for oral administration include, for example, binders,
Addition of conventional pharmaceutical carriers such as fillers, diluents, tablets, lubricants, disintegrants, colorants, flavoring agents and humectants, well known in the art such as mixing, filling, or tableting. It can be manufactured by a method. Formulations for parenteral administration include, for example, an injectable solvent (for example, the above-mentioned compound which is an active ingredient).
It is generally manufactured as a solution or suspension by adding water, ethanol, glycerin, etc.), and further sealed in a vial, etc. in the form of a unit dose preparation so that a unit dose of the active ingredient is contained. It is preferable that the information is provided to the market. A lyophilized preparation sealed in a vial is also suitable for the purpose of increasing the stability of the preparation. Although the dose varies depending on the patient's symptoms and age, the lower limit of the daily dose is 10 mg, preferably about 50 mg, and the upper limit of the daily dose is 500 mg, preferably 200 mg. It is a degree. Such a dose of the compound can be administered to an adult once a day or in several divided doses.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

[0054]

【Example】

[0055]

[Example 1] N- (2-chloroacetyl) -L-3- (2-naphthyl) a
Lanine N-benzyl-N-methylamide L-naphthylalanine N-benzyl-N-methylamide Hydrochloride (0.3 g) in THF (5 ml) was added with triethylamine (0.26 ml) and chloroacetyl chloride (74 μl) under ice cooling. In addition, after stirring for 0.5 hours at the same temperature, pour the reaction solution into water,
It was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, and the title compound as an oil (0.282 g, yield 84%) was obtained from the fraction eluted with ethyl acetate-cyclohexane (1: 3).
I got IR (CHCl ₃ ) cm ⁻¹ : 3400, 1600, 1635 ¹ H NMR (CDCl ₃ ) δ ppm: 2.61 (2H, s), 2.87 (1H, s),
3.1-3.5 (2H, m), 3.97 (2 / 3H, s), 4.05 (4 / 3H, s), 4.
30 (1H, d, J = 14Hz), 4.69 (1H, d, J = 14Hz), 5.2
-5.4 (1H, m), 6.8-7.9 (12H, m). MS m / z: 394 (M ⁺ ) The compounds of Examples (2) to (10) were synthesized in the same manner as in Example (1).

[0056]

[Example 2] N- (2-bromoacetyl) -L-3-phenylalani
N-benzyl-N-methylamide oil ¹ H NMR (CDCl ₃ ) δ ppm: 1.70 (1H, bs), 2.62 & 2.87
(3H in total, each s), 3.06 (2H, t, J = 5.5 H
z), 2.78 & 2.84 (total 2H, s for each), 4.38 (1
H, d, J = 15 Hz), 4.63 (1H, d, J = 15 Hz), 5.15 (1
H, m), 6.9-7.4 (10H, m).

[0057]

[Example 3] N- (2-bromoacetyl) -L-tyrosine N-ben
Dil-N-methylamide oil IR (CHCl ₃ ) cm ⁻¹ : 3400, 1640, 1510 ¹ H NMR (CDCl ₃ ) δ ppm: 1.71 (1H, bs), 2.72 & 2.89
(3H in total, s each), 2.96 (2H, dd, J = 13, 7
Hz), 4.19 & 4.41 (1H in total, d, J = 15H respectively
z), 4.40 & 4.64 (1H total, d, J = 15H respectively
z), 5.1-5.2 (1H, m), 6.0-6.4 (1H, bs), 6.6-7.4 (9
H, m). MS m / z: 405 (M ⁺ )

[0058]

[Example 4] N- (2-bromoacetyl) -L-3- (2-naphthyl) a
Lanine 1,2,3,4-tetrahydroisoquinoline amide oil IR (CHCl ₃ ) cm ^-1 : 3400, 1660, 1640, 1505 ¹ H NMR (CDCl ₃ ) δ ppm: 2.20-2.75 (2H, m), 3.0 -3.3
(3H, m), 3.5-3.6 (1H, m), 3.84 & 3.86 (Total 2
H, s), 3.99 & 4.55 (1H in total, d, J = 16, respectively)
17 Hz), 4.40 & 4.78 (total 1H, d, J =
16, 17 Hz), 5.22-5.37 (1H, m), 6.6-7.8 (11H, m), MS m / z: 451 (M ⁺ )

[0059]

Example 5 N- (2-bromoacetyl) -DL-3- (2-thienyl)
Alanine N-benzyl -N-methylamide IR (KBr pellet) cm ^-1 : 3281, 3064, 1679, 1631 ¹ H NMR (CDCl ₃ ) δ ppm: 2.84 (2H, s), 2.92 (1H, s),
3.1-3.4 (2H, m), 3.82 (2 / 3H, s), 3.88 (4 / 3H, s),
4.35 (1 / 3H, d, J = 17 Hz), 4.44 (2 / 3H, d, J = 15 H
z), 4.53 (1 / 3H, d, J = 17 Hz), 4.66 (2 / 3H, d, J =
15 Hz), 5.1-5.3 (1H, m), 6.7-7.6 (9H, m), MS m / z: 394 (M ⁺ )

[0060]

Example 6 N- (2-Bromoacetyl) -L-3- (2-naphthyl) a
Lanine N-benzyl -N-methylamide IR (CHCl ₃ ) cm ^-1 : 3400, 3000, 1640, 1510 ¹ H NMR (CDCl ₃ ) δ ppm: 2.61 (2H, s), 2.86 (1H, s),
3.1-3.3 (2H, m), 3.80 (2 / 3H, s), 3.86 (4 / 3H, s),
4.31 (1H, d, J = 14 Hz), 4.68 (1H, d, J = 14 Hz),
5.2-5.3 (1H, m), 6.8-7.8 (13H, m) MS m / z: 438 (M ⁺ : Br = 79)

[0061]

Example 7 N- (2-bromoacetyl) -DL-3- (4-thiazoli)
Le) Alanine N-benzyl -N-methylamide ¹ H NMR (CDCl ₃ ) δ ppm: 2.92 (1H, s), 2.95 (2H, s),
3.1-3.4 (2H, m), 3.78 (2 / 3H, s), 3.85 (4 / 3H, s),
4.36 (2 / 3H, d, J = 15 Hz), 4.46 (1 / 3H, d, J = 17 H
z), 4.68 (1 / 3H, d, J = 17 Hz), 4.76 (2 / 3H, d, J =
15 Hz), 5.35 (1H, dd, J = 15, 7 Hz), 7.0-7.6 (7H,
m), 8.73 (1H, s)

[0062]

Example 8 N- (2-Bromoacetyl) -L-2-phenylglycy
N-benzyl-N-methylamide ¹ H NMR (CDCl ₃ ) δ ppm: 2.79 (2H, s), 2.91 (1H, s),
3.7-4.0 (2H, m), 4.27 (1 / 3H, d, J = 16 Hz), 4.54
(2 / 3H, d, J = 15 Hz), 4.56 (1 / 3H, d, J = 16Hz), 4.
71 (2 / 3H, d, J = 15 Hz), 5.80 (2 / 3H, d, J = 7 Hz),
5.83 (1 / 3H, d, J = 9 Hz), 6.9-7.5 (10H, m), 8.06 &
8.04 (1H, bd) MS m / z: 374 (M ⁺ : Br = 79)

[0063]

Example 9 N- (4-chlorobutyryl) -L-3- (2-naphthyl) a
Lanine N-benzyl-N-methylamide ¹ H NMR (CDCl ₃ ) δ ppm: 2.0-2.2 (2H, m), 2.3-2.45
(2H, m), 2.64 (2H, s), 2.87 (1H, s), 3.1-3.3 (2H, s)
m), 3.3-3.7 (2H, m), 4.22 (1 / 3H, d, J = 16.5Hz),
4.33 (2 / 3H, d, J = 15.2 Hz), 4.37 (1 / 3H, d, J = 1
6.5 Hz), 4.65 (2 / 3H, d, J = 15.2 Hz), 5.2-5.4 (1H,
m), 6.50 (1 / 3H, d, J = 7.91 Hz), 6.62 (2 / 3H, d, J
= 7.91 Hz), 6.9-7.8 (12H, m), MS m / z: 422 (M ⁺ )

[0064]

Example 10 N-acryloyl-L-3- (2-naphthyl) alani
N-benzyl -N-methylamide IR (KBr pellet) cm ^-1 : 3281, 3055, 1673, 1628 ¹ H NMR (CDCl ₃ ) δ ppm: 2.60 (2H, s), 2.84 (1H, s),
3.2-3.3 (2H, m), 4.1-4.4 (4 / 3H, m), 4.65 (2 / 3H,
d, J = 15 Hz), 5.3-5.5 (1H, m), 5.6-5.8 (1H, m), 6.
0-6.4 (2H, m), 6.5-7.9 (12H, m) MS m / z: 372 (M ⁺ )

[0065]

Example 11 N- (2- (4-acetamido-4-phenylpiperidi
N-1-yl) acetyl) -L-3- (2-naphthyl) alanine
N-benzyl-N-methylamide hydrochloride trihydrate N- (2-chloroacetyl) -L-3- (2-naphthyl) alanine
N-benzyl-N-methylamide (274 mg) in DMF (2.
5 ml), diisopropylethylamine (266 μl) and
4-Acetamido-4-phenylpiperidine hydrochloride (177 m
g) was added and the mixture was heated on an oil bath at 70 ° C. for 1 hour, then the reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, the solvent was evaporated, the residue was purified by silica gel column chromatography (ethyl acetate-ethanol = 10: 1), and 4N HC was added.
The crystalline title compound (289 mg) was obtained by converting the hydrochloride into a dioxane solution of l. mp 153-155 ℃ Anal. C ₃₆ H ₄₇ N ₄ O ₆ Cl: Calcd C, 64.80; H, 7.10; N, 8.40 Found C, 65.07; H, 7.12; N, 8.33 IR (KBr) cm ^-1 : 3250 , 1683, 1640 ¹ H NMR (DMSO-d ₆ ) δ ppm: 1.95 (3H, s), 2.0-2.5 (4
H, m), 2.83 (1H, s), 2.92 (2H, s), 2.9-3.9 (6H,
m), 3.9-4.1 (2H, m), 4.36 (2 / 3H, d, J = 15 Hz), 4.1
-4.2 (4 / 3H, m), 5.11 (1 / 3H, dd, J = 6, 9 Hz), 5.21
(2 / 3H, t, J = 7 Hz), 6.9-7.9 (17H, m), 9.1-9.4 (1
H, m), 9.9-10.1 (1H, m). MS m / z: 576 (M ⁺ -HCl-3H ₂ O) The title compounds of Examples (12) to (20) were obtained by the same method as in Example (11).

[0066]

Example 12 N- (2- (4-acetamido-4-phenylpiperidi
N-1-yl) acetyl) -L-3-phenylalanine N-ben
Zir -N-methylamide hydrochloride mp 141-143 ° C IR (KBr) cm ^-1 : 3247, 1683, 1640 ¹ H NMR (DMSO-d ₆ ) δ ppm: 1.95 (3H, s), 2.1-2.6 (4
H, m), 2.82 (1H, s), 2.91 (2H, s), 2.8-3.5 (6H,
m), 3.9-4.1 (2H, m), 3.8-4.1 (2H, m), 7.4-7.7 (2H,
m), 5.0-5.1 (1H, m), 7.1-7.5 (15H, m), 8.2-8.4 (1
H, m), 9.2-9.3 (1H, m), 9.9-10.2 (1H, m) MS m / z: 526 (M ⁺ )

[0067]

Example 13 N- (2- (4-acetyl-4-phenylpiperidine-
1-yl) acetyl) -L-3-phenylalanine N-benzyl
-N-methylamide hydrochloride mp 114-117 ° C IR (KBr) cm ^-1 : 3194, 1706, 1680, 1648 ¹ H NMR (DMSO-d ₆ ) δ ppm: 1.7-2.3 (5H, m), 2.5-3.9
(11H, m), 3.7-4.0 (2H, m), 4.4-4.7 (2H, m), 4.9-5.1
(1H, m), 7.0-7.5 (15H, m), 9.0-9.3 (1H, m), 10.0-
10.2 (1H, m) MS m / z: 511 (M ⁺ -HCl)

[0068]

Example 14 N- (2- (4-acetamido-4-phenylpiperidi
N-1-yl) acetyl) -L-tyrosine N-benzyl -N-methyl
Ruamide hydrochloride ・ 1.5 hydrate mp 167-170 ℃ IR (KBr) cm ^-1 : 3247, 1683, 1640 Anal. C ₃₂ H ₃₈ N ₄ O ₄・ HCl ・ 1.5H ₂ O: Calcd C, 63.41; H , 6.98; N, 9.28 Found C, 63.24; H, 7.29; N, 9.00 ¹ H NMR (DMSO-d ₆ ) δ ppm: 1.95 (3H, s), 2.0-2.6 (4
H, m), 2.7-3.0 (5H, m), 3.1-3.4 (4H, m), 3.9-4.1 (2
H, m), 4.4-4.7 (2H, m), 4.9-5.0 (1H, m), 6.6-7.5
(14H, m), 8.2-8.4 (1H, m), 9.2-9.3 (1H, m), 9.9-1
0.1 (1H, m) MS m / z: 542 (M ⁺ -HCl-3 / 2H ₂ O)

[0069]

Example 15 N- (2- (4-acetyl-4-phenylpiperidine-
1-yl) acetyl) -L-tyrosine N-benzyl -N-methyl
Amide hydrochloride mp 154-156 ° C IR (KBr) cm ^-1 : 3209, 1705, 1683, 1637 ¹ H NMR (DMSO-d ₆ ) δ ppm: 1.8-2.4 (5H, m), 2.5-3.4
(11H, m), 3.2-4.0 (2H, m), 4.40 (1 / 3H, d, J = 15 H
z), 4.5-4.7 (2 / 3H, m), 4.9-5.0 (1H, m), 6.6-7.5 (1
4H, m), 8.9-9.4 (2H, m), 9.9-10.1 (1H, m) MS m / z: 527 (M ⁺ -HCl)

[0070]

Example 16 N- (2- (4-acetamido-4-phenylpiperidi
N-1-yl) acetyl) -L-3- (2-naphthyl) alanine
1,2,3,4-Tetrahydroisoquinolineamide hydrochloride mp 157-160 ℃ IR (KBr) cm ^-1 : 3247, 1683, 1636 ¹ H NMR (DMSO-d ₆ ) δ ppm: 1.80 & 1.90 (total 3H ,
s), 2.0-2.5 (4H, m), 2.6-2.9 (2H, m), 3.0-3.4 (6H,
m), 3.5-4.1 (4H, m), 4.51 & 4.58 (total 1H, d, J = 17, 16 Hz respectively), 4.74 & 4.76 (total 1
H, d, J = 17, 16 Hz), 5.15-5.35 (1H, m),
7.05-7.50 (12H, m), 7.7-7.9 (4H, m), 8.22 (1H, s),
9.19 & 9.24 (1H in total, each d, J = 8.0H
z), 9.9-10.1 (1H, bs) MS m / z: 588 (M ⁺ -HCl)

[0071]

Example 17 N- (2- (4-acetyl-4-phenylpiperidine-
1-yl) acetyl) -L-2-phenylglycine N-benzyl
-N-methylamide ¹ H NMR (CDCl ₃ ) δ ppm: 1.90 (2H, s), 2.05 (1H, s),
2.0-2.6 (8H, m), 2.81 (2H, s), 2.88 (1H, s), 2.7-
3.0 (2H, m), 4.27 (1 / 3H, d, J = 16 Hz), 4.51 (2 / 3H,
d, J = 15 Hz), 4.59 (1 / 3H, d, J = 16 Hz), 4.72 (2
/ 3H, d, J = 15Hz), 5.94 (1H, t, J = 8Hz), 6.9-7.5
(15H, m), 8.4-8.5 (1H, m) MS m / z: 497 (M ⁺ ) Oxalate IR (KBr pellet) of the above compound cm ^-1 : 3273, 1704, 1685, 1648 mp 82-84 ℃

[0072]

Example 18 N- (2- (4-acetylpiperidin-1-yl) acetate
Tyl) -L-2-phenylglycine N-benzyl -N-methyla
Mido ¹ H NMR (CDCl ₃ ) δ ppm: 2.08 (3H, s), 2.3-2.7 (4H,
m), 2.82 (2H, s), 2.90 (1H, s), 3.04 (2H, s), 3.4-
3.9 (4H, m), 4.27 (1 / 3H, d, J = 16 Hz), 4.52 (2 / 3H,
d, J = 15 Hz), 4.57 (1 / 3H, d, J = 16 Hz), 4.73 (2
/ 3H, d, J = 15Hz), 5.9 (1H, t, J = 8Hz), 6.9-7.5
(10H, m), 8.37 (1H, t, J = 8 Hz) MS m / z: 422 (M ⁺ ) Oxalate IR (KBr pellet) of the above compound cm ^-1 : 3272, 3060, 1722, 1684,
1648 mp 71-73 ℃

[0073]

Example 19 N- (2- (4-acetamido-4-phenylpiperidi
N-1-yl) acetyl) -DL-3- (2-thienyl) alanine
N-benzyl -N-methylamide IR (KBr pellet) cm ^-1 : 3320, 3062, 1652, 1605 ¹ H NMR (CDCl ₃ ) δ ppm: 2.02 (3H, s), 2.1-2.8 (8H,
m), 2.9-3.1 (5H, m), 3.1-3.4 (2H, m), 4.44 (2 / 3H,
d, J = 15 Hz), 4.58 (2 / 3H, d, J = 3 Hz), 4.67 (2/3
H, d, J = 15 Hz), 5.2-5.3 (1H, m), 5.49 (1H, d, J
= 5 Hz), 6.7-7.5 (13H, m), 7.7-8.0 (1H, m) MS m / z: 532 (M ⁺ ) mp 72-73 ℃

[0074]

Example 20 N- (2- (4-acetamido-4-phenylpiperidi
N-1-yl) acetyl) -DL-3- (4-thiazolyl) alani
N-benzyl-N-methylamide ¹ H NMR (CDCl ₃ ) δ ppm: 2.01 (2H, s), 2.05 (1H, s),
2.11-2.78 (8H, m), 2.86-3.10 (5H, m), 3.17-3.36
(2H, m), 4.35 (2 / 3H, d, J = 15 Hz), 4.65 (2 / 3H, d,
J = 6 Hz), 4.76 (2 / 3H, d, J = 15 Hz), 5.37-5.48
(1H, m), 5.54 (1H, s), 6.99-7.43 (11H, m), 7.90-8.0
2 (1H, m), 8.69-8.71 (1H, m) Oxalate IR of the above compound IR (KBr pellet) cm ^-1 : 3425, 3255, 1680, 1644 MS m / z: 533 (M ⁺ ) mp 112-114 ℃

[0075]

Example 21 N- (2- (4-piperidone-1-yl) acetyl) -L
-(2-Naphthyl) alanine N-benzyl -N-methylamide IR (CHCl ₃ ) cm ^-1 : 3390, 1718, 1672, 1642 ¹ H NMR (CDCl ₃ ) δ ppm: 2.28 (2H, t), 2.35 (2H , t),
2.5-2.75 (4H, m), 2.80 (2H, s), 2.95 (1H, s), 3.0
-3.4 (4H, m), 4.39 (2 / 3H, d, J = 14 Hz), 4.45-4.6
(2 / 3H, m), 4.70 (2 / 3H, d, J = 14 Hz), 5.37 (1H,
m), 7.0-8.1 (13H, m) MS m / z: 457 (M ⁺ ) Oxalate salt of the above compound mp 87 ° C

[0076]

Example 22 N- (2- (4-carbamoylpiperazin-1-yl)
Acetyl) -L-3- (2-naphthyl) alanine N-benzyl-
N-methylamide IR (CHCl ₃ ) cm ^-1 : 3529, 3427, 3370, 1660, 1649, 1
588 ¹ H NMR (CDCl ₃ ) δ ppm: 2.1-2.5 (4H, m), 2.8-3.4 (8
H, m), 2.80 (2H, s), 2.94 (1H, s), 4.36 (2H, bs),
4.37 (2 / 3H, d, J = 15 Hz), 4.51 (2 / 3H, s), 4.70 (2
/ 3H, d, J = 15 Hz), 5.3-5.6 (1H, m), 7.0-7.9 (13H,
m) MS m / z: 487 (M ⁺ ) Oxalate salt of the compound mp 105 ° C ~ (foam)

[0077]

Example 23 N- (2- (3-acetamidopyrrolidin-1-yl)
Acetyl) -L-3- (2-naphthyl) alanine N-benzyl-
N-methylamide IR (CHCl ₃ ) cm ⁻¹ : 3441, 3365, 1665, 1641 ¹ H NMR (CDCl ₃ ) δ ppm: 1.90 (2H, s), 1.93 (1H, s),
2.1-2.4 (2H, m), 2.4-2.7 (2H, m), 2.72 (2H, s),
2.88 (2H, s), 2.96 (1H, s), 3.0-3.4 (4H, m), 4.26
(1 / 3H, d, J = 16 Hz), 4.33 (2 / 3H, d, J = 15 Hz),
4.4-4.5 (4 / 3H, m), 4.69 (2 / 3H, d, J = 15 Hz), 5.2-
5.4 (1H, m), 6.1-6.3 (1H, m), 6.9-8.1 (13H, m) MS m / z: 486 (M ⁺ )

[0078]

Example 24 N- (2- (4-carbamoylpiperidin-1-yl)
Acetyl) -L-3- (2-naphthyl) alanine N-benzyl-
N-methylamide IR (CHCl ₃ ) cm ⁻¹ : 3531, 3413, 3361, 1675, 1644 ¹ H NMR (CDCl ₃ ) δ ppm: 1.5-1.95 (4H, m), 1.97-2.2
(2H, m), 2.4-2.6 (1 / 3H, m), 2.6-2.7 (2 / 3H, m), 2.7
-3.0 (4H, m), 2.77 (2H, s), 2.95 (1H, s), 3.1-3.4
(2H, m), 4.34 (2 / 3H, d, J = 15 Hz), 4.4-4.6 (2 / 3H,
m), 4.70 (2 / 3H, d, J = 15 Hz), 5.2-5.5 (1H, m), 5.
43 (2H, bs), 6.9-8.1 (13H, m) MS m / z: 486 (M ⁺ ) Oxalate salt of the above compound mp 103-105 ℃

[0079]

Example 25 N- (2- (1-phenyl-1,3,8-triazaspiro-
(4,5) Decan-4-one-8-yl) acetyl) -L-3- (2-na
(Futyl) alanine N-benzyl -N-methylamide IR (CHCl ₃ ) cm ^-1 : 3447, 2977, 2937, 1717, 1665, 1
645, 1601 ¹ H NMR (CDCl ₃ ) δ ppm: 2.2-3.4 (10H, m), 2.78 (2H,
s), 2.89 (1H, s), 2.96 (2H, s), 4.36 (2 / 3H, d, J
= 15 Hz), 4.46 (1 / 3H, d, J = 17 Hz), 4.60 (1 / 3H,
d, J = 17 Hz), 4.63-4.72 (2H, m), 4.75 (2 / 3H, d, J
= 15 Hz), 5.2-5.5 (1H, m), 6.59 (1H, bs), 6.8-8.2
(18H, m) MS m / z: 589 (M ⁺ ) Oxalate salt of the above compound mp 126-128 ℃

[0080]

Example 26 N- (2- (4- (2-pyrrolidone-1-yl) piperidi
N-1-yl) acetyl) -L-3- (2-naphthyl) alanine
N-benzyl -N-methylamide IR (CHCl ₃ ) cm ^-1 : 3400, 3050, 1669, 1645, 1603 ¹ H NMR (CDCl ₃ ) δ ppm: 1.3-1.8 (4H, m), 1.9-2.1 (2
H, m), 2.1-2.3 (2H, m), 2.39 (2H, t), 2.76-3.0 (4
H, m), 2.76 (2H, s), 2.88 (1H, s), 3.1-3.4 (4H,
m), 3.8-4.0 (1H, m), 4.36 (2 / 3H, d, J = 15 Hz), 4.
48 (2 / 3H, bs), 4.67 (2 / 3H, d, J = 15 Hz), 5.3-5.5
(1H, m), 6.9-8.1 (13H, m) MS m / z: 526 (M ⁺ ) Oxalate salt of the above compound mp 75 ℃ ~ (foam)

[0081]

Example 27 N- (2- (4-acetamido-4-phenylpiperidi
N-1-yl) butyryl) -L-3- (2-naphthyl) alanine N- (4-chlorobutyl) -L-3- (2-naphthyl) alanine N-
Benzyl-N-methylamide (448 mg) in DMF (4.5
ml), sodium hydrogen carbonate (445 mg) and sodium iodide (159 mg) were added, and the mixture was stirred at 100 ° C for 1 hr, and
The reaction solution was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, ethanol-ethyl acetate (1: 1).
The title compound (186 mg, yield 29%) was obtained as an oil from the fraction eluted with. ¹ H NMR (CDCl ₃ ) δ ppm: 1.7-1.9 (3H, m), 2.01 (3H,
s), 2.1-2.5 (9H, m), 2.6-2.9 (2H, m), 2.63 (2H,
s), 2.84 (1H, s), 3.1-3.3 (2H, m), 4.2-4.4 (4 / 3H,
m), 4.65 (2 / 3H, d, J = 15 Hz), 5.2-5.4 (1H, m), 5.
55 (1H, s), 6.8-7.9 (18H, m) Oxalate IR of the above compound IR (KBr pellet) cm ^-1 : 3269, 3054, 1641, 1541 MS m / z: 604 (M ⁺ ) mp 105-106 ℃

[0082]

Example 28 N- (3- (4-acetamido-4-phenylpiperidi
N-1-yl) propionyl) -L-3- (2-naphthyl) alani
N-benzyl-N-methylamide N-acryloyl-L-3- (2-naphthyl) alanine N-benzyl-N-methylamide (0.15 g) in ethanol (0.5
ml), triethylamine (0.093 ml) and 4-acetamido-4-phenylpiperidine (0.15 g) were added, and the mixture was stirred at room temperature.
After stirring for 66 hours, the reaction solution was concentrated and diluted with dichloromethane. The diluted solution was washed with saturated saline and then dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography, and the title compound (0.22 g, yield 91%) was obtained as a white solid from the fraction eluted with dichloromethane-ethanol (20: 1). mp 104-105 ℃ IR (KBr pellet) cm ^-1 : 3293, 3057, 1640, 1541 ¹ H NMR (CDCl ₃ ) δ ppm: 1.7-2.9 (12H, m), 2.02 (3H,
s), 2.75 (2H, s), 2.88 (1H, s), 3.1-3.3 (2H, m),
4.3-4.6 (4 / 3H, m), 4.68 (2 / 3H, d, J = 15 Hz), 5.2-
5.4 (1H, m), 5.48 (1H, bs), 6.9-7.8 (17H, m), 8.9-
9.2 (1H, m) MS m / z: 590 (M ⁺ )

[0083]

Example 29 N- (3-tetrahydropyran-2-yloxyp
Ropil) -L-3- (naphthyl) alanine N-benzyl -N-meth
Lumid L-naphthylalanine N-benzyl-N-methylamide hydrochloride (1.0 g) in DMF solution (8 ml), sodium bicarbonate
(711 mg) and bromo-3-tetrahydropyranyloxypropane (714 mg in DMF 2 ml), and add 2.5 at 100 ℃.
After stirring for an hour, the reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was separated and purified using silica gel chromatography, and the title compound (0.95 g, yield 73%) was obtained as an oil from the fraction eluted with ethyl acetate-ethanol (1: 1). ¹ H NMR (CDCl ₃ ) δ ppm: 1.4-1.9 (8H, m), 2.4-2.8 (3
H, m), 2.85 (1H, s), 2.88 (1H, s), 2.96 (1H, s),
3.0-3.3 (2H, m), 3.3-3.6 (2H, m), 3.7-4.3 (3H, m),
4.3-4.7 (2H, m), 6.7-6.9 (13H, m) MS (FAB ⁺ ) m / z: 461 (M
⁺ + H) ⁺

[0084]

Example 30 N- (3-hydroxypropyl) -L-3- (2-na
(Futyl) alanine N-benzyl -N-methylamide para
Toluenesulfonate N- (3-tetrahydropyranyloxypropyl) -L-3- (2-
Naphthyl) alanine N-benzyl -N-methylamide (0.93
Paratoluenesulfonic acid monohydrate (461 mg) was added to a methanol solution (10 ml) of g), and the mixture was stirred at 40 ° C for 4 hr, sodium bicarbonate (118 mg) was added, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated, ethyl acetate was added, the inorganic substances were removed by filtration, and the mixture was concentrated again. As a result, the title compound was white crystals.
(593 mg, yield 53%). ¹ H NMR (CDCl ₃ ) δ ppm: 1.6-2.3 (2H, m), 2.28 (1H,
s), 2.34 (2H, s), 2.9-3.2 (1H, m), 3.2-3.4 (2H,
m), 3.5-4.0 (5H, m), 4.29 (1H, d, J = 15 Hz), 4.55
(1H, d, J = 15 Hz), 4.6-4.9 (1H, m), 6.7-7.9 (16H,
m)

[0085]

Example 31 N- (t-butoxycarbonyl) -N- (3-hydroxy
Cypropyl) -L-3- (2-naphthyl) alanine N-benzyl
-N-methylamide N- (3-hydroxypropyl) -L-3- (2-naphthyl) alanine N-benzyl-N-methylamide paratoluenesulfonate (0.55 g) in acetone-water (1: 1) Triethylamine (0.35 ml) and di-tert-butyldicarbonate (0.59 g in acetone 7 ml) were added to (17 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours, then heated to 60 ° C and stirred for 6.5 hours. Then
Further, the reaction was carried out at room temperature for 4 days. The reaction solution was concentrated, the residue was purified by silica gel chromatography, and the title compound (0.30 g, yield 64%) was obtained as an oil from the fraction eluted with ethyl acetate-ethanol (5: 1). . IR (KBr pellet) cm ^-1 : 3459, 2973, 1683, 1651,
1603 ¹ H NMR (CDCl ₃ ) δ ppm: 1.06 (2H, s), 1.16 (3H, s),
1.33 (3H, d, J = 6 Hz), 1.5-1.7 (3H, m), 2.87 (3
H, s), 3.0-3.2 (1H, m), 3.3-3.8 (5H, m), 4.0-4.4
(1H, m), 4.7-4.9 (1H, m), 5.0-5.2 (1 / 2H, m), 5.5-
5.6 (1 / 2H, m), 6.7-7.8 (13H, m) MS m / z: 476 (M ⁺ )

[0086]

Example 32 N- (t-butoxycarbonyl) -N- (3-formyl
Ethyl) -L-3- (2-naphthyl) alanine N-benzyl -N-
Methylamidotriphosgene (77.4 mg) in dichloromethane (5.5 m
l) in dry ice-acetone bath (-60 ° C) with DMSO.
(0.11 ml), N- (butoxycarbonyl) -N- (3-hydroxypropyl) -L-3- (2-naphthyl) alanine N-benzyl
-N-Methylamide in dichloromethane (0.29 g in 2.
0 ml) and a solution of triethylamine in dichloromethane (0.
(25 ml in 1.5 ml) was added, and the mixture was stirred at room temperature for 1 hr, and diluted with ethyl acetate. Dilute the reaction solution with 0.2 N HCl,
The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, and the title compound (0.20 g, yield 70%) was obtained as an oil from the fraction eluted with ethyl acetate-cyclohexane (1: 2). ¹ H NMR (CDCl ₃ ) δ ppm: 1.02 (1H, s), 1.12 (2H, s),
1.31 (4H, s), 1.59 (2H, s), 2.4-2.7 (2H, m), 2.8-
3.0 (3H, m), 3.0-3.2 (1H, m), 3.3-3.5 (1H, m), 3.6
-3.8 (2H, m), 4.1-4.9 (2H, m), 5.0-5.2 (1 / 3H, m),
5.4-5.6 (2 / 3H, m), 6.7-7.9 (12H, m), 9.64 (1 / 2H,
t, J = 2 Hz), 9.75 (1 / 2H, s)

[0087]

Example 33 N- (3- (4-acetamido-4-phenylpiperidi
N-1-yl) propyl) -N- (butoxycarbonyl) -L-3-
(2-naphthyl) alanine N-benzyl -N-methylamido N- (butoxycarbonyl) -N- (3-propanal) -L-3- (2
-Naphthyl) alanine N-benzyl -N-methylamide (0.
20 g) in methanol solution (4 ml), 4-acetamido-
4-Phenylpiperidine hydrochloride (118 mg) and sodium borohydride (123 mg) were added, the mixture was stirred at room temperature for 4 hr, and the reaction solution was diluted with ethyl acetate. The diluted solution was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, and the title compound (196 mg, yield 69%) was obtained as an oil from the fraction eluted with ethyl acetate-ethanol (1: 1). ¹ H NMR (CDCl ₃ ) δ ppm: 1.0-1.5 (8H, m), 1.5-2.0 (3
H, m), 2.03 (3H, s), 2.1-2.5 (10H, m), 2.7-3.0 (1
H, m), 2.84 (1H, s), 3.0-3.2 (1H, m), 3.2-3.6 (3H,
m), 4.24 (1 / 2H, d, J = 15 Hz), 4.6-4.9 (1 / 2H, m),
5.3-5.7 (1H, m), 6.7-7.9 (17H, m) MS m / z: 676 (M ⁺ )

[0088]

Example 34 N- (3- (4-acetamido-4-phenylpiperidi
N-1-yl) propyl) -L-3- (2-naphthyl) alanine
N-benzyl -N-methylamide hydrochloride N- (3- (4-acetamido-4-phenylpiperidin-1-yl) propyl) -N- (butoxycarbonyl) -L-3- (2-naphthyl) alanine N- Benzyl-N-methylamide (192 m
g) in dichloromethane solution (0.4 ml) under ice-cooling 4 N HC
l / Ethyl acetate (0.35 ml) was added, and the mixture was stirred at room temperature for 17 hr, concentrated, and recrystallized from ethanol to give the title compound as white crystals (150 mg, yield 89%). IR (KBr pellet) cm ^-1 : 3259, 3028, 1652, 1602 ¹ H NMR (CDCl ₃ ) δ ppm: 1.97 (3H, s), 2.1-2.3 (2H,
m), 2.4-2.7 (4H, m), 2.9-3.5 (10H, m), 3.93 (1 / 4H,
d, J = 16 Hz), 4.22 (3 / 4H, d, J = 15 Hz), 4.36 (1
/ 4H, d, J = 16 Hz), 4.65 (3 / 4H, d, J = 15 Hz), 4.9
3 (1H, s), 6.7-8.4 (17H, m), 9.40 (1H, s), 9.98 (1
H, s), 11.31 (1H, s) MS m / z: 576 (M ⁺ ) mp 147-148 ° C

[0089]

Example 35 N- (4-acetamido-4-phenylpiperazine
-1-yl) carbonyl) -L-3- (2-naphthyl) alanine
N-benzyl-N-methylamide N- (3- (2-naphthyl) alanine N-benzyl-N-methylamide (300 mg) in THF (5 ml) was added with triethylamine (0.13 ml) and carbonyldiimidazole (160 mg). ) Was added and the mixture was stirred at room temperature for 5 hours, then the reaction solution was poured into water and extracted with ethyl acetate.
It was dried over magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (ethyl acetate) to obtain a carbonylimidazole derivative (314 mg). This was dissolved in DMF (3 ml), diisopropylamine (0.12 ml) and 4-acetamido-4-phenylpiperidine hydrochloride (188 mg) were added, and the mixture was stirred at room temperature for 1 hr.
The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified using silica gel chromatography. Ethyl acetate-ethanol (1
From the fraction eluted with 0: 1), the crystalline title compound (370
mg) was obtained. mp 154-155 ° C IR (KBr) cm ^-1 : 3300, 1750, 1629, 1537 ¹ H NMR (DMSO-d ₆ ) δ ppm: 1.4-1.6 (2H, m), 1.86 (3
H, s), 2.1-2.3 (2H, m), 2.54 (2H, s), 2.8-3.0 (3H,
m), 3.1-3.3 (2H, m), 3.61 (2H, s), 3.7-4.0 (2H,
m), 6.9-8.0 (17H, m), 9.12 (1H, s) MS m / z: 562 (M ⁺ )

[0090]

Example 36 N-benzyl-3,4-dichlorophenyl-N-methyl
Dissolve 3,4-dichlorophenylacetic acid (5.12 g) in luacetamide dichloromethane (100 ml), and under ice cooling, hydroxybenzotriazole (3.72 g) and water-solved carbodiimide hydrochloride (5.27 g) aqueous solution and triethylamine (3.8
ml), N-methylbenzylamine (3.3 ml) was added, and the mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, washed with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, It was dried over sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography, and the title compound (6.76 g, yield 87.7%) was obtained as an oil from the fraction eluted with cyclohexane-ethyl acetate (1: 1). MS m / z: 307 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 2.92 & 3.00 (total 3H, each s), 3.67 & 3.72 (total 2H, each s),
4.55 & 4.61 (total 2H, each s), 7.03-7.57 (8
H, m)

[0091]

Example 37 N-benzyl-N-methyl-2- (2-naphthyl) acetate
The title compound was obtained in the same manner as in Toamide Example (35). MS m / z: 289 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.92 & 2.99 (total 3H, each s), 3.92 & 3.95 (total 2H, each s),
4.56 & 4.64 (total 2H, each s), 7.12-7.50 (8
H, m), 7.66-7.84 (4H, m)

[0092]

Example 38 N-benzyl-N-methyl-2- (1-naphthyl) acetate
The title compound was obtained in the same manner as in Toamide Example (35). MS m / z: 289 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.94 & 3.03 (total 3H, each s), 4.18 & 4.20 (total 2H, each s),
4.56 & 4.66 (total 2H, each s), 7.12-7.56 (9
H, m), 7.70-8.00 (3H, m)

[0093]

Example 39 N-benzyl-2- (3,4-dichlorophenyl) -5-hi
Dissolve the compound of Example (35) (2.65 g) in droxy-N-methylpentanamide DMF (50 ml),
1.0 M NaN (TMS) ₂ / THF (9.5 ml) was added under ice-cooling under N ₂ flow, 1-bromo-3-tetrahydropyranyloxypropane (2.37 g) was added, and the mixture was kept at room temperature for 1 hour. After stirring, the reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over sodium sulfate,
The solvent was distilled off to obtain a crude oily substance. The obtained oil was dissolved in ethanol (38 ml), 4N HCl / ethyl acetate (2.6 ml) was added at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, and from the fraction eluted with cyclohexane-ethyl acetate (1: 3),
An oily title compound (2.39 g, yield 76.0%) was obtained. MS m / z: 365 (as M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.40-1.89 (4H, m), 2.12-2.3
1 (1H, m), 2.85 & 2.99 (total 3H, each s),
3.56-3.78 (3H, m), {4.35 & 4.62 (d, J = 16 Hz),
4.59 (s), 2H in total, 7.03-7.42 (8H, m) The compounds of Examples (40) to (44) were obtained in the same manner as in Example (39).

[0094]

Example 40 N-benzyl-2- (3,4-dichlorophenyl) -4-hi
Droxy -N-methylbutanamide MS m / z: 351 (as M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.64 (1H, bs), 1.84-2.02 (1
H, m), 2.27-2.45 (1H, m), 2.85 & 2.99 (3 in total
H, s), 3.50-3.66 (2H, m), 3.97-4.16 (1H,
m), 4.35-4.68 (2H, m), 7.09-7.54 (8H, m)

[0095]

Example 41 N-benzyl-2- (3,4-dichlorophenyl) -6-hi
Droxy-N-methylhexanamide MS m / z: 379 (as M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.06-1.83 (5H, m), 2.07-2.2
2 (1H, m), 2.84 & 2.98 (total 3H, each s),
3.53-3.75 (3H, m), 4.31-4.65 (2H, m), 7.04-7.54 (8
H, m)

[0096]

Example 42 N-benzyl-5-hydroxy-N-methyl-2- (2
- naphthyl) pentanoic amide MS m / z: 347 (M +) 1 H NMR (CDCl 3) δ ppm: 1.44-1.94 (3H, m), 2.25-2.4
3 (1H, m), 2.85 & 2.97 (total 3H, each s),
3.51-3.71 (2H, m), 3.81-3.95 (1H, m), {4.09 & 4.15
(D, d, J = 7 Hz), 4.20 & 4.70 (d, d, J = 16 Hz); combined 2H}, 4.61 (1H, s), 7.05-7.32 (5H, m), 7.42
-7.48 (3H, m), 7.68-7.84 (4H, m)

[0097]

Example 43 N-benzyl-5-hydroxy-N-methyl-2- (1-
Naphthyl) pentanamide MS m / z: 347 (M +) 1 H NMR (CDCl 3) δ ppm: 1.54-2.02 (3H, m), 2.30-2.4
9 (1H, m), 2.61 & 3.02 (total 3H, each s),
3.52-3.74 (2H, m), 3.49-4.54 (3H, m), 4.65 (1H,
s), 6.96-8.11 (12H, m)

[0098]

Example 44 N-benzyl-7-bromo-2- (3,4-dichlorophe
Nyl) -N-methylheptanamide MS m / z: 455 (M ⁺ ; Br = 79, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.06-1.51 (4H, m), 1.64-1.8
9 (3H, m), 2.02-2.20 (1H, m), 2.85 & 2.99 (3H for each, s), 3.31-3.41 (2H, m), 3.62 & 3.71
(Total 1H, t, J = 7 Hz each), {4.35 & 4.59
(D, d, J = 17 Hz), 4.59 (s), 2H in total}, 7.04-
7.42 (8H, m)

[0099]

Example 45 N-benzyl-2- (3,4-dichlorophenyl) -4-pho
Dissolve triphosgene (0.48 g) in rumil-N-methylbutanamide dichloromethane (96 ml) and add dimethyl sulfoxide at -50 ° C under N ₂ flow.
(0.68 ml) and dichloromethane (7.3 ml)
The alcohol (1.47 g) of (39) was added dropwise, and the mixture was stirred for 10 minutes, then triethylamine (1.56 ml) dissolved in dichloromethane (7.8 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate,
The solvent was distilled off. The residue was purified by silica gel chromatography, and the title compound as an oil (1.08 g, yield was obtained from the fraction eluted with cyclohexane-ethyl acetate (1: 1).
74.4%). MS m / z: 366 (M ⁺ ; as Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.96-2.10 (1H, m), 2.31-2.5
3 (3H, m), 2.82 & 2.99 (total 3H, each s),
3.75 & 3.87 (1H, t, t, J = 8 Hz, 8 Hz in total),
{4.37 & 4.58 (d, J = 17 Hz), 4.52 & 4.58 (d, J =
14 Hz), q _AB 2 pieces 2H}, 7.01-7.42 (8H, m), 9.65
& 9.76 (total of 1H, s for each) The compounds of Examples (46) to (49) were obtained in the same manner as in Example (45).

[0100]

Example 46 N-benzyl-2- (3,4-dichlorophenyl) -3-pho
Rumil -N-methylpropanamide MS m / z: 349 (as M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 2.59-2.71 (1H, m), 2.87 &
2.93 (3H in total, each s), 3.49-3.63 (1H, m),
4.29-4.38 (1H, m), 4.52-4.68 (2H, m), 7.05-7.42
(8H, m), 9.77 & 9.81 (1H for each, s for each)

[0101]

Example 47 N-benzyl-2- (3,4-dichlorophenyl) -5-pho
Rumil -N-methylpentanamide MS m / z: 377 (as M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.08-1.79 (3H, m), 2.05-2.2
4 (1H, m), 2.30-2.56 (2H, m), 2.84 & 2.99 (3H for each, s), 3.61-3.75 (1H, m), {4.35 & 4.62
(D, d, J = 17 Hz), 4.54 & 4.64 (d, d, J = 15 Hz),
2H in total}, 7.04-7.51 (8H, m), 9.70 & 9.75
(Total 1H, s each)

[0102]

Example 48 N-benzyl-4-formyl-N-methyl-2- (2-na
(Futyl) butanamide MS m / z: 345 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.10-2.26 (1H, m), 2.34-2.5
4 (3H, m), 2.82 & 2.98 (total 3H, each s),
3.90-4.08 (1H, m), {4.23 & 4.71 (d, d, J = 17Hz),
4.54 & 4.68 (d, d, J = 15 Hz), 2H in total, 7.
02-7.34 (5H, m), 7.41-7.52 (3H, m), 7.66-7.85 (4H,
m), 9.67 & 9.76 (1H in total, each s)

[0103]

Example 49 N-benzyl-4-formyl-N-methyl-2- (1-na
(Futyl) butanamide MS m / z: 345 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.07-2.24 (1H, m), 2.40-2.6
7 (3H, m), 2.58 & 3.00 (total 3H, each s),
{3.97 & 4.40 (d, J = 17 Hz), 4.55 & 4.71 (d, J =
15 Hz), 2H in total, 4.53-4.70 (1H, m), 6.91-8.
24 (12H, m), 9.69 & 9.80 (1H in total, each s)

[0104]

Example 50 5- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-2- (3,4-dichlorophenyl) -N-me
Cylpentanamide Amide (18.2 ml) in aldehyde (0.88)
g) was dissolved, sodium cyanoborohydride (0.31 g) and 4-acetamido-4-phenylpiperidine hydrochloride (0.61 g) were added at room temperature under N ₂ flow, and the mixture was stirred for 1 hour.
The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography, and the title compound (1.07) as an amorphous solid was obtained from the fraction eluted with chloroform-ethyl acetate-ethanol (4: 1: 1).
g, yield 78.1%) was obtained. mp 56 ℃ ~ (foam) MS m / z: 565 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.20-2.41 (12H, m), 2.01 (3
H, s), 2.68-2.98 (2H, m), 2.86 & 2.98 (3 in total
H, each s), 3.66 & 3.75 (total 1H, each
t, J = 7 Hz), {4.38 & 4.63 (d, d, J = 16 Hz, J = 16
Hz), 4.58 (d, J = 3 Hz), total 2H}, 5.49 & 5.5
2 (combined 1H, bs, bs), 6.97-7.46 (13H, m) The following salts were synthesized using various acids. Hydrochloride ・ 1/2 hydrate mp 134 ℃ ~ (foam) Anal .: Calcd C, 62.79; H, 6.42; N, 6.86; Cl, 17.37 Found C, 62.67; H, 6.99; N, 6.40; Cl, 17.62 IR (KBr) cm ^-1 : 3420, 1640 oxalate hemihydrate mp 189-190 ℃ Anal .: Calcd C, 61.35; H, 6.06; N, 6.31 Found C, 61.68; H, 6.34; N, 5.98 Fumarate monohydrate mp 99 ℃ ~ (foam) Anal .: Calcd C, 61.71; H, 6.19; N, 5.99; Cl, 10.11 Found C, 61.83; H, 6.44; N, 5.48; Cl, 9.53 Nitrate hemihydrate mp 116 ℃ ~ (foam) Anal .: Calcd C, 60.18; H, 6.16; N, 8.77; Cl, 11.10 Found C, 60.07; H, 6.23; N, 8.58; Cl, 11.07 Sulfate tetrahydrate mp 118 ℃ ~ (foam) Anal .: Calcd C, 52.17; H, 6.43; N, 5.70; Cl, 9.62 Found C, 52.64; H, 6.16; N, 5.64; Cl , 9.35 Methanesulfonate dihydrate mp 79 ℃ ~ (foam) Anal .: Calcd C, 56.72; H, 6.49; N, 6.01; Cl, 10.14 Found C, 56.33; H, 6.53; N, 5.89; Cl, 9.77 The compounds of Examples (51) to (75) were obtained by the same method as that of Example (50). ^Although only ¹ H NMR was measured in the amino free form, other physical data were measured as salts.

[0105]

Example 51 5- (4-Acetylpiperazin-1-yl) -N-ben
Dil-2- (3,4-dichlorophenyl) -N-methylpentane
Amide hydrochloride hemihydrate Anal .: Calcd C, 57.53; H, 6.37; N, 8.05; Cl, 20.37 Found C, 57.36; H, 7.16; N, 7.54; Cl, 19.97 IR (KBr) cm ^-1 : 1640 MS m / z: 475 (M ⁺ ; free form; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.34-1.84 (4H, m), 2.08 (3
H, s), 2.21-2.33 (6H, m), 2.86 & 2.99 (3 in total
H, s), 3.39-3.45 (2H, m), 3.52-3.61 (2H,
m), 3.63 & 3.71 (total 1H, t, J = 7H respectively
z), {4.36 & 4.63 (d, d, J = 17 Hz, J = 17 Hz), 4.56
& 4.61 (d, d, J = 15 Hz, J = 15 Hz), total 2H
}, 7.04-7.42 (8H, m)

[0106]

Example 52 5- (4-acetylpiperazin-1-yl) -N-ben
Dil-2- (3,4-dichlorophenyl) -N-methylpentanami
Dehydrochloride / 1/2 hydrate mp 72 ℃ ~ (foam) Anal .: Calcd C, 63.42; H, 6.48; N, 4.62; Cl, 17.55 Found C, 63.74; H, 6.72; N, 4.43; Cl , 16.72 IR (KBr) cm ^-1 : 1710, 1640 MS m / z: 550 (M ⁺ ; free form; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.33-1.76 (4H, m), 1.89 &
1.90 (total 3H, each s), 1.98-2.34 (6H, m),
2.38-2.46 (2H, m), 2.60-2.71 (2H, m), 2.84 & 2.97
(Total 3H, each s), 3.65 & 3.74 (Total 1
H, t, t, J = 7 Hz, J = 7 Hz), 4.35-4.65 (2H, m), 6.
99-7.41 (13H, m)

[0107]

Example 53 5- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl -N-methyl-2- (2-naphthyl) pe
Nantamide oxalate mp 148-151 ℃ IR (KBr) cm ^-1 : 3300, 1640 MS m / z: 547 (M ⁺ ; free form) ¹ H NMR (CDCl ₃ ) δ ppm: 1.39-2.23 (8H, m) , 2.02 (3
H, s), 2.35-2.59 (4H, m), 2.83-2.94 (2H, m), 2.88
& 2.97 (total 3H, each s), 3.87 & 3.97 (total 1H, t, t, J = 7 Hz, J = 7 Hz), {4.25 & 4.74
(d, d, J = 17 Hz, J = 17 Hz), 4.53 & 4.68 (d, d, J =
15 Hz, J = 15 Hz), 2H in total, 5.84 & 6.03 (1H, bs, bs in total), 7.03-7.48 (13H, m), 7.67-7.85
(4H, m)

[0108]

Example 54 4- (Acetylpiperazin-1-yl) -N-benzyl
Ru-N-methyl-2- (2-naphthyl) pentanamide oxalate
Monohydrate mp 93 ℃ ~ (foam) IR (KBr) cm ^-1 : 1640 MS m / z: 457 (M ⁺ ; free form) ¹ H NMR (CDCl ₃ ) δ ppm: 1.31-1.93 (4H, m), 2.06 (3
H, s), 2.11-2.39 (6H, m), 2.86 & 2.97 (3 in total
H, s), 3.38-3.44 (2H, m), 3.56-3.63 (2H,
m), 3.82 & 3.91 (total 1H, t, J = 7H respectively
z), {4.22 & 4.77 (d, d, J = 17 Hz, J = 17 Hz), 4.57
& 4.65 (d, d, J = 15 Hz, J = 15 Hz), total 2H
}, 7.05-7.34 (5H, m), 7.42-7.51 (3H, m), 7.67-7.
83 (4H, m)

[0109]

Example 55 5- (4-acetyl-4-phenylpiperidine-1-
Yl) -N-benzyl-N-methyl-2- (2-naphthyl) pentane
Amidooxalate ・ 1.5 hydrate mp 91 ℃ 〜 (foam) IR (KBr) cm ^-1 : 1700, 1640 MS m / z: 532 (M ⁺ ; free form) ¹ H NMR (CDCl ₃ ) δ ppm: 1.50-2.45 (12H, m), 1.90 (3
H, s), 2.71-2.79 (2H, m), 2.86 & 2.96 (Total 3
H, each s), 3.84 & 3.95 (total 1H, each
t, J = 7 Hz), {4.25 & 4.74 (d, d, J = 17 Hz, J = 17
Hz), 4.54 & 4.67 (d, d, J = 15 Hz, J = 15 Hz), combined 2H}, 7.03-7.48 (11H, m), 7.66-7.83 (4H, m)

[0110]

Example 56 5- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-N-methyl-2- (1-naphthyl) pen
Tanamide oxalate monohydrate mp 169-172 ℃ IR (KBr) cm ^-1 : 3290, 1640 MS m / z: 547 (M ⁺ ; free form) ¹ H NMR (CDCl ₃ ) δ ppm: 1.47-3.05 (14H, m), 2.03 (3
H, s), 2.66 & 3.03 (total 3H, each s), 3.97-
4.73 (3H, m), 5.95 & 6.19 (Total 1H, bs, bs),
6.93-8.14 (17H, m)

[0111]

Example 57 5- (4-acetyl-4-phenylpiperidine-1-
Yl) -N-benzyl-N-methyl-2- (1-naphthyl) pentane
Amidooxalate ・ 1.5 hydrate mp 80 ℃ ~ (foam) IR (KBr) cm ^-1 : 1700, 1640 MS m / z: 532 (M ⁺ ; free form) ¹ H NMR (CDCl ₃ ) δ ppm: 1.43-2.91 (14H, m), 1.91 (3
H, s), 2.62 & 3.09 (total 3H, each s), {3.99
& 4.62 (d, J = 16 Hz), 4.57 & 4.72 (d, J = 15 Hz),
2H in total}, 4.40-4.45 (1H, m), 6.87-8.17 (17
H, m)

[0112]

Example 58 5- (4-acetylpiperazin-1-yl) -N-ben
Dil-N-methyl-2- (1-naphthyl) pentanamide oxalate
・ Monohydrate mp 100 ℃ ~ (foam) IR (KBr) cm ^-1 : 1640 MS m / z: 457 (M ⁺ ; free form) ¹ H NMR (CDCl ₃ ) δ ppm: 1.40-1.85 (4H, m), 2.07 (3
H, m), 2.18-2.45 (6H, m), 2.62 & 3.04 (3 in total
H, s), 3.38-3.45 (2H, m), 3.52-3.63 (2H,
m), 3.94-4.72 (3H, m), 6.97-8.16 (12H, m)

[0113]

Example 59 4- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-2- (3,4-dichlorophenyl) -N-me
Cilbutanamide hydrochloride hemihydrate mp 140 ℃ ~ (foam) Anal .: Calcd C, 62.26; H, 6.24; N, 7.02; Cl, 17.78 Found C, 62.38; H, 6.46; N, 6.83 ; Cl, 17.33 IR (KBr) cm ^-1 : 3250, 1640 MS m / z: 551 (M ⁺ ; free form, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.98-3.13 (12H, m) , 2.11 (3
H, s), 2.83 & 2.99 (total 3H, each s), 3.45-
3.52 (1H, m), 4.26-4.87 (2H, m), 6.69-6.84 (1H,
m), 6.90-7.42 (13H, m)

[0114]

Example 60 4- (4-acetyl-4-phenylpiperazine-1-
Yl) -N-benzyl-2- (3,4-dichlorophenyl) -N-methyl
Butanamide hydrochloride mp 82 ° C ~ (foam) IR (KBr) cm ^-1 : 1710, 1640 MS m / z: 551 (M ⁺ ; free form, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.78- 2.98 (12H, m), 1.88 &
1.90 (total 3H, each s), 2.86 & 2.98 (total 3H, each s), 3.86 & 3.95 (total 1H, each t, J = 7 Hz), 4.35-4.66 (2H, m), 7.05- 7.43 (13
H, m)

[0115]

Example 61 4- (4-Acetylpiperazin-1-yl) -N-ben
Dil-2- (3,4-dichlorophenyl) -N-methylbutanamide
Hydrochloride IR (KBr) cm ^-1 : 1640 MS m / z: 461 (M ⁺ ; free form, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.61-2.36 (8H, m), 2.06 &
2.07 (total 3H, each s), 2.88 & 3.00 (total 3H, each s), 3.28-3.61 (4H, m), 3.86 & 3.93
(Total 1H, t, J = 7 Hz, respectively), {4.36 & 4.64
(d, d, J = 17 Hz, J = 17 Hz), 4.55 & 4.62 (d, d, J =
15 Hz, J = 15 Hz), 2H in total, 7.02-7.44 (8H,
m)

[0116]

Example 62 6- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-2- (3,4-dichlorophenyl) -N-me
Cylhexanamide oxalate monohydrate mp 91 ℃ ~ (foam) Anal .: Calcd C, 61.04; H, 6.29; N, 6.10; Cl, 10.29 Found C, 61.04; H, 6.78; N, 6.37; Cl , 9.92 IR (KBr) cm ^-1 : 3300, 1640 MS m / z: 579 (M ⁺ ; free form, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.17-2.31 (10H, m), 2.04 (3
H, s), 2.49-2.77 (6H, m), 2.86 & 2.98 (3 in total
H, each s), 3.67 & 3.78 (total 1H, each
t, J = 7 Hz), {4.37 & 4.61 (d, d, J = 17 Hz, J = 17
Hz), 4.52 & 4.66 (d, d, J = 15 Hz, J = 15 Hz), total 2H}, 6.00 & 6.16 (total 1H, bs, bs), 7.01
-7.42 (13H, m)

[0117]

Example 63 6- (4-acetyl-4-phenylpiperidine-1-
Yl) -N-benzyl-2- (3,4-dichlorophenyl) -N-methyl
Hexanamide oxalate mp 81 ℃ ~ (foam) Anal .: Calcd C, 64.12; H, 6.15; N, 4.27; Cl, 10.82 Found C, 63.60; H, 6.23; N, 4.31; Cl, 10.52 IR (KBr) cm ^-1 : 1710, 1640 MS m / z: 564 (M ⁺ ; free form, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.41-1.85 (10H, m), 1.91 (3
H, s), 2.06-2.21 (2H, m), 2.30-2.51 (4H, m), 2.85 &
2.98 (total 3H, each s), 3.63 & 3.74 (total 1H, each t, J = 7 Hz), {4.38 & 4.62 (d, d,
J = 17 Hz, J = 17 Hz), 4.53 & 4.63 (d, d, J = 15 H
z, J = 15 Hz), 2H in total, 6.97-7.41 (13H, m)

[0118]

Example 64 6- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-2- (3,4-dichlorophenyl) -N-me
Cylhexanamide oxalate hemihydrate mp 135-138 ℃ Anal .: Calcd C, 57.05; H, 6.15; N, 7.12; Cl, 12.02 Found C, 56.90; H, 5.87; N, 6.57; Cl , 11.87 IR (KBr) cm ^-1 : 1640 MS m / z: 489 (M ⁺ ; free form, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.20-1.84 (6H, m), 2.08 (3
H, s), 2.27-2.42 (6H, m), 2.84 & 2.98 (total 3
H, s), 3.43-3.46 (2H, m), 3.58-3.72 (3H,
m), 4.32-4.68 (2H, m), 7.06-7.41 (8H, m)

[0119]

Example 65 N-benzyl-2- (3,4-dichlorophenyl) -N-me
Cyl-5- (4-piperidone-1-yl) pentanamide IR (CHCl ₃ ) cm ⁻¹ : 2957, 2938, 1716, 1644 MS m / z: 446 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.6-2.0 (2H, m), 2.0-2.2 (2
H, m), 2.2-2.5 (6H, m), 2.5-2.8 (4H, m), 2.86 (2H,
s), 2.99 (1H, s), 3.6-3.8 (1H, m), {4.36 (d, J =
17 Hz), 4.59 (bs), 4.60 (d, J = 17 Hz), total 2
H}, 7.0-7.5 (8H, m) Oxalate salt of the above compound mp 65 ℃ ~ (foam) Anal .: Calcd C, 56.22; H, 5.80; N, 5.04; Cl, 12.77 Found C, 56.62; H, 5.73 ; N, 5.79; Cl, 15.81

[0120]

Example 66 5- (4-carbamoylpiperidin-1-yl) -N-
Benzyl-2- (3,4-dichlorophenyl) -N-methylpentane
Amide IR (CHCl ₃ ) cm ^-1 : 3532, 3413, 2948, 1679, 1644, 1
591 MS m / z: 475 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.3-2.2 (11H, m), 2.23 (1H,
t, J = 7 Hz), 2.32 (1H, t, J = 7 Hz), 2.8-3.0 (2
H, m), 2.86 (2H, m), 2.98 (1H, s), 3.65 & 3.75
(In total 1H, t, J = 7 Hz, {4.38 (d, J =
17 Hz), 4.58 (bs), 4.62 (d, J = 17 Hz), total 2H
}, 2.4-2.7 (2H, bs), 7.0-7.5 (8H, m) Oxalate of the compound mp 63 ℃ ~ (foam)

[0121]

Example 67 N-benzyl-2- (3,4-dichlorophenyl) -N-me
Cyl-5- (4- (2-piperidone-1-yl) -piperidine-1-y
) Pentanamide IR (CHCl ₃ ) cm ^-1 : 3020, 1667, 1648 MS m / z: 515 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.3-1.8 (6H, m) , 1.9-2.2 (6
H, m), 2.2-2.5 (4H, m), 2.85 (2H, s), 2.85-2.98 (2
H, m), 2.98 (1H, s), 3.63 & 3.72 (total 1H, each t, J = 7 Hz), 3.9-4.1 (1H, m), {4.36 (d, J =
17 Hz), 4.58 (bs), 5.62 (d, J = 17 Hz), total 2
H}, 7.0-7.5 (8H, m) Oxalate salt of the above compound mp 178-179 ° C

[0122]

Example 68 N-benzyl-2- (3,4-dichlorophenyl) -N-me
Cyl-5- (1-phenyl-1,3,8-triazaspiro- (4,5) deca
N-4-on-8-yl) pentanamide ── mp 134-136 ℃ IR (KBr) cm ^-1 : 3391, 3248, 2929, 1710, 1643, 160
1 MS m / z: 578 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.3-1.9 (6H, m), 2.0-2.2 (1
H, m), 2.3-2.5 (1H, m), 2.5-2.6 (1H, m), 2.6-3.0
(5H, m), 2.86 (2H, s), 2.99 (1H, s), 3.68 & 3.79
(Total 1H, t, J = 7 Hz, 4.3-4.7 (2H,
m), 4.73 (2H, bs), 6.0-6.2 (1H, bs), 6.8-7.5 (13H,
m)

[0123]

Example 69 N-benzyl-2- (3,4-dichlorophenyl) -5-
(4-hydroxy-4-phenylpiperidin-1-yl) -N-me
Cylpentanamide IR (CHCl ₃ ) cm ⁻¹ : 3720, 3610, 2953, 1643, 1603 MS m / z: 524 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.4-1.9 (6H , m), 2.0-2.3 (3
H, m), 2.3-2.6 (4H, m), 2.8-2.9 (2H, m), 2.86 (2H,
s), 2.98 (1H, s), 3.6-3.9 (1H, m), 4.3-4.7 (2H,
m), 7.0-7.6 (13H, m) Oxalate salt of the above compound mp 115-118 ° C

[0124]

Example 70 N-benzyl-2- (3,4-dichlorophenyl) -5- (4
-Hydroxypiperidin-1-yl) -N-methylpentana
Mid IR (CHCl ₃ ) cm ^-1 : 3705, 3610, 2974, 2938, 1644, 1
603 MS m / z: 448 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.3-1.8 (7H, m), 1.8-2.0 (2
H, m), 2.0-2.2 (2H, m), 2.2-2.5 (2H, m), 2.6-2.8
(2H, m), 2.85 (2H, s), 2.98 (1H, s), 3.6-3.8 (2H, s)
m), 4.3-4.7 (2H, m), 7.0-7.5 (8H, m)

[0125]

Example 71 5- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-N-methyl-2-naphthylpentane
Amido oxalate mp 193 ° C IR (KBr) cm ^-1 : 1678, 1623 MS m / z: 561 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 1.55-1.93 (5H, m), 2.04 (3
H, s), 2.2-2.4 (1H, bs), 2.65-2.77 (2H, m), 2.78 &
2.86 (3H in total, s each), 2.9-3.3 (7H, m), 3.
4-3.6 (3H, m), 4.29 & 4.40 (1H in total, each
d, J = 17 Hz), 4.17 & 4.75 (total 2H, each
d, J = 15 Hz), 6.75-7.85 (17H, m)

[0126]

Example 72 5- (4-acetyl-4-phenylpiperidine-1-
Yl) -N-benzyl-N-methyl-2- (2-naphthylmethyl) pe
Nantamide oxalate mp 85 ° C IR (KBr) cm ^-1 : 1704, 1634 MS m / z: 546 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 1.38-1.9 (5H, m), 1.93 (3H,
s), 2.29-2.47 (3H, m), 2.68 & 2.92 (total 3H,
S), 2.57-3.19 (6H, m), 3.45-3.7 (3H, m), respectively
4.24 & 4.77 (2H total, d, J = 15 Hz each),
6.80-7.85 (17H, m)

[0127]

Example 73 5- (4-acetamido-4-phenylpiperidine
-1-yl) -2, N-dibenzyl-N-methylpentanamide salt
Acid salt mp 125 ° C IR (KBr) cm ^-1 : 3419, 1677, 1637 MS m / z: 511 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.12 (3H, s), 1.44-2.16 (4
H, m), 2.68 & 2.92 (total 3H, each s), 2.61
-3.41 (10H, m), 3.26-3.40 (2H, m), 4.22 (1H, d, J =
7 Hz), 4.38 & 4.65 (total 2H, d, J =
15 Hz), 6.78-6.87 (1H, bs), 6.90-7.40 (15H, m)

[0128]

Example 74 4- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-N-methyl-2- (2-naphthylmethy
Butanamide hydrochloride mp 110 ° C IR (CHCl ₃ ) cm ^-1 : 3230, 1675, 1630 MS m / z: 547 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 1.7-2.4 (8H, m) , 2.62 & 2.9
2 (total 3H, each s), 2.5-3.5 (10H, m), 3.9
1-4.20 (2H, m), 4.68-4.81 (1H, m), 6.72-7.88 (17H,
m)

[0129]

Example 75 5- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-N-methyl-2- (2-naphthylthio)
Propionamide hydrochloride mp 133 ° C IR (KBr) cm ^-1 : 3413, 1676, 1643 MS m / z: 579 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 1.54-2.36 (8H, m), 2.97 &
2.99 (3H in total, each s), 2.55-3.45 (9H, m),
3.84-4.07 (1H, m), 4.37 & 4.38 & 4.74 & 4.76 (total 2H, each d, J = 15 Hz), 6.87-7.10 (1H, b
s), 7.10-7.96 (17H, m)

[0130]

Example 76 7- (4-acetamido-4-phenylpiperidine
-1-yl) -N-benzyl-2- (3,4-dichlorophenyl) -N-
N-benzyl-7-bromo-2- (3,4-dichlorophenyl) -N-methylheptanamide (0.457 g) D obtained in methylheptanamide oxalate / hemihydrate example (44)
4-Acetamide-4-phenylpiperidine hydrochloride (0.280 g) and triethylamine (0.15 ml) were added to the MF solution (9 ml), and the mixture was heated and dissolved at 50 ° C. In addition, NaI (0.030
g) and baking soda (0.252 g) were added, and the mixture was heated at 50 ° C. for 2 hours and at 85 ° C. for 1 hour. Pour in water, extract with ethyl acetate, water,
After washing with a saturated saline solution, it was dried over sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform-ethanol-ethyl acetate (6: 1: 1 to 4: 1: 1)) to give the amino-free form of the title compound.
(0.459 g) was obtained. After further dissolving in ethanol, oxalic acid (0.077 g) was added and the mixture was concentrated and recrystallized from methanol-isopropyl ether to give the title compound (0.471 g). mp 151-153 ℃ Anal .: Calcd C, 62.33; H, 6.39; N, 6.06; Cl, 10.22 Found C, 62.64; H, 6.43; N, 6.12; Cl, 10.32 IR (KBr) cm ^-1 : 3270, 1680, 1640 MS m / z: 593 (M ⁺ ; free form, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.06-1.76 (8H, m), 2.02 (3
H, s), 2.06-2.39 (8H, m), 2.78-2.82 (2H, m), 2.85
& 2.98 (total 3H, each s), 3.61 & 3.70 (total 1H, each t, J = 7 Hz), {4.35 & 4.63 (d,
d, J = 17 Hz), 4.59 (s), 2H in total, 5.52 (1H,
bs), 7.04-7.42 (13H, m)

[0131]

Example 77 7- (4-acetamido-4-phenylpiperazine
-1-yl) -N-benzyl-2- (3,4-dichlorophenyl) -N-
It was synthesized analogously to methyl heptanamide oxalate Example (74). mp 135-136 ℃ Anal .: Calcd C, 64.57; H, 6.32; N, 4.18; Cl, 10.59 Found C, 64.31; H, 6.42; N, 4.23; Cl, 10.40 IR (KBr) cm ^-1 : 1700, 1640 MS m / z: 578 (M ⁺ ; free form, Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.04-1.83 (8H, m), 1.90 (3
H, s), 2.01-2.28 (6H, m), 2.43-2.48 (2H, m), 2.69-
2.72 (2H, m), 2.85 & 2.98 (3H in total, each
s), 3.60 & 3.69 (1H in total, t, J = 7H respectively
z), {4.35 & 4.62 (d, d, J = 17 Hz, J = 17 Hz), 4.5
8 (s), 2H in total}, 6.99-7.41 (13H, m)

[0132]

Example 78 N-benzyl-2- (3,4-dichlorophenyl) -4-
(1,3-dioxolan-2-yl) -N-methylbutanamide DMF (60 ml) was dissolved in the amide compound (3.08 g) of Example (35) and cooled to 1.0 M under N ₂ flow with ice cooling. NaN (TMS) ₂ / THF solution
(11 ml) was added, 2- (2-bromoethyl) -1,3-dioxolane (1.32 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layers were collected, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, and the title compound (3.45 g, yield 84.4%) was obtained as an oil from the fraction eluted with cyclohexane-ethyl acetate (1: 1). MS m / z: 407 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.44-1.92 (3H, m), 2.13-2.3
0 (1H, m), 2.84 & 2.97 (total 3H, each s),
3.67-3.99 (5H, m), {4.36 & 4.61 (d, d, J = 17 Hz,
J = 17 Hz), 4.59 (d, J = 5 Hz), 2H combined,
4.77 & 4.86 (1H in total, t, J = 5 Hz each),
7.03-7.48 (8H, m)

[0133]

Example 79 N-benzyl-2- (3,4-dichlorophenyl) -3-pho
The acetal form (3.43 g) of Example (78) was dissolved in rumil-N-methylpropionamide THF (17 ml), and acetic acid (28 ml) and water (14 ml) were added at room temperature,
Stir overnight. The reaction solution was poured into a sodium hydroxide aqueous solution and extracted with ethyl acetate. The organic layers were collected, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, cyclohexane-chloroform-
Fractions eluted with ethyl acetate (1: 1: 1) gave an approximately 1: 1 mixture (3.07 g) of the title compound and starting compound as an oil.

[0134]

Example 80 2- (1,3-dioxolan-2-yl) -2- (2-naphtho
Dimethyl) dimethyl 2 -methylmalonate 2- (2-naphthyl) methylmalonate dimethyl (8.80 g)
To a DMF solution (150 ml) under ice cooling, a solution of sodium bistrimethylsilylamide in THF (1 M, 36.1 ml) and 2- (2-
Bromoethyl) -1,3-dioxolane (7.12 g) was added, and 50
Stir at 7 ° C for 7 hours. After leaving it at room temperature overnight, it was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (cyclohexane-ethyl acetate = 3: 1), 10.98 g of The title compound was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ ppm: 1.65-1.78 (2H, m), 1.92-2.0
5 (2H, m), 3.40 (2H, s), 3.72 (6H, s), 3.80-4.00
(4H, m), 4.88 (1H, t, J = 5 Hz), 7.2-7.9 (7H, m)

[0135]

Example 81 4- (1,3-dioxolan-2-yl) -2- (2-naphtho
Methyl chloromethyl) butanoate 4- (1,3-dioxolan-2-yl) -2- (2-naphthylmethyl) dimethyl malonate (3.63 g) in DMF (30 ml)
LiCl (827 mg) and water (351 μl) were added to the mixture, heated at 180 ° C. for 2 hours, poured into ice water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (cyclohexane-ethyl acetate = 3: 1) to give an oily title. A compound (1.64 g) was obtained. ¹ H NMR (CDCl ₃ ) δ ppm: 1.6-1.9 (4H, m), 2.7-2.9 (1
H, m), 2.92 (1H, dd, J = 6, 13 Hz), 3.11 (1H, dd, J
= 8, 13 Hz), 3.58 (3H, s), 3.8-4.0 (4H, m), 4.8-
4.9 (1H, m), 7.2-7.8 (7H, m)

[0136]

Example 82 4- (1,3-dioxolan-2-yl) -2- (2-naphtho
Ethyl solution of methyl 4- (1,3-dioxolan-2-yl) -2- (2-naphthylmethyl) butanoate (1.64 g) in ethyl ethanol (15 m
1 N NaOH aqueous solution (10 ml) was added to l), and the mixture was heated under reflux for 2 hours. After ethanol was distilled off, ethyl acetate was added, and 1N HCl (9.5 ml) was added under ice cooling to adjust the pH to 4. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and the solvent was evaporated to give the title compound (1.
62 g) was obtained. ¹ H NMR (CDCl ₃ ) δ ppm: 1.62-1.89 (4H, m), 2.78-2.9
1 (1H, m), 2.93 (1H, dd, J = 6, 13 Hz), 3.16 (1H,
dd, J = 7, 13 Hz), 3.75-3.98 (4H, m), 4.81-4.88 (1
H, m), 7.25-7.85 (7H, m)

[0137]

Example 83 N-benzyl-4- (1,3-dioxolan-2-yl)-
2- (2-Naphthyl) methylbutanamide The title compound was obtained in the same manner as in Example (36). ¹ H NMR (CDCl ₃ ) δ ppm: 1.6-2.1 (4H, m), 2.59 & 2.8
4 (total 3H, s for each), 2.9-3.3 (3H, m), 2.75
-4.04 (4H, m), 4.13 & 4.22 (1H in total, each
d, J = 17, 15 Hz), 4.30 & 4.77 (total 1H, d, J = 17, 15 Hz respectively), 6.64
−7.90 (12H, m)

[0138]

Example 84 N-benzyl-4-formyl-N-methyl-2- (2-
Naphthylmethyl) butanamide N-benzyl -N-methyl-4- (1,3-dioxiran-2-yl)-
A small amount of sulfuric acid was added to a solution of 2- (2-naphthylmethyl) butanoic acid amide (1.67 g) to which acetone (20 ml) and water (10 ml) were added, and the mixture was stirred for 2.5 hours. After the temperature was lowered to around room temperature, saturated aqueous sodium hydrogen carbonate was added to make the solution almost neutral. After concentrating this neutral solution under reduced pressure, ethyl acetate (100 ml x 2)
It was extracted with. The organic layers were collected, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel chromatography (cyclohexane-ethyl acetate = 1: 1),
The title compound (1.30 g) was obtained as an oily substance. IR (CHCl ₃ ) cm ⁻¹ : 1724, 1633 MS m / z: 360 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.59 & 2.87 (total 3H, s), 1.86-2.58 & 2.82 -2.93 (total 4H, m each), 3.00-3.20 (2H, m), 2.96 & 4.19 (total
1H, d, J = 4.6 Hz), 4.25 & 4.73 (combined
2H, d, J = 15 Hz), 6.73-7.79 (12H, m), 9.6
3 & 9.76 (1H in total, each s)

[0139]

Example 85 N-benzyl -N-methyl-5-t-butyldimethyl
Siloxypentanamide 5-t-butyldimethylsiloxypentanoic acid (1.0 g) and N
-Benzyl-N-methylamine (585 μl) in methylene chloride
(12 ml), 1-hydroxybenzotriazole hydrate (557 mg), 1-ethyl-3- (3 '
-Dimethylaminopropyl) carbodiimide hydrochloride (94
9 mg) and triethylamine (575 μl) were added, and the mixture was stirred at room temperature for 3 hours. Pour the reaction mixture into water and add ethyl acetate.
It was extracted with (100 ml × 2). The extract was washed with saturated aqueous ammonium chloride solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. After the filtrate was concentrated under reduced pressure, silica gel chromatography (n-
Hexane-ethyl acetate = 5: 1) to give the title compound.
(1.20 g) was obtained. ¹ H NMR (CDCl ₃ ) δ ppm: 0.08 & 0.11 (total 6H, each s), 0.95 & 0.97 (total 9H, each s), 1.5
5-1.86 (4H, m), 2.40-2.50 (2H, m), 2.97 & 2.99
(3H in total, s each), 3.62-3.74 (2H, m), 4.60
& 4.66 (2H in total, s for each), 7.19-7.45 (5H,
m)

[0140]

Example 86 2, N-dibenzyl-N-methyl-5-t-butyl dimethyl
Add tylsiloxypentanamide diisopropylamine (533 μl) in THF (4 ml).
At -78 ° C, n-butyllithium (2.4 ml) was slowly added dropwise, and the mixture was stirred for 30 minutes. A solution of the compound of Example (83) (1.16 g) in THF (4 ml) was slowly added dropwise to this solution.
After stirring for 1 minute, a THF solution (4 ml) of benzyl bromide (494 μl) was slowly added dropwise. The reaction solution was stirred at -60 ° C for 6 hours and then slowly warmed to room temperature, and saturated ammonium chloride water was added to stop the reaction. The reaction mixture was extracted with ethyl acetate (100 ml × 2), the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, silica gel chromatography (n-hexane-ethyl acetate =
Purification by 3: 1) gave the title compound (0.94 g) as an oily substance. IR (CHCl ₃ ) cm ⁻¹ : 1633 MS m / z: 425 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 0.04 (6H, s), 0.86 & 0.88
(Total 9H, each s), 2.62 & 2.86 (total 3
H, each s), 2.65-3.1 (5H, m), 3.49-3.67 (3H, m),
4.22 (1H, d, J = 7 Hz), 4.38 & 4.65 (Total 2H,
D, J = 15Hz), 6.80-7.35 (10H, m) respectively

[0141]

Example 87 2, N-dibenzyl-N-methyl-5-hydroxypep
Solution of the compound of Example (86) (0.94 g) in THF (10 ml) at room temperature with tetrabutylammonium fluoride in THF
(1.0 M, 5 ml) was added and stirred for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride, extracted with ethyl acetate (100 ml × 2), the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. did. The filtrate was concentrated under reduced pressure and then purified by silica gel chromatography (solvent: ethyl acetate) to give the title compound (0.
66 g) was obtained as an oil. IR cm ^-1 : 1630 MS m / z: 311 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 1.82-2.05 (1H, bs), 2.62 &
2.86 (3H in total, each s), 2.65-3.1 (5H, m),
3.49-3.67 (3H, m), 4.22 (1H, d, J = 7 Hz), 4.38 &
4.65 (total 2H, d, J = 15 Hz each), 6.80-7.
35 (10H, m)

[0142]

Example 88 2,4-Dibenzyl-4-formyl-N-methylbutane
The title compound was obtained in the same manner as in Example (45). IR cm ^-1 : 1715, 1630 MS m / z: 309 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.62 & 2.86 (3H in total, s each), 1.80-3.15 (6H, m), 4.22 (1H, s), 4.38 &
4.65 (total 2H, d, J = 15 Hz each), 6.80-7.
35 (10H, m), 9.68 & 9.81 (1H for each, s for each)

[0143]

Example 89 N-benzyl-N-methyl-2- (2-naphthylmethyi
) -4-pentenamide diisopropylamine (1.0 ml) in THF (22 ml)
At −78 ° C., n-butyllithium (4.5 ml) was slowly added dropwise, and the mixture was stirred for 30 minutes. N-benzyl-N-methyl in this solution
-3- (2-Naphthyl) propionamide (2.0 g) in THF
(20 ml) was slowly added dropwise, and the mixture was stirred for 30 minutes, then allyl bromide (685 μl) was added dropwise, and the mixture was stirred at -70 ° C for 1 hour and further at room temperature for 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (200 ml × 2). The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to give the title compound (1.81 g)
Was obtained as an oily substance. IR (CHCl ₃ ) cm ^-1 : 1630 MS m / z: 343 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.23-2.65 (2H, m), 2.59 &
2.82 (total 3H, each s), 2.85-3.24 (3H, m),
4.11 & 4.25 (1H in total, d, J = 16Hz each),
4.29 & 4.70 (1H in total, d, J = 15 Hz each),
5.11-5.18 (2H, m), 5.66-5.91 (1H, m), 6.62-7.85 (1
2H, m)

[0144]

Example 90 N-benzyl-3-formyl-N-methyl-2- (2-na
Fuchirumechiru) propionamide water (3.3 ml) and 1,4 compounds dioxane (example in a mixed solvent of 9.8 ml) (89) (0.1 g) and of osmium tetroxide
A THF solution (74 μl, 1 g / 10 ml) was added at room temperature and stirred for 5 minutes. Sodium periodate (1.35 g) was added to the reaction mixture.
After stirring for 30 minutes, add water and add ethyl acetate (100 ml
It was extracted in × 2). The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then filtered. After the filtrate was concentrated under reduced pressure, silica gel chromatography (n-
Hexane-ethyl acetate = 1: 1) to give the title compound.
(80 mg) was obtained as an oily substance. IR (CHCl ₃ ) cm ^-1 : 1720, 1630 MS m / z: 345 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.75 & 2.88 (total 3H, each s), 2.51-2.90 (2H, m), 3.02-3.31 (2H, m),
3.42-3.79 (1H, m), 4.40 & 4.45 & 4.58 & 4.63 (total 2H, s each), 6.88-7.84 (12H, m), 9.68 & 9.
76 (1H in total, each s)

[0145]

Example 91 N-benzyl -N-methyl-2- (2-naphthylthio)
Acetamide 2-naphthylthiol (1.0 g) in THF solution (20 ml) -70
Potassium (bistrimethylsilyl) amide (13.7 m
1, 0.5 M toluene solution) was slowly added dropwise, and the mixture was stirred for 30 minutes. A THF solution (20 ml) of N-benzyl-N-methyl-2-bromoacetic acid amide (1.59 g) was slowly added dropwise to this solution. After warming to room temperature over 1 hour, the mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (200 ml × 2). The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine,
It was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1), and the obtained crystals were recrystallized (n-hexane-ethyl acetate) to give the title compound (1.47 g). Obtained as white crystals. mp 85 ° C IR (KBr) cm ^-1 : 1646 MS m / z: 321 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.93 & 2.96 (total 3H, s each), 3.85 & 3.87 (total 2H, each s),
4.55 & 4.57 (total 2H, each s), 7.11-7.91 (1
2H, m)

[0146]

Example 92 N-benzyl-4- (1,3-dioxolan-2-yl)-
The title compound was obtained in the same manner as in N-methyl-2- (2-naphthylthio) butanamide Example (78). IR (CHCl ₃ ) cm ⁻¹ : 1645 MS m / z: 421 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 1.59-2.32 (4H, m), 2.88 &
2.95 (3H in total, s each), 3.71-3.93 (4H, m),
4.03-4.24 (1H, m), 4.30-4.69 (2H, m), 4.70-4.91
(1H, m), 7.07-7.95 (12H, m)

[0147]

Example 93 N-benzyl-4-formyl-N-methyl-2- (2-na
Futylthio) butanamide The title compound was obtained in the same manner as in Example (84). IR (CHCl ₃ ) cm ⁻¹ : 1724, 1645 MS m / z: 377 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ ppm: 2.05-2.85 (4H, m), 2.92 &
3.01 (total 3H, each s), 4.01 & 4.18 (total 1H, each t, J = 8 Hz), 4.35 & 4.41 & 4.45
& 4.70 & 4.71 & 4.76 (total 2H, each s), 7.0
5-7.97 (12H, m), 9.60 & 9.75 (1H in total, each
s)

[0148]

Example 94 2- (3,4-dichlorophenyl) -5-hydroxype
Methyl tantanate DMF (4.4 ml) was added to methyl 3,4-dichlorophenylacetate (0.22
g) was dissolved, N ₂ stream under cooling with _{ice, 1.0 M NaN (TMS) 2} /
After adding THF (1.1 ml), 1-bromo-3-tetrahydropyranyloxypropane (0.27 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into 0.1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated to give a crude oil. The obtained oily matter was treated with methanol (3.6
4N HCl / dioxane (0.3 ml) at room temperature.
Was added and stirred overnight. Dilute the reaction solution with ethyl acetate,
The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified using silica gel chromatography, and the title compound as an oil was obtained from the fraction eluted with cyclohexane-ethyl acetate (1: 1).
(0.25 g, yield 88.4%) was obtained. MS m / z: 276 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.39-1.60 (5H, m), 1.77-1.9
0 (1H, m), 2.04-2.22 (1H, m), 3.52-3.57 (1H, m),
3.68 (3H, s), 7.15 (1H, dd, J = 2.8 Hz), 7.39 (1H,
d, J = 8 Hz), 7.41 (1H, d, J = 2 Hz)

[0149]

Example 95 2- (3,4-dichlorophenyl) -4-formylbuta
Methyl phosphate dichloromethane (2.0 ml) in triphosgene (0.10 g)
Dissolved in water and dissolved in dimethyl sulfoxide (0.15 ml) and dichloromethane (4.8 ml) at -50 ° C under N ₂ flow
The alcohol derivative (0.24 g) of (94) was added dropwise, and the mixture was stirred for 10 minutes, then triethylamine (0.34 ml) dissolved in dichloromethane (1.7 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate,
The solvent was distilled off. The residue was purified by silica gel chromatography, and the title compound as an oil (0.20 g, yield was obtained from the fraction eluted with cyclohexane-ethyl acetate (3: 1).
81.4%). MS m / z: 274 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 2.00-2.13 (1H, m), 2.29-2.4
7 (3H, m), 3.58 (1H, t, J = 7 Hz), 3.68 (3H, s),
7.12 (1H, dd, J = 2.8 Hz), 7.39 (1H, d, J = 2Hz),
7.42 (1H, d, J = 8 Hz), 9.74 (1H, s)

[0150]

Example 96 5- (4-acetamido-4-phenylpiperidine
-1-yl) -2- (3,4-dichlorophenyl) pentanoic acid methyl ester
In methanol (70 ml), the aldehyde of Example (95) (3.46
g) was dissolved, sodium cyanoborohydride (1.57 g) and 4-acetamido-4-phenylpiperidine hydrochloride (3.36 g) were added under ice cooling under N ₂ flow, and the mixture was stirred at room temperature for 1 hour. . The reaction solution was diluted with ethyl acetate, washed with a 1 N sodium hydroxide aqueous solution, water, and saturated saline, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, and the title compound (3.81 g, yield 63.8%) was obtained as an oil from the fraction eluted with chloroform-ethyl acetate-ethanol (4: 1: 1). MS m / z: 476 (M ⁺ ; Cl = 35) ¹ H NMR (CDCl ₃ ) δ ppm: 1.44-2.44 (12H, m), 2.02 (3
H, s), 2.75-2.78 (2H, m), 3.53 (1H, t, J = 7 Hz),
3.67 (3H, s), 5.48 (1H, bs), 7.13-7.52 (8H, m)

[0151]

Example 97 5- (4-acetamido-4-phenylpiperidine
-1-yl) -2- (3,4-dichlorophenyl) pentanoic acid nato
The ester (3.81 g) of the example (96) was dissolved in methanol (40 ml) of lithium ・ 2.5 hydrate, 1N aqueous sodium hydroxide solution (8.4 ml) was added, and the mixture was stirred overnight. The solvent was evaporated, and the title crystal (3.95 g, yield 93.3%) was obtained in ethyl acetate. mp 161-163 ℃ MS m / z: 485 (M + 1; Cl = 35) Anal .: Calcd C, 54.25; H, 6.08; N, 5.28; Cl, 13.36; Na, 4.33 Found C, 54.08; H, 5.65; N, 4.98; Cl, 12.78; Na, 4.37 IR (KBr) cm ^-1 : 3390, 3290, 1730, 1660

[0152]

Example 98 5- (4-acetamido-4-phenyl) -2- (3,4-
Dichlorophenyl) pentanoyl-1,2,3,4-tetrahydr
Roisoquinoline oxalate hemihydrate / DMF (0.48 ml) suspended in sodium salt of Example (97) (0.24 g), added dichloromethane (4.8 ml), and hydroxybenzotriazole (0.074 g) at room temperature. After adding water-solved carbodiimide hydrochloride (WSC, 0.096 g), 1,2,3,4-tetrahydroisoquinoline (0.07 ml) was added and the mixture was refluxed for 6 hours. The reaction solution was diluted with ethyl acetate, and the solution was diluted
The organic layer was washed with a 2N aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, oxalic acid (0.036 g) was added to the fraction eluted with chloroform-ethyl acetate-ethanol (4: 1: 1), and recrystallized with ethanol-isopropyl ether. Title compound (0.19
g, yield 62.1%) was obtained. mp 212-213 ℃ MS m / z: 577 (M ⁺ ; Free body, Cl = 35) Anal .: Calcd C, 62.03; H, 5.96; N, 6.20; Cl, 10.46 Found C, 62.09; H, 5.76; N, 6.34; Cl, 10.48 IR (KBr) cm ^-1 : 3430, 3260, 1640 ¹ H NMR (CDCl ₃ ) δ ppm: 1.35-2.38 (14H, m), 2.00 (3
H, s), 2.76-2.84 (2H, m), 3.53-3.91 (3H, m), 4.39-
4.74 (2H, m), 5.53 (1H, bs), 7.07-7.42 (12H, m)

[0153]

Example 99 5- (4-acetamido-4-phenylpiperidine
-1-yl) -2- (3,4-dichlorophenyl) -N, N-dimethylpe
Tantanamide oxalate dihydrate Sodium salt of Example (97) in dichloromethane (9.6 ml)
(0.48 g) was suspended and after adding hydroxybenzotriazole (0.15 g) and water-solved carbodiimide hydrochloride (0.21 g) at room temperature, dimethylamine hydrochloride was added.
(0.25 g) and triethylamine (0.42 ml) were added, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography, oxalic acid (0.045 g) was added to the fraction eluted with chloroform-ethyl acetate-ethanol (2: 1: 1), and recrystallized with ethanol-isopropyl ether. The title compound (0.25 g, yield 44.4%) was obtained. mp 221-222 ℃ MS m / z: 489 (M ⁺ ; Free body, Cl = 35) Anal .: Calcd C, 54.55; H, 6.37; N, 6.81; Cl, 11.50 Found C, 54.97; H, 6.15; N, 6.81; Cl, 11.59 IR (KBr) cm ^-1 : 3420, 3280, 1670, 1640 ¹ H NMR (CDCl ₃ ) δ ppm: 1.24-1.83 (4H, m), 1.97-2.3
9 (8H, m), 2.02 (3H, s), 2.76-2.79 (2H, m), 2.94
(3H, s), 2.96 (3H, s), 3.70 (1H, t, J = 7 Hz), 5.4
9 (1H, bs), 7.13-7.45 (8H, m) The compounds of Examples (100) to (108) were obtained in the same manner as in Example (98).

[0154]

Example 100 5- (4-acetamido-4-phenylpiperidi
N-1-yl) -N, N-dibenzyl-2- (3,4-dichlorophenyl
Le) pentanamide oxalate mp 193-194 ℃ MS m / z: 641 (M ⁺ ; free form, Cl = 35) IR (KBr) cm ^-1 : 3270, 1640 ¹ H NMR (CDCl ₃ ) δ ppm: 1.26-1.80 (4H, m), 1.98-2.3
6 (8H, m), 2.01 (3H, s), 2.69-2.73 (2H, m), 3.68
(1H, t, J = 7 Hz), 4.28 (1H, d, J = 7 Hz), 4.32 (1
H, d, J = 15 Hz), 4.48 (1H, d, J = 7 Hz), 4.95 (1
H, d, J = 15 Hz), 5.48 (1H, bs), 7.05-7.48 (18H, m)

[0155]

Example 101 4- (5- (4-acetamido-4-phenylpiperi
Gin-1-yl) -2- (dichlorophenyl) pentanoyl)
Morpholine oxalate mp 181-182 ℃ MS m / z: 531 (M ⁺ ; free form, Cl = 35) Anal .: Calcd C, 57.88; H, 5.99; N, 6.74; Cl, 11.39 Found C, 57.49; H , 6.28; N, 6.69; Cl, 11.20 IR (KBr) cm ^-1 : 3440, 3350, 1640 ¹ H NMR (CDCl ₃ ) δ ppm: 1.25-1.79 (4H, m), 1.99 (3
H, s), 2.04-2.38 (8H, m), 2.73-2.77 (2H, m), 3.30-
3.69 (9H, m), 5.54 (1H, bs), 7.09-7.40 (8H, m)

[0156]

Example 102 5- (4-acetamido-4-phenylpiperidi
N-1-yl) -2- (3,4-dichlorophenyl) -N-diphenyl
Methylpentanamide hemihydrate mp 192-193 ℃ MS m / z: 627 (M ⁺ ; Cl = 35) Anal .: Calcd C, 69.69; H, 6.32; N, 6.59; Cl, 11.12 Found C , 69.80; H, 6.25; N, 6.60; Cl, 11.53 IR (KBr) cm ^-1 : 3300, 1650 ¹ H NMR (CDCl ₃ ) δ ppm: 1.41-1.82 (4H, m), 2.00 (3
H, s), 2.06-2.38 (8H, m), 2.72-2.76 (2H, m), 3.37
(1H, t, J = 7 Hz), 5.49 (1H, bs), 6.14 (1H, bs),
6.19 (1H, d, J = 7 Hz), 7.00-7.03 (2H, m), 7.14-7.
41 (16H, m)

[0157]

Example 103 5- (4-acetamido-4-phenylpiperidi
N-1-yl) -2- (dichlorophenyl) -Nt-butylpenta
Amide hemihydrate mp 176-177 ℃ MS m / z: 517 (M ⁺ ; Cl = 35) Anal .: Calcd C, 63.75; H, 7.26; N, 7.96; Cl, 13.44 Found C, 63.68 ; H, 7.65; N, 7.94; Cl, 13.65 IR (KBr) cm ^-1 : 3300, 1660, 1640 ¹ H NMR (CDCl ₃ ) δ ppm: 1.30 (9H, m), 1.48-1.70 (4
H, m), 2.02 (3H, s), 2.14-2.41 (8H, m), 2.76-2.80
(2H, m), 3.14 (1H, t, J = 7 Hz), 5.28 (1H, bs), 5.
49 (1H, bs), 7.16-7.41 (8H, m)

[0158]

Example 104 5- (4-acetamido-4-phenylpiperidi
N-1-yl) -N-cyclohexyl-2- (3,4-dichlorophenyl)
Le) Pentanamide hemihydrate mp 181-182 ℃ MS m / z: 543 (M ⁺ ; Cl = 35) Anal .: Calcd C, 65.09; H, 7.28; N, 7.59; Cl, 12.81 Found C, 65.36; H, 7.31; N, 7.61; Cl, 13.18 IR (KBr) cm ^-1 : 3300, 1650 ¹ H NMR (CDCl ₃ ) δ ppm: 0.97-1.81 (14H, m), 2.02 (3
H, s), 2.10-2.42 (8H, m), 2.77-2.80 (2H, m), 3.21
(1H, t, J = 7 Hz), 3.68-3.78 (1H, m), 5.34 (1H, b
s), 5.48 (1H, bs), 7.15-7.42 (8H, m)

[0159]

Example 105 5- (4-acetamido-4-phenylpiperidi
N-1-yl) -2- (3,4-dichlorophenyl) -N- (2-methoxy)
Cibenzyl) pentanamide hemihydrate mp 92 ℃ ~ (foam) MS m / z: 581 (M ⁺ ; Cl = 35) Anal .: Calcd C, 64.97; H, 6.47; N, 7.10; Cl, 11.99 Found C, 65.41; H, 6.58; N, 7.04; Cl, 11.79 IR (KBr) cm ^-1 : 3300, 1650 ¹ H NMR (CDCl ₃ ) δ ppm: 1.37-1.75 (4H, m), 2.01 (3
H, s), 2.08-2.37 (8H, m), 2.69-2.73 (2H, m), 3.26
(1H, t, J = 7 Hz), 3.74 (3H, s), 4.36-4.38 (2H,
m), 5.48 (1H, bs), 6.00 (1H, bs), 6.81-6.91 (2H,
m), 7.11-7.39 (10H, m)

[0160]

Example 106 5- (4-acetamido-4-phenylpiperidi
N-1-yl) -2- (dichlorophenyl) -N- (1,2-diphenyl
Ruethyl) pentanamide mp 196-198 ° C MS m / z: 641 (M ⁺ ; Cl = 35) Anal .: Calcd C, 71.02; H, 6.43; N, 6.54; Cl, 11.03 Found C, 70.76; H, 6.48 ; N, 6.46; Cl, 11.33 IR (KBr) cm ^-1 : 3300, 1650 ¹ H NMR (CDCl ₃ ) δ ppm: 1.34-1.73 (4H, m), 2.00 &
2.01 (3H in total, each s), 2.05-2.42 (8H, m),
2.69-2.74 (2H, m), 2.89-3.14 (2H, m), 3.20-3.27
(1H, m), 5.20-5.25 (1H, m), 5.47 (1H, d, J = 5 H
z), 5.76 (1H, bs), 6.85-7.40 (18H, m)

[0161]

Example 107 5- (4-acetamido-4-phenylpiperidi
N-1-yl) -2- (3,4-dichlorophenyl) -N- (3,5-bis
Trifluoromethylbenzyl ) pentanamide mp 86 ℃ ~ (foam) MS m / z: 687 (M ⁺ ; Cl = 35) Anal .: Calcd C, 57.57; H, 4.83; N, 6.10; Cl, 10.30 Found C, 58.38; H, 5.59; N, 6.10; Cl, 10.12 IR (KBr) cm ^-1 : 3300, 1650 ¹ H NMR (CDCl ₃ ) δ ppm: 1.39-1.82 (4H, m), 2.00 (3
H, s), 2.07-2.40 (8H, m), 2.72-2.75 (2H, m), 3.42
(1H, d, J = 7 Hz), 4.40 (1H, d, J = 6 Hz), 4.41 (1
/ 2H, d, J = 6 Hz), 4.50 (1 / 2H, d, J = 6 Hz), 5.49
(1H, bs), 6.31 & 6.32 (total 1H, bs each), 7.
12-7.43 (8H, m), 7.60 (2H, s), 7.76 (1H, s)

[0162]

Example 108 5- (4-acetamido-4-phenylpiperidi
N-1-yl) -N- (2-adamantyl) -2- (3,4-dichlorophenyl)
Phenyl ) pentanamide mp 197-199 ° C MS m / z: 595 (M ⁺ ; Cl = 35) IR (KBr) cm ^-1 : 3320, 1660 ¹ H NMR (CDCl ₃ ) δ ppm: 1.41-1.90 (18H, m), 2.01 (3
H, s), 2.05-2.42 (8H, m), 2.76-2.80 (2H, m), 3.29
(1H, d, J = 7 Hz), 4.00 (1H, d, J = 8 Hz), 5.49 (1
H, bs), 5.72 (1H, d, J = 8 Hz), 7.17-7.45 (8H, m) The chemical formulas of the compounds produced in the above examples are shown below.

[0163]

[Chemical 13]

[0164]

Embedded image

[0165]

[Chemical 15]

[0166]

Embedded image

[0167]

[Chemical 17]

[0168]

Embedded image

[0169]

[Test Example 1] Analgesic effect of the compound of the present invention in mice The analgesic potential of the compound of the present invention was determined as follows by the method of Siegmund et al. (Proceeding Society Experimental Biology Medicine, Vol. 95, p. 729, 1957). A group of 5 to 10 male ddY male mice (Japan SLC) having a body weight of about 20 g, which were fasted for about 16 hours from the day before the experiment, were used.
The test compound was dissolved or suspended in physiological saline or 0.5% carboxymethylcellulose solution and injected intraperitoneally.
Five minutes after administration, 0.03% of phenylparabenzoquinone was added to 0.1
It was injected intraperitoneally so as to become ml / mouse, and the number of agony (rising reaction) performed by the mouse for 5 minutes after that was counted for 10 minutes. 1/2 of the average writhing in control groups injected with saline alone or carboxymethylcellulose alone
Mice that decreased below were defined as effective analgesic animals, the number of effective animals / the number of animals used was determined for each dose, and the ED ₅₀ (50% effective amount) was calculated by the Probit method. The results are shown in the table below. From these results, it is clear that the compound of the present invention has an extremely excellent analgesic effect.

[0170]

[Table 1] ^* Compound number in the examples

[0171]

INDUSTRIAL APPLICABILITY Since the compound of the present invention has a strong analgesic action comparable to that of morphine, the compound of the present invention is useful as an active ingredient of medicines such as analgesics.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number for FI Technical indication C07D 211/62 C07D 211/62 277/30 277/30 295/18 295/18 A 295/20 295 / 20 A 401/12 211 401/12 211 471/10 103 103471/10 103 // A61K 31/40 AAH A61K 31/40 AAH 31/425 31/425 31/495 31/495 (72) Inventor Masuko Hide 1 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tetsuya Fukasawa 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor, Tsuji Kurata 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company

Claims (5)

[Claims] 1. The following formula: [Wherein, X represents a single bond, or represents a methylene group, a sulfur atom, or an oxygen atom; Y represents a substituted or unsubstituted aryl group or heteroaryl group; R ¹ and R ²
Each independently represent a lower alkyl group, an aralkyl group, a cycloalkyl group, or a substituted or unsubstituted aryl group or heteroaryl group, or R ¹ and R ^{2 taken} together are substituted with a nitrogen atom which they substitute. Or represents an unsubstituted cyclic amino group; Q is -CH ₂ CH _2- , -CH ₂ C
O-, -COCH _2- , -CH ₂ NR ^3- , -NR ³ CH _2- , -CONR ^3- , and -NR ³
A group selected from the group consisting of CO- (R ³ represents a hydrogen atom, a lower alkyl group, or a lower alkoxycarbonyl group);
n represents an integer of 0 to 5; W represents a heterocycloalkyl group having a substituent]. 2. X is a single bond, methylene, or a sulfur atom; Y is a naphthyl group, a substituted or unsubstituted phenyl group, a thienyl group, an indolyl group, or a thiazolyl group; R ¹ and R ² are each Independently hydrogen atom (however not simultaneously showing hydrogen atom), lower alkyl group, substituted or unsubstituted benzyl group, benzhydryl group, 4 to 8
A membered ring cycloalkyl group, a 1,2-diphenylethyl group, or an adamantyl group, or -NR ¹ R ² is a 1,2,3,4-tetrahydroisoquinolinyl group or a 1-morpholino group; n But
0, 1, 2, or 3; Q is -CH ₂ CH _2- , -COCH _2- , -C
A group selected from the group consisting of H ₂ NH-, and -CONH-; W is 1-piperidinyl group having a substituent, 1-piperazinyl group having a substituent, 1-pyrrolidinyl group having a substituent. The compound according to item 1. 3. X is a single bond, methylene, or sulfur atom; Y is 1-naphthyl group, 2-naphthyl group, phenyl group, parahydroxyphenyl group, 2-thienyl group, 4-thiazolyl group, 3, 4-dichlorophenyl group, or 3-indolyl group; R ¹ and R ² are each independently a hydrogen atom (not simultaneously representing a hydrogen atom), a methyl group, a benzyl group,
Benzhydryl group, tert-butyl group, cyclohexyl group, 2-methoxybenzyl group, 1,2-diphenylethyl group,
3,5-ditrifluoromethylbenzyl group, or adamantyl group, or -NR ¹ R ² is 1,2,3,4-tetrahydroisoquinolinyl group or 1-morpholino group; n is 0, 1 , 2,
Or 3; Q is a group selected from the group consisting of -CH ₂ CH _2- , -COCH _2- , -CH ₂ NH-, and -CONH-; W is 4-acetylamino-4-phenyl- 1-piperidinyl group; 4-acetyl-4-phenyl-1-piperidinyl group; 4-carbamoyl
-1-piperazinyl group; 4-acetyl-1-piperazinyl group;
4-oxo-1-piperidinyl group; 4-hydroxy-4-phenyl-1-piperidinyl group; 4-hydroxy-1-piperidinyl group; 3-acetylamino-1-pyrrolidinyl group; 1-phenyl
The compound according to claim 2, which is a -1,3,8-triaza-4-oxospiro [4,5] decan-8-yl group; a 4- (2-oxo-1-pyrrolidinyl) -1-piperidinyl group. 4. X is a single bond, methylene (—CH ₂ ), or a sulfur atom; Y is a 2-naphthyl group, a 1-naphthyl group, a phenyl group, a 3,4-dichlorophenyl group; and R ¹ is A methyl group and R ² is a benzyl group, or —NR ¹ R ² is
1,2,3,4-tetrahydroisoquinolinyl group; n is
1; Q is -CONH- or -CH ₂ CH _2- ; W is 4-acetylamino-4-phenyl-1-piperidinyl group, 4-acetyl-1-piperazinyl group, or 4-acetyl-4 -Phenyl-1
-The compound according to claim 3, which is a piperidinyl group. 5. An analgesic containing the compound according to claim 1 as an active ingredient.