JP2001011073A - Cyclic amide compound, and its production and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound exhibiting excellent CCR5 antagonistic activities, excellent in absorptivity in an oral administration, and useful as a prophylactic and therapeutic agent of the infection of human immunodeficiency virus to human peripheral blood mononucleosis cells, especially acquired immunodeficiency syndrome. SOLUTION: This new compound is the one of formula I [R1 is a hydrocarbon or the like; R2 is a >=2C hydrocarbon or the like; R3 is a (substituted) hydrocarbon or the like; R4 is H, a (substituted) hydrocarbon or the like; E is a divalent (substituted) linear hydrocarbon (the substituent is the one without oxo); G is CO or SO2; J is N or a (substituted) methine; Q and R are each a bond, a divalent (substituted) 1-3C linear hydrocarbon], e.g. N-[3-(4-benzyl-1- piperidyl)propyl]-N-(3,4-dichlorophenyl)-1-methyl-5-oxo-3-pyrrolidinec arboxamide. The compound of formula I is obtained by reacting a compound of formula II (X is a leaving group) with a compound of formula III in the presence of a base. The reaction temperature is preferably at room temperature to 100 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a cyclic amide compound useful for treating acquired immunodeficiency syndrome, a method for producing the compound, and a use thereof.

[0002]

2. Description of the Related Art In recent years, HIV (human immunodeficiency virus) protease inhibitors have been developed as a treatment for AIDS (acquired immunodeficiency syndrome) and can be combined with two HIV reverse transcriptase inhibitors conventionally used. As a result, the treatment of AIDS has been remarkably advanced, but it has not been sufficient for eradication of AIDS, and the development of a new anti-AIDS drug based on another mechanism of action has been desired. HI
CD4 as a receptor for V to enter target cells
Has been known for some time, but recently CCR5, a second receptor for macrophage-tropic HIV,
Seven transmembrane G protein-coupled chemokine receptors, called CXCR4, have been found as T cell-directed second receptors, and these chemokine receptors are thought to play an essential role in the establishment and transmission of HIV infection. Have been. In fact, humans who have shown resistance to HIV infection despite repeated exposure,
It has been reported that the CCR5 gene had a homozygously deleted mutation. Therefore, CCR5 antagonists are expected to be new anti-HIV drugs.

At present, as chemokine receptor antagonists, aromatic urea derivatives (J. Biol. Chem., 1998, 273,
10095-10098.), Benzdiazepine derivatives (JP-A-9-24)
9570), cyclam derivative (Nat.Med., 1998, 4, 72-7
7.), spiropiperidine derivative (WO98 / 25604, 25605,), acridine derivative (WO98 / 30218), xanthene derivative (WO98 / 045)
54), a haloperidol derivative (J. Biol. Chem., 1998, 273, 156).
87-15692., WO98 / 24325, 02151.), benzazosin compounds (JP-A-9-25572), benzimidazole derivatives (WO98 /
06703), piperazine and diazepine derivatives (WO 97/4432
9), 3-substituted piperidine derivative (JP-A-9-249566), 4
Position-substituted piperidine derivatives (WO99 / 04794) and substituted pyrrolidine derivatives (WO99 / 09984) are known.
There are no examples in which a CR5 antagonist has been developed as a therapeutic agent for AIDS. On the other hand, among heteroatom-containing cyclic compounds,
Regarding the physiological activity of the pyrrolidinone derivative, in the structure represented by the following formula (I), Q = CH ₂ , R = C
Compounds in which H ₂ , J = CH, G = CO, and R ³ = H have been used to regulate plant growth or herbicidal activity (JP-A-51-125745).
However, it also has painful and anti-inflammatory effects (Chim. Ther., 1972, 7,
398-403) and the like, but there is no report on chemokine receptor antagonism, and there is no description of the compound of the present application in which R ³ ≠ H.

[0004]

Means for Solving the Problems The present inventors have developed CCR5.
As a result of intensive studies on compounds having an antagonistic action, it has been found that a compound represented by the following general formula (I) or a salt thereof has an excellent CCR
5) It has an antagonistic effect, is useful as a prophylactic / therapeutic agent for HIV infection of human peripheral blood mononuclear cells, particularly AIDS, and has excellent oral absorbability. The present invention has been completed.

That is, the present invention provides the following: 1)

Embedded image (In the formula, R ¹ represents a hydrocarbon group, R ² represents a hydrocarbon group having 2 or more carbon atoms, and R ¹ and R ² may have a substituent together with a nitrogen atom adjacent thereto. R ³ may be a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ⁴ may have a hydrogen atom or a substituent. A hydrocarbon group or a heterocyclic group which may have a substituent, E is a divalent chain hydrocarbon group which may have a substituent other than an oxo group, G is CO or SO ₂ , J represents a nitrogen atom or a methine group which may have a substituent, and Q and R each represent a bond or a divalent C _1-3 chain hydrocarbon which may have a substituent. represents a group. or a salt thereof), ²⁾ R 2 R ¹ is in the C _1-6 alkyl group or a C _3-8 cycloalkyl group or C _2-6 alkyl group Forms a C _3-8 or a cycloalkyl group, or may have a substituent group together with R ¹ and the nitrogen atom to which R ² is adjacent attached ring,
R ³ is a C _1-6 alkyl group optionally having a substituent, a C _3-8 cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent or a substituent Wherein R ⁴ is a hydrogen atom, an alkyl group optionally having substituent (s), a carbon atom optionally having substituent (s)
_{A 3-8} cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
Is a C _2-5 alkylene group which may have a substituent other than an oxo group, G is CO or SO ₂ , J is a nitrogen atom or a methine group which may have a substituent, and Q and R
May have a bond or a substituent, respectively.
The compound according to 1) above, which is a _1-3 alkylene group,

3) The compound according to 1) or 2), wherein R ¹ and R ² are bonded to form an optionally substituted ring together with an adjacent nitrogen atom; 4) a compound having a substituent The compound according to the above 3), wherein each of the optionally substituted rings is a 1-piperidinyl group or a 1-piperazinyl group, each of which may have a substituent; (1) phenyl-C _1-4 alkyl optionally having a halogen on the benzene ring, (2) diphenylmethyl optionally having a hydroxy, (3) optionally having a halogen on the benzene ring The compound according to 4) above, which is benzoyl, (4) 2-phenylethen-1-yl, (5) phenyl optionally having halogen, (6) hydroxy, (7) phenoxy or (8) benzyloxy. , 6 The compound according to the above 3), wherein the ring which may have a substituent is a 1-piperidinyl group which may have a substituent, 7) the substituent of the 1-piperidinyl group has a halogen in a benzene ring. 8) The compound according to the above 6), which is a benzyl group which may be substituted; 8) R ³ has (1) a C _1-6 alkyl group, (2) a C _3-8 cycloalkyl group, and (3) a hydroxy group. Benzyl group, (4) naphthylmethyl group, (5) C _1-4 alkyl optionally having halogen as a substituent, C _1-4 alkoxy optionally having halogen, phenyl, cyano A phenyl group optionally having a benzyloxy or halogen atom, (6) a naphthyl group,
(7) The compound according to the above 1) or 2), which is an indanyl group or (8) a tetrahydronaphthyl group, 9) R ³ is a phenyl group optionally having a C _1-4 alkyl or a halogen as a substituent. The compound according to the above 1) or 2), 10) the compound according to the above 1) or 2), wherein E is C _2-6 polymethylene optionally having hydroxy, 11) R ⁴ is (1) a hydrogen atom, (2) halogen, pyridyl, morpholino, furyl, ethynyl or C _1-6 alkyl optionally having C _3-8 cycloalkyl, (3) halogen on the benzene ring, C _1-4 alkyl, halogeno-C ₁ 1) or 2) above, which is phenyl-C _1-4 alkyl optionally having _-4 alkyl or C _1-4 alkoxy or (4) C _3-8 cycloalkyl.
12) The above 1), wherein R ⁴ is a C _1-4 alkyl group optionally having halogen or furyl as a substituent or a benzyl group optionally having halogen on a benzene ring.
Or the compound according to 2), 13) 1-, wherein N (R ¹ ) R ² may have a substituent.
Piperidinyl group, E is a trimethylene group, R ³ is a phenyl group which may have a substituent, G is CO, J is CH,
(1) wherein Q and R are each a methylene group
14) N- [3- (4-benzyl-1-piperidinyl) propyl] -N-
(3,4-dichlorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide, 1-benzyl-N- [3- (4-benzyl-1-
Piperidinyl) propyl] -5-oxo-N-phenyl-3-pyrrolidinecarboxamide, N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (2-chlorobenzyl) -5-oxo-N- Phenyl-3-pyrrolidinecarboxamide, N- (3,4-dichlorophenyl) -N- {3- [4- (4-fluorobenzyl) -1-piperidinyl] propyl} -1-methyl-5-oxo-3-pyrrolidine Compounds selected from carboxamide and N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo-N-phenyl-1- (2,2,2-trifluoroethyl) -3-pyrrolidinecarboxamide Or a salt thereof; 15) a prodrug of the compound of 1) above; 16) a pharmaceutical composition comprising the compound of 1) or a prodrug thereof; 17) a chemokine receptor antagonist of the above 16). 18) A composition as described in 16) above, which is a CCR5 antagonist, 19) HIV sensitivity 22) a composition described in 16) above as a prophylactic / therapeutic agent for AIDS, 20) a composition described in 16) above as a prophylactic / therapeutic agent for AIDS, 21) a composition described in 16) above as an agent for suppressing AIDS pathological progression, 22) A) the composition of the above 19), which further comprises a protease inhibitor or / and a reverse transcriptase inhibitor; 2 above
2) The composition according to the above, 24) the protease inhibitor is saquinavir, ritonavir,
25) A composition according to the above 22), which is indinavir, amprenavir or nelfinavir; 25) A method for preventing or treating HIV infection with the compound according to the above (1) or a prodrug thereof and a protease inhibitor or / and a reverse transcriptase inhibitor. Use for the

Formula 26):

Embedded image (Wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula:

Embedded image (Wherein R ⁵ represents a carboxy group, a sulfonic acid group or a salt or reactive derivative thereof, and the other symbols are as defined above) or a salt thereof. A method for producing a compound represented by the formula (I) or a salt thereof, which is characterized by the following: 27) In the presence of a base, a compound represented by the formula:

Embedded image (Wherein, X represents a leaving group, and other symbols are as defined above) or a salt thereof, and a compound represented by the formula:

Embedded image (The symbols in the formula are as defined above.) Or a salt thereof, and a method for producing a compound represented by the formula (I) or a salt thereof.

Examples of the hydrocarbon group represented by R ¹ include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group and an aryl group. Preferably, it is an aliphatic chain hydrocarbon group or an alicyclic hydrocarbon group. Examples of the aliphatic chain hydrocarbon group include linear or branched aliphatic hydrocarbon groups such as an alkyl group, an alkenyl group, and an alkynyl group. Preferably it is an alkyl group. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ter
t-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,
3,3-dimethylbutyl, 3,3-dimethylpropyl, 2
-Ethylbutyl, n-heptyl, 1-methylheptyl,
_Examples thereof include C _1-10 alkyl groups such as 1-ethylhexyl, n-octyl, 1-methylheptyl, and nonyl (preferably C _1-6 alkyl). As the alkenyl group,
For example, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- Pentenyl, 4-methyl-3
-Pentenyl, 1-hexenyl, 2-hexenyl, 3-
_C2-6 such as hexenyl, 4-hexenyl and 5-hexenyl
An alkenyl group and the like can be mentioned. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-
Examples thereof include _C2-6 alkynyl groups such as pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. Examples of the alicyclic hydrocarbon group include a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkanedienyl group. Preferably it is a cycloalkyl group. Examples of the cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C _3-9 cycloalkyl such as cyclononyl (preferably C _{3 -8} cycloalkyl, etc.), etc., and 1-indanyl, Condensed rings such as 2-indanyl are exemplified. As the cycloalkenyl group,
For example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-
And C _3-6 cycloalkenyl groups such as cyclohexen-1-yl, 1-cyclobuten-1-yl and 1-cyclopenten-1-yl. As the cycloalkanedienyl group, for example, 2,4-cyclopentanedien-1
-Yl, 2,4-cyclohexanedien-1-yl, 2,
And C _4-6 cycloalkanedienyl groups such as 5-cyclohexanedien-1-yl. Examples of the aryl group include a monocyclic or condensed polycyclic aromatic hydrocarbon group, for example, a C _6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, 4-indanyl and 5-indanyl. And phenyl, 1-naphthyl, 2-naphthyl and the like are particularly preferable.

[0009] As the hydrocarbon group having 2 or more carbon atoms represented by R ² include those having two or more carbon atoms of the hydrocarbon group represented by R ^1. Preferred among those described for R ¹ are C _2-6 alkyl and C _3-8 cycloalkyl. When R ¹ and R ² are combined with each other to form a ring which may have a substituent together with an adjacent nitrogen atom, such a ring includes, in addition to one nitrogen atom, a nitrogen atom, an oxygen atom , A ring containing a sulfur atom, such as 1-azetidinyl, 1-pyrrolidinyl,
-Piperidinyl, 1-homopiperidinyl, heptamethyleneimino, 1-piperazinyl, 1-homopiperazinyl,
Condensation of monocycles such as morpholino and thiomorpholino, 2-isoindolinyl, 1,2,3,4-tetrahydro-2-isoquinolyl, 1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl Ring, indene-1-
And a cyclic amino group such as a spiro ring such as spiro-4'-piperidin-1'-yl.
May have one or more substituents. Examples of the substituent include a hydroxy group, a cyano group, a nitro group, an oxo group, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), and a general formula: -YR ^a (wherein R ^a Is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, Y is a bond (single bond), —CR ^b R
^{c -, - COO -, -} CO -, - CO-NR b -, - CS-NR b -,
-CO-S -, - CS- S -, - CO-NR b -CO-NR c -, - C
^{(= NH) -NR b -,} - NR b -, - NR b -CO -, - NR b -CS
-, -NR ^b -CO-NR ^c- , -NR ^b -CS-NR ^c- , -NR ^{b-
CO-O -, - NR b} -CS-O -, - NR b -CO-S -, - NR b
-CS-S-, -NR ^b -C (= NH) -NR ^c- , -NR ^b -SO
_2- , -NR ^b -NR ^c- , -O-, -O-CO-, -O-CS-, -O
-CO-O, -O-CO-NR ^b- , -OC (= NH) -NR ^b -,-
S -, - SO -, - SO 2 -, - SO 2 -NR b -, - S-CO -, -
S-CS-, -S-CO-NR ^b- , -S-CS-NR ^b- , -SC
(= NH) -NR ^b-, etc., wherein R ^b and R ^{c each} have a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, Optionally substituted alkynyl group, optionally substituted aryl group, optionally substituted cycloalkyl group or cycloalkenyl group, optionally substituted heterocyclic group, carboxylic acid An acyl group derived from an acid, an alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, etc.). Examples of the “hydrocarbon group” of the hydrocarbon group which may have a substituent represented by ^Ra include, for example, an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group and an aryl group. Examples of the aliphatic chain hydrocarbon group, alicyclic hydrocarbon group and aryl group include those described as the aliphatic chain hydrocarbon group, alicyclic hydrocarbon group and aryl group represented by R ^1. Can be Examples of the substituent of the hydrocarbon group include those described as the substituent in the “hydrocarbon group which may have a substituent” represented by R ³ described below.

The “optionally substituted heterocyclic group” represented by R ^a is the same as the “optionally substituted heterocyclic group” represented by R ³ described below. Things. Wherein R ^b and alkyl group which may have a substituent group represented by R ^c, which may have a substituent alkenyl group which may have a substituent alkynyl group, substituted An aryl group which may be substituted, a cycloalkyl group or a cycloalkenyl group which may have a substituent,
Examples of the optionally substituted heterocyclic group, carboxylic acid-derived acyl group, optionally substituted alkylsulfonyl group, and optionally substituted arylsulfonyl group include those described below. Examples of the substituent in the hydrocarbon group which may have a substituent represented by ³ include all. It is preferred that R ¹ and R ² combine to form a heterocyclic ring which may have a substituent together with a nitrogen atom. More preferably, NR ¹ R ² has the formula:

Embedded image (Wherein Y and ^Ra are as defined above). Here, Y and ^Ra have the same meaning as described above, but ^Ra is particularly preferably an aryl group which may have a substituent or a heterocyclic group which may have a substituent. As YRa, ^a benzyl group which may have a substituent is particularly preferred. As NR ¹ R ² , an optionally substituted 4-benzyl-1-piperidinyl group is particularly preferred.

Examples of the hydrocarbon group in the hydrocarbon group which may have a substituent represented by R ³ include the same as the hydrocarbon group represented by R ¹ , and among them, a C _1-6 alkyl group , A _C3-8 cycloalkyl group and an aryl group are preferred. These examples also include those described in R ^1. R ³
The heterocyclic group in the heterocyclic group which may have a substituent represented by is, for example, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as an atom (ring atom) constituting a ring system. 1 to 3 atoms (preferably 1 to 2 atoms)
), A saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) containing at least one (preferably 1 to 4, more preferably 1 to 2)
And the like. As the aromatic heterocyclic group, an aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4) -Oxadiazolyl, 1,3,4-
Oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, 5- or 6-membered aromatic monocyclic heterocyclic groups such as pyrimidinyl, pyrazinyl and triazinyl) and aromatic fused heterocyclic groups [eg benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzyne] Dazolyl, benzoxazolyl, 1.2
-Benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl , Β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl , Imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,
2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1,2,4-triazolo [4,3- b ] pyridazinyl and the like To a 12-membered aromatic condensed heterocyclic group (preferably, a heterocyclic ring obtained by condensing a 5- or 6-membered aromatic monocyclic heterocyclic group with a benzene ring or a 5- or 6-membered aromatic monocyclic group described above) A heterocyclic ring in which two identical or different heterocyclic rings of a heterocyclic group are condensed)].

Examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl,
3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups such as pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and piperazinyl ( Aliphatic heterocyclic group). Examples of the substituent in the heterocyclic group which may have a substituent represented by substituents and R ³ in a hydrocarbon group which may have a substituent represented by R ^3, for example, a substituent An alkyl group which may be substituted, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, A cycloalkyl group or a cycloalkenyl group, a heterocyclic group which may have a substituent, an amino group which may have a substituent, an imidoyl group which may have a substituent, An amidino group which may have a hydroxyl group which may have a substituent, a thiol group which may have a substituent, a carboxyl group which may be esterified, and a group which may have a substituent Have good carbamoyl groups and substituents A thiocarbamoyl group,
A sulfamoyl group which may have a substituent, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), a cyano group, a nitro group, an acyl group derived from a carboxylic acid, and a substituent. An alkylsulfinyl group which may be substituted, an alkylsulfonyl group which may have a substituent, an arylsulfinyl group which may have a substituent, an arylsulfonyl group which may have a substituent, and the like. These optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions. Examples of the aryl group in the “aryl group optionally having substituent (s)” as the substituent include a C _6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl. Here, as a substituent of the aryl group, a lower alkoxy group (for example, a C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, etc.), a halogen atom (for example, fluorine, chlorine,
Bromine, iodine, etc.), lower alkyl groups (eg, C _1-6 alkyl groups such as methyl, ethyl, propyl, etc.), amino groups,
Examples thereof include a hydroxyl group, a cyano group, and an amidino group, and one or two of these optional substituents may be substituted at substitutable positions.

Examples of the cycloalkyl group in the “cycloalkyl group optionally having substituent (s)” as the substituent include, for example, C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Is mentioned. Here, examples of the substituent of the cycloalkyl group include the same number of the same substituents as in the above-mentioned “aryl group optionally having substituent (s)”. Examples of the cycloalkenyl group in the “cycloalkenyl group optionally having substituent (s)” as the substituent include, for example, C _3-6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. . Here, as a substituent of the cycloalkenyl group which may have a substituent,
The same number of the same substituents as in the above-mentioned “aryl group optionally having substituent (s)” may be mentioned. Examples of the alkyl group in the “alkyl group optionally having substituent (s)” as the substituent include, for example, methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, And C _1-6 alkyl such as 3-dimethylpropyl. Here, examples of the substituent of the alkyl group include the same number of the same substituents as in the above-mentioned “aryl group optionally having substituent (s)”. Examples of the alkenyl group in the "optionally substituted alkenyl group" as a substituent include, for example, vinyl, allyl, isopropenyl,
2-methylallyl, 1-propenyl, 2-methyl-1-
Propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2
-Pentenyl, 3-pentenyl, 4-pentenyl, 4-
And C _2-6 alkenyl groups such as methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. Here, examples of the substituent of the alkenyl group include the same number of the same substituents as in the above-mentioned “aryl group optionally having substituent (s)”.

Examples of the alkynyl group in the “optionally substituted alkynyl group” as the substituent include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, - pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and a C _2-6 alkynyl group of 5-hexynyl and the like. Here, examples of the substituent of the alkynyl group include the same number of the same substituents as in the above-mentioned “aryl group optionally having substituent (s)”. The heterocyclic group in the “heterocyclic group optionally having substituent (s)” as the substituent is selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as an atom (ring atom) constituting a ring system. 1 to 3 (preferably 1 to 2) heteroatoms, at least 1 (preferably 1 to 4)
, More preferably 1 or 2), a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like. As the “aromatic heterocyclic group”, an aromatic monocyclic heterocyclic group (for example, furyl, thienyl,
Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,
3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,3-triazolyl, 1,
5- or 6-membered aromatic monocyclic heterocyclic groups such as 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl) and aromatic condensed heterocyclic groups [eg benzofuranyl, isobenzofuranyl, benzo Thienyl, indolyl, isoindolyl, 1
H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, Quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, fenoxathiinyl, thianthrenyl, phenathridinyl, phenatronilonyl, phenatronilonyl, phenatronilonyl, phenatronylonyl 2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,
2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1,2,4-triazolo [4,3- b ] pyridazinyl and the like To a 12-membered aromatic condensed heterocyclic group (preferably, a heterocyclic ring obtained by condensing a 5- or 6-membered aromatic monocyclic heterocyclic group with a benzene ring or a 5- or 6-membered aromatic monocyclic group described above) A heterocyclic ring in which two identical or different heterocyclic rings of a heterocyclic group are condensed)].

The "non-aromatic heterocyclic group" includes, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl,
Piperidinyl, tetrahydropyranyl, morpholinyl,
Examples thereof include a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as thiomorpholinyl and piperazinyl. As the substituent which the “heterocyclic group optionally having substituent (s)” may have, a lower alkyl group (for example, a C _1-6 alkyl group such as methyl, ethyl, propyl and the like) An acyl group (eg, formyl, acetyl,
And C _1-6 alkanoyl such as propionyl and pivaloyl, and benzoyl. As the substituent, "an amino group which may have a substituent", "an imidoyl group which may have a substituent", "an amidino group which may have a substituent", " Examples of the substituent in the “optionally possessed hydroxyl group” and the “optionally substituted thiol group” include lower alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
C _1-6 alkyl groups such as t-butyl, pentyl, hexyl, etc., acyl groups (eg, C _1-6 alkanoyl (eg, formyl, acetyl, propionyl, pivaloyl, etc.), benzoyl, etc.), C _1-6 alkylsulfonyl ( For example, methanesulfonyl, ethanesulfonyl, etc.), C _3-14, arylsulfonyl (eg, benzenesulfonyl, p-toluenesulfonyl, etc.), and optionally halogenated C _1-6.
Alkoxy-carbonyl (e.g., trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.) and the like. The “amino group” in the “amino group optionally having” is substituted with an imidoyl group optionally having a substituent (eg, C _1-6 alkylimidoyl, formylimidoyl, amidino, etc.). And two substituents may form a cyclic amino group together with the nitrogen atom. In such a case, examples of the cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, -Piperidinyl, morpholino, 1-piperazinyl and a lower alkyl group at the 4-position (e.g. methyl, ethyl, propyl, isop A C _1-6 alkyl group such as propyl, butyl, t-butyl, pentyl, hexyl, etc., an aralkyl group (eg, a C _7-10 aralkyl group such as benzyl, phenethyl, etc.), an aryl group (eg, phenyl, 1-naphthyl, And a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino such as 1-piperazinyl which may have a C _6-10 aryl group such as 2-naphthyl and the like.

The "carbamoyl group optionally having substituent (s)" includes unsubstituted carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl. “N-monosubstituted carbamoyl group” means a carbamoyl group having one substituent on a nitrogen atom,
Examples of the substituent include a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like), a cycloalkyl group (eg, cyclopropyl, C _3-6 cycloalkyl groups such as cyclobutyl, cyclopentyl, cyclohexyl, etc., aryl groups (eg, C _6-10 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl), aralkyl groups (eg, benzyl, phenethyl, etc.) C _7-10 aralkyl group, preferably phenyl-C _1-4
An alkyl group), a heterocyclic group (for example, the same as the “heterocyclic group” as a substituent in the “hydrocarbon group which may have a substituent” represented by R ³ ), and the like. Can be The lower alkyl group, cycloalkyl group, aryl group, aralkyl group and heterocyclic group may have a substituent, for example, a hydroxyl group, an amino group which may have a substituent [ The amino group is, for example, a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (eg, formyl, acetyl, propionyl) C, such as pivaloyl
_1-6 alkanoyl, benzoyl, etc.) or the like. ], A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, and 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) may have a substituent. A lower alkyl group, a lower alkoxy group which may have a substituent with 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.) and the like are mentioned. Examples of the lower alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ter
Examples thereof include C _1-6 alkyl groups such as t-butyl, pentyl, and hexyl, and particularly preferred are methyl and ethyl. Examples of the lower alkoxy group include methoxy, ethoxy, n
-C _1-6 alkoxy groups such as -propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, and methoxy, ethoxy and the like are particularly preferable. Further, these substituents may be the same or different from each other.
Alternatively, it is preferable that two or three (preferably one or two) are substituted.

"N, N-disubstituted carbamoyl group" means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is the above-mentioned "N-monosubstituted carbamoyl group". And the other examples thereof include, for example, lower alkyl groups (for example, methyl, ethyl, propyl, isopropyl, butyl,
C _1-6 alkyl groups such as t-butyl, pentyl, hexyl, etc., C _3-6 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl groups (eg, benzyl, phenethyl, etc.) And preferably a phenyl-C _1-4 alkyl group). In some cases, two substituents may form a cyclic amino group together with a nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl group include 1-azetidinylcarbonyl and 1-pyrrolidinyl. Carbonyl, 1
-Piperidinylcarbonyl, morpholinocarbonyl, 1
-Piperazinylcarbonyl and a lower alkyl group at the 4-position (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (eg, benzyl, phenethyl, etc.) C _7-10 aralkyl group), an aryl group (e.g. phenyl, 1-naphthyl, such as C _6-10 aryl group, etc.) may 1- piperazinylcarbonyl which may have a like 2-naphthyl 3 And a cyclic amino-carbonyl of 8 to 8 members (preferably 5 to 6 members). Examples of the substituent of the “optionally substituted thiocarbamoyl group” include the same substituents as those of the aforementioned “optionally substituted carbamoyl group”. As the “sulfamoyl group optionally having a substituent”, in addition to unsubstituted sulfamoyl, an N-monosubstituted sulfamoyl group and N, N-
And disubstituted sulfamoyl groups. "N-monosubstituted sulfamoyl group" refers to a sulfamoyl group having one substituent on a nitrogen atom, wherein the substituent is N-
Examples are the same as the substituents of the monosubstituted carbamoyl group. "N, N-disubstituted sulfamoyl group" means a sulfamoyl group having two substituents on a nitrogen atom, and the substituent is the same as the substituent of N, N-disubstituted carbamoyl group. Is mentioned.

The "carboxyl group which may be esterified" includes, in addition to a free carboxyl group, for example, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group and the like.
As the "lower alkoxycarbonyl group", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neo And C _1-6 alkoxy-carbonyl groups such as pentyloxycarbonyl, etc., among which, among others, C _1-3 alkoxy- such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
A carbonyl group and the like are preferred. As the “aryloxycarbonyl group”, for example, a phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, etc.
_{A 7-12} aryloxy-carbonyl group and the like are preferred. As the “aralkyloxycarbonyl group”, for example, a C _7-10 aralkyloxy-carbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably a C _6-10 aryl-C _1-4 alkoxy-carbonyl and the like) are preferable. . The "aryloxycarbonyl group",
The “aralkyloxycarbonyl group” may have a substituent, and examples of the substituent include those described as examples of the substituent of the above-mentioned N-monosubstituted carbamoyl group, such as an aryl group and an aralkyl group. Similar numbers are used for similar numbers.

Examples of the "acyl group derived from carboxylic acid" as a substituent include those in which a hydrogen atom or a substituent having one of the above-mentioned "N-monosubstituted carbamoyl groups" on the nitrogen atom is bonded to carbonyl. Of these, preferred are acyl such as C _1-6 alkanoyl such as formyl, acetyl, propionyl and pivaloyl, and benzoyl. Examples of the alkyl in the “optionally substituted alkylsulfinyl group” and the “optionally substituted alkylsulfonyl group” as the substituent include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , T-butyl, pentyl, hexyl and the like
_And lower alkyl groups such as C1-6 alkyl groups. As the aryl in the `` arylsulfinyl group optionally having a substituent '' and the `` arylsulfonyl group optionally having a substituent '' as the substituent, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like And a C _6-14 aryl group. As the substituents of these alkyl and aryl, lower alkoxy groups (for example, C.sub.2 such as methoxy, ethoxy, propoxy, etc.)
_1-6 alkoxy group, etc.), halogen atom (for example, fluorine,
Chlorine, bromine, iodine, etc.), lower alkyl groups (eg, C _1-6 alkyl groups such as methyl, ethyl, propyl, etc.), amino groups, hydroxyl groups, cyano groups, amidino groups, etc., and any substituents thereof. May be substituted one or two times at substitutable positions. R hydrocarbon group which may have a substituent group represented by ⁴ include those similar to the hydrocarbon group which may have a substituent represented by R ^3, also represented by R ⁴ substituents The heterocyclic group which may have a group is the same as the heterocyclic group which may have a substituent represented by R ³ . Examples of the divalent chain hydrocarbon group in the divalent chain hydrocarbon group which may have a substituent other than the oxo group represented by E include C 4 such as methylene and ethylene.
Examples thereof include C _2-6 alkenylene such as _1-6 alkylene and ethenylene, and C _2-6 alkynylene such as ethinylene. Preferred is C _1-5 alkylene, most preferred is trimethylene. The substituent of the divalent hydrocarbon group may be other than an oxo group, and specific examples thereof include, for example, an alkyl group which may have a substituent, and an alkyl group which may have a substituent. A good aryl group, a cycloalkyl group or cycloalkenyl group which may have a substituent, a carboxyl group which may be esterified,
A carbamoyl group or a thiocarbamoyl group which may have a substituent, an amino group which may have a substituent,
A hydroxyl group which may have a substituent, a thiol (mercapto) group which may have a substituent, an acyl group derived from a carboxylic acid, an alkylsulfonyl group which may have a substituent, An arylsulfonyl group which may be
Examples include halogen (eg, fluorine, chlorine, bromine, etc.), nitro, cyano, and the like. The number of substituents may be 1 to 3. An alkyl group which may have these substituents,
An aryl group which may have a substituent, a cycloalkyl group or a cycloalkenyl group which may have a substituent, a carboxyl group which may have an esterification group,
A carbamoyl group or a thiocarbamoyl group which may have a substituent, an amino group which may have a substituent,
A hydroxyl group which may have a substituent, a thiol (mercapto) group which may have a substituent, an acyl group derived from a carboxylic acid, an alkylsulfonyl group which may have a substituent, Examples of the optionally substituted arylsulfonyl group include the same as those described above as the substituent for the optionally substituted heterocyclic group represented by R ³ .

The substituent of the optionally substituted methine group represented by J is the same as the substituent of the optionally substituted heterocyclic group represented by R ^3. Are included. The divalent C _1-3 chain hydrocarbon group in substituents having 2 may be divalent C _1-3 chain hydrocarbon group represented by Q and R, E
2 which may have a substituent other than the oxo group represented by
Among the divalent chain hydrocarbon groups in the divalent chain hydrocarbon group, those having 1 to 3 carbon atoms are exemplified. The substituent in the divalent C _1-3 chain hydrocarbon group which may have a substituent represented by Q and R may have a substituent other than the oxo group represented by E Examples include the same substituents as those in the divalent chain hydrocarbon group. Examples of the salt of a carboxy group or a sulfonic acid group represented by R ⁵ include salts with alkali metals such as sodium, potassium and lithium, salts with alkaline earth metals such as calcium, magnesium and strontium, and ammonium salts. And the like. As the reactive derivative of the carboxy group represented by R ⁵ , for example, a reactive derivative such as an acid halide, an acid azide, an acid anhydride, a mixed acid anhydride, an active amide, an active ester, or an active thioester is subjected to the acylation reaction. . Examples of the acid halide include acid chloride and acid bromide.
_1-6 alkyl carbonic acid mixed anhydrides (e.g., free acid and monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate,
Monoisobutyl carbonate, mono-tert- butyl carbonate, monobenzyl carbonate, mono (p- nitrobenzyl) carbonate, mixed acid anhydride and the like monoallyl carbonate), C _1-6 aliphatic carboxylic acid mixed acid anhydride (e.g. the free acid Mixed acid anhydrides with acetic acid, trichloroacetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid), _C7-12
Mixed acid anhydrides of aromatic carboxylic acids (for example, mixed acid anhydrides of free acid and benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc.), and mixed acid anhydrides of organic sulfonic acids (for example, free acid and methanesulfonic acid) Ethanesulfonic acid, benzenesulfonic acid, mixed acid anhydrides with p-toluenesulfonic acid, etc.) as active amides such as amides with nitrogen-containing heterocyclic compounds [for example, free acid and pyrazole, imidazole, benzotriazole, etc. in the acid amide, these nitrogen-containing heterocyclic compound _C1-6 alkyl group (e.g., methyl,
Ethyl, etc.), C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.), halogen atom (eg, fluorine, chlorine, bromine, etc.), oxo group, thioxo group, C _1-6 alkylthio group (eg, methylthio, ethylthio) Etc.). ].

As the active ester, those used for this purpose in the field of β-lactam and peptide synthesis can be used. For example, organic phosphates (eg, diethoxy phosphate, diphenoxy phosphate, etc.) and p-nitro Phenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester,
1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester, 1-
And hydroxy-1H-2-pyridone esters. As the active thioester, an ester with an aromatic heterocyclic thiol compound [eg, 2-pyridylthiol ester, 2-benzothiazolylthiol ester, etc., and these heterocycles are a C _1-6 alkyl group (eg, methyl,
Substituted with a C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, etc.), a C _1-6 alkylthio group (eg, methylthio, ethylthio, etc.) It may be. ]. Examples of the reactive derivative of the sulfonic acid group represented by R ⁵ include sulfonyl halides (eg, sulfonyl chloride, sulfonyl blemide, etc.), sulfonyl azides, and acid anhydrides thereof. Examples of the leaving group represented by X include a halogen atom (eg, chlorine atom, bromine atom, iodine atom, etc.), an alkyl or arylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p- Toluenesulfonyloxy, etc.). Examples of the salt of the compound represented by the formula (I) of the present invention include an acid addition salt, for example, an inorganic acid salt (for example, hydrochloride, sulfate, hydrobromide, phosphate and the like), an organic acid salt (for example, Acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.) And salts with bases (eg, alkali metal salts such as potassium salt, sodium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, trimethylamine salt,
Triethylamine salt, tert-butyldimethylamine salt,
A salt with an organic base such as a dibenzylmethylamine salt, a benzyldimethylamine salt, an N, N-dimethylaniline salt, a pyridine salt, and a quinoline salt).
The compound represented by the general formula (I) or a salt thereof may be a hydrate, and hereinafter the compound including the salt and the hydrate will be referred to as the compound (I).

The prodrug of the compound (I) is a compound which is converted into the compound (I) by a reaction with an enzyme, gastric acid or the like in a living body. As a prodrug of the compound (I), when the compound (I) has an amino group, a compound in which the amino group is acylated, alkylated or phosphorylated (eg, the amino group of the compound (I) is eicosanoylated, Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butyl When compound (I) has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, Propanoylated, pivaloyylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.)
When the compound (I) has a carboxyl group, a compound in which the carboxyl group is esterified or amidated (eg, the carboxyl group of the compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl ester , Pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,
Phthalidyl esterification, (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyl esterification,
Cyclohexyloxycarbonylethyl esterified compound, methylamidated compound, etc.); These compounds can be produced by a method known per se. The prodrug of compound (I) is described in “Development of Pharmaceuticals”, 1990, Hirokawa Shoten, Vol.
The compound may be converted to the compound (I) under physiological conditions as described on pages 198 to 198. The prodrug of compound (I) may be itself or a pharmacologically acceptable salt. Such salts include, when the prodrug of compound (I) has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, zinc, Transition metals such as iron and copper), organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, organic amines such as N, N'-dibenzylethylenediamine, arginine , Lysine, or basic amino acids such as ornithine, etc.).

When the prodrug of compound (I) has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid,
Nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), aspartic acid, glutamic acid, and other acidic amino acids. Compound (I)
May be any of hydrates and non-hydrates. Compound (I) may have one or more asymmetric carbons in the molecule, and both R configuration and S configuration with respect to these asymmetric carbons are included in the present invention. In the present specification, unless otherwise specified, “lower” represented by a lower alkyl group, a lower alkoxy group and the like means a chain, branched or cyclic carbon chain having 1 to 6 carbon atoms. Formula (II)
In the compounds represented by the formulas (VI) to (VI), a compound having a basic group or an acidic group can form a salt with an acid addition salt or a salt with a base, respectively. Examples of the acid addition salt and the salt with a base include those similar to the salts of the compound represented by the formula (I). Hereinafter, the compound represented by each formula is abbreviated as a compound (the symbol of the formula) including its salt. For example, the compound represented by the formula (II) and a salt thereof are simply referred to as compound (II).

Compound (I) can be produced, for example, by the method shown below. Production Method 1 As shown by the following formula, compound (I) can be produced by reacting compound (II) with compound (III).

Embedded image (Wherein each symbol has the same meaning as described above.) This reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include ether solvents (eg, ethyl ether, diisopropyl ether, dimethoxyethane,
Tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), aromatic solvents (eg, toluene, chlorobansen, xylene, etc.), acetonitrile, N, N-dimethylformylamide (DMF), acetone, Methyl ethyl ketone, dimethyl sulfoxide (DMSO), water and the like can be used alone or as a mixture thereof. Among them, acetonitrile, dichloromethane, chloroform and the like are preferable. This reaction is generally carried out by reacting 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (III) with compound (II). Reaction temperature is -20 ° C
To 50 ° C, preferably 0 ° C to room temperature, and the reaction time is usually 5 minutes to 100 hours. In addition, in this reaction, by allowing a base to coexist, the reaction sometimes proceeds more smoothly. As the base, both inorganic bases and organic bases are effective. Examples of inorganic bases include hydroxides, hydrides, carbonates, bicarbonates, and organic acid salts of alkali metals and alkaline earth metals. Among them, potassium carbonate, sodium carbonate, sodium hydroxide, hydroxide Potassium, sodium bicarbonate and potassium bicarbonate are preferred. Organic bases such as triethylamine
Secondary amines are preferred. The reactive derivative includes an acid anhydride,
Acid halides (eg, acid chloride, acid bromide), active esters and the like can be mentioned, among which acid halides are preferable.
The amount of the base to be used is generally 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (II).

When acylating from a carboxylic acid, 1 to 1.5 equivalents of carboxylic acid is added to 1 to 1 equivalent to 1 equivalent of compound (II) in an inert solvent (eg, a halogen-based solvent, acetonitrile). The reaction is carried out in the presence of a dehydration condensing agent such as 5 equivalents of dicyclohexylcarbodiimide (DCC). This reaction is usually performed at room temperature, and the reaction time is 0.5 to 24 hours. In the compound (II) used in this method, a divalent chain hydrocarbon group which may be substituted with a group other than the oxo group represented by E has a formula:

Embedded image (Wherein R ⁶ represents a substituent other than an oxo group), for example, a group represented by Synthetic Comm., 1991,
20,3167-3180. That is, it can be produced by the following method utilizing an addition reaction of an amine amide to an unsaturated bond.

Embedded image (Wherein each symbol has the same meaning as described above.) The substituent other than the oxo group represented by R ⁶ may be a divalent chain which may have a substituent other than the oxo group represented by E. It means a substituent other than an oxo group in a hydrocarbon group. It can be obtained by reacting the acrolein derivative (VI) with the compound (V), and then reacting the product with the compound (VIII) under reducing conditions. The reaction between compound (VI) and compound (V) is usually performed in a solvent inert to the reaction in the presence of a base. Examples of the base include: 1) a strong base such as an alkali metal or alkaline earth metal hydride (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an alkali metal or alkaline earth metal amide (Eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), lower alkoxides of alkali metals or alkaline earth metals (eg, , Sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.) 2) Inorganic bases such as hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, water Oxidized burrs Alkali metal or alkaline earth metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonate (eg, sodium bicarbonate, potassium bicarbonate, etc.) ), 3) Organic bases and the like, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0])
Amines such as -7-undecene) and DBN (1,5-diazabicyclo [4.3.0] non-5-ene), and basic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine. Can be Examples of the solvent include the solvents described in the reaction of compound (II) with compound (III), and these can be used alone or as a mixture. In this reaction, compound (VII) is obtained.

Examples of the reducing agent in the reaction between compound (VII) and compound (VIII) include sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like. The amount of these reducing agents to be used is generally 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound (VII).
Is equivalent. The reaction temperature is -20 to 50C, preferably 0.
C. to room temperature, and the reaction time is 0.5 to 24 hours.
The catalytic reduction method involves contacting a catalytic amount of a metal such as Raney nickel, platinum oxide, metallic palladium, or palladium-carbon with an inert solvent (for example, an alcoholic solvent such as methanol, ethanol, isopropanol, or t-butanol) at room temperature to 100 ° C. At a hydrogen pressure of 1 to 100 atm for 1 to 48 hours.
Compound (II) used in this method is, for example, Ch
em. Pharm. Bull. 47 (1) 28-36 (1999), JP-A-56-
53654 or the like or a method analogous thereto. Compound (III) used in this method is described, for example, in J. Am. Chem. Soc., 1950, 7
2,1415., J.Am.Chem.Soc., 1952,74,4549. And J.Org.Che.
m., 1956, 21, 1087. and the like, or a method analogous thereto. Production Method 2 As shown by the following formula, compound (I) can be produced by reacting compound (IV) with compound (V).

Embedded image (Wherein each symbol has the same meaning as described above.) This reaction is carried out, for example, by using ORGANIC FUNCTIONAL GROUP P.
REPARATIONS) 2nd edition, Academic Press (ACADEM)
IC PRESS, INC. ) Can be carried out according to the method described in the above. This reaction is usually performed in a solvent inert to the reaction.
Examples of such a solvent include alcohol solvents, ether solvents, halogen solvents, aromatic solvents, acetonitrile, N, N
-Dimethylformamide (DMF), acetone, methyl ethyl ketone, dimethylsulfoxide (DMSO) and the like can be used alone or as a mixture thereof. Among them, acetonitrile, dimethylformamide, acetone, ethanol and the like are preferable. The reaction temperature is usually from room temperature to 1
The reaction is carried out at 00 ° C, preferably at room temperature to 50 ° C, and the reaction time is usually 0.5 to 1 day. This reaction is usually, but not always, required to add 1 to 3 equivalents of the base to the compound (IV). As the base, the base used in the reaction between compound (II) and compound (III) can be used. Compound (IV) used as a raw material in this reaction can be synthesized from compound (III) by a known general method.

Production method 3 In the compound (I), E is a compound represented by the formula:

Embedded image (Wherein E ′ represents a group obtained by subtracting one carbon from E, and R ⁷ represents a hydrogen atom or a hydrocarbon group). The compound represented by the formula (IX) is represented by the following formula. And the compound represented by the formula (V) are reacted under reducing conditions.

Embedded image (Wherein each symbol has the same meaning as described above.) A group obtained by subtracting one carbon from E represented by E ′ is a divalent chain carbon which may have a substituent other than an oxo group. It is a hydrogen group, a group obtained by subtracting one carbon from E. Examples of the hydrocarbon group represented by R ⁷ include the substituents described as the substituents other than the oxo group in the divalent chain hydrocarbon group which may have a substituent other than the oxo group represented by E. Of the optionally substituted alkyl group, the optionally substituted aryl group, the optionally substituted cycloalkyl group, and the optionally substituted cycloalkenyl group, It means an unsubstituted alkyl group, aryl group, cycloalkyl group, cycloalkenyl group. In this reaction, compound (IX) and compound (V) are usually dissolved in a suitable solvent (eg, water, alcohol, ether, halogen, acetonitrile, a mixed solvent of two or more of these, etc.), , A compound in which a carbonyl group is added to an alkyl group (1-
5 equivalents, preferably 1 to 1.5 equivalents) and in the presence of a reducing agent. The reducing agent and other conditions are as described in Production Method 1
The described method is available. Compound (IV) used as a raw material in this reaction can be produced by a known general method using compound (III) as a raw material.

Production Method 4 In the compound (I), E is a compound represented by the formula:

Embedded image (Wherein E ″ represents a group obtained by subtracting two carbons from E, and R ⁸
Represents a hydrocarbon group. The compound represented by the formula (X)
And a compound represented by the formula (V).

Embedded image (Wherein each symbol has the same meaning as described above.) The group obtained by subtracting 2 carbon atoms from E represented by E ″ is a divalent linear hydrocarbon which may have a substituent other than an oxo group. A group obtained by subtracting 2 carbon atoms from E. Examples of the hydrocarbon group represented by R ⁸ include those described as the hydrocarbon group represented by R ⁷ . The solvent may be any of those described in the reaction of the compound (II) with the compound (III), in which case a Lewis acid such as a Lewis acid is used to accelerate the reaction. Anhydrous zinc chloride, anhydrous aluminum chloride, anhydrous iron (II) chloride, titanium tetrachloride, tin tetrachloride, cobalt chloride (II) chloride, boron trifluoride etherate or the above bases can be used as a catalyst. The reaction temperature is usually −40 ° C. Is 180 ° C.. Compounds used as the starting compound in the reaction (X) can be prepared by common methods known to the compound (III) as a raw material.

Production method 5 Compound (I) can be produced by reacting compound (XI) with compound (XII).

Embedded image (In the formula, X ′ represents a leaving group, and other symbols are as defined above.) As the leaving group represented by X ′, those described as the leaving group represented by X can be mentioned. . This reaction can be carried out according to the method of Production Method 2. Compound (XII) used as a raw material in this reaction can be produced from compound (V) by a known general method. Compound (XI) used as a raw material in this reaction is compound (II)
Compound (VIII) can be produced by reacting I) with compound (VIII) according to the method of Production Method 1. Production Method 6 As shown by the following formula, compound (I) can be produced by reacting a compound with compound (XIV).

Embedded image (In the formula, X ″ represents a leaving group, and other symbols have the same meanings as described above.) This reaction can be carried out according to the above Production Method 2.
Examples of the leaving group represented by X "include those described as the leaving group represented by X.

The compound (I) of the present invention can be used as a prophylactic / therapeutic agent for other HIV infections (in particular, a prophylactic / therapeutic agent for AIDS).
May be used in combination. In this case, these drugs are separately or simultaneously mixed and formulated with pharmacologically acceptable carriers, excipients, binders, diluents, and the like,
It can be orally or parenterally administered as a pharmaceutical composition for preventing or treating HIV infection. When formulating drugs separately, they can be administered separately by mixing them with a diluent at the time of use.However, the separately formulated products can be administered simultaneously or with a time lag. And may be separately administered to the same subject. A kit product for administering separately formulated products using a diluent or the like at the time of use (for example, mixing and dissolving a powdered ampoule containing each drug and two or more drugs at the time of use) Kits for injection containing diluents, etc.), separately formulated individual formulations,
Alternatively, kit products for administration to the same subject separately at different times (for example, tablets containing individual drugs are placed in the same or separate bags, and if necessary, a description column for the time of drug administration is provided. Further, a tablet kit for administering two or more tablets simultaneously or separately at a time interval, etc.) are also included in the pharmaceutical composition of the present invention. Specific examples of the preventive / therapeutic agent for other HIV infections used in combination with the compound (I) of the present invention include zidovudine, didanosine, zalcitabine, and lamivudine. ), Stavudine, abacavir, adefovir, adefovir, adefovir dipivoxil, fozivudine tidoxil, and other nucleic acid reverse transcriptase inhibitors; nevirapine, deravidin
rdine), efavirenz, lobride
viride), immunocal (immunocal), oltipraz (o
ltipraz) and non-nucleic acid reverse transcriptase inhibitors (including drugs having an antioxidant effect such as immunocal and oltipraz); saquinavir (sa
quinavir), ritonavir (ritonavir), indinavir (indinavir), nelfinavir (nelfinavir), amprenavir (amprenavir), parinavir (palinavi)
r), protease inhibitors such as lasinavir; and the like.

Examples of the nucleic acid reverse transcriptase inhibitors include zidovudine, didanosine, zalcitabine, and lamivudin.
e), stavudine and the like are preferable, and as a non-nucleic acid reverse transcriptase inhibitor, nevirapin (nevirapin)
e), delavirdine and the like are preferred, and as the protease inhibitor, saquinavir (saquinavirin)
r), ritonavir, indinavir
vir), nelfinavir and the like. The compound (I) of the present invention may be, for example, CXC which is a second receptor for T cell-directed HIV-1 in addition to the above-mentioned protease inhibitors, nucleic acid reverse transcriptase inhibitors, etc.
R4 antagonists (eg, AMD-3100 etc.), HIV-
It can be used in combination with an antibody against one surface antigen or an HIV-1 vaccine. Since the compound (I) of the present invention has CCR antagonism, particularly strong CCR5 antagonism, various HIV infections in humans,
For example, it is used for the prevention and treatment of AIDS. The compound (I) of the present invention has low toxicity and can be used safely. The compound (I) of the present invention can be used as a CCR5 antagonist, for example, a prophylactic or therapeutic agent for AIDS and an agent for suppressing the progression of AIDS pathology. The daily dose of compound (I) varies depending on the condition and weight of the patient, and the method of administration.
0Kg) About 5 to 1000 mg, preferably about 10 to 600 mg as active ingredient [compound (I)] per person
And more preferably about 10 to 300 mg;
Particularly preferred is about 15 to 150 mg, which is administered once or twice or three times a day.

When compound (I) is used in combination with a reverse transcriptase inhibitor and / or a protease inhibitor, the dose of the reverse transcriptase inhibitor or the protease inhibitor may be, for example, about 1 times the usual dose. / 200 to 1
/ 2 or more and about 2 to 3 times or less. In addition, when two or more drugs are used in combination, when one drug affects the metabolism of another drug, the dose of each drug is appropriately adjusted. The dose at the time of single administration of the drug is used. Typical dosages of typical reverse transcriptase inhibitors and protease inhibitors are, for example, as follows. Zidovudine: 100 mg didanosine: 125 to 200 mg zalcitabine: 0.75 mg lamivudine: 150 mg stavudine: 30 to 40 mg saquinavir: 600 mg ritonavir: 600 mg indinavir: 800 mg nelfinavir: 750 mg Further, compound (I) and a reverse transcriptase inhibitor or / and protease inhibitor Specific embodiments when using in combination with an agent are shown below. Adult (weight 50Kg) 1
About 10 to 300 mg of compound (I) is administered to the same subject in combination with about 50 to 200 mg of zidovudine per person. The individual drugs may be administered at the same time, or may be administered with a time difference of 12 hours or less. Compound (I) per adult (50 kg body weight)
About 10 to 300 mg of saquinavir is about 300 to 1200.
It is administered to the same subject in the form of a combination with mg. The individual drugs may be administered at the same time, or may be administered with a time difference of 12 hours or less.

[0033]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Examples, reference examples, experimental examples,
The present invention will be described in more detail by showing formulation examples. However, these are merely examples and do not limit the present invention in any way. The genetic manipulation methods described below are
niatis et al., Molecular Cloning, Cold Spring
Harbor Laboratory, 1989) or according to the protocol attached to the reagent.

EXAMPLES Example 1 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
Oxo -N- phenyl-3-pyrrolidinecarboxamide hydrochloride of the compound obtained in Reference Example 3 (400 mg, 80 from pure ¹ H NMR
%), 4-benzylpiperidine (0.239 ml, 1.4 mmol), potassium iodide (225 mg, 1.4 mmol), potassium carbonate (282 mg, 2.0 m
mol) and acetonitrile (20 ml) was stirred at 100 ° C. for 24 hours. The reaction solution was concentrated under reduced pressure, water (15 ml) was added to the residue, and the mixture was extracted with ethyl acetate (30 ml × 3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 10 g, ethyl acetate / methanol =
1/0 → 9/1). After the target fraction was concentrated under reduced pressure, the residue was dissolved in diethyl ether, 1N hydrogen chloride (diethyl ether solution, 2 ml) was added, and the precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried under reduced pressure to give the title compound (282
mg, 0.6 mmol, yield 44%) as a hygroscopic pale yellow amorphous. ¹ H NMR (D ₂ O) δ 1.35-1.65 (2H, m), 1.75-2.1 (5H,
m), 2.45 (1H, dd, J = 8.7, 17.7Hz), 2.55-2.75 (1H,
m), 2.63 (2H, d, J = 6.8Hz), 2.77 (3H, s), 2.8-3.0
(2H, m), 3.0-3.7 (7H, m), 3.75-3.9 (2H, m), 7.2-7.
45 (7H, m), 7.45-7.65 (3H, m). Anal.Calcd for C ₂₇ H ₃₅ N ₃ O ₂・ HCl ・ 0.5H ₂ O: C, 67.69;
H, 7.78; Cl, 7.40; N, 8.77. Found: C, 67.58; H, 7.
75; Cl, 7.17; N, 8.59.

Example 2 1-methyl-5-oxo-N-phenyl-N- [3- (1-piperidinyl)
[Propyl] -3-pyrrolidinecarboxamide hydrochloride The same reaction and purification treatment as in Example 1 was performed using piperidine to obtain the title compound. Yield 48%. ¹ H NMR (D ₂ O) δ 1.3-2.1 (8H, m), 2.46 (1H, dd, J =
9.0, 17.2Hz), 2.66 (1H, dd, J = 6.0, 17.2Hz), 2.75-3.
2 (4H, m), 2.78 (3H, s), 3.2-3.65 (3H, m), 3.42 (1
H, t, J = 10.0Hz), 3.57 (1H, dd, J = 5.5, 10.0Hz), 3.7
5-3.95 (2H, m), 7.3-7.4 (2H, m), 7.5-7.7 (3H, m). Anal.Calcd for C ₂₀ H ₂₉ N ₃ O ₂・ HCl ・ 0.2H ₂ O: C, 62.63 ;
H, 7.99; Cl, 9.24; N, 10.96. Found: C, 62.63; H,
7.80; Cl, 9.19; N, 10.99. Example 3 N- {3- [cyclohexyl (methyl) amino] propyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide hydrochloride N-methylcyclohexyl The same reaction and purification treatment as in Example 1 were carried out using luminamine to obtain the title compound. Yield 12%. ¹ H NMR (D ₂ O) δ 1.0-2.1 (12H, m), 2.47 (1H, dd, J =
9.7, 17.1Hz), 2.65 (1H, dd, J = 6.1, 17.1Hz), 2.78
(3H + 3H, s), 3.0-3.5 (4H, m), 3.43 (1H, t, J = 9.7H
z), 3.57 (1H, dd, J = 5.4, 9.7Hz), 3.7-4.0 (2H, m),
7.3-7.45 (2H, m), 7.5-7.65 (3H, m). Anal.Calcd for C ₂₂ H ₃₃ N ₃ O ₂・ HCl ・ 0.8H ₂ O: C, 62.56;
H, 8.50; Cl, 8.39; N, 9.95. Found: C, 62.46; H, 8.
48; Cl, 8.34; N, 9.86.

EXAMPLE 4 1-Methyl-5-oxo-N-phenyl-N- [3- (1,2,3,4-tetrahydro-2-isoquinolyl) propyl] -3-pyrrolidinecarboxamide hydrochloride 1,2 The same reaction and purification treatment as in Example 1 were performed using, 3,4-tetrahydroisoquinoline to obtain the title compound. Yield 39
%. ¹ H NMR (D ₂ O) δ 2.0-2.2 (2H, m), 2.44 (1H, dd, J =
9.8, 16.8Hz), 2.55-2.75 (1H, m), 2.77 (3H, s), 3.1-
3.7 (9H, m), 3.75-4.0 (2H, m), 4.45 (2H, s), 7.15-
7.45 (6H, m), 7.45-7.7 (3H, m). Anal.Calcd for C ₂₄ H ₂₉ N ₃ O ₂・ HCl ・ 1.1H ₂ O: C, 64.37;
H, 7.25; Cl, 7.92; N, 9.38. Found: C, 64.35; H, 7.
08; Cl, 7.49; N, 9.33.Example 5 1-methyl-5-oxo-N-phenyl-N- [3- (1,2,4,5-tetrahydro-3H-3-benzazepine-3- Il) propyl] -3-pyrrolidinecarboxamide fumarate The same reaction and purification treatment as in Example 1 was carried out using 1,2,4,5-tetrahydro-3H-3-benzazepine to obtain the title compound. Yield 33%. ¹ H NMR (D ₂ O) δ 1.9-2.15 (2H, m), 2.45 (1H, dd, J =
9.5, 17.9Hz), 2.65 (1H, dd, J = 5.7, 17.9Hz), 2.76
(3H, s), 2.95-3.4 (9H, m), 3.41 (1H, t, J = 9.8Hz),
3.56 (1H, dd, J = 5.3, 9.8Hz), 3.6-3.95 (4H, m), 6.6
2 (2H, s), 7.28 (4H, s), 7.3-7.4 (2H, m), 7.45-7.6
5 (3H, m). Anal.Calcd for C ₂₅ H ₃₁ N ₃ O ₂・ C ₄ H ₄ O ₄・ 0.2H ₂ O: C, 66.3
2; H, 6.79; N, 8.00. Found: C, 66.23; H, 6.71; N,
7.95.

Example 6 Using 1-methyl-5-oxo-N-phenyl-N- [3- (4-phenyl-1-piperidinyl) propyl] -3-pyrrolidinecarboxamide fumarate 4-phenylpiperidine hydrochloride The same reaction and purification treatment as in Example 1 were performed to obtain the title compound. Yield 42%. ¹ H NMR (D ₂ O) δ 1.7-2.3 (6H, m), 2.45 (1H, dd, J =
9.0, 17.3Hz), 2.65 (1H, dd, J = 5.7, 17.3Hz), 2.77 (3
H, s), 2.8-4.0 (12H, m), 6.67 (2H, s), 7.25-7.65
(10H, m). Anal.Calcd for C ₂₆ H ₃₃ N ₃ O ₂・ C ₄ H ₄ O ₄・ 0.8H ₂ O: C, 65.5
1; H, 7.07; N, 7.64. Found: C, 65.53; H, 6.97; N,
7.65. Example 7 N- [3- (4-acetamido-4-phenyl-1-piperidinyl) propyl] -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide hydrochloride 4-acetamido-4- The same reaction and purification treatment as in Example 1 were performed using phenylpiperidine hydrochloride to obtain the title compound. Yield 40%. ¹ H NMR (D ₂ O) δ 1.85-2.8 (8H, m), 2.07 (3H, s), 2.
77 (3H, s), 3.1-3.7 (9H, m), 3.7-4.0 (2H, m), 7.25
-7.7 (10H, m). Anal. Calcd for C ₂₈ H ₃₆ N ₄ O ₃・ HCl ・ 1.4H ₂ O: C, 62.48;
H, 7.45; Cl, 6.59; N, 10.41. Found: C, 62.56; H,
7.23; Cl, 7.02; N, 10.11. Example 8 N- [3- (indene-1-spiro-4'-piperidin-1'-yl) propyl] -1-methyl-5-oxo-N-phenyl- 3-Pyrrolidinecarboxamide fumarate The same reaction and purification treatment as in Example 1 was performed using indene-1-spiro-4'-piperidine to obtain the title compound. Yield 43
%. ¹ H NMR (D ₂ O) δ 1.45-1.65 (2H, m), 1.95-2.2 (2H,
m), 2.3-2.55 (3H, m), 2.67 (1H, dd, J = 6.2, 17.2H
z), 2.77 (3H, s), 3.2-3.45 (5H, m), 3.42 (1H, t, J
= 9.8Hz), 3.59 (1H, dd, J = 5.4, 9.8Hz), 3.65-3.8 (2
H, m), 3.8-3.95 (2H, m), 6.63 (2H, s), 6.97 (1H, d,
J = 5.8Hz), 7.02 (1H, d, J = 5.8Hz), 7.25-7.7 (9H,
m). Anal.Calcd for C ₂₈ H ₃₃ N ₃ O ₂・ C ₄ H ₄ O ₄・ 1.0H ₂ O: C, 66.5
3; H, 6.80; N, 7.27. Found: C, 66.60; H, 6.62; N,
7.30.

Example 9 N- (3- {4- [hydroxy (diphenyl) methyl] -1-piperidinyl} propyl) -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide 4- [hydroxy ( The same reaction and purification treatment as in Example 1 were carried out using diphenyl) methyl] piperidine to obtain the title compound. Yield 51%. ¹ H NMR (CDCl ₃ ) δ 1.35-2.55 (12H, m), 2.6-2.8 (1H,
m), 2.76 (3H, s), 2.8-3.15 (3H, m), 3.17 (1H, t,
J = 9.1Hz), 3.55-3.8 (3H, m), 7.05-7.55 (15H, m). Anal.Calcd for C ₃₃ H ₃₉ N ₃ O ₃・ 0.6H ₂ O: C, 73.88; H, 7.
55; N, 7.83. Found: C, 73.81; H, 7.58; N, 7.83. Example 10 N- [3- (4-benzyl-1-piperazinyl) propyl] -1-methyl
-5-oxo-N-phenyl-3-pyrrolidinecarboxamide 2
The same reaction and purification treatment as in Example 1 were performed using 1-benzylpiperazine hydrochloride to give the title compound. Yield 51%. ¹ H NMR (D ₂ O) δ 1.9-2.1 (2H, m), 2.44 (1H, dd, J =
9.2, 17.1Hz), 2.64 (1H, dd, J = 6.5, 17.1Hz), 2.76 (3
H, s), 3.15-3.7 (13H, m), 3.7-4.0 (2H, m), 4.38 (2
H, s), 7.3-7.4 (2H, m), 7.45-7.65 (8H, m). Anal.Calcd for C ₂₆ H ₃₄ N ₄ O ₂・ 2HCl ・ 1.2H ₂ O: C, 59.02;
H, 7.31; Cl, 13.40; N, 10.59. Found: C, 59.00; H,
7.34; Cl, 13.36; N, 10.49.Example 11 1-methyl-5-oxo-N-phenyl-N- [3- (1-piperazinyl)
Propyl] -3-pyrrolidinecarboxamide N- [3- (4-benzyl-1-piperazinyl) propyl] -1-methyl
-5-oxo-N-phenyl-3-pyrrolidinecarboxamide (46
3 mg, 1.1 mmol) was dissolved in methanol (10 ml), palladium hydroxide-carbon (20%, 93 mg) was added, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The insoluble material was separated by filtration, and the insoluble material was washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (364 mg,
1.1 mmol, yield 99%) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.6-1.85 (2H, m), 2.15-2.6 (9H,
m), 2.6-2.9 (3H, m), 2.77 (3H, s), 2.95-3.2 (1H,
m), 3.19 (1H, t, J = 8.9Hz), 3.64 (1H, dd, J = 6.8, 8.
9Hz), 3.65-3.8 (2H, m), 7.1-7.2 (2H, m), 7.3-7.55
(3H, m).

Example 12 N- [3- (4-benzoyl-1-piperazinyl) propyl] -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide
Fumarate Compound (192 mg, 0.56 mmol) obtained in Example 11, triethylamine (0.101 ml, 0.72 mmol) was dissolved in THF (5 ml),
Under ice cooling, benzoyl chloride (0.078 ml, 0.67 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (15 ml) was added, and the mixture was extracted with ethyl acetate (30 ml × 3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 10 g, ethyl acetate / methanol = 1/0 → 9/1 → 4/1). The target fraction was concentrated under reduced pressure to obtain N- [3- (4-benzoyl-1-piperazinyl) propyl] -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide (221 mg, 0.49 mmol). The obtained compound was dissolved in methanol, fumaric acid (57 mg, 0.49 mmol) was added, the mixture was concentrated under reduced pressure, diethyl ether was added, and the precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried under reduced pressure to give the title compound (228 mg, 0.40 mmol, yield 72%) as a hygroscopic pale yellow amorphous. ¹ H NMR (D ₂ O) δ 1.9-2.15 (2H, m), 2.44 (1H, dd, J =
9.0, 17.6Hz), 2.65 (1H, dd, J = 6.0, 17.6Hz), 2.76
(3H, s), 3.1-4.0 (15H, m), 6.63 (2H, s), 7.3-7.4
(2H, m), 7.4-7.65 (8H, m). Anal.Calcd for C ₂₆ H ₃₂ N ₄ O ₃・ C ₄ H ₄ O ₄・ 0.9H ₂ O: C, 62.0
3; H, 6.56; N, 9.65. Found: C, 61.97; H, 6.36; N,
9.35. Example 13 N- {3- [4- (4-fluorobenzoyl) -1-piperidinyl] propyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide 4- (4-fluoro The same reaction and purification treatment as in Example 1 were carried out using benzoyl) piperidine hydrochloride to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.56-1.90 (6H, m), 1.97-2.44 (5
H, m), 2.60-2.80 (4H, m), 2.85-3.26 (5H, m), 3.58-
3.80 (3H, m), 7.06-7.20 (4H, m), 7.34-7.53 (3H, m
m), 7.95 (2H, dd, J = 5.1, 8.8Hz).

Example 14 N- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide 4- ( The same reaction and purification treatment as in Example 1 were carried out using 4-chlorophenyl) -4-hydroxypiperidine to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.44-1.95 (7H, m), 2.03-2.91 (10
H, m), 2.97-3.25 (3H, m), 3.60-3.84 (3H, m), 7.13-
7.54 (9H, m). Example 15 N- {3- [4- (4-fluorophenyl) -1-piperazinyl] propyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide 1- The same reaction and purification treatment as in Example 1 were performed using (4-fluorophenyl) piperazine to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.56-1.87 (2H, m), 2.16-2.84 (11
H, m), 2.93-3.26 (6H, m), 3.56-3.84 (3H, m), 6.69-
7.21 (6H, m), 7.29-7.52 (3H, m). Example 16 N- {3- [4- (diphenylmethyl) -1-piperazinyl] propyl} -1-methyl-5-oxo-N-phenyl The same reaction and purification treatment as in Example 1 was performed using -3-pyrrolidinecarboxamide 1- (diphenylmethyl) piperazine to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.60-1.86 (2H, m), 2.12-2.50 (11
H, m), 2.58-2.80 (4H, m), 2.94-3.21 (2H, m), 3.55-
3.77 (3H, m), 4.19 (1H, s), 7.07-7.30 (8H, m), 7.3
Example 17 N- {4- [4- (4-fluorobenzoyl) -1-piperidinyl] butyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide Compound obtained in Reference Example 4 and 4- (4-fluorobenzoyl)
The same reaction and purification treatment as in Example 1 were performed using piperidine hydrochloride to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.39-1.64 (4H, m), 1.71-2.43 (9
H, m), 2.60-2.80 (4H, m), 2.86-3.27 (5H, m), 3.59-
3.68 (3H, m), 7.06-7.20 (4H, m), 7.35-7.53 (3H,
m), 7.97 (2H, dd, J = 5.5, 8.9Hz).

Example 18 N- {4- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] butyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide Reference Example 4 Using the compound obtained in the above and 4- (4-chlorophenyl) -4-hydroxypiperidine, the same reaction and purification treatment as in Example 1 were performed to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.42-1.93 (7H, m), 1.97-2.52 (7
H, m), 2.56-2.89 (6H, m), 2.95-3.25 (2H, m), 3.55-
3.81 (3H, m), 7.07-7.20 (2H, m), 7.23-7.56 (7H,
m). Example 19 N- {4- [4- (4-fluorophenyl) -1-piperazinyl] butyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide Obtained in Reference Example 4. Using the compound thus obtained and 1- (4-fluorophenyl) piperazine, the same reaction and purification treatment as in Example 1 were performed to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.46-1.64 (4H, m), 2.23 (1H, dd,
J = 9.2, 16.9Hz), 2.33-2.46 (2H, m), 2.53-2.80 (8H,
m), 3.00-3.24 (6H, m), 3.60-3.80 (3H, m), 6.81-7.
02 (4H, m), 7.11-7.20 (2H, m), 7.35-7.53 (3H, m). Example 20 N- {4- [4- (diphenylmethyl) -1-piperazinyl] butyl}-
1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide Using the compound obtained in Reference Example 4 and 1- (diphenylmethyl) piperazine, the same reaction and purification treatment as in Example 1 were performed to give the title compound. I got ¹ H NMR (CDCl ₃ ) δ 1.35-1.62 (4H, m), 2.08-2.53 (11
H, m), 2.58-2.80 (4H, m), 2.93-3.22 (2H, m), 3.54-
3.77 (3H, m), 4.20 (1H, s), 7.06-7.51 (15H, m).

Example 21 N- {5- [4- (4-Fluorobenzoyl) -1-piperidinyl] pentyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide Obtained in Reference Example 5. Compound and 4- (4-fluorobenzoyl)
The same reaction and purification treatment as in Example 1 were performed using piperidine hydrochloride to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.22-1.63 (6H,
m), 1.68-1.92 (4H, m), 1.
97-2.40 (5H, m), 2.60-2.8
0 (4H, m), 2.91-3.28 (5H,
m), 3.58-3.76 (3H, m),
7.06-7.21 (4H, m), 7.35-
7.53 (3H, m), 7.96 (2H, d
d, J = 5.5, 8.8 Hz). Example 22 N- {2- [4- (4-fluorobenzoyl) -1-piperidinyl] ethyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide fumarate In Reference Example 6-4 Using the obtained compound and 4- (4-fluorobenzoyl) piperidine hydrochloride, the same reaction and purification treatment as in Example 1 were performed to obtain the title compound. Yield 20%. ¹ H NMR (D ₂ O) δ 1.75-2.3 (4H, m), 2.43 (1H, dd, J =
9.4, 17.6Hz), 2.55-2.75 (1H, m), 2.76 (3H, s), 3.0
5-4.0 (10H, m), 4.05-4.3 (2H, m), 6.66 (2H, s), 7.2
9 (2H, t, J = 8.8Hz), 7.3-7.45 (2H, m), 7.45-7.65 (3
H, m), 8.06 (2H , dd, J = 5.5, 8.7Hz) Anal Calcd for C 26 H 30 FN 3 O 3 · C 4 H 4 O 4 · 1.5H 2 O:.. C, 60.6
0; H, 6.27; N, 7.07. Found: C, 60.68; H, 6.13; N,
7.15.

Example 23 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-
Dichlorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 7, the same reaction and purification treatment as in Example 1 were performed to obtain the title compound. Yield 69%. ¹ H NMR (D ₂ O) δ 1.35-1.65 (2H, m), 1.75-2.1 (5H,
m), 2.47 (1H, dd, J = 9.4, 18.0Hz), 2.55-2.75 (1H,
m), 2.65 (2H, d, J = 7.2Hz), 2.75-3.2 (4H, m), 2.79
(3H, s), 3.2-3.7 (5H, m), 3.7-3.9 (2H, m), 7.25-7.
45 (6H, m), 7.63 (1H, d, J = 2.2Hz), 7.72 (1H, d, J =
8.4Hz). Anal. Calcd for C ₂₇ H ₃₃ Cl ₂ N ₃ O ₂・ HCl ・ 0.7H ₂ O: C, 58.8
0; H, 6.47; Cl, 19.28; N, 7.62. Found: C, 58.77; H,
6.41; Cl, 18.91; N, 7.56. Example 24 N- (3,4-dichlorophenyl) -N- {3- [4- (4-fluorobenzoyl) -1-piperidinyl] propyl} -1-methyl-5 -Oxo-3
-Pyrrolidinecarboxamide hydrochloride The compound obtained in Reference Example 7 and 4- (4-fluorobenzoyl)
The same reaction and purification treatment as in Example 1 were performed using piperidine hydrochloride to obtain the title compound. Yield 68%. ¹ H NMR (D ₂ O) δ 1.7-2.3 (6H, m), 2.4-2.75 (2H, m),
2.79 (3H, s), 3.0-4.0 (12H, m), 7.2-7.4 (3H, m),
7.6-7.8 (2H, m), 8.0-8.15 (2H, m). Anal.Calcd for C ₂₇ H ₃₀ Cl ₂ FN ₃ O ₃・ HCl ・ 0.4H ₂ O: C, 56.0
9; H, 5.54; Cl, 18.40; N, 7.27. Found: C, 56.14; H,
5.66; Cl, 17.80; N, 7.22.

Example 25 N- [3- (4-benzylidene-1-piperidinyl) propyl] -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide hydrochloride Obtained in Reference Example 8-2 Compound (274 mg, 1.0 mmol), 4-benzylidenepiperidine hydrochloride (231 mg, 1.10 mmol), THF (10 m
l) in a mixture of triethylamine (0.209 ml, 1.5 mmol), sodium triacetoxyborohydride (318 mg, 1.5 mmol)
Were added in order, and the mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium bicarbonate (15m
l) and water (10 ml) were added, and the mixture was extracted with ethyl acetate (20 ml × 3).
The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 10 g, ethyl acetate / methanol = 1/0 → 9/1 → 6/1). The target fraction was concentrated under reduced pressure, the residue was dissolved in methanol, and 1N hydrogen chloride was added.
(Diethyl ether solution, 2 ml) and concentrated under reduced pressure.
Diethyl ether was added to the residue, and the precipitate was collected by filtration.
The precipitate was washed with diethyl ether and dried under reduced pressure to give the title compound (380 mg, 0.81 mmol, yield 81%) as a hygroscopic pale yellow amorphous. ¹ H NMR (D ₂ O) δ 1.9-2.15 (2H, m), 2.3-4.0 (17H,
m), 2.78 (3H, s), 6.61 (1H, s), 7.25-7.65 (10H,
m). Anal. Calcd for C ₂₇ H ₃₃ N ₃ O ₂・ HCl ・ 0.7H ₂ O: C, 67.47;
H, 7.42; Cl, 7.38; N, 8.74. Found: C, 67.48; H, 7.
44; Cl, 7.40; N, 8.70. Example 26 1-Methyl-5-oxo-N- [3- (4-phenoxy-1-piperidinyl) propyl] -N-phenyl-3-pyrrolidinecarboxamide hydrochloride 4- The same reaction and purification treatment as in Example 25 were performed using phenoxypiperidine hydrochloride to obtain the title compound. Yield 78%. ¹ H NMR (DMSO-d ₆ ) δ 1.7-2.35 (7H, m), 2.35-2.55 (1
H, m), 2.63 (3H, s), 2.85-3.85 (11H, m), 4.4-4.8
(1H, m), 6.9-7.1 (3H, m), 7.2-7.6 (7H, m). Anal.Calcd for C ₂₆ H ₃₃ N ₃ O ₃・ HCl ・ 0.8H ₂ O: C, 64.20;
H, 7.38; Cl, 7.29; N, 8.64. Found: C, 64.17; H, 7.
50; Cl, 7.99; N, 8.66.

Example 27 1-Methyl-5-oxo-N-phenyl-N- (3- {4-[(E) -2-phenylethenyl] -1-piperidinyl} propyl) -3-pyrrolidinecarboxamide hydrochloride The same reaction and purification treatment as in Example 25 were carried out using 4-[(E) -2-phenylethenyl] piperidine hydrochloride to obtain the title compound. 89% yield. ¹ H NMR (D ₂ O) δ 1.55-1.9 (2H, m), 1.9-2.2 (5H, m),
2.46 (1H, dd, J = 9.3, 17.2Hz), 2.66 (1H, dd, J = 6.3,
17.2Hz), 2.78 (3H, s), 2.85-3.75 (9H, m), 3.75-3.9
5 (2H, m), 6.30 (1H, dd, J = 6.5, 16.0Hz), 6.56 (1H,
d, J = 16.0Hz), 7.25-7.65 (10H, m). Anal.Calcd for C ₂₈ H ₃₅ N ₃ O ₂・ HCl ・ 0.6H ₂ O: C, 68.23;
H, 7.61; Cl, 7.19; N, 8.53. Found: C, 68.18; H, 7.
44; Cl, 7.20; N, 8.52. Example 28 1-Methyl-5-oxo-N- [3- (4-phenethyl-1-piperidinyl) propyl] -N-phenyl-3-pyrrolidinecarboxamide hydrochloride 4- The same reaction and purification treatment as in Example 25 were performed using phenethylpiperidine hydrochloride to obtain the title compound. Yield 62%. ¹ H NMR (D ₂ O) δ 1.3-1.85 (5H, m), 1.85-2.15 (4H,
m), 2.45 (1H, dd, J = 8.7, 17.7Hz), 2.55-3.65 (12H,
m), 2.77 (3H, s), 3.75-3.95 (2H, m), 7.2-7.45 (7H,
m), 7.5-7.65 (3H, m). Anal.Calcd for C ₂₈ H ₃₇ N ₃ O ₂・ HCl ・ 1.0H ₂ O: C, 66.98;
H, 8.03; Cl, 7.06; N, 8.37. Found: C, 66.99; H, 8.
10; Cl, 7.52; N, 8.31. Example 29 N- {3- [4- (benzyloxy) -1-piperidinyl] propyl}-
Example 25 using 1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide hydrochloride 4- (benzyloxy) piperidine hydrochloride
The same reaction and purification treatments as described above were performed to obtain the title compound. yield
75%. ¹ H NMR (D ₂ O) δ 1.7-2.4 (6H, m), 2.46 (1H, dd, J =
8.8, 17.4Hz), 2.66 (1H, dd, J = 6.1, 17.4Hz), 2.78 (3
H, s), 3.0-3.65 (9H, m), 3.75-4.0 (3H, m), 4.64 (2
H, s), 7.3-7.45 (2H, m), 7.45 (5H, s), 7.5-7.65 (3
H, m). Anal. Calcd for C ₂₇ H ₃₅ N ₃ O ₃・ HCl ・ 0.6H ₂ O: C, 65.27;
H, 7.55; Cl, 7.14; N, 8.46. Found: C, 65.27; H, 7.
63; Cl, 7.14; N, 8.51.

Example 30 N- {3- [4- (diphenylmethyl) -1-piperidinyl] propyl} -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide fumarate 4- (diphenylmethyl) Example using piperidine hydrochloride
The same reaction and purification treatment as in 25 were performed to obtain the title compound. Yield 70%. ¹ H NMR (DMSO-d ₆ ) δ 1.0-1.3 (2H, m), 1.3-1.75 (4H,
m), 1.95-2.55 (5H, m), 2.62 (3H, s), 2.8-3.1 (3H,
m), 3.13 (1H, t, J = 9.2Hz), 3.37 (1H, dd, J = 6.1,
9.2Hz), 3.5-3.7 (4H, m), 3.54 (1H, d, J = 11.0Hz),
6.57 (2H, s), 7.05-7.55 (15H, m). Anal.Calcd for C ₃₃ H ₃₉ N ₃ O ₂・ C ₄ H ₄ O ₄・ 0.3H ₂ O: C, 70.4
1; H, 6.96; N, 6.66. Found: C, 70.48; H, 7.06; N,
6.67. Example 31 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-N- (4-methylphenyl) -5-oxo-3-pyrrolidinecarboxamide hydrochloride 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid (358 mg, 2.
Oxalyl chloride (0.256 ml, 3.0 mmol) was added to a mixture of 5 mmol), DMF (0.023 ml), and dichloromethane (10 ml) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes and while rising to room temperature for 1 hour. The resulting solution was prepared using the compound obtained in Reference Example 9 (395 m
g, 1.0 mmol), triethylamine (1.39 ml, 10 mmol), and a mixture of dichloromethane (15 ml) with stirring at −20 ° C.
The mixture was stirred for 1 hour while being raised. Saturated aqueous sodium bicarbonate (15 ml)
After adding and removing the organic solvent under reduced pressure, the mixture was extracted with ethyl acetate (15 ml × 3).
And washed in order. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 1).
0 g, ethyl acetate / methanol = 1/0 → 9/1). The target fraction was concentrated under reduced pressure, the residue was dissolved in methanol, and 1N hydrogen chloride (diethyl ether solution, 2 ml) was added, followed by concentration under reduced pressure. Diethyl ether was added to the residue, and the precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried under reduced pressure to give the title compound (409 mg, 0.84 mmol, yield 85%) as a hygroscopic pale yellow amorphous. ¹ H NMR (DMSO-d ₆ ) δ 1.3-1.95 (7H, m), 2.11 (1H, d
d, J = 9.9, 16.5Hz), 2.3-2.6 (3H, m), 2.35 (3H, s),
2.6-3.5 (9H, m), 2.63 (3H, s), 3.5-3.75 (2H, m), 7.
1-7.4 (9H, m). Anal.Calcd for C ₂₈ H ₃₇ N ₃ O ₂・ HCl ・ 0.6H ₂ O: C, 67.96;
H, 7.98; Cl, 7.16; N, 8.49. Found: C, 67.99; H, 7.
94; Cl, 7.45; N, 8.28.

Example 32 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (4-ter
(t-butylphenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 11, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. 75% yield. ¹ H NMR (DMSO-d ₆ ) δ 1.31 (9H, s), 1.35-1.95 (7H,
m), 2.11 (1H, dd, J = 9.6, 16.4Hz), 2.35-2.6 (3H,
m), 2.6-3.5 (9H, m), 2.63 (3H, s), 3.55-3.75 (2H,
m), 7.1-7.4 (7H, m), 7.51 (2H, d, J = 8.4Hz). Anal.Calcd for C ₃₁ H ₄₃ N ₃ O ₂・ HCl ・ 0.6H ₂ O: C, 69.34;
H, 8.48; Cl, 6.60; N, 7.83. Found: C, 69.27; H, 8.
52; Cl, 6.40; N, 7.82. Example 33 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (5-indanyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide Hydrochloride The same reaction and purification treatment as in Example 31 were carried out using the compound obtained in Reference Example 12 to obtain the title compound. Yield 69%. ¹ H NMR (D ₂ O) δ 1.44-1.58 (2H, m), 1.88-2.14 (7H,
m), 2.44-2.49 (1H, m), 2.60-2.69 (3H, m), 2.77 (3H,
s), 2.81-2.98 (6H, m), 3.06-3.14 (2H, m), 3.28-3.5
3 (5H, m), 3.76-3.82 (2H, m), 7.08 (1H, d, J = 8.2H
z), 7.22-7.43 (7H, m). Anal.Calcd for C ₃₀ H ₃₉ N ₃ O ₂・ HCl ・ 1.5H ₂ O: C, 67.08;
H, 8.07; N, 7.82. Found: C, 67.19; H, 7.97; N, 8.0
1. Example 34 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (4-methoxyphenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride obtained in Reference Example 13. The same reaction and purification treatment as in Example 31 were performed using the obtained compound to obtain the title compound. Yield 88%. ¹ H NMR (D ₂ O) δ 1.35-1.65 (2H, m), 1.75-2.1 (5H,
m), 2.45 (1H, dd, J = 9.7, 17.7Hz), 2.55-2.75 (1H,
m), 2.63 (2H, d, J = 7.0Hz), 2.75-3.0 (2H, m), 2.78
(3H, s), 3.0-3.2 (2H, m), 3.2-3.65 (5H, m), 3.7-3.
9 (2H, m), 3.89 (3H, s), 7.13 (2H, d, J = 8.8Hz), 7.
2-7.45 (7H, m). Anal. Calcd for C ₂₈ H ₃₇ N ₃ O ₃・ HCl ・ 0.6H ₂ O: C, 65.83;
H, 7.73; Cl, 6.94; N, 8.22. Found: C, 65.79; H, 7.
70; Cl, 6.98; N, 8.06.

Example 35 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-
(Dimethoxyphenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 14, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. Yield 78%. ¹ H NMR (D ₂ O) δ 1.35-1.7 (2H, m), 1.7-2.1 (5H, m),
2.46 (1H, dd, J = 8.6,17.4Hz), 2.55-2.75 (1H, m),
2.63 (2H, d, J = 6.0Hz), 2.75-4.1 (11H, m), 2.79 (3
H, s), 3.89 (3H, s), 3.92 (3H, s), 6.9-7.1 (2H,
m), 7.15 (1H, d, J = 8.2Hz), 7.2-7.5 (5H, m). Anal.Calcd for C ₂₉ H ₃₉ N ₃ O ₄・ HCl ・ 0.7H ₂ O: C, 64.18;
H, 7.69; Cl, 6.53; N, 7.74. Found: C, 64.21; H, 7.
69; Cl, 6.65; N, 7.77.Example 36 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-
Diethoxyphenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 15, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. Yield 78%. ¹ H NMR (D ₂ O) δ 1.40-1.52 (8H, m), 1.82-2.00 (5H,
m), 2.46-2.64 (5H, m), 2.70-2.95 (5H, m), 3.07-3.14
(2H, m), 3.30-3.56 (6H, m), 4.10-4.22 (4H, m), 6.9
1-7.02 (2H, m), 7.13-7.17 (1H, m), 7.25-7.38 (5H,
m). Anal. Calcd for C ₃₁ H ₄₃ N ₃ O ₄・ HCl ・ 1.0H ₂ O: C, 64.62;
H, 8.05; N, 7.29. Found: C, 64.39; H, 8.11; N, 7.4
2. Example 37 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (4-chlorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride obtained in Reference Example 16. The same reaction and purification treatment as in Example 31 were carried out using the obtained compound to obtain the title compound. 86% yield. ¹ H NMR (D ₂ O) δ 1.35-1.65 (2H, m), 1.8-2.1 (5H,
m), 2.45 (1H, dd, J = 9.6,17.6Hz), 2.55-2.75 (1H,
m), 2.64 (2H, d, J = 7.2Hz), 2.75-3.65 (9H, m), 2.78
(3H, s), 3.65-3.95 (2H, m), 7.2-7.45 (7H, m), 7.5
9 (2H, d, J = 8.6Hz). Anal. Calcd for C ₂₇ H ₃₄ ClN ₃ O ₂・ HCl ・ 0.6H ₂ O: C, 62.93;
H, 7.08; Cl, 13.76; N, 8.15. Found: C, 63.04; H,
7.14; Cl, 13.60; N, 8.16.

Example 38 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3-chlorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride obtained in Reference Example 17 The same reaction and purification treatment as in Example 31 were performed using the obtained compound to obtain the title compound. 79% yield. ¹ H NMR (D ₂ O) δ 1.40-1.55 (2H, m), 1.85-2.03 (5H,
m), 2.47-2.95 (9H, m), 3.06-3.59 (7H, m), 3.71-3.85
(2H, m), 7.25-7.55 (9H, m). Anal.Calcd for C ₂₇ H ₃₄ ClN ₃ O ₂・ HCl ・ 0.7H ₂ O: C, 62.71;
H, 7.10; N, 8.13. Found: C, 62.77; H, 7.05; N, 8.
24.Example 39 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-
Difluorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride The same reaction and purification treatment as in Example 31 were carried out using the compound obtained in Reference Example 19 to obtain the title compound. 80% yield. ¹ H NMR (D ₂ O) δ 1.40-1.55 (2H, m), 1.89-2.00 (5H,
m), 2.48-2.64 (4H, m), 2.77-2.94 (5H, m), 3.06-3.14
(2H, m), 3.30-3.55 (5H, m), 3.73-3.79 (2H, m), 7.2
0-7.46 (8H, m). Anal.Calcd for C ₂₇ H ₃₃ F ₂ N ₃ O ₂・ HCl ・ 0.6H ₂ O: C, 62.74;
H, 6.86; N, 8.13. Found: C, 62.44; H, 6.88; N, 8.
27.Example 40 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (2,4-
Difluorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 20, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. 63% yield. ¹ H NMR (D ₂ O) δ 1.43-1.58 (2H, m), 1.88-1.95 (5H,
m), 2.47-2.65 (4H, m), 2.77-2.91 (5H, m), 3.07-3.11
(2H, m), 3.26 (1H, m), 3.36-3.55 (4H, m), 3.66-3.8
2 (2H, m), 7.10-7.49 (8H, m). Anal.Calcd for C ₂₇ H ₃₃ F ₂ N ₃ O ₂・ HCl ・ 1.0H ₂ O: C, 61.88;
H, 6.92; N, 8.02. Found: C, 62.14; H, 6.95; N, 8.
26.

Example 41 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (2,6-
Difluorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 21, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. Yield 88%. ¹ H NMR (D ₂ O) δ 1.40-1.58 (2H, m), 1.76-2.07 (5H,
m), 2.50-2.64 (4H, m), 2.71-2.94 (5H, m), 3.08-3.29
(3H, m), 3.42-3.56 (4H, m), 3.76-3.81 (2H, m), 7.1
9-7.38 (7H, m), 7.53-7.58 (1H, m). Anal.Calcd for C ₂₇ H ₃₃ F ₂ N ₃ O ₂・ HCl ・ 1.1H ₂ O: C, 61.67;
H, 6.94; N, 7.99. Found: C, 61.52; H, 6.92; N, 8.
29. Example 42 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3-chloro-4-fluorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Reference The same reaction and purification treatment as in Example 31 were performed using the compound obtained in Example 22 to give the title compound. Yield 68%. ¹ H NMR (D ₂ O) δ 1.40-1.58 (2H, m), 1.89-1.96 (5H,
m), 2.47-2.64 (4H, m), 2.77-2.95 (5H, m), 3.01-3.13
(2H, m), 3.32-3.56 (5H, m), 3.73-3.79 (2H, m), 7.2
5-7.40 (6H, m), 7.55-7.60 (2H, m). Anal.Calcd for C ₂₇ H ₃₃ ClFN ₃ O ₂・ HCl ・ 0.75H ₂ O: C, 60.5
0; H, 6.39; N, 7.84. Found: C, 60.70; H, 6.71; N,
8.16. Example 43 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-5-oxo-N- (4-trifluoromethylphenyl) -3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 23, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. . Yield 70%. ¹ H NMR (DMSO-d ₆ ) δ 1.44-1.57 (2H, m), 1.70-1.85
(5H, m), 2.10-2.21 (2H, m), 2.39-2.54 (3H, m), 2.64
(3H, s), 2.70-3.05 (4H, m), 3.13-3.45 (4H, m), 3.6
5-3.75 (2H, m), 7.16-7.34 (5H, m), 7.65-7.69 (2H, m
m), 7.85-7.90 (2H, m). Anal.Calcd for C ₂₈ H ₃₄ F ₃ N ₃ O ₂・ HCl ・ 0.5H ₂ O: C, 61.47;
H, 6.63; N, 7.68. Found: C, 61.43; H, 6.73; N, 7.
97.

Example 44 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- [3,5-
Bis (trifluoromethyl) phenyl] -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 24, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. Was. Yield 50%. ¹ H NMR (D ₂ O) δ 1.44-1.51 (2H, m), 1.89-2.01 (5H,
m), 2.45-2.63 (4H, m), 2.69-2.96 (5H, m), 3.08-3.85
(9H, m), 7.25-7.38 (5H, m), 8.06 (2H, s), 8.26 (1
H, s). Example 45 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-5-oxo-N- (4-trifluoromethoxyphenyl) -3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 25, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. . Yield 60%. ¹ H NMR (D ₂ O) δ 1.45-1.58 (2H, m), 1.69-1.85 (5H,
m), 2.06-2.19 (2H, m), 2.39-2.54 (3H, m), 2.64 (3H,
s), 2.70-3.05 (4H, m), 3.12-3.46 (4H, m), 3.63-3.7
1 (2H, m), 7.16-7.34 (5H, m), 7.47-7.61 (4H, m) .Anal.Calcd for C ₂₈ H ₃₄ F ₃ N ₃ O ₃・ HCl ・ 0.6H ₂ O: C, 59.53 ;
H, 6.46; N, 7.44. Found: C, 59.31; H, 6.54; N, 7.
70. Example 46 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-N- (1-Naphthyl) -5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 26, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. Yield 67%. ¹ H NMR (D ₂ O) δ 1.43-1.56 (2H, m), 1.86-2.10 (5H,
m), 2.58-2.80 (6H, m), 2.86-3.40 (8H, m), 3.47-3.57
(4H, m), 7.23-7.40 (5H, m), 7.54-7.82 (5H, m), 8.0
9-8.13 (2H, m). Anal. Calcd for C ₃₁ H ₃₇ N ₃ O ₂・ HCl ・ 1.5H ₂ O: C, 68.05;
H, 7.55; N, 7.68. Found: C, 67.79; H, 7.47; N, 7.6
2.

Example 47 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3-biphenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride obtained in Reference Example 27 The same reaction and purification treatment as in Example 31 were performed using the obtained compound to obtain the title compound. 85% yield. ¹ H NMR (DMSO-d ₆ ) δ 1.3-2.0 (7H, m), 2.14 (1H, dd,
J = 9.5, 17.3Hz), 2.4-2.6 (3H, m), 2.6-3.5 (9H, m),
.. 2.63 (3H, s) , 3.6-3.85 (2H, m), 7.1-7.8 (14H, m) Anal Calcd for C 33 H 39 N 3 O 2 · HCl · 0.5H 2 O: C, 71.40;
H, 7.44; Cl, 6.39; N, 7.57. Found: C, 71.31; H, 7.
49; Cl, 6.37; N, 7.53. Example 48 N- [3- (benzyloxy) phenyl] -N- [3- (4-benzyl-1-
Piperidinyl) propyl] -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 28, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. 82% yield. ¹ H NMR (DMSO-d ₆ ) δ 1.3-1.95 (7H, m), 2.09 (1H, d
d, J = 10.0, 17.2Hz), 2.35-2.6 (3H, m), 2.6-3.5 (9H,
m), 2.63 (3H, s), 3.55-3.75 (2H, m), 5.17 (2H,
s), 6.9-7.55 (14H, m). Anal.Calcd for C ₃₄ H ₄₁ N ₃ O ₃ .HCl.0.5H ₂ O: C, 69.78;
H, 7.41; Cl, 6.06; N, 7.18. Found: C, 69.72; H, 7.
42; Cl, 5.94; N, 7.16.Example 49 N- [4- (benzyloxy) phenyl] -N- [3- (4-benzyl-1-
Piperidinyl) propyl] -1-methyl-5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 29, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. Yield 78%. ¹ H NMR (DMSO-d ₆ ) δ 1.3-1.95 (7H, m), 2.10 (1H, d
d, J = 9.4, 16.8Hz), 2.35-2.6 (3H, m), 2.6-3.5 (9H,
m), 2.63 (3H, s), 3.5-3.75 (2H, m), 5.13 (2H, s),
7.05-7.55 (14H, m). Anal.Calcd for C ₃₄ H ₄₁ N ₃ O ₃・ HCl ・ 0.6H ₂ O: C, 69.57;
H, 7.42; Cl, 6.04; N, 7.16. Found: C, 69.60; H, 7.
38; Cl, 6.14; N, 7.18.

Example 50 N- [3- (4-Benzyl-1-piperidinyl) propyl] -N-phenyl-trans-4-cotininecarboxamide dihydrochloride The compound obtained in Reference Example 10 and trans-4-cotinine The same reaction and purification treatment as in Example 31 were carried out using carboxylic acid to give the title compound. 93% yield. ¹ H NMR (D ₂ O) δ 1.42-1.48 (2H, m), 1.83-1.95 (5H,
m), 2.60-2.63 (5H, m), 2.69-2.92 (5H, m), 3.02-3.60
(6H, m), 5.04 (1H, d, J = 6.0Hz), 7.24-7.41 (10H,
m), 7.97 (1H, t, J = 7.4Hz), 8.24 (1H, d, J = 8.4Hz),
8.55 (1H, d, J = 1.8Hz), 8.77 (1H, d, J = 5.2Hz). Anal. Calcd for C ₃₂ H ₃₈ N ₄ O ₂・ 2HCl ・ 1.5H ₂ O: C, 62.94;
H, 7.10; N, 9.18.Found: C, 62.80; H, 7.29; N, 8.8
8. Example 51 1-benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo-N-phenyl-3-pyrrolidinecarboxamide Compound obtained in Reference Examples 10 and 44 Example using
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 68% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.15-1.33 (2H, m), 1.40-1.86 (7
H, m), 2.23-2.36 (3H, m), 2.50 (2H, d, J = 6.6 H
z), 2.68-2.90 (3H, m), 2.92-3.12 (2H, m), 3.53 (1H,
dd, J = 7.6, 5.4 Hz), 3.64-3.72 (2H, m), 4.33 (1
H, d, J = 14.6 Hz), 4.43 (1H, d, J = 14.6 Hz), 7.00
-7.30 (15H, m). Anal.Calcd for C ₃₃ H ₃₉ N ₃ O ₂・ 0.5H ₂ O: C, 76.41; H, 7.
77; N, 8.10. Found: C, 76.37; H, 7.63; N, 8.23. Example 52 N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo
-N, 1-Diphenyl-3-pyrrolidinecarboxamide Using the compounds obtained in Reference Examples 10 and 43,
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 62% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.10-2.00 (9H, m), 2.27-2.45 (3
H, m), 2.51 (2H, d, J = 6.6 Hz), 2.81-2.99 (3H, m),
3.10-3.27 (1H, m), 3.62 (1H, t, J = 9.0 Hz), 3.71
-3.79 (2H, m), 4.18 (1H, t, J = 9.0 Hz), 7.09-7.53
(15H, m). Anal.Calcd for C ₃₂ H ₃₇ N ₃ O ₂・ 0.5H ₂ O: C, 76.16; H, 7.
59; N, 8.33. Found: C, 75.91; H, 7.85; N, 8.35.

Example 53 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-cyclohexyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide Obtained in Reference Examples 10 and 45. Examples using compounds
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 57% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.00-1.86 (19H, m), 2.15-2.32 (3
H, m), 2.50 (2H, d, J = 6.6 Hz), 2.58-2.70 (1H, m),
2.67-3.06 (3H, m), 3.18 (1H, t, J = 9.0 Hz), 3.56
-3.94 (4H, m), 7.10-7.50 (10H, m). Anal.Calcd for C ₃₂ H ₄₃ N ₃ O ₂・ 0.5H ₂ O: C, 75.26; H, 8.
68, N, 8.23. Found: C, 75.19; H, 8.37; N, 8.32.Example 54 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-butyl
-5-oxo-N-phenyl-3-pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 10 and 46
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 46% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 0.88 (3H, t, J = 7.2 Hz), 1.05-
1.90 (13H, m), 2.22 (1H, dd, J = 16.8, 8.8 Hz), 2.
28 (2H, t, J = 7.4 Hz), 2.50 (2H, d, J = 6.6Hz),
2.66 (1H, dd, J = 16.8, 8.8 Hz), 2.75-2.90 (2H,
m), 2.94-3.45 (4H, m), 3.62-3.75 (3H, m), 7.10-7.50
(10H, m). Anal.Calcd for C ₃₀ H ₄₁ N ₃ O ₂・ 0.5H ₂ O: C, 74.34; H, 8.
73; N, 8.67. Found: C, 74.60; H, 8.77; N, 8.89. Example 55 N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo
Example 1 using the compounds obtained in 1-phenethyl-N-phenyl-3-pyrrolidinecarboxamide Reference Examples 10 and 47
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 59% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.12-1.37 (2H, m), 1.38-1.90 (7
H, m), 2.13-2.31 (3H, m), 2.51 (2H, d, J = 6.6 H
z), 2.61-2.85 (5H, m), 2.92-3.06 (2H, m), 3.44 (2H,
t like, J = 7.4 Hz), 3.54-3.59 (1H, m), 3.69 (2H,
t like, J = 7.4 Hz), 7.07-7.44 (15H, m).

Example 56 N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo
Example using the compounds obtained in -N-phenyl-1- (3-phenylpropyl) -3-pyrrolidinecarboxamide Reference Examples 10 and 48
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 84% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.10-1.31 (2H, m), 1.35-1.91 (9
H, m), 2.13-2.32 (3H, m), 2.49-2.71 (5H, m), 2.80-
3.03 (3H, m), 3.13 (1H, t, J = 9.0 Hz), 3.22-3.43
(2H, m), 3.59-3.74 (3H, m), 7.10-7.48 (15H, m) .Example 57 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (4-methoxy (Benzyl) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 10 and 49
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 81% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.15-1.85 (9H, m), 2.05-2.34 (3
H, m), 2.50 (2H, d, J = 6.6 Hz), 2.65-2.83 (3H, m),
2.94-3.10 (2H, m), 3.51 (1H, dd, J = 8.0, 5.8 H
z), 3.64-3.72 (2H, m), 3.78 (3H, s), 4.27 (1H, d,
J = 14.8 Hz), 4.36 (1H, d, J = 14.8 Hz), 6.80-6.86
(2H, m), 7.07-7.45 (12H, m). Example 58 N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo
-N-phenyl-3-pyrrolidinecarboxamide In a mixed solution of the compound obtained in Example 57 (65 mg, 0.12 mmol) in acetonitrile / water (1.5 mL / 0.5 mL) at 0 ° C., CAN
(132 mg, 0.24 mmol) was added and the mixture was stirred at room temperature for 1 hour. C
AN (66 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 14 hours. Water (5 mL) was added to the reaction solution, and ethyl acetate (10 mL ×
Extracted in 2). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained oil was purified by column chromatography (basic alumina activity III, 20 g, eluted with ethyl acetate / methanol = 9/1) to give the title compound (25 mg, 50%, oil). ¹ H NMR (CDCl ₃ ) δ 1.10-1.33 (2H, m), 1.38-1.87 (7
H, m), 2.08-2.32 (3H, m), 2.51 (2H, d, J = 6.6 H
z), 2.59-2.85 (3H, m), 3.09-3.28 (2H, m), 3.55-3.7
5 (3H, m), 5.42 (1H, br), 7.10-7.49 (10H, m). MS m / z = 420 (MH ⁺ ).

Example 59 1-benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-dichlorophenyl) -5-oxo-3-pyrrolidinecarboxamide Reference Example 18 Example using the compound obtained in Example 44
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 58% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.10-1.38 (2H, m), 1.38-1.86 (7
H, m), 2.22-2.40 (3H, m), 2.50 (2H, d, J = 6.6 H
z), 2.66-2.82 (3H, m), 2.90-3.15 (2H, m), 3.45-3.7
0 (3H, m), 4.34 (1H, d, J = 14.8 Hz), 4.46 (1H, d,
J = 14.8 Hz), 6.97 (1H, dd, J = 8.6, 2.6 Hz), 7.10
-7.40 (11H, m), 7.49 (1H, d, J = 8.6 Hz) .Example 60 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-
(Dichlorophenyl) -5-oxo-1-phenethyl-3-pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 18 and 47
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 40% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.10-1.35 (2H, m), 1.37-1.87 (7
H, m), 2.17-2.30 (3H, m), 2.51 (2H, d, J = 6.6 H
z), 2.61-3.04 (6H, m), 3.41-3.55 (4H, m), 3.62-3.6
9 (2H, m), 6.96 (1H, dd, J = 8.8, 2.6 Hz), 7.11-7.
31 (11H, m), 7.51 (1H, d, J = 8.8 Hz). Example 61 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-
Dichlorophenyl) -5-oxo-1- (3-phenylpropyl)-
Example using the compounds obtained in 3-Pyrrolidinecarboxamide Reference Examples 18 and 48,
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 75% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.10-1.37 (2H, m), 1.38-1.85 (9
H, m), 2.15-2.30 (3H, m), 2.49-2.68 (5H, m), 2.78-
2.98 (3H, m), 3.16 (1H, t, J = 9.0 Hz), 3.29 (2H,
t, J = 7.0 Hz), 3.58-3.71 (3H, m), 7.00 (1H, dd, J
= 8.4, 2.6 Hz), 7.03-7.31 (11H, m), 7.53 (1H, d, J
= 8.4 Hz).

Example 62 N-benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl-5-oxo-3-pyrrolidinecarboxamide The compound obtained in Reference Example 32 (200 mg , 0.62 mmol) in acetonitrile (6 mL) solution, 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid (89 mg, 0.62 mmol) and 1-hydroxybenzotriazole monohydrate (104 mg, 0.68 mmo
l) and then dicyclohexylcarbodiimide
(141 mg, 0.68 mmol) was added. Mix this mixture at 80 ° C for 1
Stirred for hours. After cooling, the reaction solution was concentrated under reduced pressure, ethyl acetate (20 mL) was added, and the insoluble matter was removed by filtration. The mother liquor was washed with a 2N aqueous sodium hydroxide solution (5 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was subjected to column chromatography (basic alumina activity II
I, 35 g, eluted with ethyl acetate) to give the title compound (125
mg, 45%, oil). ¹ H NMR (CDCl ₃ ) (about 1: 1 mixture of isomers) δ 1.10-1.40
(2H, m), 1.41-1.88 (7H, m), 2.19-2.78 (8H, m), 2.8
0 (1.5H, s), 2.88 (1.5H, s), 3.21-3.82 (5H, m), 4.4
8-4.73 (2H, m), 7.11-7.37 (10H, m). Anal.Calcd for C ₂₈ H ₃₇ N ₃ O ₂・ 0.25H ₂ O: C, 74.38; H,
8.36; N, 9.29. Found: C, 74.38; H, 8.49; N, 9.09.Example 63 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (4-hydroxybenzyl) -1 -Methyl-5-oxo-3-pyrrolidinecarboxamide Using the compound obtained in Reference Example 33, the same reaction and purification treatment as in Example 62 were performed to obtain the title compound. 45% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.10-2.00 (11H, m), 2.18-2.90 (9
H, m), 3.20-3.83 (5H, m), 4.32 (1H, d, J = 14.4 H
z), 4.41 (1H, s), 4.69 (1H, d, J = 14.4 Hz), 6.69-
6.76 (2H, m), 6.90 (1H, d, J = 8.4 Hz), 7.02 (1H,
d, J = 8.4 Hz), 7.11-7.32 (5H, m).

Example 64 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-N- (1-Naphthylmethyl) -5-oxo-3-pyrrolidinecarboxamide Using the compound obtained in Reference Example 34, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. . 87% yield _{^{(oil) 1 H NMR (CDCl 3)}} ( approximately 0.4: 0.6 mixture of isomers) δ 1.10-
1.38 (2H, m), 1.39-1.93 (7H, m), 2.17 (0.60 × 2H, t
like, J = 6.8 Hz), 2.32 (0.40 × 2H, t like, J = 7.4
Hz), 2.49-3.00 (9H, m), 3.10-3.83 (5H, m), 5.00-5.
23 (2H, m), 7.11-7.60 (9H, m), 7.80-8.00 (3H, m). Example 65 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-N- (2-Naphthylmethyl) -5-oxo-3-pyrrolidinecarboxamide Using the compound obtained in Reference Example 35, the same reaction and purification treatment as in Example 62 were performed to obtain the title compound. . 64% yield _{^{(oil) 1 H NMR (CDCl 3)}} ( approximately 1: 1 mixture of isomers) δ 1.06-2.00
(9H, m), 2.17-2.34 (2H, m), 2.41-2.56 (3H, m), 2.6
0-2.89 (6H, m), 3.20-3.84 (5H, m), 4.66-4.89 (2H,
m), 7.11-7.88 (12H, m). Example 66 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (2,3-
Dihydro-1H-inden-2-yl) -1-methyl-5-oxo-3-
Pyrrolidinecarboxamide Using the compound obtained in Reference Example 41, the same reaction and purification treatment as in Example 31 were performed to give the title compound. . 54% yield _{^{(oil) 1 H NMR (CDCl 3)}} ( approximately 1: 1 mixture of isomers) δ 1.00-
1.90 (9H, m), 2.14-2.30 (2H, m), 2.50 (2H, d, J =
6.2Hz), 2.59-2.80 (4H, m), 2.86 (0.5 × 3H, s), 2.87
(0.5 × 3H, s), 2.98-3.17 (4H, m), 3.20-3.30 (2H,
m), 3.40-3.59 (2H, m), 3.69-3.82 (1H, m), 4.60-4.80
(0.5H, m), 5.01-5.16 (0.5H, m), 7.10-7.27 (9H,
m).

Example 67 N-benzyl-N- {3- [4- (4-chlorophenyl) -4-hydroxy
[1-Piperidinyl] propyl} -1-methyl-5-oxo-3-pyrrolidinecarboxamide Using the compound obtained in Reference Example 36, the same reaction and purification treatment as in Example 62 were performed to obtain the title compound. . 54% yield _{^{(oil) 1 H NMR (CDCl 3)}} ( approximately 0.4: 0.6 mixture of isomers) δ 1.60-
1.90 (5H, m), 1.90-2.20 (2H, m), 2.30-2.53 (5H, m),
2.60-2.80 (3H, m), 2.82 (0.6 × 3H, s), 2.87 (0.4 × 3
H, s), 3.27-3.90 (5H, m), 4.54-4.75 (2H, m), 7.13-
7.46 (9H, m). Example 68 N- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl} -N-isopropyl-1-methyl-5-oxo-3-
Pyrrolidinecarboxamide The same reaction and purification treatment as in Example 62 were carried out using the compound obtained in Reference Example 37, to give the title compound. . 11% yield _{^{(oil) 1 H NMR (CDCl 3)}} ( approximately 0.35: isomer mixture of 0.65) [delta] 1.18
(0.35 × 6H, d, J = 7.0Hz), 1.24 (0.65 × 6H, d, J =
7.0 Hz), 1.60-1.90 (4H, m), 2.00-2.23 (2H, m), 2.40
-2.95 (11 + 0.65H, m), 3.24 (2H, dd, J = 10.0, 6.0 H
z), 3.38-3.55 (2 + 0.35H, m), 3.60-3.85 (1H, m), 3.90
-4.10 (0.65H, m), 4.55-4.70 (0.35H, m), 7.28-7.50
Example 69 N- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl} -N-cyclohexyl-1-methyl-5-oxo-
3-Pyrrolidinecarboxamide Using the compound obtained in Reference Example 38, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. 57% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.00-2.20 (15H, m), 2.37-3.00 (1
2H, m), 3.15-4.40 (7H, m), 7.29-7.48 (4H, m).

Example 70 N- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl} -N-cyclopentyl-1-methyl-5-oxo-
3-Pyrrolidinecarboxamide The same reaction and purification treatment as in Example 31 were performed using the compound obtained in Reference Example 39, to give the title compound. . 77% yield _{^{(oil) 1 H NMR (CDCl 3)}} ( approximately 0.3: 0.7 mixture of isomers) δ 0.80-
2.00 (11H, m), 2.02-2.20 (2H, m), 2.30-2.80 (9H,
m), 2.85 (3H, s), 3.15-3.35 (2H, m), 3.37-3.55 (3H,
m), 3.57-3.85 (1H, m), 3.95-4.20 (0.7H, m), 4.35-
4.60 (0.3H, m), 7.29-7.50 (4H, m). Example 71 N- {3- [4- (4-fluorobenzoyl) -1-piperidinyl] -2-
Hydroxypropyl} -1-methyl-5-oxo-N-phenyl-3
-Pyrrolidinecarboxamide The same reaction and purification treatment as in Example 31 were performed using the compound obtained in Reference Example 42, to give the title compound. 50% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.76-2.50 (9H, m), 2.61-3.26 (6
H, m), 2.78 (3H, s), 3.51-4.01 (5H, m), 7.10-7.46
(7H, m), 7.92-8.00 (2H, m) .Mass: MH ⁺ = 482 Example 72 1-benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (1- Example using the compounds obtained in (Naphthylmethyl) -5-oxo-3-pyrrolidinecarboxamide Reference Examples 34 and 44
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. . 82% yield _{^{(oil) 1 H NMR (CDCl 3)}} ( approximately 0.4: 0.6 mixture of isomers) δ 1.00-
1.35 (2H, m), 1.36-1.90 (7H, m), 2.14 (0.60 × 2H, t
like, J = 6.6 Hz), 2.29 (0.40 × 2H, t like, J = 7.5
Hz), 2.49 (2H, d, J = 6.6 Hz), 2.55-2.97 (4H, m),
3.09-3.70 (5H, m), 4.30-4.67 (2H, m), 5.02 (0.8H,
s), 5.09 (1.2H, s), 7.11-7.60 (14H, m), 7.78-7.95
(3H, m).

Example 73 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (cyclohexylmethyl) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide In Reference Examples 10 and 52, Example using the obtained compound
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 70% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 0.80-1.03 (2H, m), 1.04-1.38 (5
H, m), 1.39-1.90 (13H, m), 2.16-2.32 (3H, m), 2.51
(2H, d, J = 6.6 Hz), 2.61-3.20 (7H, m), 3.63-3.75
(3H, m), 7.10-7.50 (10H, m) .Example 74 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (4-fluorobenzyl) -5-oxo-N- Phenyl-3-pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 10 and 51
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 82% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.10-1.38 (2H, m), 1.39-1.85 (7
H, m), 2.23-2.36 (3H, m), 2.50 (2H, d, J = 6.6 H
z), 2.66-2.80 (3H, m), 2.96-3.10 (2H, m), 3.45-3.7
2 (3H, m), 4.35 (2H, s), 6.94-7.50 (14H, m). Example 75 N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo
Example using the compounds obtained in -N-phenyl-1- (4-pyridylmethyl) -3-pyrrolidinecarboxamide Reference Examples 10 and 50
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. 63% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.00-1.86 (9H, m), 2.24-2.41 (3
H, m), 2.50 (2H, d, J = 6.2 Hz), 2.70-2.90 (3H, m),
3.02-3.15 (2H, m), 3.50-3.74 (3H, m), 4.40 (2H, m
s), 7.05-7.50 (12H, m), 8.55 (2H, d, J = 5.8 Hz).

Example 76 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (2-chlorobenzyl) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide Reference Examples 10 and Example using compound obtained in 53
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 72% (oil). ¹ H NMR (CDCl ₃ ) δ 1.1-1.35 (2H, m), 1.35-1.85 (7H,
m), 2.23-2.37 (3H, m), 2.50 (2H, d, J = 6.6 Hz),
2.69-2.90 (3H, m), 2.96-3.18 (2H, m), 3.58 (1H, d
d, J = 8.4, 6.2 Hz), 3.69 (2H, t, J = 7.8 Hz), 4.4
8 (1H, d, J = 15.2 Hz), 4.58 (1H, d, J = 15.2 Hz),
7.10-7.64 (14H, m). Example 77 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (3-chlorobenzyl) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide Example using the compounds obtained in Reference Example 10 and Reference Example 54
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 81% (oil). ¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (9H, m), 2.23-2.37 (3H,
m), 2.50 (2H, d, J = 6.6 Hz), 2.67-2.83 (3H, m),
2.98-3.12 (2H, m), 3.5-3.6 (1H, m), 3.69 (2H, t lik
e, J = 7.6 Hz), 4.30 (1H, d, J = 14.6 Hz), 4.41 (1
H, d, J = 14.6 Hz), 7.0-7.5 (14H, m) .Example 78 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (4-chlorobenzyl) -5- Oxo-N-phenyl-3-pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 10 and 55
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 78% (oil). ¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (9H, m), 2.23-2.36 (3H,
m), 2.50 (2H, d, J = 6.6 Hz), 2.67-2.83 (3H, m),
2.96-3.10 (2H, m), 3.5-3.6 (1H, m), 3.69 (2H, t lik
e, J = 7.4 Hz), 4.35 (2H, s), 7.0-7.5 (14H, m).

Example 79 N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo
-N-phenyl-1- [4- (trifluoromethyl) benzyl] -3-
Using the compounds obtained in Reference Example 10 and Reference Example 56, pyrrolidine carboxamide,
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 63% (oil). ¹ H NMR (CDCl ₃ ) δ 1.15-1.30 (2H, m), 1.35-1.85 (7
H, m), 2.23-2.38 (3H, m), 2.50 (2H, d, J = 6.6 H
z), 2.68-2.90 (3H, m), 2.99-3.13 (2H, m), 3.50-3.7
3 (3H, m), 4.44 (2H, s), 7.08-7.50 (12H, m), 7.57
(2H, d, J = 8.4 Hz). Example 80 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (2-morpholinoethyl) -5-oxo-N-phenyl-3- Using the compounds obtained in pyrrolidine carboxamide reference example 10 and reference example 57,
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 74% (oil). ¹ H NMR (CDCl ₃ ) δ 1.0-1.9 (11H, m), 2.16-2.52 (10
H, m), 2.68 (1H, dd, J = 17.0, 8.8 Hz), 2.82 (2H, b
rd, J = 11.4 Hz), 2.97-3.10 (1H, m), 3.22-3.50 (3
H, m), 3.50-3.80 (6H, m), 7.0-7.6 (10H, m) .Example 81 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (2-furylmethyl ) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 10 and 58
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 18% (oil). ¹ H NMR (CDCl ₃ ) δ 1.15-1.33 (2H, m), 1.40-1.86 (7
H, m), 2.19-2.31 (3H, m), 2.50 (2H, d, J = 6.6 H
z), 2.68 (1H, t, J = 8.8 Hz), 2.81 (2H, br d, J = 1
1.4 Hz), 2.92-3.10 (1H, m), 3.18 (1H, t, J = 8.8 H
z), 3.57-3.73 (3H, m), 4.31 (1H, d, J = 15.4 Hz),
4.44 (1H, d, J = 15.4 Hz), 6.20-6.30 (2H, m), 7.1
0-7.50 (11H, m).

Example 82 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (4-methylbenzyl) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide Reference Examples 10 and Example using the compound obtained in 59
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 40% (oil). ¹ H NMR (CDCl ₃ ) δ 1.1-1.37 (2H, m), 1.37-1.88 (7H,
m), 2.32 (3H, s), 2.21-2.37 (3H, m), 2.50 (2H, d,
J = 6.6 Hz), 2.66-2.88 (3H, m), 2.95-3.15 (2H,
m), 3.45-3.60 (1H, m), 3.65 (2H, t like, J = 8.0 H
z), 4.44 (2H, s), 7.05-7.60 (14H, m) .Example 83 N- {3- [4- (4-fluorobenzyl) -1-piperidinyl] propyl} -1-methyl-5- Oxo-N-phenyl-3-pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 64, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. Yield 43%. ¹ H NMR (CD ₃ OD) δ 1.3-1.7 (2H, m), 1.75-2.10 (5H,
m), 2.31 (1H, dd, J = 17.2, 9.6 Hz), 2.56-2.71 (3H,
m), 2.77 (3H, s), 2.92 (2H, t like, J = 12.4 Hz),
3.09-3.36 (4H, m), 3.53-3.70 (3H, m), 3.70-3.90
(2H, m), 6.97-7.10 (2H, m), 7.17-7.24 (2H, m), 7.3
Example 84 N- (3,4-Dichlorophenyl) -N- {3- [4- (4-fluorobenzyl) -1-piperidinyl] propyl} -1-methyl-5- Oxo-3-
Pyrrolidinecarboxamide hydrochloride Using the compound obtained in Reference Example 65, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. Yield 65%. ¹ H NMR (CD ₃ OD) δ 1.4-1.7 (2H, m), 1.70-2.10 (5H,
m), 2.36 (1H, dd, J = 17.2, 9.8 Hz), 2.50-2.70 (3H,
m), 2.78 (3H, s), 2.92 (2H, t like, J = 12.0 Hz),
3.08-3.60 (4H, m), 3.50-3.70 (3H, m), 3.70-3.90
(2H, m), 7.02 (2H, t, J = 8.8 Hz), 7.17-7.24 (2H,
m), 7.35 (1H, dd, J = 8.4, 2.2 Hz), 7.68-7.72 (2H,
m).

Example 85 1-Benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3-chlorophenyl) -5-oxo-3-pyrrolidinecarboxamide Reference Examples 17 and 44 Example using the compound obtained in
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 39% (oil). ¹ H NMR (CDCl ₃ ) δ 1.10-1.30 (2H, m), 1.30-1.85 (7
H, m), 2.23-2.38 (3H, m), 2.50 (2H, d, J = 6.6 H
z), 2.68-2.85 (3H, m), 2.96-3.13 (2H, m), 3.48-3.7
0 (3H, m), 4.48 (2H, s), 7.08-7.60 (14H, m) .Example 86 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (2,6-
(Difluorobenzyl) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 10 and 60
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 76% (oil). ¹ H NMR (CDCl ₃ ) δ 1.2-1.9 (9H,
m), 2.23-2.30 (3H, m),
51 (2H, d, J = 6.6 Hz),
2.60-2.73 (1H, m), 2.81
(2H, brd, J = 11.0 Hz),
2.95-3.14 (2H, m), 3.55 (1
H, t, J = 7.7 Hz), 3.68
(2H, t like, J = 7.5 Hz),
4.52 (2H, s), 6.88 (2H, s)
t, J = 7.0 Hz), 7.09-7.40
(11H, m). Example 87 1-benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (2,3-dihydro-1H-inden-1-yl) -5-oxo
-3-Pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 62 and 44
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 67% (oil). ¹ H NMR (CDCl ₃ ) (1: 1 mixture of isomers) δ 1.0-2.2 (1
1H, m), 2.3-3.8 (13H, m), 2.49 (2H, d, J = 6.6 Hz),
4.30-4.70 (2H, m), 5.25-5.40 (0.5H, m), 6.00-6.10
(0.5H, m), 6.91-7.50 (14H, m).

Example 88 1-benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo-N- (1,2,3,4-tetrahydro-1-naphthyl) -3
-Pyrrolidinecarboxamide Example using compounds obtained in Reference Examples 63 and 44
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 73% (oil). ¹ H NMR (CDCl ₃ ) (about 0.4: 0.6 mixture of isomers) δ 1.0-2.
2 (12H, m), 2.25-2.40 (1H, m), 2.52 (2H, d, J = 5.8
Hz), 2.60-3.80 (13H, m), 4.30-4.60 (2H, m), 4.80-
4.95 (0.6H, m), 5.60-5.80 (0.4H, m), 6.76-7.40 (14
Example 89 1-benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-dichlorophenyl) -6-oxo-3-piperidinecarboxamide Reference Example 18 And using the compound obtained in Reference Example 61,
The same reaction and purification treatment as in 31 were carried out to obtain the title compound. Yield 77% (oil). ¹ H NMR (CDCl ₃ ) δ 1.20-1.35 (2H, m), 1.35-1.9 (7H,
m), 1.9-2.2 (2H, m), 2.2-2.3 (3H, m), 2.4-2.65 (4
H, m), 2.79 (2H, br d, J = 11.8 Hz), 2.95-3.10 (1
H, m), 3.38-3.70 (3H, m), 4.31 (1H, d, J = 9.0 H
z), 4.74 (1H, d, J = 9.0 Hz), 6.85-6.95 (1H, m), 7.
1-7.31 (11H, m), 7.40 (1H, d, J = 8.4 Hz). Example 90 N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo
-N-phenyl-1-propargyl-3-pyrrolidinecarboxamide DMF of the compound (100 mg, 0.24 mmol) obtained in Example 58 (1.
Sodium hydride (60%, 12.4 mg,
0.31 mmol) and stirred at room temperature for 30 minutes. Subsequently, propargyl bromide (34 mg, 0.29 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the DMF was distilled off under reduced pressure, the residue was extracted with ethyl acetate (10 ml × 2) and a 1N aqueous solution of sodium hydroxide (10 ml). The organic layer is dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue is subjected to column chromatography (basic alumina activity II
I 3g, ethyl acetate / hexane = 1/1 → 1/0). The desired fraction was concentrated under reduced pressure to give the title compound (77 mg, 71%) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (9H, m), 2.19 (1H, t, J
= 2.6 Hz), 2.24-2.37 (3H, m), 2.51 (2H, d, J = 6.6
Hz), 2.71 (1H, dd, J = 16.8, 8.8 Hz), 2.87 (2H, br
d, J = 11.0 Hz), 3.00-3.17 (1H, m), 3.34 (1H, t,
J = 8.8 Hz), 3.65-3.76 (3H, m), 3.94 (1H, dd, J =
17.6, 2.6 Hz), 4.12 (1H, dd, J = 17.6, 2.6 Hz), 7.
11-7.50 (10H, m).

Example 91 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (2-methylbenzyl) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide 2-methylbenzyl bromide The same reaction and purification procedures as in Example 90 were carried out to obtain the title compound. Yield 63% (oil). ¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (9H, m), 2.25 (3H, s),
2.2-2.36 (3H, m), 2.50 (2H, d, J = 6.4 Hz), 2.67-2.
85 (3H, m), 2.95-3.10 (2H, m), 3.4-3.6 (1H, m), 3.6
7 (2H, t like, J = 7.8 Hz), 4.40 (2H, s), 7.0-7.5
Example 92 N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (2-fluorobenzyl) -5-oxo-N-phenyl-3-pyrrolidinecarboxamide 2-fluoro The same reaction and purification treatment as in Example 90 were performed using benzyl bromide to give the title compound. 83% yield
(Oil). ¹ H NMR (CDCl ₃ ) δ 1.1-2.0 (9H, m), 2.21-2.34 (3H,
m), 2.50 (2H, d, J = 6.6 Hz), 2.66-2.89 (3H, m),
2.9-3.1 (2H, m), 3.13 (2H, t, J = 8.8 Hz), 3.58 (1
H, dd, J = 8.6, 6.8 Hz), 4.45 (2H, s), 6.97-7.50
Example 93 N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo
Using -N-phenyl-1- (2,2,2-trifluoroethyl) -3-pyrrolidinecarboxamide 2,2,2-trifluoroethyl triflate, the same reaction and purification treatment as in Example 90 was performed. The title compound was obtained. Yield 30% (oil). ¹ H NMR (CDCl ₃ ) δ 1.15-1.35 (2H, m), 1.4-1.85 (7H,
m), 2.22-2.36 (3H, m), 2.51 (2H, d, J = 6.2 Hz),
2.65-2.90 (3H, m), 3.03-3.20 (1H, m), 3.37 (1H, t,
J = 8.4 Hz), 3.60-3.80 (4H, m), 3.85-4.02 (1H,
m), 7.10-7.30 (8H, m), 7.32-7.50 (2H, m).

Example 94 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3-chlorophenyl) -5-oxo-1- [2- (trifluoromethyl) benzyl] -3- Using pyrrolidinecarboxamide 2,4-dimethoxybenzylamine, the same reaction and purification treatment as in Reference Example 43 were performed to synthesize 1- (2,4-dimethoxybenzyl) -5-oxo-3-pyrrolidinecarboxylic acid (698 mg,
Oxalyl chloride (0.256 ml, 3.0 mmol) was added to a mixture of 2.5 mmol), DMF (0.024 ml), and dichloromethane (10 ml) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes and while rising to room temperature for 1 hour. The resulting solution was prepared using the compound (4
16mg, 1.0mmol), triethylamine (1.39ml, 10mmol),
The mixture was added to a mixture of dichloromethane (15 ml) with stirring at -20 ° C.
The mixture was stirred for 1 hour while being raised to ° C. Saturated aqueous sodium bicarbonate (15m
l) and the organic solvent was distilled off under reduced pressure, and then ethyl acetate (20 ml x 2)
And the organic layer was washed with saturated aqueous sodium bicarbonate (10 ml × 2) and saturated saline (10 mL).
(ml). After drying over anhydrous magnesium sulfate,
After concentration under reduced pressure, the residue was subjected to column chromatography (basic alumina activity III 30 g, ethyl acetate / hexane = 1/1). The desired fraction was concentrated under reduced pressure, and the residue (200 mg) was dissolved in trifluoroacetic acid (4 ml) and stirred at 70 ° C. for 4 hours. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate (15 ml) was added, and ethyl acetate (20 ml ×
The mixture was extracted in 2), and the organic layer was washed with saturated saline (20 ml). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (basic alumina activity III 10 g,
(Ethyl acetate). The target fraction was concentrated under reduced pressure, and N- [3- (4
-Benzyl-1-piperidinyl) propyl] -N- (3-chlorophenyl) -5-oxo-3-pyrrolidinecarboxamide (75 mg, 50
%). Using this compound and 2-trifluorobenzyl bromide, the same reaction and purification treatment as in Example 90 were performed to obtain the title compound. Yield 76% (oil). ¹ H NMR (CDCl ₃ ) δ 1.1-2.1 (9H, m), 2.26 (2H, t, J
= 7.4 Hz), 2.31-2.44 (1H, m), 2.50 (2H, d, J = 6.6
Hz), 2.72-2.90 (3H, m), 2.96-3.16 (2H, m), 3.53 (1
H, dd, J = 8.4, 5.8 Hz), 3.67 (2H, t, J = 7.8 Hz),
4.52 (1H, d, J = 15.8 Hz), 4.70 (1H, d, J = 15.8 H
z), 6.98-7.04 (1H, m), 6.98-7.04 (1H, m), 7.10-7.3
9 (9H, m), 7.48-7.65 (2H, m).

Example 95 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-5-oxo-N- [3- (trifluoromethyl) phenyl] -3-pyrrolidinecarboxamide hydrochloride 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid (358 mg, 2.
Oxalyl chloride (0.256 ml, 3.0 mmol) was added to a mixture of 5 mmol), DMF (0.023 ml), and dichloromethane (10 ml) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes and while rising to room temperature for 1 hour. The resulting solution was prepared using the compound (449) obtained in Reference Example 66.
mg, 1.0 mmol), triethylamine (1.39 ml, 10 mmol), and a mixture of dichloromethane (15 ml) with stirring at -20 ° C.
The mixture was stirred for 1 hour while being raised. Saturated aqueous sodium bicarbonate (15 ml)
After adding and removing the organic solvent under reduced pressure, the mixture was extracted with ethyl acetate (15 ml × 3).
And washed in order. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 1).
0 g, ethyl acetate / methanol = 1/0 → 9/1). The desired fraction was concentrated under reduced pressure to obtain the free base of the title compound (383 mg). ¹ H NMR (CDCl ₃ ) δ 1.05-1.95 (9H, m), 2.15-2.35 (3
H, m), 2.51 (2H, d, J = 6.6Hz), 2.6-3.1 (4H, m), 2.7
8 (3H, s), 3.19 (1H, t, J = 9.1Hz), 3.6-3.8 (3H, m),
7.05-7.45 (7H, m), 7.55-7.75 (2H, m). The free base (383 mg) was dissolved in methanol, 1N hydrogen chloride diethyl ether solution (2 ml) was added, and the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitate was collected by filtration. The precipitate is washed with diethyl ether and dried under reduced pressure to give the title compound.
(376 mg, 0.70 mmol, yield 70%) was obtained as a hygroscopic amorphous. Anal.Calcd for C ₂₈ H ₃₄ F ₃ N ₃ O ₂・ HCl ・ 0.6H ₂ O: C, 61.27;
H, 6.65; Cl, 6.46; F, 10.38; N, 7.66. Found: C, 6
1.29; H, 6.60; Cl, 6.37; F, 10.44; N, 7.69. Example 96 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-N- (3-methylphenyl) -5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound (395 mg) obtained in Reference Example 67, the same reaction and purification treatment as in Example 95 were carried out to release the title compound. Base (420
mg). ¹ H NMR (CDCl ₃ ) δ 1.05-1.95 (9H, m), 2.1-2.4 (3H,
m), 2.38 (3H, s), 2.51 (2H, d, J = 6.6Hz), 2.55-2.9
(3H, m), 2.76 (3H, s), 2.95-3.25 (2H, m), 3.55-3.7
5 (3H, m), 6.85-7.0 (2H, m), 7.05-7.35 (7H, m). The free base (420 mg) was obtained in the same manner as in Example 95 to give the title compound.
(405 mg). Anal. Calcd for C ₂₈ H ₃₇ N ₃ O ₂・ HCl ・ 0.5H ₂ O: C, 68.20;
H, 7.97; Cl, 7.19; N, 8.52. Found: C, 68.18; H, 8.
12; Cl, 7.10; N, 8.63.

Example 97 N- [3- (4-benzyl-1-piperidinyl) propyl] -1-methyl
-N- (2-methylphenyl) -5-oxo-3-pyrrolidinecarboxamide hydrochloride Using the compound (395 mg) obtained in Reference Example 68, the same reaction and purification treatment as in Example 95 were carried out to release the title compound. Base (318
mg). ¹ H NMR (CDCl ₃ ) δ 1.05-1.95 (9H, m), 2.05-2.35 (3
H, m), 2.21 (3H, s), 2.45-3.25 (6H, m), 2.51 (2H,
d, J = 6.6Hz), 2.75 (0.5 × 3H, s), 2.76 (0.5 × 3H, s),
3.4-3.8 (1H, m), 4.0-4.25 (1H, m), 7.0-7.35 (9H,
m). The free base (318 mg) was prepared in the same manner as in Example 95 to give the title compound.
(283 mg). Anal.Calcd for C ₂₈ H ₃₇ N ₃ O ₂・ HCl ・ 0.7H ₂ O: C, 67.71;
H, 8.00; Cl, 7.14; N, 8.46. Found: C, 67.68; H, 7.
97; Cl, 7.36; N, 8.50. Example 98 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (4-cyanophenyl) -1-methyl-5-oxo-3-pyrrolidine The same reaction and purification treatment as in Example 31 were performed using the compound obtained in Carboxamide Reference Example 69 to give the title compound. ^{IR (KBr) 2230 cm -1.} 1 H NMR (CDCl 3) δ 1.21-1.99 (9H, m), 2.03-2.54 (6
H, m), 2.78 (3H, s), 2.58-3.15 (4H, m), 3.58-3.78
(3H, m), 7.10-7.36 (7H, m), 7.77 (2H, d, J = 8.0 Hz). Example 99 N- [3- (4-benzyl-1-piperidinyl) propyl] -N- ( 3-Cyanophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide Using the compound obtained in Reference Example 70, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. ^{IR (KBr) 2232 cm -1.} 1 H NMR (CDCl 3) δ 1.16-2.00 (9H, m), 2.10-2.59 (5
H, m), 2.78 (3H, s), 2.59-3.09 (3H, m), 3.09-3.40
(2H, m), 3.54-3.81 (3H, m), 7.09-7.32 (5H, m), 7.4
1-7.70 (4H, m). Example 100 N- [3- (2-benzyl-4-morpholinyl) propyl] -1-methyl
-5-oxo-N-phenyl-3-pyrrolidinecarboxamide Using the compound obtained in Reference Example 71, the same reaction and purification treatment as in Example 31 were performed to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 2.78 and 2.81 (3H, s × 2), 2.19-
3.15 (14H, m), 3.28-3.90 (6H, m), 7.10-7.32 (10H,
m).

Reference Example 1 1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid (8.59 g, 60
mmol), aniline (5.59 g, 60 mmol), 1-hydroxybenzotriazole (8.92 g, 66 mmol) in DMF (60 ml) solution was N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (17.25 g, 90 mmol) and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (120 ml) was added to the residue, and the mixture was extracted with dichloromethane (120 ml × 5). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 170 g, ethyl acetate / methanol = 1/0 → 9/1). The desired fraction was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried under reduced pressure to give the title compound (1
1.04 g, 51 mmol, 84%) as white crystals. ^{mp 163-165 ℃ 1 H NMR (CDCl} 3) δ 2.67 (1H, dd, J = 9.9, 17.1Hz), 2.
81 (1H, dd, J = 8.4, 17.1Hz), 2.88 (3H, s), 3.15-3.3
1 (1H, m), 3.58 (1H, dd, J = 9.6, 9.6Hz), 3.77 (1H, d
d, J = 7.0, 9.6Hz), 7.14 (1H, t, J = 7.3Hz), 7.34 (2H,
dd, J = 7.3, 8.0Hz), 7.53 (2H, d, J = 8.0Hz), 7.60 (1
H, br s). Anal.Calcd for C ₁₂ H ₁₄ N ₂ O ₂ : C, 66.04; H, 6.47; N,
12.84. Found: C, 66.00; H, 6.44; N, 12.89. Reference Example 2 Using N- (3,4-dichlorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide 3,4-dichloroaniline The same reaction and purification treatment as in Reference Example 1 were performed to obtain the title compound. Yield 58%. mp 164-166 ° C ¹ H NMR (CDCl ₃ ) δ 2.67 (1H, dd, J = 10.0, 17.0Hz),
2.78 (1H, dd, J = 7.8, 17.0Hz), 2.89 (3H, s), 3.16-
3.33 (1H, m), 3.59 (1H, dd, J = 9.6, 9.6Hz), 3.78 (1
H, dd, J = 6.6, 9.6Hz), 7.38 (1H, s), 7.39 (1H, s),
7.80 (1H, s), 7.97 (1H, br s). Anal.Calcd for C ₁₂ H ₁₂ Cl ₂ N ₂ O ₂ : C, 50.19; H, 4.21;
Cl, 24.69; N, 9.76. Found: C, 50.22; H, 4.26; Cl,
24.54; N, 9.94.

Reference Example 3 N- (3-chloropropyl) -1-methyl-5-oxo-N-phenyl-
3-Pyrrolidinecarboxamide The compound obtained in Reference Example 1 (2.00 g, 9.2 mmol) in DMF (20 ml)
Sodium hydride (60%, 733mg, 18m
mol) was added and the mixture was stirred at the same temperature for 1 hour. Then 1-bromo-
Add 3-chloropropane (1.81 ml, 18 mmol) and add 30
The mixture was stirred for 1 hour while being raised to room temperature for 1 minute. Water (100 ml) was added under ice cooling, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 60 g, ethyl acetate / methanol = 1/0 → 9/1). The desired fraction was concentrated under reduced pressure to give the title compound (2.43 g, approximately 80% by purity ¹ H NMR) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.95-2.15 (2H, m), 2.24 (1H, dd,
J = 9.3, 17.0Hz), 2.68 (1H, dd, J = 8.5, 17.0Hz), 2.77
(3H, s), 2.95-3.25 (1H, m), 3.19 (1H, t, J = 8.8H
z), 3.56 (2H, t, J = 6.6Hz), 3.65 (1H, dd, J = 7.0, 8.
8Hz), 3.8-3.9 (2H, m), 7.1-7.25 (2H, m), 7.35-7.55
(3H, m). Reference Example 4 N- (4-chlorobutyl) -1-methyl-5-oxo-N-phenyl-3-
The same reaction and purification treatment as in Reference Example 3 were carried out using pyrrolidinecarboxamide 1-bromo-4-chlorobutane to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.58-1.89 (4H, m), 2.23 (1H, dd,
J = 9.3, 16.7Hz), 2.60-2.80 (4H, m), 2.97-3.25 (2H,
m), 3.50-3.81 (5H, m), 7.11-7.20 (2H, m), 7.36-7.
53 (3H, m). Reference Example 5 N- (5-chloropentyl) -1-methyl-5-oxo-N-phenyl-
The same reaction and purification treatment as in Reference Example 3 were performed using 3-pyrrolidinecarboxamide 1-bromo-5-chloropentane to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.35-1.87 (6H, m), 2.23 (1H, dd,
J = 9.3, 16.3Hz), 2.60-2.80 (4H, m), 2.95-3.24 (2H,
m), 3.52 (2H, t, J = 6.4Hz), 3.59-3.77 (3H, m), 7.1
0-7.20 (2H, m), 7.38-7.53 (3H, m).

Reference Example 6-1 2-{[(1-methyl-5-oxo-3-pyrrolidinyl) carbonyl]
Anilino} ethyl acetate The compound obtained in Reference Example 1 (2.00 g, 9.2 mmol) was added to DMF (20 ml).
Sodium hydride (60%, 916mg, 23m
mol) was added and the mixture was stirred at the same temperature for 1 hour. Subsequently, ethyl bromoacetate (3.05 ml, 28 mmol) was added, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 6 hours. The reaction solution was poured into 0.5N hydrochloric acid (100 ml) under ice cooling, and extracted with ethyl acetate (50 ml × 3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 70 g, ethyl acetate / methanol = 1/0 → 95/5). The desired fraction was concentrated under reduced pressure to give the title compound (2.43 g, 8.0 mmol, 87%). _{^{mp72-74 ℃ 1 H NMR (CDCl 3}} ) δ 1.28 (3H, t, J = 7.2Hz), 2.28 (1H,
dd, J = 9.4, 16.4Hz), 2.75 (1H, dd, J = 7.8, 16.4Hz),
2.78 (3H, s), 3.1-3.35 (2H, m), 3.6-3.8 (1H, m),
4.22 (2H, q, J = 7.2Hz), 4.26 (1H, d, J = 17.1Hz), 4.4
5 (1H, d, J = 17.1Hz), 7.3-7.55 (5H, m). Reference Example 6-2 2-{[(1-methyl-5-oxo-3-pyrrolidinyl) carbonyl]
Anilino} acetic acid The compound (1.83 g, 6.0 mmol) obtained in Reference Example 6-1 was dissolved in methanol (20 ml), and an 8N aqueous sodium hydroxide solution (1.5 m
l) was added and the mixture was stirred at room temperature for 10 hours. 1N Hydrochloric acid (13 ml) was added, the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was dried over anhydrous magnesium sulfate. After filtering the insolubles, the filtrate was concentrated under reduced pressure to obtain the title compound (1.54 g, 5.6 mmol, 93%). ¹ H NMR (CDCl ₃ ) δ 2.35 (1H, dd, J = 9.0, 17.0Hz), 2.
75-2.95 (1H, m), 2.80 (3H, s), 3.1-3.35 (2H, m), 3.
65-3.8 (1H, m), 4.31 (1H, d, J = 17.4Hz), 4.45 (1H,
d, J = 17.4Hz), 7.3-7.55 (5H, m).

Reference Example 6-3 N- (2-hydroxyethyl) -1-methyl-5-oxo-N-phenyl-3-pyrrolidinecarboxamide The compound obtained in Reference Example 6-2 (829 mg, 3.0 mmol), Triethylamine (0.627 ml, 4.5 mmol) was dissolved in THF (15 ml),
Ethyl chloroformate (0.43 ml, 4.5 mmol) was added at 15 ° C to -15
The mixture was stirred at a temperature between -10 ° C and 30 ° C for 30 minutes. Subsequently, a solution of sodium borohydride (227 mg, 6.0 mmol) dissolved in water (1.5 ml) was added at −10 ° C., and the mixture was stirred at −10 ° C. to 0 ° C. for 1 hour. At 0 ° C., 1N hydrochloric acid was added, and the organic solvent was distilled off under reduced pressure, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 10).
g, ethyl acetate / methanol = 1/0 → 95/5). Concentrate the target fraction under reduced pressure to give the title compound (662 mg, 2.5 mmol, 84%)
Was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 2.27 (1H, dd, J = 9.5, 16.9Hz), 2.
71 (1H, dd, J = 8.4, 16.9Hz), 2.78 (3H, s), 3.0-3.25
(1H, m), 3.22 (1H, t, J = 8.9Hz), 3.66 (1H, dd, J =
6.6, 8.9Hz), 3.7-4.1 (4H, m), 7.15-7.3 (2H, m), 7.
3-7.55 (3H, m). Reference Example 6-4 N- (2-chloroethyl) -N-phenyl-1-methyl-5-oxo-3-
Pyrrolidine carboxamide The compound obtained in Reference Example 6-3 (659 mg, 2.5 mmol), triphenylphosphine (857 mg, 3.3 mmol), carbon tetrachloride (10 ml)
Was stirred for 1 hour while heating under reflux. The insoluble material was separated by filtration, and the insoluble material was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 40 g, ethyl acetate / methanol = 1/0 → 95/5). The desired fraction was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried under reduced pressure to give the title compound (366 mg, 1.3 mmol, 52%). ¹ H NMR (CDCl ₃ ) δ 2.25 (1H, dd, J = 9.3, 16.9Hz), 2.
70 (1H, dd, J = 8.2, 16.9Hz), 2.78 (3H, s), 2.95-3.2
5 (1H, m), 3.21 (1H, t, J = 8.9Hz), 3.55-3.75 (3H,
m), 4.00 (1H, dt, J = 13.9, 6.2Hz), 4.11 (1H, dt, J =
13.9, 6.6Hz), 7.2-7.3 (2H, m), 7.35-7.55 (3H, m).

Reference Example 7 N- (3-chloropropyl) -N- (3,4-dichlorophenyl) -1-methyl-5-oxo-3-pyrrolidinecarboxamide Reference example using the compound obtained in Reference Example 2. The same reaction and purification treatment as in 3 were performed to obtain the title compound. About ¹ H NMR purity
50%. ¹ H NMR (CDCl ₃ ) δ 1.95-2.15 (2H, m), 2.28 (1H, dd,
J = 9.7, 17.1Hz), 2.6-2.8 (1H, m), 2.80 (3H, s), 2.
95-3.2 (1H, m), 3.24 (1H, t, J = 9.2Hz), 3.56 (2H, t,
J = 6.4Hz), 3.66 (1H, dd, J = 7.0, 9.2Hz), 3.75-3.9
(2H, m), 7.05 (1H, dd, J = 2.4, 8.6Hz), 7.31 (1H, d,
J = 2.4Hz), 7.57 (1H, d, J = 8.6Hz). Reference Example 8-1 N- [2- (1,3-dioxolan-2-yl) ethyl] -1-methyl-5-
Oxo-N-phenyl-3-pyrrolidinecarboxamide The compound obtained in Reference Example 1 (2.40 g, 11 mmol) was converted into DMF (22 ml).
Dissolved in water and cooled with ice (60%, 880mg, 22m
mol) was added and the mixture was stirred at the same temperature for 1 hour. Subsequently, 2- (2-bromoethyl) -1,3-dioxolane (2.58 ml, 22 mmol) was added.
Stirred at 80 ° C. for 12 hours. The reaction solution was concentrated under reduced pressure, added with water (45 ml), and extracted with dichloromethane (45 ml × 3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 70 g, ethyl acetate / methanol = 1/0 → 9/1). The desired fraction was concentrated under reduced pressure, the residue was recrystallized from a mixed solvent of diisopropyl ether and ethyl acetate, and the precipitate was collected by filtration. The precipitate was washed with diisopropyl ether and dried under reduced pressure to give the title compound (2.47
g, 7.8 mmol, 70%) as pale yellow crystals. mp108-110 ° C ¹ H NMR (CDCl ₃ ) δ 1.91 (2H, dt, J = 4.4, 7.3 Hz), 2.2
3 (1H, dd, J = 9.1, 16.9Hz), 2.70 (1H, dd, J = 8.0, 1
6.9Hz), 2.77 (3H, s), 2.95-3.15 (1H, m), 3.18 (1H,
t, J = 9.1Hz), 3.66 (1H, dd, J = 6.9, 9.1Hz), 3.75-4.0
(6H, m), 4.93 (1H, t, J = 4.4Hz), 7.15-7.25 (2H,
m), 7.35-7.55 (3H, m).

Reference Example 8-2 N- [2-formylethyl] -1-methyl-5-oxo-N-phenyl-
3-pyrrolidinecarboxamide The compound obtained in Reference Example 8-1 (1.95 g, 6.1 mmol) was treated with 1N hydrochloric acid.
(10 ml) and stirred at room temperature for 18 hours. Dichloromethane
(20 ml × 3), the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.66 g, 6.1 mmol, 99%)
Was obtained as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 2.23 (1H, dd, J = 9.4, 16.6Hz), 2.
6-2.8 (3H, m), 2.77 (3H, s), 2.95-3.15 (1H, m), 3.
18 (1H, t, J = 9.1Hz), 3.61 (1H, dd, J = 6.9, 9.1Hz),
3.98 (1H, dt, J = 14.0, 6.6Hz), 4.14 (1H, dt, J = 14.
0, 6.9Hz), 7.1-7.25 (2H, m), 7.35-7.55 (3H, m), 9.
77 (1H, t, J = 1.9 Hz). Reference Example 9 N- [3- (4-benzyl-1-piperidyl) propyl] -4-methylaniline dihydrochloride 4-benzylpiperidine (3.51 g, 20 mmol), DBU (0.030ml,
0.2 mmol) in THF (40 ml) was added dropwise with stirring at −20 ° C. at a temperature of −20 ° C. in a solution of acrolein (90%, 1.49 ml, 20 mmol) in THF (5 ml) over 5 minutes, and the temperature increased from −20 ° C. to −10 ° C. The mixture was stirred for 1 hour. Subsequently, p-toluidine (2.14 g, 20 mmol) and sodium triacetoxyborohydride (8.48 g, 40 mmol) were sequentially added at −10 ° C., and the mixture was stirred for 23 hours while warming to room temperature. Saturated aqueous sodium bicarbonate (160 ml) and water were added, and the mixture was extracted with ethyl acetate (60 ml × 3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 100).
g, ethyl acetate / methanol = 1/0 → 9/1 → 4/1). The target fraction was concentrated under reduced pressure to give oily N- [3- (4-benzyl-1-piperidyl) propyl] -4-methylaniline (4.07 g, 12.6 mmol,
63%). ¹ H NMR (CDCl ₃ ) δ 1.15-1.95 (9H, s), 2.23 (3H, s),
2.42 (2H, t, J = 6.8Hz), 2.55 (2H, d, J = 6.6Hz), 2.8
5-3.0 (2H, m), 3.13 (2H, t, J = 6.4Hz), 6.51 (2H, d,
J = 8.4Hz), 6.98 (2H, d, J = 8.4Hz), 7.1-7.35 (5H,
m). N- [3- (4-benzyl-1-piperidyl) propyl] -4-methylaniline (4.07 g, 12.6 mmol) in 2-propanol (20 ml), 4N
Hydrogen chloride (ethyl acetate solution, 8 ml) was added, and the resulting precipitate was collected by filtration. The precipitate was washed with 2-propanol and dried under reduced pressure to give the title compound (4.52 g, 11 mmol, 57%) as white crystals. mp 182-192 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.9 (5H, m), 2.0-2.25 (2H,
m), 2.31 (3H, s), 2.45-2.6 (2H, m), 2.7-2.95 (2H,
.. m), 2.95-3.55 (6H , m), 7.1-7.45 (9H, m) Anal Calcd for C 22 H 30 N 2 · 2HCl · 0.5H 2 O: C, 65.34; H,
8.22; Cl, 17.53; N, 6.93. Found: C, 65.24; H, 8.3
8; Cl, 17.37; N, 6.98.

Reference Example 10 N- [3- (4-benzyl-1-piperidyl) propyl] aniline 2
The same reaction and purification treatment as in Reference Example 9 were performed using aniline hydrochloride to give the title compound. Yield 47%. mp 217 ° C (dec) ¹ H NMR (D ₂ O) δ 1.44-1.56 (2H, m), 1.81-1.84 (3H,
m), 2.08-2.24 (2H, m), 2.62 (2H, d, J = 6.6Hz), 2.85-
2.96 (2H, m), 3.12-3.20 (2H, m), 3.48-3.56 (4H, m),
7.25-7.65 (10H, m). Anal.Calcd for C ₂₁ H ₂₈ N ₂・ 2HCl ・ 0.5H ₂ O: C, 64.61; H,
8.00; N, 7.18. Found: C, 64.71; H, 7.92; N, 7.32. Reference Example 11 N- [3- (4-benzyl-1-piperidyl) propyl] -4-tert-butylaniline dihydrochloride 4 The same reaction and purification treatment as in Reference Example 9 were carried out using -tert-butylaniline to obtain the title compound. Yield 51%. mp 203-213 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.27 (9H, s), 1.4-1.9 (5H, m),
2.0-2.2 (2H, m), 2.45-2.6 (2H, m), 2.75-2.95 (2H, m
m), 3.0-3.7 (6H, m), 7.1-7.4 (7H, m), 7.44 (2H, d,
J = 8.4Hz). Anal. Calcd for C ₂₅ H ₃₆ N ₂・ 2HCl ・ 0.2H ₂ O: C, 68.07; H,
8.77; Cl, 16.07; N, 6.35. Found: C, 68.10; H, 8.8
0; Cl, 15.85; N, 6.35. Reference Example 12 Same as Reference Example 9 using N- [3- (4-benzyl-1-piperidyl) propyl] -5-indanylamine dihydrochloride 5-aminoindane And the purification treatment were performed to obtain the title compound. Yield 28%. mp 175 ° C. (dec) ¹ H NMR (D ₂ O) δ 1.42-1.50 (2H,
m), 1.87-1.93 (3H, m), 2.
08-2.15 (4H, m), 2.61 (2H,
d, J = 6.6 Hz), 2.82-2.94
(6H, m), 3.10-3.18 (2H,
m), 3.26-3.54 (4H, m), 7.1
2 (1H, d, J = 7.8 Hz), 7.24-
7.41 (7H, m). Anal. Calcd for C ₂₄ H ₃₂ N ₂・
_{2HCl · 0.25H 2 O: C,} 67.67;
H, 8.25; N, 6.57. Found:
C, 67.73; H, 7.97; N, 6.5.
0.

Reference Example 13 N- [3- (4-benzyl-1-piperidyl) propyl] -4-
Methoxyaniline dihydrochloride The same reaction and purification treatment as in Reference Example 9 was performed using 4-methoxyaniline to obtain the title compound. Yield 38%. mp 154-159 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.95 (5H, m), 1.95-2.2 (2
H, m), 2.45-2.65 (2H, m), 2.7-3.0 (2H, m), 3.0-3.5
5 (6H, m), 3.76 (3H, s), 7.02 (2H, d, J = 8.8Hz), 7.
1-7.45 (7H, m). Anal.Calcd for C ₂₂ H ₃₀ N ₂ O ・ 2HCl ・ 0.4H ₂ O: C, 63.12;
H, 7.90; Cl, 16.94; N, 6.69. Found: C, 63.12; H, 7.
84; Cl, 16.71; N, 6.78. Reference Example 14 Reference Example Using N- [3- (4-benzyl-1-piperidyl) propyl] -3,4-dimethoxyaniline dihydrochloride 3,4-dimethoxyaniline The same reaction and purification treatment as in 9 were performed to obtain the title compound. Yield 61%. mp 149-159 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.9 (5H, m), 2.0-2.25 (2H,
m), 2.45-2.6 (2H, m), 2.75-3.0 (2H, m), 3.0-3.65
(6H, m), 3.77 (3H, s), 3.79 (3H, s), 7.03 (2H, s),
7.05-7.4 (6H, m). Anal.Calcd for C ₂₃ H ₃₂ N ₂ O ₂・ 2HCl ・ 1.0H ₂ O: C, 60.13;
H, 7.90; Cl, 15.43; N, 6.10. Found: C, 60.13; H, 7.
72; Cl, 15.26; N, 6.06. Reference Example 15 N- [3- (4-benzyl-1-piperidyl) propyl] -3,4-diethoxyaniline dihydrochloride Using 3,4-diethoxyaniline The same reaction and purification treatment as in Reference Example 9 were performed to obtain the title compound. Yield 24%. mp 160 ° C (dec) ¹ H NMR (D ₂ O) δ 1.38-1.51 (8H, m), 1.89-1.96 (3H,
m), 2.10-2.19 (2H, m), 2.63 (2H, d, J = 6.6Hz), 2.86-
2.94 (2H, m), 3.12-3.20 (2H, m), 3.45-3.55 (4H, m),
4.13-4.23 (4H, m), 7.02-7.39 (8H, m). Anal.Calcd for C ₂₅ H ₃₆ N ₂ O ₂・ 2HCl ・ 0.6H ₂ O: C, 62.51;
H, 8.23; N, 5.83.Found: C, 62.30; H, 8.10; N, 5.8
Four.

Reference Example 16 N- [3- (4-Benzyl-1-piperidyl) propyl] -4-chloroaniline dihydrochloride The same reaction and purification treatment as in Reference Example 9 was carried out using 4-chloroaniline. The compound was obtained. Yield 70%. mp 155-159 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.9 (5H, m), 1.9-2.1 (2H,
m), 2.45-2.6 (2H, m), 2.7-2.95 (2H, m), 2.95-3.5 (6
.. H, m), 6.85 (2H, d, J = 9.2Hz), 7.1-7.4 (7H, m) Anal Calcd for C 21 H 27 ClN 2 · 2HCl: C, 60.66; H, 7.0
3; Cl, 25.58; N, 6.74.Found: C, 60.85; H, 6.81; C
l, 25.33; N, 6.79. Reference Example 17 N- [3- (4-benzyl-1-piperidyl) propyl] -3-chloroaniline dihydrochloride The same reaction as in Reference Example 9 using 3-chloroaniline Purification was performed to obtain the title compound. Yield 41%. mp 202 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.53-2.01 (7H, m), 2.50-2.55
(2H, m), 2.66-2.92 (2H, m), 3.08-3.20 (4H, m), 3.38
-3.44 (2H, m), 6.61-6.69 (3H, m), 7.07-7.30 (6H,
m). Anal. Calcd for C ₂₁ H ₂₇ ClN ₂・ 2HCl ・ 0.1H ₂ O: C, 60.39;
H, 7.04; N, 6.71.Found: C, 60.33; H, 6.93; N, 6.8
4. Reference Example 18 N- [3- (4-benzyl-1-piperidyl) propyl] -3,4-dichloroaniline dihydrochloride The same reaction and purification treatment as in Reference Example 9 using 3,4-dichloroaniline. Was performed to obtain the title compound. Yield 53%. mp 203 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.49-1.76 (5H, m), 1.91-1.96
(2H, m), 2.50-2.55 (2H, m), 2.79-3.17 (6H, m), 3.38
-3.44 (2H, m), 6.68 (1H, dd, J = 2.8, 8.8Hz), 6.75 (1
H, d, J = 2.6Hz), 7.17-7.30 (6H, m). Anal.Calcd for C ₂₁ H ₂₆ Cl ₂ N ₂・ 2HCl ・ 0.5H ₂ O: C, 54.92;
H, 6.36; N, 6.10. Found: C, 55.11; H, 6.64; N, 6.
37.

Reference Example 19 The same reaction and purification as in Reference Example 9 using N- [3- (4-benzyl-1-piperidyl) propyl] -3,4-difluoroaniline dihydrochloride 3,4-difluoroaniline Treatment gave the title compound. Yield 53%. mp 177 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.53-1.75 (5H, m), 1.94-1.98
(2H, m), 2.51-2.54 (2H, m), 2.66-2.84 (2H, m), 3.06
-3.10 (4H, m), 3.38-3.44 (2H, m), 6.51-6.55 (1H,
.. m), 6.67-6.77 (1H , m), 7.11-7.34 (6H, m) Anal Calcd for C 21 H 26 F 2 N 2 · 2HCl: C, 60.43; H, 6.7
6; N, 6.71. Found: C, 59.93; H, 6.67; N, 6.74. Reference Example 20 N- [3- (4-benzyl-1-piperidyl) propyl] -2,4-difluoroaniline dihydrochloride 2 The same reaction and purification treatment as in Reference Example 9 were performed using, 4-difluoroaniline to obtain the title compound. Yield 43%. mp 181 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.53-1.75 (5H, m), 1.95-2.02
(2H, m), 2.50-2.54 (2H, m), 2.66-2.84 (2H, m), 3.05
-3.18 (4H, m), 3.37-3.43 (2H, m), 6.72-6.94 (2H,
.. m), 7.04-7.34 (6H , m) Anal Calcd for C 21 H 26 F 2 N 2 · 2HCl · 1.0H 2 O: C, 57.93;
H, 6.95; N, 6.43. Found: C, 57.46; H, 7.04; N, 6.1
4. Reference Example 21 The same reaction and purification treatment as in Reference Example 9 using N- [3- (4-benzyl-1-piperidyl) propyl] -2,6-difluoroaniline dihydrochloride 2,6-difluoroaniline Was performed to obtain the title compound. Yield 15%. mp 168 ° C (dec) ¹ H NMR (D ₂ O) δ 1.41-1.50 (2H, m), 1.83-2.08 (5H,
m), 2.61 (2H, d, J = 6.4Hz), 2.82-2.94 (2H, m), 3.12
-3.55 (6H, m), 7.06-7.42 (8H, m) Anal Calcd for C 21 H 26 F 2 N 2 · 2HCl:.. C, 60.43; H, 6.6
6; N, 6.71. Found: C, 60.27; H, 6.66; N, 6.64.

Reference Example 22 N- [3- (4-benzyl-1-piperidyl) propyl] -3-chloro-4
The same reaction and purification treatment as in Reference Example 9 were performed using -fluoroaniline dihydrochloride 3-chloro-4-fluoroaniline to obtain the title compound. Yield 40%. mp 197 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.53-1.75 (5H, m), 1.94-2.02
(2H, m), 2.50-2.55 (2H, m), 2.80-2.85 (2H, m), 3.07
-3.10 (4H, m), 3.38-3.45 (2H, m), 6.67-6.73 (1H,
m), 6.84 (1H, dd, J = 3.0, 6.0Hz), 7.13-7.34 (6H,
m). Anal. Calcd for C ₂₁ H ₂₆ ClFN ₂・ 2HCl ・ 0.5H ₂ O: C, 56.96;
H, 6.60; N, 6.33. Found: C, 57.12; H, 6.43; N, 6.
46. Reference Example 23 N- [3- (4-benzyl-1-piperidyl) propyl] -4- (trifluoromethyl) aniline dihydrochloride The same as in Reference Example 9 using 4- (trifluoromethyl) aniline. The reaction and purification were performed to obtain the title compound. Yield 36
%. mp 168 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.56-1.75 (5H, m), 1.95-2.06
(2H, m), 2.50-2.55 (2H, m), 2.80-2.90 (2H, m), 3.04
-3.18 (4H, m), 3.38-3.45 (2H, m), 6.70 (2H, d, J = 8.
.. 6Hz), 7.16-7.40 (7H , m) Anal Calcd for C 22 H 27 F 3 N 2 · 2HCl: C, 58.80; H, 6.5
0; N, 6.23. Found: C, 58.64; H, 6.47; N, 6.32. Reference Example 24 N- [3- (4-benzyl-1-piperidyl) propyl] -3,5-bis
Reference example using (trifluoromethyl) aniline dihydrochloride 3,5-bis (trifluoromethyl) aniline
The same reaction and purification treatment as in 9 were performed to obtain the title compound. Yield 19%. mp 185 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.50-1.76 (5H, m), 1.91-1.97
(2H, m), 2.50-2.55 (2H, m), 2.80-2.86 (2H, m), 3.08
-3.24 (4H, m), 3.40-3.47 (2H, m), 7.05-7.34 (8H,
m). Anal. Calcd for C ₂₃ H ₂₆ F ₆ N ₂・ 2HCl ・ 1.0H ₂ O: C, 51.60;
H, 5.65; N, 5.23. Found: C, 51.69; H, 5.54; N, 5.4
3.

REFERENCE EXAMPLE 25 N- [3- (4-Benzyl-1-piperidyl) propyl] -4- (trifluoromethoxy) aniline dihydrochloride Same as Reference Example 9 using 4- (trifluoromethoxy) aniline And the purification treatment were performed to obtain the title compound. Yield 35
%. mp 175 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.54-1.75 (5H, m), 1.98-2.06
(2H, m), 2.50-2.55 (2H, m), 2.80-2.90 (2H, m), 3.12
-3.19 (4H, m), 3.39-3.45 (2H, m), 6.68 (2H, d, J = 8.
8Hz), 7.16-7.34 (7H, m). Anal.Calcd for C ₂₂ H ₂₇ F ₃ N ₂ O ・ 2HCl ・ 1.1H ₂ O: C, 54.45;
H, 6.48; N, 5.77. Found: C, 54.26; H, 6.17; N, 5.
97. Reference Example 26 Using N- [3- (4-benzyl-1-piperidyl) propyl] -1-naphthylamine dihydrochloride 1-aminonaphthalene, the same reaction and purification treatment as in Reference Example 9 were carried out to give the title compound. Obtained. Yield 48%. mp 175 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.55-1.75 (5H, m), 2.10-2.20
(2H, m), 2.50-2.55 (2H, m), 2.80-2.90 (2H, m), 3.10
-3.18 (2H, m), 3.33-3.45 (4H, m), 6.82-6.86 (1H,
m), 7.16-7.37 (7H, m), 7.46-7.50 (2H, m), 7.81-7.8
.. 6 (1H, m) , 8.21-8.26 (1H, m) Anal Calcd for C 25 H 30 N 2 · 2HCl · 1.0H 2 O: C, 66.81; H,
7.62; N, 6.23. Found: C, 66.60; H, 7.53; N, 6.25. Reference Example 27 N- [3- (4-benzyl-1-piperidyl) propyl] -3-phenylaniline dihydrochloride 3-amino The same reaction and purification treatment as in Reference Example 9 were performed using biphenyl to give the title compound. 55% yield. mp 164-169 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.9 (5H, m), 1.9-2.2 (2H,
m), 2.45-2.6 (2H, m), 2.7-3.0 (2H, m), 3.0-3.55 (6
H, m), 6.95-7.1 (1H, m), 7.1-7.55 (11H, m), 7.64 (2
H, d, J = 7.0Hz). Anal.Calcd for C ₂₇ H ₃₂ N ₂・ 2HCl ・ 0.9H ₂ O: C, 68.46; H,
7.62; Cl, 14.97; N, 5.91. Found: C, 68.55; H, 7.6
2; Cl, 14.87; N, 5.96.

Reference Example 28 3- (benzyloxy) -N- [3- (4-benzyl-1-piperidyl)
The same reaction and purification treatment as in Reference Example 9 were performed using propyl] aniline dihydrochloride 3- (benzyloxy) aniline to obtain the title compound. Yield 58%. mp 134-139 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.9 (5H, m), 1.9-2.15 (2H,
m), 2.45-2.6 (2H, m), 2.7-2.95 (2H, m), 2.95-3.5
(6H, m), 5.08 (2H, s), 6.6-6.85 (3H, m), 7.1-7.5
(11H, m). Anal.Calcd for C ₂₈ H ₃₄ N ₂ O ・ 2HCl: C, 68.98; H, 7.44;
Cl, 14.54; N, 5.75. Found: C, 68.90; H, 7.37; Cl,
14.23; N, 5.74.Reference Example 29 4- (benzyloxy) -N- [3- (4-benzyl-1-piperidyl)
Propyl] aniline dihydrochloride The same reaction and purification treatment as in Reference Example 9 were performed using 4- (benzyloxy) aniline to obtain the title compound. Yield 72%. mp 160-170 ° C (dec) ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.95 (5H, m), 2.0-2.25 (2
H, m), 2.45-2.6 (2H, m), 2.7-2.95 (2H, m), 2.95-3.
5 (6H, m), 5.12 (2H, s), 7.05-7.5 (14H, m). Anal.Calcd for C ₂₈ H ₃₄ N ₂ O ・ 2HCl: C, 68.98; H, 7.44;
Cl, 14.54; N, 5.75. Found: C, 68.73; H, 7.41; Cl,
14.24; N, 5.64.

Reference Example 30 3- (4-Benzyl-1-piperidinyl) propylamine A solution of 4-benzylpiperidine (24.6 g, 140 mmol) in N, N'-dimethylformamide (250 mL) was added with N- (3- (Bromopropyl) phthalimide (37.5 g, 140 mmol) was added, followed by potassium carbonate (38.7 g, 280 mmol), and the mixture was stirred at room temperature for 14 hours. Water (200 mL) was added to the reaction solution, and ethyl acetate was added.
(300 mL × 2). The organic layer was washed with water (400 mL) and a saturated aqueous sodium chloride solution (400 mL), dried over anhydrous magnesium sulfate, filtered through silica gel (100 g) (eluted with ethyl acetate), and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give 2- [3- (4-benzyl-1-piperidinyl) propyl] -1H-isoindole-
27.4 g (yield 69%) of 1,3 (2H) -dione was obtained. To a solution of 500 mg (1.38 mmol) of this compound in ethanol (5 mL) was added
Add hydrazine monohydrate (345 mg, 6.9 mmol) and add 90 ° C
And refluxed for 2 hours. After cooling, insolubles were removed by filtration, and the mother liquor was concentrated under reduced pressure. 2N aqueous sodium hydroxide solution in the residue
(10 mL), and ethyl acetate / tetrahydrofuran = 1 /
1 Extracted with a mixed solvent (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from acetonitrile to give 329 mg of the title compound (yield
95%). mp 59-61 ° C. ¹ H NMR (CDCl ₃ + D ₂ O) δ 1.20-1.38 (2
H, m), 1.40-1.70 (5H, m),
1.71-1.89 (2H, m), 2.26-
2.43 (2H, m), 2.53 (2H,
d, J = 6.6 Hz), 2.72 (2H,
t, J = 7.0 Hz), 2.90-3.00
(2H, m), 7.10-7.30 (5H,
m). Reference Example 31 1- (3-aminopropyl) -4- (4-chlorophenyl) -4-
The same reaction and purification treatment as in Reference Example 30 were carried out using piperidinol 4- (4-chlorophenyl) -4-hydroxypiperidine to obtain the title compound. Yield 67% mp 102-104 ° C ¹ H NMR (CDCl ₃ ) δ 1.60-1.80 (5H, m), 2.00-2.20 (2
H, m), 2.30-2.50 (4H, m), 2.72 (2H, t, J = 7.0 H
z), 2.75-2.90 (2H, m), 4.80 (2H, br), 7.20-7.50 (4
H, m).

Reference Example 32 N-benzyl-3- (4-benzyl-1-piperidinyl) -1-propanamine A solution of the compound obtained in Reference Example 30 (500 mg, 2.15 mmol) in tetrahydrofuran (3 mL) was added to Benzaldehyde (32
3 mg, 2.20 mmol) in tetrahydrofuran (2 mL).
The mixture was added dropwise at 0 ° C and stirred at room temperature for 1 hour. 0 ° C
Acetic acid (168 mg, 2.80 mmol) in tetrahydrofuran (5
mL) solution was added dropwise, and then sodium triacetoxyborohydride (593 mg, 2.80 mmol) was added, followed by stirring at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, a mixed solvent of ethyl acetate / tetrahydrofuran = 1/1 (10 mL) was added to the residue, and the insoluble material was removed by filtration. After concentration of the mother liquor, the resulting oil was subjected to column chromatography (basic alumina activity I
II, 50 g, ethyl acetate to ethyl acetate / methanol = 4/1
And eluted with) to give the title compound (340 mg, 49%, oil). ¹ H NMR (CDCl ₃ ) δ 1.10-1.88 (10H, m), 2.35 (2H, t,
J = 7.5 Hz), 2.52 (2H, d, J = 6.6 Hz), 2.66 (2H,
t, J = 6.8 Hz), 2.88-3.00 (2H, m), 3.78 (2H, s), 7.
11-7.36 (10H, m). Reference Example 33 4-({[3- (4-benzyl-1-piperidinyl) propyl] amino}
Methyl) phenol The same reaction and purification treatment as in Reference Example 32 were carried out using 4-hydroxybenzaldehyde to give the title compound. Yield 59%
_{^{(Oil). 1 H NMR (CDCl 3}} ) δ 1.20-2.00 (9H, m), 2.40 (2H, tl
ike, J = 7.0 Hz), 2.50 (2H, d, J = 6.2 Hz), 2.68 (2
H, t like, J = 7.0 Hz), 2.88-3.00 (2H, m), 3.65 (2
H, s), 3.80-4.66 (2H, br), 6.57 (2H, d, J = 8.4 H
z), 7.03 (2H, d, J = 8.4 Hz), 7.10-7.31 (5H, m). Reference Example 34 3- (4-benzyl-1-piperidinyl) -N- (1-naphthylmethyl)
The same reaction and purification treatment as in Reference Example 32 were performed using 1-propanamine 1-naphthaldehyde to obtain the title compound. 57% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.05-1.35 (2H, m), 1.37-1.93 (7
H, m), 2.22 (1H, br s), 2.37 (2H, t, J = 7.3 Hz),
2.47 (2H, d, J = 6.8 Hz), 2.79 (2H, t, J = 6.8 H
z), 2.85-2.95 (2H, m), 4.24 (2H, s), 7.10-7.32 (4
H, m), 7.39-7.57 (4H, m), 7.76-7.90 (2H, m), 8.09-
8.13 (2H, m).

Reference Example 35 3- (4-benzyl-1-piperidinyl) -N- (2-naphthylmethyl)
The same reaction and purification treatment as in Reference Example 32 were carried out using 1-propanamine 2-naphthaldehyde to obtain the title compound. 43% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.15-1.35 (2H, m), 1.40-1.93 (8
H, m), 2.36 (2H, t, J = 7.4 Hz), 2.49 (2H, d, J =
6.6 Hz), 2.70 (2H, t, J = 7.0 Hz), 2.80-3.00 (2H,
m), 3.95 (2H, s), 7.09-7.32 (5H, m), 7.40-7.51 (3
H, m), 7.76-7.84 (4H, m). Reference Example 36 1- [3- (benzylamino) propyl] -4- (4-chlorophenyl) -4-piperidinol Using the compound obtained in Reference Example 31 The same reaction and purification treatment as in Reference Example 32 were carried out to obtain the title compound. 48% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 1.60-1.90 (6H, m), 2.06 (2H, td,
J = 13.4, 4.4 Hz), 2.33-2.52 (4H, m), 2.73 (2H,
t, J = 6.8 Hz), 2.80-2.86 (2H, m), 3.80 (2H, m), 7.
20-7.50 (9H, m). Reference Example 37 4- (4-chlorophenyl) -1- [3- (isopropylamino) propyl] -4-piperidinol Using the compound obtained in Reference Example 31 and acetone, The same reaction and purification treatment as in Example 32 were performed to give the title compound. Yield 45%. ¹ H NMR (DMSO-d ₆ ) δ 1.24 (6H, d, J = 6.6 Hz), 1.50
-1.70 (2H, m), 1.70-2.00 (4H, m), 2.40-2.60 (5H,
m), 2.70-2.90 (2H, m), 2.95 (2H, t, J = 7.3 Hz),
3.20-3.40 (2H, m), 7.37 (2H, d, J = 8.7 Hz), 7.49
(2H, d, J = 8.7 Hz). Reference Example 38 4- (4-chlorophenyl) -1- [3- (cyclohexylamino) propyl] -4-piperidinol Using the compound obtained in Reference Example 31 and cyclohexanone. The same reaction and purification treatment as in Reference Example 32 were performed to obtain the title compound. Yield 58%. ¹ H NMR (CDCl ₃ ) δ 1.10-1.40 (6H, m), 1.50-1.96 (10
H, m), 2.08 (2H, td, J = 11.6, 4.4 Hz), 2.38-2.60
(4H, m), 2.77-2.92 (4H, m), 2.80-3.40 (1H, br), 7.
31 (2H, d, J = 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz).

Reference Example 39 4- (4-chlorophenyl) -1- [3- (cyclopentylamino) propyl] -4-piperidinol The same procedure as in Reference Example 32 was carried out using the compound obtained in Reference Example 31 and cyclopentanone. And the purification treatment were performed to obtain the title compound. Yield ^{57%. 1 H NMR (DMSO-d} 6) δ 1.40-2.20 (13H, m), 2.30-2.60
(2H, m), 3.00-3.60 (8H, m), 5.62 (1H, s), 7.43 (2
H, d, J = 9.2 Hz), 7.50 (2H, d, J = 9.2 Hz), 9.06
(1H, br s). Reference Example 40 4-Benzyl-1- (3-chloropropyl) piperidine N, N'- of 4-benzylpiperidine (100 mg, 0.57 mmol)
To a dimethylformamide (2 mL) solution was added 1-chloro-3-iodopropane (117 mg, 0.57 mmol), followed by triethylamine (58 mg, 0.57 mmol), and the mixture was stirred at room temperature for 14 hours. Water (10 mL) was added to the reaction solution, and ethyl acetate (20 mL) was added.
mL × 2). The organic layer was washed with water (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained oil was subjected to column chromatography (basic alumina activity III, 50 g, ethyl acetate / N-hexane = 1/20
And eluted with) to give the title compound (86 mg, 60%, oil). ¹ H NMR (CDCl ₃ ) δ 1.15-2.05 (9H, m), 2.43 (2H, t,
J = 7.0Hz), 2.53 (2H, d, J = 6.6 Hz), 2.80-3.00 (2
H, m), 3.58 (2H, t, J = 6.6 Hz), 7.12-7.33 (5H, m). Reference Example 41 N- [3- (4-benzyl-1-piperidinyl) propyl] -2-indanamine To a solution of the compound obtained in Reference Example 40 (755 mg, 3 mmol) in acetonitrile (5 mL) was added 2-aminoindane (266 mg,
2 mmol) in acetonitrile (5 mL) and triethylamine (304 mg, 3 mmol) were added, and the mixture was heated with stirring at 80 ° C. for 5 hours. After concentration of the solvent under reduced pressure, the residue was purified by column chromatography (basic alumina activity III, 60 g, eluted with ethyl acetate) to give the title compound (150 mg, 22%, oil)
I got ¹ H NMR (CDCl ₃ ) δ 1.10-1.32 (2H, m), 1.38-1.88 (8
H, m), 2.36 (2H, t, J = 7.3Hz), 2.51 (2H, d, J = 6.
8 Hz), 2.67-3.00 (6H, m), 3.16 (2H, dd, J = 15.4,
7.0 Hz), 3.61 (1H, qui., J = 7.0 Hz), 7.12-7.32 (9
H, m).

Reference Example 42 [1- (3-anilino-2-hydroxypropyl) -4-piperidinyl]-(4-fluorophenyl) methanone (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride (1.05 g, 4.3 mmol) in ethyl acetate (50 mL) and 1
The mixture was added to a mixture of a normal aqueous sodium hydroxide solution (10 mL), and extracted with ethyl acetate. The organic layer was washed with water (20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was dissolved in acetonitrile (30 mL), N- (2-oxiranylmethyl) aniline (700 mg, 4.7 mmol) was added, and the mixture was heated under reflux for 24 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (silica gel 100 g, ethyl acetate / methanol = 9/1) to give the title compound (510 mg, 33%, oil). . ¹ H NMR (DMSO-d ₆ ) δ 1.57-1.86 (4H, m), 2.11-2.52
(4H, m), 2.86-3.33 (5H, m), 3.78-3.81 (1H, m), 4.62
-4.64 (1H, m), 5.64 (1H, br), 6.47-6.60 (3H, m), 7.
02-7.09 (2H, m), 7.29-7.37 (2H, m), 8.02-8.09 (2H, m
m). Reference Example 43 5-Oxo-1-phenyl-3-pyrrolidinecarboxylic acid Itaconic acid (25 g, 190 mmol) was added to aniline (18 g, 190
mmol) and heated to reflux at 150 ° C. for 1 hour. After cooling,
The obtained crude crystals were recrystallized from methanol (200 mL) to give the title compound (35 g, 90%). mp 188-189 ° C (methanol). ¹ H NMR (CDCl ₃ ) δ 2.60-2.86 (2H, m), 3.20-3.50 (1
H, m), 3.92-4.10 (2H, m), 7.14 (1H, t, J = 7.6 H
z), 7.37 (2H, t, J = 7.6 Hz), 7.64 (2H, d, J = 7.6
Hz), 12.80 (1H, br s). Anal.Calcd for C ₁₁ H ₁₁ NO ₃ : C, 64.38; H, 5.40; N,
6.83. Found: C, 64.34; H, 5.53; N, 6.91.

Reference Example 44 The same reaction and purification treatment as in Reference Example 43 were carried out using benzylamine 1-benzyl-5-oxo-3-pyrrolidinecarboxylate to obtain the title compound. Yield 76%. Mp 192-193 ° C. _{^{(methanol). 1 H NMR (CDCl 3}} ) δ 2.69-2.92 (2H, m), 3.14-3.30 (1
H, m), 3.43-3.59 (2H, m), 4.39 (1H, d, J = 14.6 H
z), 4.53 (1H, d, J = 14.6 Hz), 7.19-7.38 (5H, m), 1
0.29 (1H, br s) Anal Calcd for C 12 H 13 NO 3:.. C, 65.74; H, 5.98; N,
6.39. Found: C, 65.80; H, 5.84; N, 6.48. Reference Example 45 The same reaction and purification treatment as in Reference Example 43 was performed using 1-cyclohexyl-5-oxo-3-pyrrolidinecarboxylic acid cyclohexylamine to obtain the title. The compound was obtained. Yield 62% .mp 186-187 ° C (methanol-diethyl ether). ¹ H NMR (CDCl ₃ ) δ 1.00-1.77 (10H, m), 2.34-2.57 (2
H, m), 3.08-3.23 (1H, m), 3.30-4.00 (4H, m) .Reference Example 46 Same as Reference Example 43 using 1-butyl-5-oxo-3-pyrrolidinecarboxylic acid N-butylamine. And the purification treatment were performed to obtain the title compound. 67% yield _{^{(oil). 1 H NMR (CDCl 3}} ) δ 0.93 (3H, t, J = 7.0 Hz), 1.23-
1.59 (4H, m), 2.64-2.88 (2H, m), 3.19-3.40 (3H, m),
3.56-3.74 (2H, m), 7.20-7.60 (1H, br). Reference Example 47 The same reaction and purification treatment as in Reference Example 43 were carried out using phenethylamine 5-oxo-1-phenethyl-3-pyrrolidinecarboxylate. The title compound was obtained. Yield 60%. Mp 185-186 ° C (methanol). ¹ H NMR (CDCl ₃ ) δ 2.54-2.88 (4H,
m), 3.05-3.21 (1H, m), 3.0.
40-3.62 (4H, m), 7.19-7.4
0 (5H, m), 7.70-8.20 (1H,
br).

Reference Example 48 The same reaction and purification treatment as in Reference Example 43 were carried out using 3-phenylpropylamine 5-oxo-1- (3-phenylpropyl) -3-pyrrolidinecarboxylate to obtain the title compound. Yield 51%. Mp 88-90 ° C. (ethyl _{^{acetate). 1 H NMR (CDCl 3}} ) δ 1.78-1.93 (2H, m), 2.57-2.80 (4
H, m), 3.09-3.69 (5H, m), 7.15-7.32 (5H, m), 8.34
(1H, br s). Reference Example 49 1- (4-methoxybenzyl) -5-oxo-3-pyrrolidinecarboxylic acid The same reaction and purification treatment as in Reference Example 43 was performed using 4-methoxybenzylamine to give the title compound. I got 83% yield. Mp 153-155 ° C. _{^{(methanol). 1 H NMR (CDCl 3}} ) δ 2.61-2.86 (2H, m), 3.08-3.24 (1
H, m), 3.39-3.55 (2H, m), 3.80 (3H, s), 4.33 (1H,
d, J = 14.2 Hz), 4.46 (1H, d, J = 14.2 Hz), 6.82-
6.89 (2H, m), 7.13-7.20 (2H, m), 7.50-9.00 (1H, b
r). Reference Example 50 5-oxo-1- (4-pyridylmethyl) -3-pyrrolidinecarboxylic acid The same reaction and purification treatment as in Reference Example 43 was performed using 4- (aminomethyl) pyridine to obtain the title compound. Was. Yield 15% .mp 190-191 ° C (water-methanol). ¹ H NMR (DMSO-d ₆ ) δ 2.25-2.71 (2H, m), 3.15-3.57
(3H, m), 4.36 (1H, d, J = 16.0 Hz), 4.47 (1H, d, J
= 16.0 Hz), 7.23 (2H, d, J = 5.6 Hz), 8.53 (2H, d,
J = 5.6 Hz) .Reference Example 51 The same reaction and purification treatment as in Reference Example 43 was carried out using 4-fluorobenzylamine 1- (4-fluorobenzyl) -5-oxo-3-pyrrolidinecarboxylate to give the title compound. Obtained. Yield 72%. Mp 142-143 ℃ _{^{(methanol). 1 H NMR (CDCl 3}} ) δ 2.64-2.88 (2H, m), 3.11-3.27 (1
H, m), 3.41-3.57 (2H, m), 4.43 (2H, s), 6.97-7.32
(4H, m), 9.40-10.40 (1H, br).

Reference Example 52 The same reaction and purification treatment as in Reference Example 43 were carried out using 1- (cyclohexylmethyl) -5-oxo-3-pyrrolidinecarboxylic acid (aminomethyl) cyclohexane to obtain the title compound. Yield 50% mp 96-97 ℃.. (Methanol - diethyl _{^{ether) 1 H NMR (CDCl 3)}} δ 0.80-1.32 (5H, m), 1.50-1.80 (6
H, m), 2.66-2.89 (2H, m), 3.04-3.35 (3H, m), 3.55-
3.73 (2H, m), 6.40-7.20 (1H, br). Reference Example 53 1- (2-chlorobenzyl) -5-oxo-3-pyrrolidinecarboxylic acid Same as Reference Example 43 using 2-chlorobenzylamine. And the purification treatment were performed to obtain the title compound. Yield 77%. ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ 2.62-2.87 (2H, m), 3.14-
3.30 (1H, m), 3.42-3.58 (2H, m), 4.60 (2H, s), 7.2
2-7.40 (4H, m). Reference Example 54 The same reaction and purification treatment as in Reference Example 43 were performed using 3-chlorobenzylamine of 1- (3-chlorobenzyl) -5-oxo-3-pyrrolidinecarboxylic acid. The title compound was obtained. Yield 69%. ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ 2.60-2.90 (2H, m), 3.10-
3.28 (1H, m), 3.45-3.60 (2H, m), 4.58 (2H, s), 7.2
0-7.45 (4H, m). Reference Example 55 The same reaction and purification treatment as in Reference Example 43 were performed using 4-chlorobenzylamine of 1- (4-chlorobenzyl) -5-oxo-3-pyrrolidinecarboxylic acid. The title compound was obtained. Yield 66%. ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ 2.65-2.90 (2H, m), 3.10-
3.30 (1H, m), 3.45-3.61 (2H, m), 4.53 (2H, s), 7.3
4 (2H, d, J = 7.5Hz), 7.58 (2H, d, J = 7.5Hz), 7.6
-8.5 (1H, br).

Reference Example 56 Reference Example Using 4- (trifluoromethyl) benzylamine 5-oxo-1- [4- (trifluoromethyl) benzyl] -3-pyrrolidinecarboxylate
The same reaction and purification treatment as in 43 were performed to give the title compound. Yield 69%. ¹ H NMR (CDCl ₃ ) δ 2.80-2.84 (2H, m), 3.19-3.35 (1
H, m), 3.46-3.61 (2H, m), 4.53 (2H, s), 7.36 (2H,
d, J = 7.6Hz), 7.60 (2H, d, J = 7.6Hz), 7.6-8.2 (1
Reference Example 57 1- (2-morpholinoethyl) -5-oxo-3-pyrrolidinecarboxylic acid Using 2-morpholinoethylamine, the same reaction and purification treatment as in Reference Example 43 were performed to obtain the title compound. . Yield 44%. ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ 2.45-2.81 (8H, m), 3.13-
3.76 (9H, m), 9.2-9.6 (1H, br) .Reference Example 58 Using 1- (2-furylmethyl) -5-oxo-3-pyrrolidinecarboxylic acid furfurylamine, the same reaction as in Reference Example 43 was performed. Purification was performed to obtain the title compound. 63% yield. mp 155-156 ° C (ethanol). ¹ H NMR (CDCl ₃ ) δ 2.60-2.85 (2H, m), 3.12-3.28 (1
H, m), 3.51-3.68 (2H, m), 4.39 (1H, d, J = 15.4 H
z), 4.53 (1H, d, J = 15.4 Hz), 6.26 (1H, d, J = 3.6
Hz), 6.31-6.34 (1H, m), 7.36 (1H, d, J = 1.8 Hz),
8.30-10.00 (1H, br). Reference Example 59 The same reaction and purification treatment as in Reference Example 43 were performed using 4-methylbenzylamine 1- (4-methylbenzyl) -5-oxo-3-pyrrolidinecarboxylate. The title compound was obtained. 79% yield. ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ 2.33 (3H, s), 2.61-2.87
(2H, m), 3.09-3.25 (1H, m), 3.40-3.55 (2H, m), 4.
34 (1H, d, J = 14.6 Hz), 4.48 (1H, d, J = 14.6 H
z), 7.12 (4H, s), 7.2-7.8 (1H, br).

Reference Example 60 The title compound was subjected to the same reaction and purification treatment as in Reference Example 43 using 2,6-difluorobenzylamine 1- (2,6-difluorobenzyl) -5-oxo-3-pyrrolidinecarboxylate. I got Yield 62%. ¹ H NMR (DMSO-d ₆ ) δ 2.40-2.60 (2H, m), 3.10-3.60
(3H, m), 4.46 (2H, s), 7.05-7.16 (2H, m), 7.37-7.50
(1H, m), 12.4-12.8 (1H, br) .Reference Example 61 1-benzyl-6-oxo-3-piperidinecarboxylic acid diethyl 2-methylenepentanedioate (Tetrahedron
Lett. 1989, 30 , 7381) (1.00 g, 5.0 mmol) in ethanol
(1.5ml), benzylamine (0.546ml, 5.0mmol)
And stirred at 60 ° C. for 6 days. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 25 g, ethyl acetate / hexane = 1/1 → 1/0). The desired fraction was concentrated under reduced pressure to obtain ethyl 1-benzyl-6-oxo-3-piperidinecarboxylate (1.01 g, 3.9 mmol, yield 77%). ¹ H NMR (CDCl ₃ ) δ 1.22 (3H, t, J = 7.2Hz), 1.85-2.25
(2H, m), 2.35-2.85 (3H, m), 3.3-3.55 (2H, m), 4.1
2 (2H, qd, J = 7.2Hz, 2.0Hz), 4.52 (1H, d, J = 14.8H
z), 4.71 (1H, d, J = 14.8Hz), 7.2-7.4 (5H, m) .Ethyl 1-benzyl-6-oxo-3-piperidinecarboxylate (2
61 mg, 1 mmol) was dissolved in methanol (1 ml), a 1N aqueous sodium hydroxide solution (1.2 ml) was added, and the mixture was stirred at room temperature for 1 hour.
1N-hydrochloric acid (1.5 ml) was added to the reaction solution, and the resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (200 mg, 86%). ¹ H NMR (CDCl ₃ ) δ 1.90-2.30 (2H, m), 2.43-2.90 (3
H, m), 3.34-3.52 (2H, m), 4.46 (1H, d, J = 14.6 H
z), 4.77 (1H, d, J = 14.6 Hz), 7.23-7.36 (5H, m),
8.6-9.4 (1H, br). Reference Example 62 N- [3- (4-Benzyl-1-piperidinyl) propyl] -1-indanamine dihydrochloride The same reaction as in Reference Example 41 using 1-indanamine And purified to give the title compound. Yield 33%. ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.9 (6H, m), 2.0-2.3 (3H,
m), 2.3-2.6 (2H, m), 2.6-3.6 (11H, m), 4.74 (1H, b
rs), 7.17-7.4 (8H, m), 7.7-7.9 (1H, m), 9.2-9.8
(2H, br).

Reference Example 63 N- [3- (4-benzyl-1-piperidinyl) propyl] -1,2,3,4-
Tetrahydro-1-naphthylamine dihydrochloride The same reaction and purification treatment as in Reference Example 41 was carried out using 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride to obtain the title compound. Yield 56%. ¹ H NMR (DMSO-d ₆ ) δ 1.4-3.4 (24H, m), 4.46 (1H, br
s), 7.0-7.5 (8H, m), 7.71 (1H, br d, J = 6.2 Hz),
9.2-10.0 (2H, br). Reference Example 64 N- {3- [4- (4-fluorobenzyl) -1-piperidinyl] propyl} aniline dihydrochloride Using 4- (4-fluorobenzyl) piperidine and aniline The same reaction and purification treatment as in Reference Example 9 were carried out to obtain the title compound. Yield 54%. mp 230 ° C (dec.) ¹ H NMR (DMSO-d ₆ ) δ 1.35-1.9 (5H, m), 1.95-2.2 (2
H, m), 2.45-2.6 (2H, m), 2.83 (2H, br t, J = 11.5H
z), 3.11 (2H, br t, J = 7.4Hz), 3.24 (2H, br t, J = 6.
.. 8Hz), 3.42 (2H , br d, J = 10.6Hz), 6.9-7.2 (9H, m) Anal Calcd for C 21 H 27 FN 2 · 2HCl · 0.8H 2 O: C, 60.96;
H, 7.45; N, 6.77; Cl, 17.14; F, 4.59. Found: C, 6
1.02; H, 7.37; N, 6.76; Cl, 17.04; F, 4.30. Reference Example 65 3,4-dichloro-N- {3- [4- (4-fluorobenzyl) -1-piperidinyl] propyl} aniline di The same reaction and purification treatment as in Reference Example 9 was carried out using 4- (4-fluorobenzyl) piperidine hydrochloride and 3,4-dichloroaniline to obtain the title compound. Yield 48%. mp 203-209 ° C (dec.) ¹ H NMR (DMSO-d ₆ ) δ 1.35-2.05 (7H, m), 2.45-2.6 (2
H, m), 2.6-3.3 (6H, m), 3.41 (2H, br d, J = 10.6Hz),
6.57 (1H, dd, J = 2.7, 8.8Hz), 6.75 (1H, d, J = 2.7H
.. z), 7.05-7.3 (5H , m) Anal Calcd for C 21 H 25 Cl 2 FN 2 · 2HCl · 0.5H 2 O: C, 52.
85; H, 5.91; N, 5.87.Found: C, 52.90; H, 6.12; N,
5.94.

Reference Example 66 N- [3- (4-Benzyl-1-piperidinyl) propyl] -3- (trifluoromethyl) aniline dihydrochloride Same as Reference Example 9 using 3- (trifluoromethyl) aniline And the purification treatment were performed to synthesize the title compound. yield
56%. mp 167-173 ° C (dec.) ¹ H NMR (DMSO-d ₆ ) δ 1.4-2.1 (7H, m), 2.45-2.6 (2H,
m), 2.6-2.95 (2H, m), 2.95-3.3 (2H, m), 3.13 (2H,
t, J = 6.6Hz), 3.41 (2H, br d, J = 11.6Hz), 6.75-6.95
(3H, m), 7.1-7.4 (6H, m). Anal.Calcd for C ₂₂ H ₂₇ F ₃ N ₂・ 2HCl ・ 0.8H ₂ O: C, 56.9
7; H, 6.65; N, 6.04. Found: C, 56.87; H, 6.64; N,
6.10. Reference Example 67 Using N- [3- (4-benzyl-1-piperidinyl) propyl] -3-methylaniline dihydrochloride m-toluidine, the same reaction and purification treatment as in Reference Example 9 were performed to give the title compound. Obtained. Yield 67%. ¹ H NMR (DMSO-d ₆ ) δ 1.4-2.25 (7H, m), 2.31 (3H,
.. s), 2.45-3.5 (10H , m), 6.95-7.4 (9H, m) Anal Calcd for C 22 H 30 N 2 · 2HCl · 0.2H 2 O:
C, 66.22; H, 8.18; N, 7.0
2; Cl, 17.77. Found: C, 6
6.30; H, 8.12; N, 6.99; C
1, 17.56. Reference Example 68 N- [3- (4-benzyl-1-piperidinyl) propyl]-
The same reaction and purification treatment as in Reference Example 9 were carried out using 2-methylaniline dihydrochloride o-toluidine to obtain the title compound. Yield 69%. ¹ H NMR (DMSO-d ₆ ) δ 1.4-2.25 (7H, m), 2.32 (3H,
.. s), 2.45-3.5 (10H , m), 6.9-7.4 (9H, m) Anal Calcd for C 22 H 30 N 2 · 2HCl · 1.0H 2 O: C, 63.91;
H, 8.29; N, 6.78; Cl, 17.15.Found: C, 64.01; H, 8.
18; N, 6.74; Cl, 16.93. Reference Example 69 N- [3- (4-benzyl-1-piperidinyl) propyl] -4-cyanoaniline The same reaction and purification as in Reference Example 9 using 4-cyanoaniline. Treatment gave the title compound. ¹ H NMR (CDCl ₃ ) δ 1.19-1.39 (2H, m), 1.45-1.96 (7
H, m), 2.42-2.49 and 2.56-2.60 (2H and 2H, m), 2.9
0-2.97 and 3.15-3.24 (2H and 2H, m), 6.17-6.30 (1
H, br s), 6.45 (2H, d, J = 9.0Hz), 7.14-7.42 (7H,
m).

Reference Example 70 N- [3- (4-Benzyl-1-piperidinyl) propyl] -3-cyanoaniline The same reaction and purification treatment as in Reference Example 9 was performed using 3-cyanoaniline to obtain the title compound. Was. ¹ H NMR (CDCl ₃ ) δ 1.20-1.40 (2H, m), 1.41-1.95 (7
H, m), 2.42-2.49 and 2.56-2.60 (2H and 2H, m), 2.9
1-2.98 and 3.11-3.19 (2H and 2H, m), 6.68-6.74 (2
H, m), 6.89-6.93 (1H, m), 7.14-7.30 (6H, m). Reference Example 71 N- [3- (2-benzyl-4-morpholinyl) propyl] aniline 2-benzylmorpholine (J. Pharm. Pharmacol. 1990, 4
The same reaction and purification treatment as in Reference Example 9 were carried out using 2 , 797) and aniline to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.62-2.10 (4H, m), 2.45 (2H, t,
J = 6.6Hz), 2.61-2.93 (4H, m), 3.16 (2H, t, J = 6.2H
z), 3.58-3.93 (3H, m), 6.54-6.75 (3H, m), 7.11-7.2
9 (7H, m). Experimental Examples (1) Cloning of Human CCR5 Chemokine Receptor The CCR5 gene was cloned from human spleen cDNA by PCR. 0.5 ng of spleen cDNA (Toyobo,
QUICK-Clone cDNA) as a template and reported by Samson et al. (Biochemistry 35 (11), 3362-336).
7 (1996)) A primer set prepared by referring to the base sequence of the CCR5 gene, 5'-CAGGATCCGATGGATTATCAAGTGTCAAGTCCAA-3 'and 5'-TCTAGATCACAAGCCCACAGATATTTCCTGCTCC-3', each of which is added in an amount of 25 pmol, respectively, is added to TaKaRa EX Taq (Takara Shuzo).
The PCR reaction is performed using a DNA thermal cycler 4
80 (Perkin Elmer) (reaction conditions: 95
30 ° C. for 1 minute, 60 ° C. for 1 minute, and 75 ° C. for 5 minutes). The PCR product was subjected to agarose gel electrophoresis, and a DNA fragment of about 1.0 kb was recovered.
The CCR5 gene was cloned using TA Cloning Kit (Funakoshi). (2) Preparation of plasmid for human CCR5 expression The plasmid obtained above was digested with the restriction enzyme XbaI (Takara Shuzo).
After digestion with BamHI (Takara Shuzo), a DNA fragment of about 1.0 kb was recovered by agarose gel electrophoresis. That D
The NA fragment and the expression plasmid pcDNA3.1 (Funakoshi) for animal cells digested with XbaI and BamHI were mixed, and DN
A Ligation Kit Ver. 2 (Takara Shuzo) and transformed into competent cells of Escherichia coli JM109 (Takara Shuzo) to obtain plasmid pCKR5.

(3) C of plasmid for human CCR5 expression
Introduction and expression into HO-K1 cells CHO-K1 cells grown in a 750 ml tissue culture flask (Becton Dickinson) using a Ham F12 medium (Nippon Pharmaceutical) containing 10% fetal bovine serum (Lifetech Oriental) were used. 5 g / L trypsin
After detachment with 0.2 g / L EDTA (Lifetech Oriental), the cells were washed with PBS (Lifetech Oriental), centrifuged (1000 rpm, 5 minutes), and PBS was removed.
And suspended. Next, Gene Pulsar (Bio-Rad)
Was used to introduce DNA into cells according to the following conditions. That is, 8 × 10 ⁶ in a 0.4 cm gap cuvette
Cells and 10 μg of plasmid pCK for expression of human CCR5
Add R5, voltage 0.25 kV, capacitance 960μ
Electroporated under F. The cells were then transferred to Ham's F12 medium containing 10% fetal calf serum and
After culturing for hours, the cells were detached again and centrifuged, and then Geneticin (Lifetech Oriental) was added at 500 μg /
Ham F containing 10% fetal bovine serum
The cells were suspended in 12 media, diluted to 10 ⁴ cells / ml, and seeded on a 96-well plate (Becton Dickinson) to obtain a geneticin-resistant strain. Next, after the obtained geneticin-resistant strain was cultured in a 96-well plate (Becton Dickinson), CCR5-expressing cells were selected from the resistant strains. That is, 200 pM [ ¹²⁵ I] -RA
Assay buffer (0.5% BSA, 20 mM HEPE) with NTES (Amersham) added as ligand
S (ham F12 medium containing Wako Junyaku, pH 7.2) for 40 minutes at room temperature, washing with ice-cold PBS, adding 1 M NaOH at 50 μl / well, stirring and adding γ -By measuring the radioactivity with a counter, cells to which the ligand specifically bound, the CHO / CCR5 strain were selected. (4) Evaluation of Compound Based on CCR5 Antagonistic Activity The CHO / CCR5 strain was seeded at 5 × 10 ⁴ cells / well in a 96-well microplate, cultured for 24 hours, the medium was removed by suction, and the test compound (1 μM) was contained. Assay buffer is added to each well and the ligand [ ¹²⁵ I]
After adding RANTES (Amersham) to 100 pM, the mixture was reacted at room temperature for 40 minutes. Next, the assay buffer was removed by suction and then washed twice with cooled PBS. Next, 200 μl of Microscint-20 (Packard) was added to each well, and the radioactivity was measured with a top count (Packard).

According to the method described above, the CCR of the test compound
5 The binding inhibition rate was measured. The results are shown in [Table 1].

[Table 1] CCR5 antagonists containing compound (I) of the present invention as an active ingredient (eg, a preventive and therapeutic agent for HIV infection, AID
S preventive therapeutic agent etc.) can be manufactured by the following prescription, for example. After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule.

[0098] 2. Tablets (1) 40 mg of the compound obtained in Example 51 (2) Lactose 58 mg (3) Corn starch 18 mg (4) Microcrystalline cellulose 3.5 mg (5) Magnesium stearate 0.5 mg 1 tablet 120 mg (1), (2) ), (3), 2/3 of (4) and (5)
And then granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

[0099]

The compound of the formula (I) of the present invention or a salt thereof has an excellent CCR5 antagonistic effect, and is therefore advantageously used for prevention and treatment of various HIV infections in humans, for example, AIDS. Can be used.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4725 A61K 31/4725 31/496 31/496 31/5377 31/5377 31/55 31/55 A61P 31/18 A61P 31/18 43/00 43/00 C07D 207/277 C07D 207/277 221/20 221/20 401/04 401/04 403/12 403/12 413/12 413/12 (72) Inventor Nori Nishimura 586-2, Higashihiratsuka, Oaza, Tsukuba, Ibaraki Pref. No. F-term (reference) 4C034 CK02 4C063 AA01 BB01 BB09 CC10 CC12 CC15 CC19 CC54 DD03 EE01 4C069 AB13 BD06 CC19 4C086 AA01 AA02 AA03 AA04 BC21 BC27 BC30 BC32 BC50 BC73 GA07 GA08 GA09 MA01 MA02 MA03 MA04 NA14 Z

Claims (27)

[Claims] [Claim 1] The formula: (In the formula, R ¹ represents a hydrocarbon group, R ² represents a hydrocarbon group having 2 or more carbon atoms, and R ¹ and R ² may have a substituent together with an adjacent nitrogen atom bonded thereto. R ³ may be a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ⁴ may have a hydrogen atom or a substituent. A hydrocarbon group or a heterocyclic group which may have a substituent, E is a divalent chain hydrocarbon group which may have a substituent other than an oxo group, G is CO or SO ₂ , J represents a nitrogen atom or a methine group which may have a substituent, and Q and R each represent a bond or a divalent C _1-3 chain hydrocarbon which may have a substituent. Or a salt thereof. (2) R ¹ is a C _1-6 alkyl group or a C _3-8 cycloalkyl group and R ² is a C _2-6 alkyl group or a C _3-8 cycloalkyl group, or R ¹ and R ² Are bonded to form an optionally substituted ring together with an adjacent nitrogen atom, and R ³ has an optionally substituted C _1-6 alkyl group or an optionally substituted substituent. An optionally substituted C _3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, wherein R ⁴ has a hydrogen atom or a substituent. An optionally substituted alkyl group, an optionally substituted C _3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, wherein E is C which may have a substituent other than an oxo group
_2-5 alkylene group, G is CO or SO ₂ , J is a nitrogen atom or a methine group which may have a substituent, and Q and R may have a bond or a substituent, respectively. The compound according to claim 1, which is a C _1-3 alkylene group. 3. The method according to claim 1, wherein R ¹ and R ² are bonded to form an optionally substituted ring together with an adjacent nitrogen atom.
Or the compound of 2. 4. A ring which may have a substituent may be a 1-piperidinyl group or a 1-piperidinyl group which may have a substituent.
The compound according to claim 3, which is a piperazinyl group. 5. The method according to claim 1, wherein the substituent of the 1-piperidinyl group or 1-piperazinyl group has (1) a phenyl-C _1-4 alkyl optionally having a halogen on the benzene ring, and (2) a hydroxy. Good diphenylmethyl, (3) benzoyl optionally having a halogen on the benzene ring, (4) 2
The compound according to claim 4, which is -phenylethen-1-yl, (5) phenyl optionally having halogen, (6) hydroxy, (7) phenoxy or (8) benzyloxy. 6. The compound according to claim 3, wherein the ring which may have a substituent is a 1-piperidinyl group which may have a substituent. 7. The compound according to claim 6, wherein the substituent of the 1-piperidinyl group is a benzyl group which may have a halogen on the benzene ring. (8) R ³ is (1) a C _1-6 alkyl group;
_3-8 cycloalkyl group, (3) benzyl group optionally having hydroxy group, (4) naphthylmethyl group, (5)
C _1-4 alkyl optionally having a halogen as a substituent, C _1-4 alkoxy optionally having a halogen, phenyl, cyano, benzyloxy or a phenyl group optionally having a halogen atom, 3. The compound according to claim 1, which is (6) a naphthyl group, (7) an indanyl group or (8) a tetrahydronaphthyl group. 9. The method according to claim 1, wherein R ³ is a phenyl group optionally having C _1-4 alkyl or halogen as a substituent.
Or the compound according to 2, 10. C wherein E may have hydroxy
3. The compound according to claim 1, which is _2-6 polymethylene. 11. C _1-6 wherein R ⁴ may have (1) a hydrogen atom, (2) halogen, pyridyl, morpholino, furyl, ethynyl or C _3-8 cycloalkyl.
Alkyl, (3) halogen on the benzene ring, C _1-4 alkyl, halogeno -C _1-4 alkyl or C _1-4 phenyl which may have an alkoxy -C _1-4 alkyl or (4) C _3- 3. The compound according to claim 1, which is ₈ cycloalkyl. 12. The method according to claim 1, wherein R ⁴ is a C _1-4 alkyl group optionally having halogen or furyl as a substituent or a benzyl group optionally having halogen on a benzene ring. Compound. 13. —N (R ¹ ) R ² is an optionally substituted 1-piperidinyl group, E is a trimethylene group, R ³ is an optionally substituted phenyl group, and G is an optionally substituted phenyl group. The compound according to claim 1, wherein CO and J are CH, and Q and R are each a methylene group. 14. N- [3- (4-benzyl-1-piperidinyl) propyl] -N- (3,4-dichlorophenyl) -1-methyl-5-oxo-3
-Pyrrolidinecarboxamide, 1-benzyl-N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo-N-phenyl-
3-pyrrolidinecarboxamide, N- [3- (4-benzyl-1-piperidinyl) propyl] -1- (2-chlorobenzyl) -5-oxo
-N-phenyl-3-pyrrolidinecarboxamide, N- (3,4-dichlorophenyl) -N- {3- [4- (4-fluorobenzyl) -1-piperidinyl] propyl} -1-methyl-5-oxo- Selected from 3-pyrrolidinecarboxamide and N- [3- (4-benzyl-1-piperidinyl) propyl] -5-oxo-N-phenyl-1- (2,2,2-trifluoroethyl) -3-pyrrolidinecarboxamide Or a salt thereof. (15) a prodrug of the compound according to the above (1); 16. A pharmaceutical composition comprising the compound according to claim 1 or a prodrug thereof. 17. The composition according to claim 16, which is a chemokine receptor antagonist. 18. The composition according to claim 16, which is a CCR5 antagonist. 19. The composition according to claim 16, which is an agent for preventing or treating HIV infection. 20. The method of claim 1, which is an agent for preventing or treating AIDS.
6. The composition according to 6. (21) the composition according to the above (16), which is an agent for suppressing the progress of AIDS disease state; 22. The composition according to claim 19, further comprising a protease inhibitor and / or a reverse transcriptase inhibitor. 23. The composition according to claim 22, wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, nevirapine, delavirdine or efavirenz. 24. The composition according to claim 22, wherein the protease inhibitor is saquinavir, ritonavir, indinavir, amprenavir or nelfinavir. (25) Use of the compound according to (1) or a prodrug thereof and a protease inhibitor or / and a reverse transcriptase inhibitor for the prevention and treatment of HIV infection. 26. A compound of the formula: (In the formula, R ¹ represents a hydrocarbon group, R ² represents a hydrocarbon group having 2 or more carbon atoms, and R ¹ and R ² may have a substituent together with a nitrogen atom adjacent thereto. R ³ may be a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and E may have a substituent other than an oxo group. Or a salt thereof, which may be a divalent chain hydrocarbon group which may be represented by the following formula: (Wherein, R ⁴ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent,
J represents a nitrogen atom or a methine group which may have a substituent; Q and R each represent a bond or a divalent C _1-3 chain hydrocarbon group which may have a substituent; ⁵ represents a carboxy group, a sulfonic acid group or a salt or reactive derivative thereof. ) Or a salt thereof is reacted with a compound represented by the following formula: (Wherein, G represents CO or SO ₂ , and other symbols are as defined above) or a salt thereof. 27. A compound of the formula: in the presence of a base. (Wherein, R ³ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ⁴ represents a hydrogen atom or a hydrocarbon group which may have a substituent. E represents a hydrogen group or a heterocyclic group which may have a substituent, E represents a divalent chain hydrocarbon group which may have a substituent other than an oxo group,
Represents CO or SO ₂ , J represents a nitrogen atom or a methine group which may have a substituent, and Q and R each represent a bond or a divalent C _1-3 chain which may have a substituent. And X represents a leaving group. Or a salt thereof and a compound represented by the formula: (In the formula, R ¹ represents a hydrocarbon group, R ² represents a hydrocarbon group having 2 or more carbon atoms, and R ¹ and R ² may have a substituent together with a nitrogen atom adjacent thereto. Which may form a ring) or a salt thereof. (Wherein each symbol has the same meaning as described above) or a method for producing a salt thereof.