JPH0687810A - 4-@(3754/24)aminomethyl)cyclohexanecarboxamide derivative - Google Patents

Abstract

PURPOSE:To provide a new 4-(aminomethyl)cyclohexanecarboxamide derivative digestive tract motion enhancer. CONSTITUTION:The compound of formula I {R<1> is H or of formula II (m is 0 or 1; X is CH2 or CH=CH; R<5> is (substituted) phenyl, (substituted) naphthyl, (substituted) heterocyclic group, alkoxy-substituted alkyl or cycloalkyl); R<2> is H or combined with R<1> into homophthaloyl; R<3> is (CH2)m-R<6> [n is 1-3; R<6> is H, alkyl, (substituted) phenyl, (alkyl-substituted) amino, CN, (alkyl-substituted) thiol, alkoxy, carbamoyl or of formula III (p is 0 or 1; q is 0-2; R<7> is (substituted) heterocyclic group)]; R<4> is H or combined with both R<3> and bound N into 5 to 6membered ring} and an acid-added salt thereof, e.g. 4(benzamidomethyl)-N-(3-pyridyl)methyl-trans-cyclohexane-1-carboxamide. The compound of the formula I is effective for improving the general malaise of the upper digestive tracts, digestive tract function recovery after celiotomy, or aperitiveness.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 4- (aminomethyl) cyclohexanecarboxamide derivative having an action of promoting gastrointestinal motility and an acid addition salt thereof.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 64-56661 discloses a 4- (aminomethyl) cyclohexanecarboxamide derivative as one of aminopyridine derivatives having antihypertensive action and coronary circulatory organ improving action. Also, JP-A-62-5
JP-A-4 describes N- (O-carboxy or alkoxycarbonyl-substituted phenyl) -trans-4-guanidinomethylcyclohexanecarboxamide derivatives having antiulcer activity. Examples of the drug having a gastrointestinal motility enhancing action include N- (3-hydroxy-4-piperidinyl) benzamide derivatives (see JP-A-58-90552) and N-substituted benzamides (JP-A-64-50883).
(See Japanese Patent Publication) and the like are known.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have a gastrointestinal motility enhancing action for improving upper gastrointestinal indefinite complaints due to gastrointestinal function deterioration, recovering gastrointestinal function after laparotomy or increasing appetite. However, for the purpose of developing a new drug having excellent safety, the inventors have made earnest studies.

[0004]

As a result, the present inventors have found that the novel 4- (aminomethyl) cyclohexanecarboxamide derivative and its acid addition salt have a gastrointestinal motility-promoting action and low acute toxicity. After finding out that, the present invention has been completed.

That is, according to the present invention, there is provided a 4- (aminomethyl) cyclohexanecarboxamide derivative represented by the formula (1) and an acid addition salt thereof.

[0006]

[Chemical 4]

(Wherein R ¹ is hydrogen or the formula:

[0008]

[Chemical 5]

(Where m is an integer of 0 to 1, X is —CH ₂ — or —CH═CH—, R ⁵ is hydrogen, phenyl which may have a substituent, or a substituent. Naphthyl, a heterocyclic monovalent group which may have a substituent, a lower alkoxy-substituted alkyl (preferably a lower alkyl group) or a cycloalkyl),

R ² represents hydrogen, or R ¹ and R ²
Together represent homophthaloyl and R ³ is of the formula — (CH
₂ ) _n -R ⁶ (where n is an integer of 1 to 3, R ⁶ is hydrogen, lower alkyl, phenyl which may have a substituent, amino group which may have a lower alkyl substituent, cyano group , A thiol which may have a lower alkyl substituent, a lower alkoxy,
Carbamoyl or formula:

[0011]

[Chemical 6]

[0012] (where p is an integer of 0 to 1, q is an integer of 0 to 2, R ⁷ is shown a monovalent group of heterocycle which may have a substituent group) are shown) of, R ⁴ Represents hydrogen, or R
³ and R ⁴ represent a group that forms a 5- or 6-membered ring with the nitrogen to which it is attached)

In the present invention, the monovalent group of the heterocycle means
Pyridyl, piperidyl, indolyl, pyrazinyl, quinolyl, isoquinolyl, imidazolyl, pyrrolyl, pyrrolidinyl, morpholyl, piperazinyl,

[0014]

[Chemical 7]

Pyranyl, thienyl, etc. are shown, and cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., together with nitrogen atom.
The group forming a 6-membered ring means pyrrolidinyl, piperidyl,
Piperazinyl and the like are shown.

Further, among the groups of the formula (1), the substituent which may be possessed is a halogen such as fluorine, chlorine, bromine or iodine, a lower alkyl, a lower alkoxy or a lower alkyl group. Also represents an amino group, a hydroxyl group, methylenedioxy and the like.

In the present invention, the lower alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like having 1 carbon atom.
Is a C6 alkyl group, and lower alkoxy is a methoxy, ethoxy, propoxy, butoxy or the like having 1 to 6 carbon atoms.
6 refers to an alkoxy group.

When the compound of formula (1) of the present invention has an asymmetric carbon, optical isomers, racemates thereof and the like may exist, but the present invention includes all of them. These isomers can be isolated by a conventional method or can be produced by using each isomer raw material.

The compound provided by the present invention can be produced by the following two methods (a) and (a). (A) A commercially available trans-4- (aminomethyl) cyclohexanecarboxylic acid is methyl-esterified by a conventional method, and the obtained ester and carboxylic acid (R ¹ -OH; R ¹ is as defined above) are condensed. (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, hereinafter WSCI.HCl
Represented) is used to condense. Alternatively, a mixed acid anhydride derived from a carboxylic acid or an acid chloride is synthesized and condensed with the obtained ester. Then, this ester is hydrolyzed by a usual method to obtain a compound represented by the following formula (2), and further

[0020]

[Chemical 8] And condense in the same manner as above.

[0021]

[Chemical 9]

(A) A commercially available trans-4- (aminomethyl) cyclohexanecarboxylic acid is converted to an amino group by a conventional method.
protected with tert-butoxycarbonyl, amine

[0023]

[Chemical 10]

[0024] The condensed, using an acid tert- butoxycarbonyl were detached, after obtaining the hydrochloride salt of the compound represented by the formula (3), carboxylic acid (R ¹ -OH; R ¹ is same as defined above Is used) and a condensing agent (WSCI.HCl), or a carboxylic acid is introduced into a mixed acid anhydride or acid chloride for condensation.

[0025]

[Chemical 11]

The compound having an amino group of the compound according to the present invention can be made into an acid addition salt. Examples of such acid addition salts include pharmacologically acceptable salts such as hydrochloride, p-toluenesulfonate, tartrate, maleate, fumarate and oxalate.

Some of the compounds obtained by the above method have stronger activity than known gastrointestinal motility enhancers, and the compounds represented by the following formulas (4) (5) (6) (7) are This is an example of a compound that is excellent as a gastrointestinal motility enhancer in consideration of toxicity and the like.

[0028]

[Chemical 12]

As described above, the compound according to the present invention is a useful gastrointestinal motility enhancer, and is used as a medical drug for improving upper gastrointestinal indefinite complaints, recovering gastrointestinal function after laparotomy or increasing appetite. Are better.

When the compound of the present invention is used as a medicine, it is mixed with an appropriate pharmacologically acceptable excipient, carrier, diluent or the like additive for pharmaceutical preparations to give tablets, granules, powders,
It can be administered orally or parenterally in the form of capsules, injections, ointments and suppositories. The dosage is
It may vary depending on the patient's age, body weight, symptoms, etc., but it is usually 1 to 1,000 mg, preferably 10 to 100 mg, as an oral administration per day for an adult, and this should be administered once or in several divided doses. You can

[0031]

[Examples] Examples and the following show the gastrointestinal motility enhancing effect,
The present invention will be described more specifically.

Example 1 4- (benzamidomethyl) -N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0033]

[Chemical 13]

Process 4- (aminomethyl) -N- (3-pyridyl) methyl-
trans-Cyclohexane-1-carboxamide dihydrochloride
Dissolve 1.0 g (3.12 mmol) in 50 ml of pyridine and add benzoic acid.
0.34 g (2.78 mmol), triethylamine 1 ml, WSCI · HC
1.05 g (5.48 mmol) and 1 ml of water were added, and the mixture was stirred overnight at room temperature. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Ethanol: n
Recrystallization from -hexane gave colorless needle crystals (500 mg, 1.42 mmol) (yield 46%). Melting point: 180-183 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98 (2H m), 1.44-1.72 (3H m), 1.87-2.03 (4H m), 2.03
-2.17 (1H m), 3.33 (2H t J = 6.6Hz), 4.45 (2H d J = 5.9),
5.87-6.01 (1H br), 6.16-6.27 (1H br), 7.24-7.31 (1H
m), 7.39-7.57 (3H m), 7.61 (1H d J = 7.9Hz), 7.75 (2H d
J = 6.6Hz), 8.51 (2H d J = 2.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3297, 2928, 1642, 1547

Example 2 4- (2-methoxybenzamidomethyl) -N- (3-
Pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0036]

[Chemical 14]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.0 g (3.12 mmol) was dissolved in 50 ml of pyridine, 0.475 g (3.12 mmol) of o-anisic acid, 0.9 g (4.69 mmol) of WSCI.HCl, 1 ml of triethylamine and 1 ml of water were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Ethanol: recrystallized from n-hexane, colorless needle crystals 500mg
(1.31 mmol) was obtained (yield 42%). Melting point: 160-162 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.18 (2H m), 1.43-1.81 (3H m), 1.87-2.05 (4H m),
2.06-2.19 (1H m), 3.32 (2H dd J = 5.9Hz, 6.6Hz), 3.97 (3
H s), 4.45 (2H d J = 5.9Hz), 5.91-6.06 (1H br), 6.98 (1H
d J = 7.9Hz), 7.07 (1H dd J = 7.3Hz, 7.9Hz), 7.23-7.29 (1
H br), 7.41-7.49 (1H br), 7.61 (1H dd J = 2.0Hz, 7.9H
z), 7.83-7.97 (1H br), 8.18 (1H dd J = 2.0 Hz, 6.6Hz),
8.51 (2H d J = 2.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3315, 2935, 1638, 1530

Example 3 4- (3-Methoxybenzamidomethyl) -N- (3-
Pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0039]

[Chemical 15]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.0 g (3.12 mmol) was dissolved in 50 ml of pyridine, 0.475 g (3.12 mmol) of m-anisic acid, 1.19 g (4.69 mmol) of WSCI.HCl, 1 ml of triethylamine and 1 ml of water were added and stirred overnight. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from ethanol: n-hexane gave 900 mg (2.35 mmol) of colorless prism crystals (yield 76%). Melting point: 158-159 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.96-1.11 (2H m), 1.42-1.68 (3H m), 1.78-1.99 (4H m),
2.06-2.19 (1H m), 3.29 (2H dd J = 5.9Hz, 6.6Hz), 3.81 (3
H s), 4.41 (2H d J = 5.9Hz), 6.41-6.54 (2H m), 6.99-7.0
4 (1H m), 7.19-7.36 (4H m), 7.54-7.61 (1H m), 8.48-8.5
3 (2H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3301, 2932, 1642, 1586, 1549, 1489, 1448, 1424, 13
19, 1248, 1234, 1206

Example 4 4- (4-methoxybenzamidomethyl) -N- (3-
Pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0042]

[Chemical 16]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.0 g (3.12 mmol) was dissolved in 50 ml of pyridine, and 0.475 g (3.12 mmol) of p-anisic acid, 1.19 g (4.69 mmol) of WSCI.HCl, 1 ml of triethylamine and 1 ml of water were stirred overnight. After evaporation under reduced pressure, water was added and the mixture was extracted with chloroform, dried and filtered, and then the solvent was evaporated. Recrystallization from ethanol: n-hexane gave 940 mg (2.46 mmol) of colorless prism crystals (yield 79%). Melting point: 182-183 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.96-1.16 (2H m), 1.44-1.72 (3H m), 1.86-2.03 (4H m),
2.04-2.20 (1H m), 3.31 (2H dd J = 5.9Hz, 6.6Hz), 3.85 (3
H s), 4.45 (2H d J = 5.9Hz), 5.91-6.03 (1H br), 6.06-6.
20 (1H br), 6.87-6.96 (2H m), 7.24-7.34 (1H m), 7.56-
7.65 (1H m), 7.69-7.78 (2H m), 8.51 (2H d J = 2.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3274, 2932, 1656, 1629, 1606, 1557, 1508, 1255

Example 5 4- (2,3-dimethoxybenzamidomethyl) -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0045]

[Chemical 17]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
Dissolve 1.5 g (4.68 mmol) in 100 ml of pyridine,
-Dimethoxybenzoic acid 0.90 g (4.94 mmol), WSCI · HCl
3.00 g (15.64 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 8 days. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from ethanol: ether gave 200 mg (0.49 mmol) of colorless prism crystals (yield 10%). Melting point: 146.7-147.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.01-1.16 (2H m), 1.47-1.60 (3H m), 1.90-2.04 (4H m),
2.06-2.15 (1H m), 3.34 (2H dd J = 5.9Hz, 6.6Hz), 3.896
(3H s), 3.903 (3H s), 4.46 (2H d J = 5.9Hz), 5.87 (1H b
r), 7.04 (1H dd J = 2.0Hz, 7.9Hz), 7.15 (1H t J = 7.9Hz),
7.27 (1H br), 7.61 (1H d J = 7.9Hz), 7.68 (1H dd J = 2.0H
z, 7.9Hz), 8.02 (1H br), 8.52 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3358, 3302, 2928, 1665, 1638, 1476, 1550, 1474, 14
25, 1266 Mass spectrum FAB M / e 412, 321, 276, 217

Example 6 4- (2,4-dimethoxybenzamidomethyl) -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0048]

[Chemical 18]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.0 g (3.12 mmol) was dissolved in 50 ml of pyridine, and 2,4-
Dimethoxybenzoic acid 0.57 g (3.13 mmol), WSCI · HCl 1.
20 g (6.26 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Chloroform: n-
Recrystallized from hexane and colorless prism crystals 1.0g (2.43
Mmol) was obtained (yield 78%). Melting point: 160-162 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.18 (2H m), 1.44-1.70 (3H m), 1.88-2.03 (4H m),
2.05-2.19 (1H m), 3.32 (2H dd J = 5.9Hz, 6.6Hz), 3.85 (3
H s), 3.94 (3H s), 4.45 (2H d J = 5.9Hz), 5.91-6.03 (1H
br), 6.48 (1H d J = 2.6Hz), 6.59 (1H dd J = 2.0Hz, 8.6H
z), 7.23-7.31 (1H m), 7.57-7.64 (1H m), 7.82 (1H br),
8.15 (1H d J = 8.6Hz), 8.52 (2H d J = 3.3Hz), infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3314, 2934, 1638, 1610, 1546, 1504, 1311 , 1280, 12
12

Example 7 4- (2,5-dimethoxybenzamidomethyl) -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0051]

[Chemical 19]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.0 g (3.12 mmol) was dissolved in 50 ml of pyridine, and 2,4-
Dimethoxybenzoic acid 0.57 g (3.13 mmol), WSCI · HCl 1.
20 g (6.26 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Chloroform: n-
Recrystallized from hexane to give colorless prism crystals 870mg (2.11
Mmol) (yield 68%). Melting point: 166-167 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.19 (2H m), 1.42-1.73 (3H m), 1.87-2.04 (4H m),
2.05-2.19 (1H m), 3.30-3.39 (2H m), 3.81 (3H s), 3.92
(3H s), 4.45 (2H d J = 5.9Hz), 5.89-6.02 (1H m), 6.86-
7.02 (2H m), 7.21-7.31 (2H m), 7.55-7.66 (1H m), 7.75
(1H d J = 3.3Hz), 8.01-8.11 (1H m), 8.51 (2H d J = 3.3H
z), infrared absorption spectrum (cm ^-1 ) (measurement method KBr-tab.) 3323, 2935, 1639, 1553, 1529, 1500, 1226

Example 8 4- (3,4-dimethoxybenzamidomethyl) -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0054]

[Chemical 20]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
Dissolve 1.5 g (4.68 mmol) in 100 ml of pyridine,
-Dimethoxybenzoic acid 1.00 g (5.49 mmol), WSCI · HCl
3.00 g (15.65 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Chloroform: n
-Recrystallized from hexane to give colorless prism crystals 870 mg (2.
11 mmol) was obtained (yield 68%). Melting point: 202-204 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.99-1.13 (2H m), 1.48-1.56 (3H m), 1.91-1.99 (4H m),
2.06-2.15 (1H m), 3.33 (2H t J = 6.6Hz), 3.92 (3H s),
3.94 (3H s), 4.46 (2H d J = 5.9Hz), 5.79 (1H br), 6.09 (1
H br), 6.86 (1H d J = 7.9Hz), 7.23 (2H d J = 2.0Hz), 7.42
(1H d J = 7.3Hz), 7.60 (1H d J = 7.3Hz), 8.52 (2H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3313, 3278, 2932, 1641, 1624 , 1583, 1543, 1512, 15
00, 1315, 1273, 1238, 1186, 1146, 1108, 1024 Mass spectrum FAB M / e 412, 369, 321, 277, 217

Example 9 4- (3,4,5-trimethoxybenzamidomethyl)
-N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0057]

[Chemical 21]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.50 g (4.68 mmol) and 0.461 g (4.27 mmol) of 3,4,5-trimethoxybenzoic acid were dissolved in 80 ml of pyridine, and WSCI was added.
-HCl 1.80g (9.39 mmol), water 1 ml, and triethylamine 1 ml were added, and it stirred at room temperature all day and night. The reaction mixture was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from ethanol: n-hexane gave 1.02 g (2.31 mmol) of colorless prism crystals (yield.
49%). Melting point: 189-190 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.98-1.18 (2H m), 1.42-1.75 (3H m), 1.84-1.97 (4H m),
2.14-2.29 (1H m), 3.29 (2H d J = 7.3Hz), 3.82 (3H s),
3.90 (6H s), 4.39 (2H s), 7.17 (2H s), 7.36-7.41 (1H
m), 7.74 (1H dd J = 2.0Hz, 5.9Hz), 8.46 (1H d J = 2.0Hz), infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3303, 2932, 1941, 1584 , 1537, 1502, 1431, 1342, 12
38, 1139, 1120

Example 10 4- (2,3,4-trimethoxybenzamidomethyl)
-N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0060]

[Chemical formula 22]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
0.76 g (2.37 mmol) and 3,4,5-trimethoxybenzoic acid 0.50 g (2.36 mmol) were dissolved in 80 ml of pyridine, and WSCI.
HCl 0.59 g (3.08 mmol), triethylamine 0.7 g (6.
(92 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from chloroform: ether gave 0.77 g (1.74 mmol) of colorless prism crystals (yield 74%). Melting point: 156-157 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.18 (2H m), 1.42-1.76 (3H m), 1.88-2.04 (4H m),
2.04-2.19 (1H m), 3.31 (2H dd J = 5.9Hz, 6.6Hz), 3.88 (3
H s), 3.90 (3H s), 3.96 (3H s), 4.46 (2H d J = 5.9Hz),
5.79-5.89 (1H br), 6.77 (1H d J = 9.2Hz), 7.24-7.28 (1H
m), 7.61 (1H dd J = 2.0Hz, 7.9Hz), 7.89 (1H d J = 9.2Hz),
7.95-8.04 (1H br), 8.52 (2H d J = 2.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3384, 3286, 2925, 1662, 1633, 1535, 1490, 1460, 12
93, 1096

Example 11 N- (3-pyridyl) methyl-4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0063]

[Chemical formula 23]

Process 4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.50 g (4.
27 mmol) and 0.461 g (4.27 mmol) of 3-aminomethylpyridine were dissolved in 50 ml of chloroform, and 1.23 g of WSCI · HCl was dissolved.
(6.40 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with water, dried and filtered, and the solvent was distilled off. Chloroform: recrystallized from n-hexane, colorless prism crystals 1.70
g (3.85 mmol) was obtained (yield 90%). Melting point: 194-195 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.00-1.14 (2H m), 1.45-1.61 (3H m), 1.90-1.99 (4H m),
2.04-2.15 (1H m), 3.33 (2H t J = 6.6Hz), 3.90 (3H s),
3.94 (3H s), 3.96 (3H s), 4.46 (2H d J = 5.9Hz), 5.84 (1H
br), 6.53 (1H s), 7.26 (1H m), 7.61 (1H d J = 7.9Hz),
7.75 (1H s), 7.93 (1H br), 8.52 (2H d J = 2.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3313, 2934, 2920, 1639, 1621, 1606, 1552, 1530, 15
15, 1281, 1216, 1028

Example 12 4- (4-Fluorobenzamidomethyl) -N- (3-
Pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0066]

[Chemical formula 24]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.14 g (3.57 mmol) was dissolved in 20 ml of pyridine, and 0.50 g (3.57 mmol) of 4-fluorobenzoic acid and 0.3 of triethylamine.
909 ml (8.92 mmol) and WSCI.HCl 1.029 g (5.35 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from chloroform: n-hexane gave 0.54 g (1.46 mmol) of colorless needle crystals. (Yield 41%) Melting point: 212-214 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.08 (2H m), 1.45-1.59 (3H m), 1.90-1.98 (4H m),
2.04-2.16 (1H m), 3.32 (2H t J = 6.6Hz), 4.45 (2H d J =
5.3Hz), 5.84 (1H br), 6.14 (1H br), 7.11 (2H dd J = 8.6H
z, 9.6Hz), 7.26 (1H m), 7.60 (1H d J = 7.9Hz), 7.75 (2H d
d J = 5.9Hz, 8.6Hz), 8.51 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3303, 2926, 1641, 1604, 1551, 1505, 1229

Example 13 4- (4-amino-5-chloro-2-methoxybenzamidomethyl) -N- (3-pyridyl) methyl-trans-
Cyclohexane-1-carboxamide

[0069]

[Chemical 25]

Preparation 4- (4-amino-5-chloro-2-methoxybenzamidomethyl) -trans-cyclohexanecarboxylic acid 0.80
g (2.62 mmol) was dissolved in 60 ml of pyridine, 0.34 g (3.14 mmol) of 3- (aminomethyl) pyridine, WSCI · HCl 0.76
g (3.96 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from methanol gave 0.55 g (1.28 mmol) of colorless prism crystals (yield 44%). Melting point: 248 (decomposition) ° C H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.98-1.19 (2H m), 1.41-1.71 (3H m), 1.81-1.96 (4H m),
2.13-2.27 (1H m), 3.33 (2H d J = 1.3Hz), 3.93 (3H s),
4.38 (2H s), 6.50 (1H s), 7.35-7.42 (m 1H), 7.72-7.75
(1H m), 7.78 (1H s), 8.39-8.44 (1H m), 8.46 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3303, 2926, 1641, 1604, 1551 , 1505, 1229

Example 14 4- (4-amino-3-methoxybenzamidomethyl)
-N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0072]

[Chemical formula 26]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.00 g (3.12 mmol) was dissolved in 50 ml of pyridine, 0.52 g (3.11 mmol) of 4-amino-3-methoxybenzoic acid and 1 m of water.
1, WSCI.HCl (1.19 g, 5.74 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallized from chloroform: ether to give colorless needle crystals 0.64g (1.73g).
Mmol) was obtained (yield 52%). Melting point: 186-188 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.16 (2H m), 1.41-1.67 (3H m), 1.86-2.03 (4H m),
2.03-2.19 (1H m), 3.30 (2H dd J = 5.9Hz, 6.6Hz), 3.90 (3
H s), 4.06-4.15 (1H br), 4.45 (2H d J = 5.9Hz), 5.79-5.
91 (1H br), 6.02-6.12 (1H br), 6.65 (1H br), 7.10 (1H d
d J = 2.0Hz, 7.9Hz), 7.21-7.31 (1H m), 7.36 (1H d J = 2.0
Hz), 7.59-7.65 (1H m), 8.52 (2H d J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measuring method KBr-tab.) 3286, 2922, 1648, 1619, 1548, 1512, 1308 , 1228

Example 15 4- (4-amino-2-methoxybenzamidomethyl)
-N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0075]

[Chemical 27]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.00 g (3.12 mmol) was dissolved in 50 ml of pyridine, 0.46 g (2.75 mmol) of 4-amino-2-methoxybenzoic acid and 1 m of water.
1, 1.19 g (5.74 mmol) of WSCI.HCl and 1 ml of triethylamine were added, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Ethanol: recrystallized from n-hexane,
0.59 g (1.60 mmol) of pale brown needle crystals were obtained (yield 52
%). Melting point: 200-202 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98 (2H m), 1.43-1.70 (3H m), 1.81-1.99 (4H m), 2.14
-2.30 (1H m), 3.24-3.39 (2H m), 3.92 (3H s), 4.39 (2H
s), 4.72-4.91 (2H m), 6.29-6.39 (2H m), 7.36-7.43 (1H
m), 7.72-7.83 (3H m), 8.00-8.22 (1H br), 8.46 (1H d J =
2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3400, 3368, 3190, 2926, 1664, 1629, 1603, 1560, 15
08, 1288, 1280,1213, 1028

Example 16 4- (2-Dimethylaminobenzamidomethyl) -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0078]

[Chemical 28]

Preparation method 2-Dimethylaminobenzoic acid (0.86 g, 5.21 mmol) was dissolved in methylene chloride (5 ml), oxaline chloride (25 ml) was slowly added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was distilled off under reduced pressure, the residue was dissolved in 200 ml of methylene chloride, and 4- (aminomethyl) -N- (3-pyridylmethyl) -trans-cyclohexane-1-carboxamide dihydrochloride 1.7 g (5.
31 mmol), triethylamine 2.5 ml, potassium carbonate 2.5
g was added, and the mixture was stirred overnight at room temperature. Wash the reaction mixture with water,
After drying and filtering, the solvent was distilled off and silica gel column chromatography (200 g ethyl acetate: n-hexane = 9: 1).
And was recrystallized from ethanol: ether to obtain 0.91 g (2.31 mmol) of pale yellow needle crystals (yield 44%). Melting point: 171.1 to 171.8 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.08 (2H dq J = 3.3Hz, 11.9Hz), 1.56 (3H m J = 3.3Hz, 11.9
Hz), 1.95 (4H m J = 3.3Hz, 11.9Hz, 13.9Hz), 2.11 (1H tt J
= 3.3Hz, 11.9Hz), 2.73 (6H s), 3.34 (2H d J = 5.9Hz), 4.4
6 (2H dd J = 5.9Hz, 6.6Hz), 5.90 (1H brt J = 5.3Hz), 7.42
(1H m J = 1.3Hz, 8.6Hz), 7.61 (1H d J = 7.9Hz), 8.13 (1H
dd J = 1.3Hz, 7.9Hz), 8.52 (2H d J = 2.6Hz), 9.77 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3240, 2919, 1642, 1544, 1499, 1448, 1436, 1424, 13
38, 1273, 1209, 748, 711 Mass spectrum FAB M / e 395, 377, 304, 287

Example 17 N- (3-Pyridyl) methyl-4- (2,4,5-trimethoxycinnamamidomethyl) -trans-cyclohexane-1-carboxamide

[0081]

[Chemical 29]

Preparation method At room temperature, 4- (2,4,5-trimethoxycinnamamidomethyl) -trans-cyclohexanecarboxylic acid 1.00 g
(2.65 mmol), 3- (aminomethyl) pyridine 0.286 g
(2.65 mmol) and 0.761 g (3.97 mmol) of WSCI.HCl were stirred in 20 ml of pyridine for 3 hours. The reaction solution was distilled off under reduced pressure, water was added, and the generated crystals were collected by filtration and recrystallized from chloroform: n-hexane to give 1.22 g (2.52 mmol) of colorless needle crystals.
Was obtained (yield 95%). Melting point: 212 to 213 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.96-1.11 (2H m), 1.43-1.61 (3H m), 1.87-1.98 (4H m),
2.04-2.14 (1H m), 3.26 (2H t J = 6.6Hz), 3.85 (3H s),
3.86 (3H s), 3.92 (3H s), 4.45 (2H d J = 5.9Hz), 5.66 (1H
br t J = 5.9Hz), 5.95 (1H br dd J = 6.6Hz, 5.9Hz), 6.39
(1H d J = 15.8Hz), 6.50 (1H s), 6.98 (1H s), 7.27 (1H m
J = 7.3Hz), 7.61 (1H dd J = 7.3Hz, 1.3Hz) 7.80 (1H d J = 15.8Hz), 8.52 (2H d J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr -tab.) 3294, 3277, 2930, 1641, 1605, 1547, 1517, 1468, 12
99, 1233, 1209, 1190, 1042, 1028

Example 18 4- (3,4-methylenedioxybenzamidomethyl)
-N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0084]

[Chemical 30]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.43 g (4.47 mmol) was dissolved in 50 ml of pyridine, and 3,4-
Methylenedioxybenzoic acid 1.00 g (6.02 mmol), WSCI
HCl 2.30 g (12.00 mmol), triethylamine 1.83 g (18.
(08 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with chloroform. After dry filtration, it was recrystallized from methanol: chloroform: n-hexane to obtain 1.48 g (3.74 mmol) of colorless prism crystals (yield 84
%). Melting point: 202-205 ° C. H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.98-1.16 (2H m), 1.41-1.72 (3H m), 1.79-1.95 (4H m),
2.14-2.27 (1H m), 3.21 (2H d J = 6.6Hz), 4.39 (2H s),
6.02 (2H s), 6.85 (1H d J = 8.6Hz), 7.29 (1H d J = 2.0Hz),
7.39 (2H dd J = 2.0Hz, 5.3Hz), 7.72-7.77 (1H m), 8.42 (1
H dd J = 2.0Hz, 5.3Hz), 8.46 (1H d J = 1.3Hz), infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3303, 2926, 2916, 1642, 1540, 1506, 1485, 1441, 14
30, 1316, 1263, 1040

Example 19 4- (2-Methoxy-4,5-methylenedioxybenzamidomethyl) -N- (3-pyridyl) methyl-trans
-Cyclohexane-1-carboxamide

[0087]

[Chemical 31]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.10 g (3.46 mmol) was dissolved in 200 ml of pyridine, and 0.60 g of 2-methoxy-4,5-methylenedioxybenzoic acid (3.
(06 mmol), WSCI.HCl (2.00 g, 10.43 mmol) and water (2 ml) were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated, water was added, and the mixture was extracted with methylene chloride. After drying and filtering, the solvent was distilled off. Recrystallization from ethanol: n-hexane gave 0.70 g (1.65 mmol) of colorless needle crystals (yield 54%). Melting point: 190.8〜191.1 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.06 (2H m J = 12.5Hz), 1.51 (3H m), 1.89 (4H m J = 12.5H
z), 2.10 (1H m J = 11.9Hz), 3.31 (2H d J = 5.9Hz), 3.91 (3
H s), 4.46 (2H d J = 5.9Hz), 5.81 (1H br), 5.99 (2H s),
6.56 (1H s), 7.26 (1H m), 7.61 (1H dt J = 2.2Hz, 7.9Hz),
7.67 (1H s), 7.87 (1H br) 8.52 (2H d J = 2.2Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3320, 2934, 2851, 1639, 1611, 1552, 1506 , 1485, 14
64, 1448, 1426,1273, 1201, 1180, 1045, 927, 715 Mass spectrum FAB M / e 426, 369, 335, 290, 277

Example 20 4- (2-Dimethylamino-4,5-methylenedioxybenzamidomethyl) -N- (3-pyridyl) methyl-
trans-cyclohexane-1-carboxamide

[0090]

[Chemical 32]

Manufacturing method To 0.50 g (2.39 mmol) of 2-dimethylamino-4,5-methylenedioxybenzoic acid, 25 ml of oxalyl chloride was slowly added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. Excess oxalyl chloride was distilled off under reduced pressure, the residue was dissolved in 50 ml of methylene chloride,
4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
0.80 g (2.50 mmol), triethylamine 2.0 ml, and potassium carbonate 2.0 g were added, and the mixture was stirred at room temperature for 2 days. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Crystallization of ethanol gave pale yellow needle crystals 0.34 g (0.78 mmol) (yield 32%). Melting point: 172.2-174.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.05-1.14 (2H m), 1.47-1.57 (3H m), 1.89-2.10 (5H m),
2.66 (6H s), 3.31 (2H t J = 5.9Hz), 4.46 (2H d J = 5.9H
z), 5.82 (1H br), 5.99 (2H s), 6.80 (1H s), 7.26 (1H
m), 7.61 (1H d J = 7.9Hz), 7.70 (1H s), 8.51 (2H m), 10.
34 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3271, 2932, 2849, 1638, 1522, 1508, 1482, 1241, 12
02, 1042, 1038 Mass spectrum FAB M / e 439, 421, 303

Example 21 4- (1-methoxy-2-naphthamidomethyl) -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0093]

[Chemical 33]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
0.80 g (2.50 mmol) was dissolved in 50 ml of pyridine, 0.50 g (2.47 mmol) of 1-methoxy-2-naphthoic acid, WSCI · HCl
1.50 g (7.82 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. Wash the extract with saturated aqueous sodium hydrogen carbonate,
After drying and filtering, the solvent was distilled off. Recrystallization from ethanol: n-hexane gave 0.13 g (0.30 mmol) of colorless needle crystals (yield 12%). Melting point: 169-170 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.11-1.25 (2H m), 1.45-1.54 (3H m), 1.99 (4H br d J = 1
1.2Hz), 2.12 (1H br d J = 12.5Hz), 3.42 (2H t J = 6.6Hz),
4.00 (3H s), 4.47 (2H d J = 5.9Hz), 5.83 (1H br), 7.27
(1H d J = 7.3Hz), 7.54-7.63 (3H m), 7.69 (1H d J = 8.6H
z), 7.88 (1H m J = 6.6Hz), 8.02 (1H br), 8.10 (1H d J = 8.
6Hz), 8.16 (1H dd J = 3.3Hz, 6.6Hz), 8.52 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3304, 2936, 1638, 1534, 1432, 1370, 1206

Example 22 N- (3-pyridylmethyl) -4-[(1,2,3,4)
-Tetrahydro-1,3-dioxo-2-quinolyl) methyl] -trans-cyclohexane-1-carboxamide

[0096]

[Chemical 34]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.975 g (6.17 mmol) of N, N-dimethylformamide
Dissolve in 50 ml, 1.00 g (6.17 mmol) of homophthalic anhydride,
Add 2 ml (14.35 mmol) of triethylamine, and add 1 at 150 ℃.
Stir for 50 minutes. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and recrystallized from ethanol: n-hexane to give pale yellow needle crystals.
0.10 g (0.26 mmol) was obtained (yield 4.1%). Melting point: 213 to 216 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.85-0.94 (2H m), 1.32-1.35 (3H m), 1.75 (4H br d J = 1
0.6Hz), 2.09 (1H m), 2.91 (2H dd J = 6.6Hz, 5.3Hz), 3.82
(2H s), 4.27 (2H d J = 5.9Hz), 7.26-7.33 (2H m), 7.43 (1
H d J = 7.3Hz), 7.60 (1H d J = 7.9Hz), 7.80 (1H d J = 7.9H
z), 8.01 (1H br), 8.26 (1H m), 8.44 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3289, 2929, 1710, 1646, 1556, 1448, 1264 , 1251

Example 23 4- [2- (Ethoxycarbonylamino) benzamidomethyl] -N- (2-pyridylmethyl) -trans-cyclohexane-1-carboxamide

[0099]

[Chemical 35]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
3.17 g (15.15 mmol) was dissolved in 100 ml of pyridine, and 2-
(Ethoxycarbonylamino) benzoic acid 5.00 g (15.62 mmol), WSCI.HCl 5.00 g (26.08 mmol) and water 1 ml were added,
Stir at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtration, the solvent was distilled off and recrystallization from ethanol: n-hexane was performed to obtain 0.35 g (0.80 mmol) of colorless needle crystals (yield 5.3%). Melting point: 194-195 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.94 (2H m), 1.25 (3H t J = 7.3Hz), 1.17-1.57 (3H m),
1.78-1.82 (4H m), 2.14 (1H m), 3.12 (2H t J = 5.9Hz), 4.
13 (2H q J = 7.3Hz), 4.27 (2H d J = 5.3Hz), 7.07 (1H t J =
7.9Hz), 7.31 (1H dd J = 4.6Hz, 7.9Hz), 7.46 (1H dd J = 7.3
Hz, 8.6Hz), 7.60 (1H dd J = 2.0Hz, 7.9Hz), 7.73 (1H d J =
7.9Hz), 8.21 (1H d J = 8.6Hz), 8.26-8.29 (1H m), 8.44
(2H m), 8.70 (1H m), 10.88 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3298, 2928, 1732, 1637, 1592, 1526, 1450, 1219, 10
63, 766, 754 Mass spectrum FAB M / e 439, 421, 393, 365, 294, 274, 248, 217, 192

Example 24 4-[(pyrazine-2-carboxamido) methyl] -N
-(3-pyridyl) methyl-trans-cyclohexane-
1-carboxamide

[0102]

[Chemical 36]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
0.52 g (4.20 mmol) of trans-cyclohexane-1-carboxamide dihydrochloride was dissolved in 50 ml of pyridine, and 0.52 g (4.19 mmol) of pyrazine-2-carboxylic acid and WSCI · HCl 1.
60 g (8.35 mmol), triethylamine 1.30 g (9.33 mmol)
Was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtration, recrystallization from chloroform: ether gave 1.07 g (3.03 mmol) of colorless prism crystals (yield 72%). Melting point: 214 to 215 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.29 (2H m), 1.45-1.72 (3H m), 1.86-2.02 (4H m),
2.03-2.19 (1H m), 3.37 (2H t J = 6.6Hz), 4.46 (2H d J =
5.9Hz), 5.79-5.90 (1H br), 7.23-7.31 (1H m), 7.61 (1H
dd J = 2.0Hz, 7.9Hz), 7.83-7.93 (1H m), 8.52 (3H dd J = 1.
3Hz, 2.6Hz), 8.75 (1H d J = 2.6Hz), 9.40 (1H d J = 1.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3296, 2922, 1659, 1639, 1538, 1426, 1203, 1022, 71
3

Example 25 N- (3-pyridyl) methyl-4-[(quinoline-4-
Carboxamido) methyl] -trans-cyclohexane-
1-carboxamide

[0105]

[Chemical 37]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
0.65 g (2.03 mmol) was dissolved in 50 ml of pyridine, quinoline-3-carboxylic acid 0.30 g (2.02 mmol), WSCI.HCl 1.50
g (7.83 mmol) and 1.0 ml of water were added, and the mixture was stirred overnight at room temperature.
The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off. ethanol:
Recrystallization from ether gave colorless needle crystals 0.36 g (0.86 mmol) (yield 44%). Melting point: 213-214 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.98-1.06 (2H m), 1.39-1.59 (3H m), 1.89 (4H br t J = 1
3.2Hz), 2.11-2.15 (1H m), 3.21 (2H t J = 6.6Hz), 4.27 (2
H d J = 5.9Hz), 7.32 (1H dd J = 4.6Hz, 7.9Hz), 7.63 (1H dd
J = 7.3Hz, 9.2Hz), 7.70 (1H d J = 7.9Hz), 7.85 (1H t J = 7.
9Hz), 8.08 (2H d J = 8.6Hz), 8.29 (1H m), 8.45 (2H br),
8.77-8.81 (2H m), 9.27 (1H d J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3284, 2916, 1642, 1547, 1431, 1302, 1208, 786, 712

Example 26 N- (3-pyridyl) methyl-4-[(quinoline-4-
Carboxamido) methyl] -trans-cyclohexane-
1-carboxamide

[0108]

[Chemical 38]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.00 g (3.12 mmol) was dissolved in 50 ml of pyridine, quinoline-4-carboxylic acid 0.54 g (3.12 mmol), WSCI.HCl 1.05
g (5.48 mmol), triethylamine 1.0 ml, and water 1.0 ml were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After dry filtration, the solvent was distilled off and recrystallized from chloroform: n-hexane,
0.34 g (0.84 mmol) of pale yellow needle crystals were obtained (yield 27
%). Melting point: 200 to 202 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.02-1.20 (2H m), 1.45-1.74 (3H m), 1.89-2.05 (4H m),
2.05-2.19 (1H m), 3.43 (2H dd J = 5.9Hz, 6.6Hz), 4.45 (2
H d J = 5.9Hz), 5.81-5.90 (1H br), 6.10-6.19 (1H br),
7.21-7.29 (1H m), 7.43 (1H d J = 4.0Hz), 7.57-7.66 (2H
m), 7.74-7.81 (1H m), 8.13-8.23 (2H m), 8.51 (2H br),
9.84 (1H d J = 4.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3302, 2926, 1638, 1582, 1541, 1508, 1426, 1312, 12
06, 762, 712

Example 27 N- (3-pyridyl) methyl-4-[(quinoline-2-
Carboxamido) methyl] -trans-cyclohexane-
1-carboxamide

[0111]

[Chemical Formula 39]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
Dissolve 1.00 g (3.12 mmol) in 50 ml of pyridine, quinoline-2-carboxylic acid 0.54 g (3.12 mmol), WSCI.HCl 1.20
g (6.26 mmol), triethylamine 2.0 ml, and water 1.0 ml were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After dry filtration, the solvent was distilled off and recrystallized from chloroform: n-hexane,
0.51 g (0.84 mmol) of pale green needle crystals were obtained (yield 41
%). Melting point: 156-159 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.12-1.21 (2H m), 1.46-2.05 (7H m), 2.06-2.21 (1H m),
3.41 (2H t J = 6.6Hz), 4.45 (2H d J = 5.3Hz), 5.95-6.04
(1H br), 7.21-7.29 (1H m), 7.57-7.76 (2H m), 7.77 (1H
t J = 8.6Hz), 7.78 (1H d J = 9.2Hz), 8.11 (1H d J = 8.6Hz),
8.25-8.42 (3H m), 8.51 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3297, 2935, 1646, 1552, 1506, 1425, 1238, 838, 77
9,714

Example 28 4-[(2H-pyran-2-one-5-carboxamido) methyl] -N- (3-pyridyl) methyl-trans-
Cyclohexane-1-carboxamide

[0114]

[Chemical 40]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
0.65 g (2.03 mmol) was dissolved in 50 ml of pyridine, and coumarinic acid 0.30 g (2.14 mmol), WSCI · HCl 1.50 g (7.83 mmol),
1.0 ml of water was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After dry filtration, the solvent was distilled off, ether was added, and the precipitated crystals were recrystallized from ethanol: n-hexane to obtain 0.23 g (0.62 mmol) of reddish purple needle crystals (yield 31%). Melting point: 214 to 215 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.99 (2H br q J = 12.5Hz), 1.37 (2H br q J = 13.2Hz), 1.
56 (1H m), 1.76 (4H br t J = 13.2Hz), 2.11 (1H m), 3.29
(2H s), 4.26 (2H d J = 5.9Hz), 5.50 (1H d J = 9.2Hz), 7.3
3 (1H dd J = 4.9Hz, 7.9Hz), 7.47 (1H d J = 9.2Hz), 7.60 (1H
d J = 7.3Hz), 7.98 (1H d J = 14.5Hz), 8.30 (1H m), 8.43
(2H m), 9.71 (1H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3286, 2923, 1717, 1672, 1637, 1618, 1687, 1552, 13
29, 1203, 796

Example 29 4-[(indole-5-carboxamido) methyl]-
N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0117]

[Chemical 41]

Preparation 4-[(indole-5-carboxamido) methyl]-
trans-Cyclohexanecarboxylic acid 0.80 g (2.66 mmol)
Was dissolved in 50 ml of pyridine, 0.31 g (2.87 mmol) of 3- (aminomethyl) pyridine and 0.76 g (3.96 mmol) of WSCI.HCl were added, and the mixture was stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure,
Chloroform was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from methanol: ether to give colorless prism crystals 0.83.
g (2.13 mmol) was obtained (80% yield). Melting point: 196-198 ° C. H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.99-1.21 (2H m), 1.41-1.78 (3H m), 1.81-2.01 (4H m),
2.12-2.29 (1H m), 3.17-3.43 (2H m), 4.39 (2H s), 4.66
-4.91 (2H m), 6.55 (1H d J = 3.3Hz), 7.36 (1H d J = 5.3H
z), 7.36-7.45 (2H m), 7.61 (1H dd J = 2.0Hz, 8.6Hz), 7.7
3 (1H d J = 8.6Hz), 7.77 (1H s), 8.10 (1H s), 8.15-8.2
6 (1H m), 8.41 (1H dd J = 1.3Hz, 5.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3303, 2932, 1646, 1541, 1432, 1322

Example 30 4-[(indole-3-carboxamido) methyl]-
N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0120]

[Chemical 42]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.60 g (5.00 mmol) was dissolved in pyridine (50 ml), indole-3-carboxylic acid 0.80 g (4.96 mmol), WSCI.HCl 1.
24 g (6.47 mmol), triethylamine 1.50 g (15.82 mmol)
Was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water and chloroform were added to the residue, and the precipitated crystals were collected by filtration and recrystallized from methanol: ether to give 0.47 g (1.20 mmol) of colorless prism crystals (yield 24%). . Melting point: 220-222 ° C. H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.98-1.18 (2H m), 1.42-1.76 (3H m), 1.79-2.03 (4H m),
2.15-2.29 (1H m), 3.20-3.30 (2H m), 4.38 (2H s), 7.11
-7.22 (2H m), 7.36-7.45 (2H m), 7.71-7.75 (1H m), 7.86
(1H s), 8.06-8.11 (1H m), 8.41 (1H dd J = 2.0Hz, 4.6Hz),
8.45 (1H d J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3388, 3321, 3283, 2942, 2930, 1633, 1615, 1552, 14
56, 1425, 1243, 1204, 1096, 762, 712

Example 31 4-[(6-Methoxyindole-5-carboxamido) methyl] -N- (3-pyridyl) methyl-trans-
Cyclohexane-1-carboxamide

[0123]

[Chemical 43]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
0.23 g (0.72 mmol) was dissolved in 20 ml of pyridine, and 0.13 g (0.68 mmol) of 6-methoxyindole-5-carboxylic acid,
WSCI.HCl (0.52 g, 2.71 mmol) and triethylamine (1 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from methanol: ether gave 0.15 g (0.36 mmol) of pale yellow needle crystals (yield 52%). Melting point: 183-186 ° C. H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.96-1.17 (2H m), 1.32-1.51 (3H m), 1.79-1.84 (4H m),
2.09-2.18 (1H m), 3.14 (2H dd J = 5.3Hz, 5.9Hz), 3.92 (3
H s), 4.27 (2H d J = 5.3Hz), 6.42 (1H br), 7.00 (1H s),
7.23-7.25 (1H m), 7.29-7.34 (1H m), 7.61 (1H d J = 7.3H
z), 8.06-8.12 (2H m), 8.26-8.31 (2H m), 8.42-8.46 (2H
m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3318, 2934, 1634, 1615, 1555, 1523, 1316, 1204, 71
8 Mass spectrum FAB M / e 421, 393, 369, 347, 330, 321, 277

Example 32 4-[(isoquinoline-3-carboxamido) methyl]
-N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0126]

[Chemical 44]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.09 g (3.40 mmol) was dissolved in 50 ml of pyridine, isoquinoline-3-carboxylic acid 0.62 g (3.58 mmol), WSCI · HCl
2.50 g (13.04 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallized from methanol: n-hexane, colorless needle crystals 0.15g
(0.37 mmol) was obtained (10% yield). Melting point: 191-193 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.05-1.19 (2H m), 1.48-1.66 (3H m), 1.98 (4H br d J = 1
1.2Hz), 2.06-2.17 (1H m), 3.41 (2H t J = 6.6Hz), 4.46 (2
H d J = 5.9Hz), 5.84 (1H br), 7.26 (1H m), 7.61 (1H d J =
7.9Hz), 7.68-7.81 (2H m), 7.99 (1H d J = 7.9Hz), 8.04 (1
H d J = 7.9Hz), 8.34 (1H br), 8.52 (2H d J = 3.3Hz), 8.6
1 (1H s), 9.16 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3299, 2919, 1639, 1534, 1425, 1201

Example 33 4-[(isoquinoline-1-carboxamido) methyl]
-N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0129]

[Chemical formula 45]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.00 g (3.12 mmol) was dissolved in 50 ml of pyridine, isoquinoline-1-carboxylic acid 0.80 g (4.62 mmol), WSCI · HCl
3.00 g (15.65 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off, and ethanol: n
Recrystallization from hexane gave 0.25 g (0.62 mmol) of brown needle crystals (yield 20%). Melting point: 156-159 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.06-1.23 (2H m), 1.48-1.77 (3H m), 1.99 (4H br d J = 1
1.2Hz), 2.01-2.17 (1H m), 3.40 (2H t J = 6.6Hz), 4.46 (2
H d J = 5.9Hz), 5.78 (1H br), 7.25 (1H m), 7.60-7.88 (5H
m), 8.31 (1H br), 8.46 (1H d J = 5.3Hz), 8.52 (2H d J =
2.6Hz), 9.61 (1H d J = 8.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3315, 2926, 1646, 1549, 1429, 1292, 1206

Example 34 N- (3-pyridyl) methyl-4-[(thiophene-2
-Carboxamide) methyl] -trans-cyclohexane-1-carboxamide

[0132]

[Chemical formula 46]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
2.50 g (7.81 mmol) was dissolved in 50 ml of pyridine, thiophenine-2-carboxylic acid 1.00 g (7.80 mmol), WSCI · HCl
2.00 g (10.43 mmol) and 1.0 ml of water were added, and the mixture was stirred at room temperature for 2 days. Furthermore, 2.20 g (11.48 mmol) of WSCI.HCl and water
1.0 ml was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered,
The solvent was distilled off. Recrystallization from ethanol: n-hexane gave colorless needle crystals 0.32 g (0.90 mmol) (yield 11
%). Melting point: 179 to 180 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.03-1.11 (2H m), 1.46-1.64 (3H m), 1.86-1.98 (4H m),
2.06-2.16 (1H m), 3.30 (2H t J = 6.6Hz), 4.45 (2H d J =
5.9Hz), 5.99 (1H br), 6.10 (1H br), 7.05-7.08 (1H m),
7.26 (1H m), 7.45-7.50 (2H m), 7.61 (1H d J = 7.2Hz), 8.
52 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3276, 3084, 2917, 2847, 1652, 1622, 1558, 1421, 13
54, 1311, 1274, 1236, 1211, 722, 711

Example 35 4-[(Pyridin-3-carboxamido) methyl] -N
-(3-pyridyl) methyl-trans-cyclohexane-
1-carboxamide

[0135]

[Chemical 47]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
Dissolve 1.00 g (3.12 mmol) in 50 ml of pyridine, 0.52 g (4.23 mmol) picolinic acid, 1.20 g (6.23 mmol) WSCI · HCl,
Water (1 ml) and triethylamine (1.30 g) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, dried and filtered, and the solvent was evaporated. Chloroform: Recrystallized with ether, colorless prism crystals 0.
35 g (0.99 mmol) was obtained (yield 32%). Melting point: 186-187 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.94-1.03 (2H m), 1.33-1.38 (2H m), 1.52-1.54 (1H m),
1.77-1.82 (4H m), 2.10-2.14 (1H m), 3.14 (2H dd J = 5.9
Hz, 6.6Hz), 4.26 (2H d J = 5.9Hz), 7.32 (1H dd J = 5.3Hz,
7.9Hz), 7.48 (1H dd J = 5.3Hz, 7.9Hz), 7.61 (1H d J = 7.9H
z), 8.17 (1H dt J = 7.9Hz, 2.0Hz), 8.27-8.31 (1H m), 8.4
2-8.44 (2H m), 8.59-8.63 (1H m), 8.68 (1H dd J = 4.6Hz,
1.3Hz), 8.99 (1H d J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3300, 2962, 1638, 1592, 1552, 1448, 1426, 1322, 12
30, 1206, 1028, 712

Example 36 4-[(Pyridin-2-carboxamido) methyl] -N
-(3-pyridyl) methyl-trans-cyclohexane-
1-carboxamide

[0138]

[Chemical 48]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.00 g (3.12 mmol) was dissolved in 50 ml of pyridine, 0.34 g (2.76 mmol) picolinic acid, 1.05 g (5.48 mmol) WSCI · HCl,
2 ml of water was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, water was dissolved in the residue, and the mixture was extracted with chloroform.
After drying and filtering, the solvent was distilled off, and the residue was recrystallized from chloroform: n-hexane to obtain 0.34 g (0.96 mmol) of purple needle crystals (yield 35%). Melting point: 144-146 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.05-1.16 (2H m), 1.46-1.69 (3H m), 1.95 (4H br d J = 1
0.6Hz), 2.04-2.15 (1H m), 3.35 (2H dd J = 5.9Hz, 7.3Hz),
4.46 (2H d J = 5.9Hz), 5.81 (1H br), 7.23-7.27 (1H m),
7.42 (1H ddd J = 1.3Hz, 5.3Hz, 7.9Hz), 7.61 (1H dd J = 1.3H
z, 5.3Hz), 7.85 (1H dt J = 1.3Hz, 7.9Hz), 8.14 (1H br),
8.19 (1H d J = 7.9Hz), 8.52-8.56 (3H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3297, 2927, 1667, 1642, 1534, 1426 Mass spectrometry spectrum FAB M / e 353, 217, 185

Example 37 4-[(Pyridin-4-carboxamido) methyl] -N
-(3-pyridyl) methyl-trans-cyclohexane-
1-carboxamide

[0141]

[Chemical 49]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.00 g (3.12 mmol) was dissolved in pyridine (50 ml), and isonicotinic acid (0.34 g, 2.76 mmol), WSCI.HCl (1.05 g, 5.48 mmol), water (2 ml) and triethylamine (2 ml) were added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and recrystallized from chloroform: n-hexane to give pale yellow needle crystals.
0.22 g (0.62 mmol) was obtained (yield 22%). Melting point: 178-180 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.98 (2H dq J = 2.0Hz, 12.5Hz), 1.36 (2H dq J = 2.0Hz, 12.
5Hz), 1.54 (1H m), 1.80 (4H d J = 11.2Hz), 2.13 (1H br t
J = 11.9Hz), 3.14 (2H t J = 5.3Hz), 4.27 (2H d J = 4.0Hz),
7.31 (1H dd J = 5.3Hz, 7.9Hz), 7.60 (1H d J = 7.9Hz), 7.7
4 (2H d J = 5.3Hz), 8.28 (1H d J = 5.3Hz), 8.43 (2H d J =
5.9Hz), 8.69 (3H d J = 5.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3306, 2928, 2860, 1642, 1543, 1445, 1426, 1322, 12
29, 1204 Mass spectrum FAB M / e 353, 313, 291, 248, 235

Example 38 4-[(2-Aminopyridine-3-carboxamido) methyl] -N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0144]

[Chemical 50]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
Dissolve 1.00 g (3.12 mmol) in 50 ml of pyridine, 0.38 g (2.75 mmol) of 2-aminonicotinic acid, 1.05 g of WSCI · HCl
(5.48 mmol), water (2 ml) and triethylamine (2 ml) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After dry filtration, the solvent was distilled off and recrystallized from chloroform to give colorless prism crystals.
36 g (0.98 mmol) was obtained (yield 36%). Melting point: 193-195 ° C. H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.97-1.16 (2H m), 1.43-1.72 (3H m), 1.81-1.94 (4H m),
2.15-2.29 (1H m), 3.20 (2H d J = 6.6Hz), 4.39 (2H s),
6.65 (1H dd J = 5.3Hz, 7.9Hz), 7.35-7.42 (1H m), 7.73 (1H
d J = 2.0Hz), 7.82-7.88 (1H m), 8.01-8.04 (1H m), 8.42
(1H dd J = 1.3Hz, 5.3Hz), 8.46 (1H d J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3388, 3331, 2924, 1946, 1576, 1540, 1435, 1316, 13
00, 1258

Example 39 4-[(2-Aminopyridine-5-carboxamido) methyl] -N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0147]

[Chemical 51]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
Dissolve 1.00 g (3.12 mmol) in 50 ml of pyridine, 0.38 g (2.75 mmol) of 4-aminonicotinic acid, 1.05 g of WSCI · HCl
(5.48 mmol), water (2 ml) and triethylamine (2 ml) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and recrystallization from ethanol: n-hexane was performed to obtain 0.15 g (0.41 mmol) of colorless prism crystals (yield 15%). Melting point: 210 to 213 ° C. H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.97-1.16 (2H m), 1.41-1.71 (3H m), 1.81-1.95 (4H m),
2.14-2.26 (1H m), 3.20 (2H d J = 6.6Hz), 4.38 (2H s),
6.56 (1H d J = 8.6Hz), 7.36-7.43 (1H m), 7.71-7.78 (1H
m), 7.84-7.89 (1H m), 8.38-8.49 (3H m) Infrared absorption spectrum (cm ^-1 ) (Measuring method KBr-tab.) 3302, 2929, 1636, 1606, 1549, 1505, 1339, 1316

Example 40 4-[(2-Chloropyridine-3-carboxamido) methyl] -N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0150]

[Chemical 52]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
0.60 g (1.87 mmol) was dissolved in 20 ml of pyridine, and 2-chloronicotinic acid 0.30 g (1.90 mmol) and WSCI · HCl 0.55 g
(2.88 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, dried and the solvent was distilled off. Addition of ether gave 0.04 g (0.10 mmol) of colorless needle crystals (yield 5.5%). Melting point: 188-191 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.95-1.00 (2H m), 1.35-1.40 (3H m), 1.78 (4H br t J = 1
1.8Hz), 2.08-2.17 (1H m), 3.10 (2H t J = 5.9Hz), 4.27 (2
H d J = 6.1Hz), 7.32 (1H dd J = 4.6Hz, 7.9Hz), 7.47 (1H dd
J = 4.6Hz, 7.3Hz), 7.61 (1H ddd J = 2.0Hz, 3.8Hz, 7.9Hz),
7.85 (1H dd J = 2.0Hz, 7.3Hz), 8.29-8.31 (2H m), 8.42-8.
46 (2H m), 8.55-8.56 (1H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3301, 2934, 1642, 1634, 1582, 1560, 1542, 1432, 14
03, 1325, 1312, 1209

Example 41 4-[(2-chloropyridine-5-carboxamido) methyl] -N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0153]

[Chemical 53]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
Dissolve 1.00 g (3.12 mmol) in 50 ml of pyridine, 0.43 g (2.73 mmol) of 4-chloronicotinic acid, 1.05 g of WSCI · HCl
(5.78 mmol) and 2 ml of triethylamine were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, dried and the solvent was distilled off. Recrystallized from chloroform: n-hexane to give pale yellow needle crystals 0.17
g (0.44 mmol) was obtained (16% yield). Melting point: 205 to 207 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.17 (2H m), 1.42-1.72 (3H m), 1.85-2.03 (4H m),
2.03-2.19 (1H m), 3.34 (2H dd J = 5.9Hz, 6.6Hz), 4.45 (2
H d J = 5.9Hz), 5.85-5.96 (1H m), 6.27-6.41 (1H m), 7.2
4-7.32 (1H m), 7.41 (1H d J = 8.6Hz), 7.57-7.65 (1H m),
8.08 (1H dd J = 2.6Hz, 7.9Hz), 8.52 (2H br), 8.73 (1H d
J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3290, 2926, 1640, 1590, 1548, 1458, 1107

Example 42 4-[(3-Pyridylacetamido) methyl] -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0156]

[Chemical 54]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.00 g (3.12 mmol) was dissolved in 50 ml of pyridine, 0.54 g (3.11 mmol) of 3-pyridylacetic acid, 1.20 g (6.26 mmol) of WSCI.HCl and 2 ml of triethylamine were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, dried and the solvent was distilled off. Chloroform:
Recrystallized from n-hexane to give colorless needle crystals 0.48 g (1.31
Mmol) was obtained (yield 43%). Melting point: 162-163 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.84-1.03 (2H m), 1.37-1.57 (3H m), 1.64-1.97 (4H m),
1.99-2.13 (1H m), 3.09 (2H t J = 6.6Hz), 3.54 (2H s),
4.43 (2H d J = 5.9Hz), 5.62-5.75 (1H m), 5.98-6.09 (1H
m), 7.21-7.32 (2H m), 7.56-7.70 (2H m), 8.48-8.56 (4H
m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3291, 2926, 1640, 1558, 1428, 711

Example 43 4-[[trans-3- (3-pyridyl) acrylamido] methyl] -N- (3-pyridyl) methyl-trans-
Cyclohexane-1-carboxamide

[0159]

[Chemical 55]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.20 g (3.75 mmol) was dissolved in 50 ml of pyridine and trans-
0.83 g (5.56 mmol) of 3- (3-pyridyl) acrylic acid,
2.50 g (13.04 mmol) of WSCI.HCl and 1 ml of water were added and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, dried and the solvent was distilled off. Ethanol: recrystallized from n-hexane, colorless needle crystals 0.60
g (1.59 mmol) was obtained (yield 42%). Melting point: 209 ~ 211 ℃ H-nuclear magnetic resonance (δ) (solvent DMSO + D ₂ O) 0.84-1.01 (2H m), 1.16-1.48 (3H m), 1.78 (4H br d J = 1
0.6Hz), 2.12 (1H br t J = 11.9Hz), 3.05 (2H d J = 2.0Hz),
4.26 (2H s), 6.75 (1H d J = 15.8Hz), 7.32 (1H dd J = 4.6H
z, 7.9Hz), 7.41-7.47 (2H m), 7.61 (1H br d J = 7.9Hz),
7.95 (1H d J = 7.9Hz), 8.42-8.44 (2H m), 8.53 (1H dd J =
2.0Hz, 5.3Hz), 8.73 (1H d J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3291, 3081, 2932, 2861, 2845, 1657, 1639, 1615, 15
52, 1476, 1442, 1421, 1393, 1338, 1237, 1206, 1026,
996, 978, 803, 712

Example 44 4-[(2-methoxypyridine-5-carboxamide)
Methyl] -N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0162]

[Chemical 56]

Preparation Method 2-Methoxypyridine-5-carboxylic acid ethyl ester
0.76 g (4.19 mmol) was dissolved in 50 ml of methanol, 2.00 g (35.64 mmol) of potassium hydroxide dissolved in 30 ml of water was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in pyridine (50 ml) and water (1 ml), and 4- (aminomethyl) -N- (3-pyridylmethyl) -trans-cyclohexane-1-carboxamide dihydrochloride 1.20 g (3.75 mmol). , 2.50 g (13.04 mmol) of WSCI.HCl was added, and 2 at room temperature.
It was stirred for a day. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from ethanol: n-hexane gave colorless needle crystals 0.26 g (0.68 mmol) (yield 16%). Melting point: 233-234 ℃ H-nuclear magnetic resonance (δ) (solvent DMSO) 0.91-1.07 (2H m), 1.17-1.50 (3H m), 1.78 (4H br d J = 1
1.9Hz), 2.12 (1H m), 3.08 (2H t J = 5.9Hz), 3.48 (3H s),
4.27 (2H d J = 5.9Hz), 6.38 (1H d J = 9.2Hz), 7.31 (1H dd
J = 4.6Hz, 7.3Hz), 7.60 (1H d J = 8.6Hz), 7.85 (1H dd J =
2.6Hz, 9.9Hz), 8.12 (1H br t J = 5.9Hz), 8.27 (1H m), 8.
33 (1H d J = 2.6Hz), 8.43 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3303, 2927, 1665, 1642, 1540, 1315, 1300, 832

Example 45 4-[(5-methoxyindole-3-acetamide)
Methyl] -N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0165]

[Chemical 57]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.18 g (3.69 mmol) was dissolved in 100 ml of pyridine, 0.76 g (3.70 mmol) of 5-methoxyindoleacetic acid, WSCI · HCl
4.00 g (20.87 mmol) and 1 ml of water were added, and the mixture was stirred at room temperature for 6 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off. ethanol:
Recrystallized from n-hexane, colorless prism crystals 0.48g
(1.10 mmol) was obtained (yield 30%). Melting point: 174.0-174.9 ℃ H-nuclear magnetic resonance (δ) (solvent DMSO) 0.86 (2H m J = 11.9Hz), 1.31 (3H m J = 12.5Hz), 1.74 (4H
br d J = 11.2Hz), 2.08 (1H br t J = 12.5Hz), 2.91 (2H t J
= 6.0Hz), 3.46 (2H s), 3.74 (3H s), 4.26 (2H d J = 5.9H
z), 6.70 (1H dd J = 8.6Hz, 2.6Hz), 7.04 (1H d J = 2.0Hz),
7.11 (1H d J = 2.6Hz), 7.21 (1H d J = 9.2Hz), 7.32 (1H dd
J = 4.6Hz, 7.9Hz), 7.60 (1H d J = 7.9Hz), 7.80 (1H dd J =
5.3Hz, 5.9Hz), 8.26 (1H dd J = 4.6Hz, 5.9Hz), 8.44 (2H b
r), 10.03 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3298, 2943, 2928, 2863, 2844, 1636, 1540, 1492, 14
44, 1430, 1271, 1214, 1177, 1044, 831, 791, 716 Mass spectrum FAB M / e 435, 369, 277, 185

Example 46 4- (Cyclohexanecarboxamidomethyl) -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0168]

[Chemical 58]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
2.00 g (6.25 mmol) was dissolved in 100 ml of methylene chloride, 10 ml of triethylamine was added, and 0.85 ml (6.35 mmol) of cyclohexanecarbonyl chloride was slowly added under ice cooling. The reaction solution was stirred overnight at room temperature, water was added, and the precipitated crystals were collected by filtration. After washing with chloroform, ethanol: n-
Recrystallization from hexane gave colorless needle crystals (1.51 g, 4.11 mmol) (yield 66%). Melting point: 227.9-228.1 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.79-0.95 (2H m), 1.15-1.42 (8H m), 1.57-1.79 (9H m),
2.05-2.13 (2H m), 2.88 (2H dd J = 5.9Hz, 6.6Hz), 4.26 (d
2H d J = 5.9Hz), 7.31 (1H dd J = 4.6Hz, 7.9Hz), 7.55-7.6
1 (2H m), 8.24-8.28 (1H m), 8.44 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3294, 2930, 2854, 1642, 1560, 1546 Mass spectrum FAB M / e 358, 248

Example 47 4- (piperidine-2-carboxamidomethyl) -N-
(3-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0171]

[Chemical 59]

Preparation method BOC-dl-pipecolic acid 4.82 g (21.20 mmol), N-
2.5 ml (22.74 mmol) of methylmorpholine was dissolved in 100 ml of tetrahydrofuran, and isobutyl chlorocarbonate was added under ice cooling.
2.8 ml (21.59 mmol) was slowly added and stirred for 30 minutes.
Further, 6.90 g (21.55 mmol) of 4- (aminomethyl) -N- (3-pyridylmethyl) -trans-cyclohexane-1-carboxamide dihydrochloride, N-methylmorpholine 2.
4 ml (21.83 mmol) of N, N-dimethylformamide 100 m
What was melt | dissolved in 1 was added, and it stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform, dried and filtered, the solvent was distilled off, and recrystallized from ethanol: n-hexane. 25 ml of trifluoroacetic acid was added to the obtained colorless needle crystals.
Was added, the mixture was stirred at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure,
The residue is ion exchange column (Dowx-50x8 200-300mesh 50m
It was purified by l) and recrystallized from methanol: water to obtain 0.12 g (0.33 mmol) of colorless scaly crystals (yield 1.6%). Melting point: 136 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.90-1.01 (8H m), 1.43-1.55 (4H m), 1.84-2.07 (6H m),
3.04 (2H dd J = 4.0Hz, 5.4Hz), 3.83 (2H d J = 4.6Hz), 4.4
6 (2H d J = 5.3Hz), 4.68 (1H br), 5.79 (1H br), 7.24-7.2
8 (1H m), 7.61 (1H d J = 7.9Hz), 8.52 (2H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3306, 2936, 1691, 1634, 1542, 1286, 1261, 1027, 71
6

Example 48 4-Methoxyacetamidomethyl-N- (3-pyridyl) methyl-trans-cyclohexane-1-carboxamide

[0174]

[Chemical 60]

Process 4- (aminomethyl) -N- (3-pyridylmethyl)-
trans-Cyclohexane-1-carboxamide dihydrochloride
1.20 g (3.75 mmol) was dissolved in 200 ml of pyridine, 0.50 g (5.55 mmol) of methoxyacetic acid, 2.5 g (13.04 mmol) of WSCI.HCl and 2 ml of water were added, and the mixture was stirred for 2 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After dry filtration
The solvent was distilled off and recrystallized from ethanol: n-hexane to obtain 0.27 g (0.85 mmol) of colorless needle crystals (yield 23
%). Melting point: 164 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.93-1.06 (2H m), 1.46-1.58 (3H m), 1.84-2.13 (5H m),
3.16 (2H dd J = 5.9Hz, 6.6Hz), 3.42 (3H s), 3.89 (2H s),
4.46 (2H d J = 5.9Hz), 5.88 (1H br), 6.56 (1H br), 7.24
-7.29 (1H m), 7.61 (1H d J = 7.9Hz), 8.53 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3310, 2932, 1653, 1640, 1552, 1118 , 713 Mass spectrum FAB M / e 320, 304, 231

Example 49 4-Aminomethyl-N- (3-pyridylmethyl) -tran
s-Cyclohexane-1-carboxamide dihydrochloride

[0177]

[Chemical formula 61]

Process 4- (tert-butoxycarbonylaminomethyl) -N-
(3-pyridylmethyl) -trans-cyclohexane-1
31.14 g (89.62 mmol) of carboxamide in ethanol 1
It was dissolved in 00 ml, 50 ml of 4N hydrochloric acid dioxane solution was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol: n-hexane to give 30.16 g of colorless needle crystals.
(89.32 mmol) was obtained (quantitative yield). Melting point: 222.4-223.7 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.95-1.07 (2H m), 1.29-1.44 (3H m), 1.55-1.60 (1H m),
1.84 (4H br d J = 11.9Hz), 2.13-2.22 (1H m), 2.65 (2H t
J = 5.9Hz), 4.45 (2H d J = 5.9Hz), 7.96 (3H br), 8.03 (1H
dd J = 5.9Hz, 7.9Hz), 8.43 (1H d J = 7.9Hz), 8.64 (1H t J
= 5.9Hz), 8.81 (1H s), 8.83 (1H d J = 5.9Hz) Mass spectrum FAB M / e 248, 231, 217, 185

Example 50 N- (4-pyridyl) methyl-4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0180]

[Chemical formula 62]

Process 4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.50 g (4.
(27 mmol) dissolved in 100 ml of chloroform, 0.46 g (4.25 mmol) of 4- (aminomethyl) pyridine, WSCI · HCl 1.23
g (6.42 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Recrystallized from chloroform: ether to give 1.41 g of colorless prism crystals (3.
19 mmol) was obtained (yield 75%). Melting point: 173-176 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.97-1.25 (2H m), 1.43-1.69 (3H m), 1.84-2.28 (5H m),
3.34 (2H dd J = 5.9Hz, 6.6Hz), 3.89 (3H s), 3.93 (3H s),
3.96 (3H s), 4.45 (2H d J = 5.9Hz), 5.92-5.96 (1H m),
6.53 (1H s), 7.16 (2H d J = 5.3Hz), 7.74 (1H s), 7.90-7.
94 (1H br), 8.53-8.55 (2H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3270, 2910, 1635, 1595, 1505, 1275, 1205, 1020

Example 51 N- (2-pyridyl) methyl-4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0183]

[Chemical formula 63]

Process N- (2-pyridyl) methyl-4- (tert-butoxycarbonylaminomethyl) -trans-cyclohexane-1
-Carboxamide 2.63 g (7.56 mmol) was dissolved in a 4N hydrochloric acid dioxane solution, stirred at room temperature for 4 hours, and concentrated under reduced pressure. The residue was suspended in 100 ml of chloroform and added to 2,4,5-
Trimethoxybenzoic acid 1.60 g (7.54 mmol), triethylamine 1.57 g (15.52 mmol) and WSCI.HCl 2.20 g (11.48 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off. Recrystallization from chloroform: ether: n-hexane gave 1.60 g (3.62 mmol) of colorless prism crystals (yield 48%). Melting point: 167-169 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.97-1.23 (2H m), 1.38-1.67 (3H m), 1.82-2.08 (4H m),
2.08-2.27 (1H m), 3.48 (2H t J = 7.3Hz), 3.90 (3H s),
3.93 (3H s), 3.96 (3H s), 4.55 (2H d J = 5.3Hz), 6.53 (1H
s), 6.71-6.90 (1H m), 7.16-7.31 (2H m), 7.58-7.72 (1H
m), 7.76 (1H s), 7.86-8.02 (1H m), 8.53 (1H d J = 5.3H
z) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3300, 2915, 1640, 1605, 1510, 1440, 1280, 1220, 10
45

Example 52 4- (3,4-dimethoxybenzamidomethyl) -N-
(2-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0186]

[Chemical 64]

Process 4- (3,4-dimethoxybenzamidomethyl) -tran
1.00 g (3.11 mmol) of s-cyclohexane-1-carboxylic acid was dissolved in 50 ml of chloroform and 0.34 g (3.14 mmol) of 2- (aminomethyl) pyridine, 1.0 ml of pyridine, WS
CI.HCl (0.78 g, 4.07 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off.
Recrystallized with chloroform: ether, colorless prism crystals
1.02 g (2.48 mmol) was obtained (80% yield). Melting point: 209 to 211 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.00-1.29 (2H m), 1.45-1.76 (3H m), 1.84-2.07 (4H m),
2.11-2.26 (1H m), 3.32 (2H dd J = 5.9Hz, 6.6Hz), 3.92 (3
H s), 3.93 (3H s), 4.54 (2H d J = 4.6Hz), 6.06-6.20 (1H
br), 6.76-6.81 (1H br), 6.86 (1H d J = 7.9Hz), 7.17-7.3
4 (3H m), 7.42 (1H d J = 2.0Hz), 7.62-7.70 (1H m), 8.53
(1H d J = 4.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3250, 2900, 1625, 1500, 1310, 1265, 1220, 1125, 10
Ten

Example 53 4- (2,4-dimethoxybenzamidomethyl) -N-
(2-pyridyl) methyl-trans-cyclohexane-1
-Carboxamide

[0189]

[Chemical 65]

Process 4- (2,4-dimethoxybenzamidomethyl) -tran
1.50 g (4.67 mmol) of s-cyclohexane-1-carboxylic acid was dissolved in 70 ml of chloroform, and 0.50 g (4.62 mmol) of 2- (aminomethyl) pyridine, 1.16 g of WSCI · HCl.
(6.05 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Chloroform:
Recrystallized from n-hexane, colorless prism crystals 1.57g
(3.82 mmol) was obtained (yield 83%). Melting point: 160-163 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.00-1.20 (2H m), 1.47-1.73 (3H m), 1.86-2.27 (5H m),
3.26-3.42 (2H m), 3.85 (3H s), 3.94 (3H s), 4.52-4.66
(2H m), 6.49 (1H d J = 2.0Hz), 6.60 (1H dd J = 2.0Hz, 8.6H
z), 6.73-6.85 (1H m), 7.17-7.38 (2H m), 7.63-7.73 (1H
m), 7.73-7.90 (1H br), 8.16-8.20 (1H m), 8.54 (1H d J =
4.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3280, 2900, 2830, 1630, 1535, 1495, 1455, 1430, 13
05, 1270, 1200, 1165, 1115, 1040

Example 54 N- (2-pyridyl) methyl-4- (3,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0192]

[Chemical formula 66]

Process 4- (3,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.50 g (4.
(27 mmol) dissolved in 70 ml of chloroform, 0.45 g (4.16 mmol) of 2- (aminomethyl) pyridine, 1.18 g of WSCI · HCl
(6.16 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Chloroform:
Recrystallization from ether gave 1.41 g (3.19 mmol) of colorless prism crystals (yield 77%). Melting point: 186-188 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.99-1.19 (2H m), 1.44-1.72 (3H m), 1.85-2.10 (4H m),
2.10-2.29 (1H m), 3.33 (2H dd J = 5.9Hz, 6.6Hz), 3.88 (3
H s), 3.91 (6H s), 4.54 (2H d J = 4.6Hz), 6.10-6.21 (1H
br), 6.81 (1H br), 6.99 (2H s), 7.17-7.22 (2H m), 7.62
-7.69 (1H m), 8.53 (1H d J = 5.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3250, 2915, 1640, 1580, 1440, 1500, 1415, 1335, 12
30, 1125

Example 55 4- (4-amino-5-chloro-2-methoxybenzamidomethyl) -N- (2-pyridyl) methyl-trans-
Cyclohexane-1-carboxamide

[0195]

[Chemical formula 67]

Preparation Method 4- (4-Amino-5-chloro-2-methoxybenzamidomethyl) -trans-cyclohexane-1-carboxylic acid 1.20 g (3.52 mmol) was dissolved in 60 ml of chloroform and 2
0.43 g (3.98 mmol) of-(aminomethyl) pyridine, 1.0 ml of pyridine and 1.13 g (5.89 mmol) of WSCI.HCl were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, water was added,
It was extracted with chloroform. After drying and filtering, the solvent was distilled off. Recrystallization from chloroform: ether gave 1.10 g (2.55 mmol) of colorless prism crystals (yield 64%). Melting point: 198 to 201 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.16 (2H m), 1.44-1.66 (3H m), 1.84-2.06 (4H m),
2.09-2.26 (1H m), 3.31 (2H dd J = 5.9Hz, 6.6Hz), 3.90 (3
H s), 4.36 (2H s), 4.55 (2H d J = 4.6Hz), 6.30 (1H s),
6.75-6.85 (1H br), 7.17-7.27 (2H m), 7.61-7.77 (2H
m), 8.11 (1H s), 8.53 (1H d J = 5.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3200, 2895, 1620, 1580, 1520, 1300, 1245, 1195

Example 56 N- [2- (2-pyridyl) ethyl] -4- (2,4)
5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0198]

[Chemical 68]

Process 4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.00 g (2.
85 mmol) was dissolved in 50 ml of pyridine, and 0.35 g (2.86 mmol) of 2- (2-aminoethyl) pyridine and 0.80 g of WSCI · HCl.
(4.17 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform.
After drying and filtering, the solvent was distilled off, and the residue was recrystallized from chloroform: n-hexane to obtain 1.20 g (2.63 mmol) of colorless prism crystals (yield 92%). Melting point: 181-184 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.97-1.15 (2H m), 1.32-1.72 (3H m), 1.81-2.12 (5H m),
2.94-3.01 (2H m), 3.28-3.36 (2H m), 3.59-3.72 (2H m),
3.90 (3H s), 3.94 (3H s), 3.96 (3H s), 6.46-6.58 (2H
br), 7.15-7.18 (2H m), 7.59-7.66 (1H m), 7.75 (1H s),
7.87-8.00 (1H br), 8.51-8.54 (1H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3320, 2928, 1640, 1609, 1552, 1520, 1469, 1282, 12
17, 1029

Example 57 N- (2-pyrazinylmethyl) -4-[(2,4,5-
Trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxamide

[0201]

[Chemical 69]

Production method 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 0.38 g
(1.08 mmol) was dissolved in 20 ml of pyridine, and 2- (aminomethyl) pyridine 0.12 g (1.10 mmol) and WSCI.HCl 0.32 g
(1.67 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was concentrated and recrystallized from chloroform: ether to give 0.40 g (0.90 mmol) of colorless prism crystals (yield 84%). Melting point: 182-184 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.19 (2H m), 1.45-1.73 (3H m), 1.83-2.08 (4H m),
2.11-2.38 (1H m), 3.33 (2H dd J = 5.9Hz, 6.6Hz), 3.90 (3
H s), 3.94 (3H s), 3.96 (3H s), 4.61 (2H d J = 5.3Hz),
6.50-6.61 (2H m), 7.26-7.31 (1H m), 7.55 (1H s), 7.94
(1H br), 8.49-8.54 (1H m), 8.59-8.46 (1H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3303, 2930, 2855, 1643, 1608, 1560, 1520 , 1472, 14
39, 1405, 1281, 1217, 1028

Example 58 N- [3- (1-Imidazolyl) propyl] -4-
[(Pyridine-2-carboxamido) methyl] -trans
-Cyclohexane-1-carboxamide

[0204]

[Chemical 70]

Process 4-[(pyridine-2-carboxamido) methyl] -tr
Ans-cyclohexane-1-carboxylic acid 1.00 g (3.81 mmol) was dissolved in pyridine 50 ml, 1- (3-aminopropyl) imidazole 0.48 g (3.83 mmol), WSCI.HCl 0.95
g (4.96 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off, and the residue was recrystallized from chloroform: n-hexane to obtain 0.95 g (2.57 mmol) of colorless needle crystals (yield 67%). Melting point: 128-130 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.16 (2H m), 1.37-1.78 (3H m), 1.82-2.09 (7H m),
3.27 (2H q J = 6.6Hz), 3.34 (2H t J = 6.6Hz), 3.98 (2H dd
J = 6.6Hz, 7.3Hz), 5.56-5.70 (1H br), 6.94 (1H s), 7.06
(1H s), 7.39-7.50 (2H m), 7.80-7.90 (1H m), 8.06-8.18
(1H br), 8.19 (1H d J = 7.3Hz), 8.55 (1H dd J = 2.0Hz, 4.0
Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3282, 2946, 2920, 1855, 1578, 1568, 1539, 1511, 14
50, 1238, 1082

Example 59 N- [3- (1-Imidazolyl) propyl] -4-
[(Pyridin-4-carboxamido) methyl] -trans
-Cyclohexane-1-carboxamide

[0207]

[Chemical 71]

Preparation 4-[(pyridine-4-carboxamido) methyl] -tr
Ans-cyclohexane-1-carboxylic acid 1.00 g (3.81 mmol) was dissolved in pyridine 50 ml, 1- (3-aminopropyl) imidazole 0.48 g (3.83 mmol), WSCI.HCl 0.95
g (4.96 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off, and the residue was recrystallized from chloroform: n-hexane to obtain 0.43 g (1.16 mmol) of colorless needle crystals (yield 31%). Melting point: 144-145 ° C H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.99-1.17 (2H m), 1.39-1.74 (3H m), 1.80-2.05 (6H m),
2.09-2.21 (1H m), 3.17 (2H dd J = 6.6Hz, 7.3Hz), 3.26 (2
H d J = 7.3Hz), 4.03 (2H dd J = 6.6Hz, 7.3Hz), 6.69 (1H
s), 7.12 (1H s), 7.64 (1H s), 7.75-7.80 (2H m), 8.68 (2
H dd J = 1.3Hz, 4.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3261, 2941, 2927, 2901, 2864, 1667, 1645, 1558, 15
09, 1306

Example 60 N- [2- (1-methyl-2-pyrrolyl) ethyl] -4
-[(2,4,5-Trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxamide

[0210]

[Chemical 72]

Preparation 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.00 g
(2.85 mmol) was dissolved in 100 ml of methylene chloride, and 0.36 g (2.90 mmol) of 2-aminomethyl-1-methylpyrrole, 1.0 ml (7.17 mmol) of triethylamine, and 1.00 g of WSCI · HCl.
(5.22 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. The residue was recrystallized from ethanol: n-hexane to give colorless needle crystals 0.45 g (0.
98 mmol) was obtained (35% yield). Melting point: 180.5-182.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.01-1.06 (2H m), 1.44-1.56 (4H m), 1.88-2.00 (5H m),
2.77 (2H t J = 6.6Hz), 3.32 (2H dd J = 5.9Hz, 6.6Hz), 3.48
(2H dd J = 6.6Hz, 7.3Hz), 3.56 (3H s), 3.90 (3H s), 3.9
4 (3H s), 3.96 (3H s), 5.62 (1H br), 5.90 (1H dd J = 1.3H
z, 3.3Hz), 6.06 (1H dd J = 2.6Hz, 3.3Hz), 6.52 (1H s), 6.
57 (1H dd J = 2.6Hz, 1.8Hz), 7.75 (1H s), 7.92 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3307, 2928, 1638, 1608, 1552 , 1519, 1282, 1218, 10
28

Example 61 N- [2- (1-methyl-2-pyrrolyl) ethyl] -4
-[(Pyridine-2-carboxamido) methyl] -tran
s-Cyclohexane-1-carboxamide

[0213]

[Chemical formula 73]

Process 4-[(pyridine-2-carboxamido) methyl] -tr
1.00 g (3.81 mmol) of ans-cyclohexane-1-carboxylic acid was dissolved in 50 ml of pyridine, 0.47 g (3.78 mmol) of 2- (2-aminoethyl) -1-methylpyrrole, WSCI.
HCl 0.95 g (4.96 mmol) was added, and the mixture was stirred at room temperature for 24 hours.
The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and chloroform:
Recrystallization from n-hexane gave 0.56 g (1.52 mmol) of colorless needle crystals (yield 40%). Melting point: 114-116 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.12 (2H m), 1.38-1.74 (3H m), 1.84-2.07 (5H m),
2.72-2.82 (2H m), 3.28-3.40 (2H m), 3.42-3.55 (2H m),
3.56 (3H s), 5.59-5.70 (1H br), 5.91 (1H br), 6.05-6.
10 (1H m), 6.57 (1H s), 7.40-7.50 (1H m), 7.81-7.92 (1H
m), 8.06-8.19 (1H br), 8.22 (1H d J = 4.0Hz), 8.55 (1H
d J = 4.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3374, 3360, 1668, 1655, 1540, 1529

Example 62 N- [2- (1-methyl-2-pyrrolyl) ethyl] -4
-[(Pyridine-4-carboxamido) methyl] -tran
s-Cyclohexane-1-carboxamide

[0216]

[Chemical 74]

Process 4-[(pyridine-4-carboxamido) methyl] -tr
1.00 g (3.81 mmol) of ans-cyclohexane-1-carboxylic acid was dissolved in 50 ml of pyridine, 0.47 g (3.78 mmol) of 2- (2-aminoethyl) -1-methylpyrrole, WSCI.
HCl 0.95 g (4.96 mmol) was added, and the mixture was stirred at room temperature for 24 hours.
The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and chloroform:
Recrystallization from n-hexane gave 1.20 g (3.26 mmol) of colorless needle crystals (yield 85%). Melting point: 188-189 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.96-1.15 (2H m), 1.44-1.69 (3H m), 1.78-2.08 (5H m),
2.77 (2H dd J = 4.0Hz, 6.6Hz), 3.32 (2H t J = 4.0Hz), 3.48
(2H dd J = 6.6Hz, 7.3Hz), 3.56 (3H s), 5.58-5.68 (1H b
r), 5.88-5.95 (1H br), 6.04-6.10 (1H m), 6.18-6.28 (1H
br), 6.57-6.57 (1H m), 7.58-7.61 (2H m), 8.73-8.77 (2
H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3302, 2932, 1639, 1552

Example 63 N-[(1-ethyl-2-pyrrolidinyl) methyl] -4
-[(2,4,5-Trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxamide

[0219]

[Chemical 75]

Preparation 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.00 g
(2.85 mmol) was dissolved in 50 ml of methylene chloride, 0.37 g (2.89 mmol) of 2-amino-1-ethylpyrrolidine, 0.8 ml (5.74 mmol) of triethylamine and 1.00 g (5.22 mmol) of WSCI · HCl were added, and the mixture was stirred at room temperature overnight. did. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. The residue is ethanol:
Recrystallized from n-hexane, colorless prism crystals 0.71g
(1.54 mmol) was obtained (yield 54%). Melting point: 148 to 149 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.06-1.17 (5H m), 1.43-1.98 (12H m), 2.10-2.25 (3H
m), 2.57-2.88 (2H m), 3.27-3.31 (2H m), 3.33 (2H t J =
5.9Hz), 3.50-3.52 (1H m), 3.90 (3H s), 3.94 (3H s), 3.
96 (3H s), 6.53 (1H s), 7.76 (1H s), 7.94 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3306, 2930, 1654, 1637, 1560, 1555, 1535, 1518, 15
08, 1459, 1438, 1280, 1217, 1026

Example 64 N-[(1-ethyl-2-pyrrolidinyl) methyl] -4
-[(Pyridine-2-carboxamido) methyl] -tran
s-Cyclohexane-1-carboxamide

[0222]

[Chemical 76]

Process 4-[(pyridine-2-carboxamido) methyl] -tr
0.60 g (2.29 mmol) of ans-cyclohexane-1-carboxylic acid was dissolved in 50 ml of pyridine, and 2-aminomethyl-1-
Ethylpyrrolidine 0.30 g (2.34 mmol), WSCI · HCl 0.66
g (3.44 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and recrystallized from chloroform: n-hexane to give pale yellow needle crystals 0.36 g (0.97 mmol).
Was obtained (yield 42%). Melting point: 102-105 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.99-1.24 (5H m), 1.32-2.03 (11H m), 2.03-2.45 (3H
m), 2.68-2.95 (2H m), 3.13-3.40 (4H m), 3.48-3.62 (1H
m), 6.36-6.61 (1H br), 7.39-7.49 (1H m), 7.79-7.91 (1H
m), 8.14-8.21 (2H m), 8.54-8.56 (1H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3303, 2926, 1655, 1642, 1536

Example 65 4-[(3,4-dimethoxybenzamido) methyl]-
N-[(1-ethyl-2-pyrrolidinyl) methyl] -tr
ans-cyclohexane-1-carboxamide

[0225]

[Chemical 77]

Process 4-[(3,4-dimethoxybenzamido) methyl]-
trans-cyclohexane-1-carboxylic acid 1.00 g (3.11
Mmol) in 50 ml of chloroform and 1 ml of pyridine, 2
0.40 g (3.12 mmol) of -aminomethyl-1-ethylpyrrolidine and 0.78 g (4.07 mmol) of WSCI.HCl were added, and the mixture was stirred at room temperature overnight. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. The crystals were recrystallized from chloroform: n-hexane to obtain 1.00 g (2.32 mmol) of colorless prism crystals (yield 74%). Melting point: 145 to 147 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.19 (5H m), 1.38-2.29 (14H m), 2.49-2.63 (1H b
r), 2.66-2.85 (1H m), 3.02-3.18 (2H m), 3.32 (2H dd J =
5.9Hz, 6.6Hz), 3.92 (3H s), 3.93 (3H s), 6.02-6.24 (2H
m), 6.86 (2H d J = 8.6Hz), 7.24-7.26 (1H m), 7.43 (1H d
(J = 1.3Hz)

Example 66 4-[(2,4-dimethoxybenzamido) methyl]-
N-[(1-ethyl-2-pyrrolidinyl) methyl] -tr
ans-cyclohexane-1-carboxamide

[0228]

[Chemical 78]

Preparation 4-[(2,4-dimethoxybenzamido) methyl]-
trans-cyclohexane-1-carboxylic acid 1.50 g (4.67
Mmol) in 70 ml of chloroform, 0.60 g (4.68 mmol) of 2-aminomethyl-1-ethylpyrrolidine, WSCI · HC
1.16 g (6.05 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Chloroform: Recrystallized from n-hexane to give colorless prism crystals 1.
18 g (2.73 mmol) was obtained (59% yield). Melting point: 149 to 151 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.97-1.17 (5H m), 1.39-2.28 (14H m), 2.49-2.62 (1H b
r), 2.69-2.86 (1H m), 3.01-3.21 (2H m), 3.27-3.38 (2H
m), 3.46-3.58 (1H m), 3.85 (3H s), 3.94 (3H s), 5.99-
6.14 (1H br), 6.49 (1H d J = 2.6Hz), 6.56-6.66 (1H m),
7.73-7.86 (1H br), 8.18 (1H d J = 8.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3260, 2910, 1632, 1604, 1550, 1500, 1450, 1268, 12
04, 1100, 1028

Example 67 N-[(1-ethyl-2-pyrrolidinyl) methyl] -4
-[(3,4,5-Trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxamide

[0231]

[Chemical 79]

Production method 4-[(3,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.50 g
(4.27 mmol) was dissolved in 50 ml of methylene chloride and 2 ml of pyridine, and 0.53 g of 2-aminomethyl-1-ethylpyrrolidine
(4.13 mmol) and WSCI.HCl 1.18 g (6.16 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution is washed with water, dried and filtered,
The solvent was distilled off. Recrystallization from chloroform: n-hexane gave 1.68 g (3.64 mmol) of colorless prism crystals (yield.
88%). Melting point: 190-193 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.97-1.18 (5H m), 1.39-2.30 (12H m), 2.51-2.63 (1H b
r), 2.68-2.85 (1H m), 3.01-3.21 (2H m), 3.32 (2H d J =
6.6Hz), 3.46-3.58 (1H m), 3.88 (3H s), 3.91 (6H s), 6.
01-6.21 (2H br), 6.99 (2H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3300, 2920, 1632, 1580, 1440, 1410, 1336, 1228, 11
twenty four

Example 68 4-[(4-Amino-5-chloro-2-methoxybenzamido) methyl] -N-[(1-ethyl-2-pyrrolidinyl) methyl] -trans-cyclohexane-1-carboxamide

[0234]

[Chemical 80]

Preparation Method 4-[(4-Amino-5-chloro-2-methoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.21 g (3.55 mmol) was dissolved in 60 ml of chloroform to give 2-aminomethyl-1. -Ethylpyrrolidine 0.50g
(3.90 mmol), WSCI.HCl 1.00 g (5.22 mmol), pyridine
1.0 ml was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off, and the residue was recrystallized from chloroform: n-hexane to obtain 0.80 g (1.77 mmol) of colorless prism crystals (yield 50%). Melting point: 158-160 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.96-1.15 (5H m), 1.39-2.00 (11H m), 2.00-2.27 (3H
m), 2.49-2.60 (1H m), 2.69-2.85 (1H m), 3.01-3.19 (2H
m), 3.30 (2H dd J = 5.9Hz, 6.6Hz), 3.46-3.57 (1H m), 3.9
0 (3H s), 4.38 (2H s), 6.06-6.30 (1H br), 6.30 (1H s),
7.70-7.73 (1H br), 8.11 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3300, 2930, 1640, 1590, 1540, 1452, 1320, 1260, 12
Ten

Example 69 N-[(1-methyl-2-pyrrolidinyl) ethyl] -4
-[(2,4,5-Trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxamide

[0237]

[Chemical 81]

Preparation 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.00 g
(2.85 mmol) was dissolved in 50 ml of methylene chloride and 1.1 ml (7.89 mmol) of triethylamine, 2- (2-aminoethyl)
-1-Methylpyrrolidine 0.40 g (3.12 mmol), WSCI · HC
1.50 g (7.82 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Wash the reaction mixture with water and perform silica gel column chromatography.
(100 g, ethyl acetate), and recrystallized from ethanol: n-hexane to give 0.40 g (0.87 mmol) of colorless prism crystals.
Was obtained (yield 30%). Melting point: 165.1-166.5 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.04-1.14 (m 2H), 1.36-1.77 (m 9H), 1.85-2.02 (m 5H),
2.16-2.29 (m 2H), 2.32 (s 3H), 3.03-3.10 (m 1H), 3.19
-3.26 (m 1H), 3.33 (dd 2H J = 5.9Hz, 6.6Hz), 3.47 (dd 1H
J = 5.9Hz, 13.2Hz), 3.90 (s 3H), 3.94 (s 3H), 3.96 (s 3
H), 6.53 (s 1H), 6.96 (br 1H), 7.76 (br 1H), 7.95 (br 1
H) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3300, 2932, 1638, 1564, 1542, 1519, 1442, 1280, 12
14, 1026 Mass spectrum FAB M / e 462, 306, 284

Example 70 N- [3- (1-morpholino) propyl] -4-[(pyridine-2-carboxamido) methyl] -trans-cyclohexane-1-carboxamide

[0240]

[Chemical formula 82]

Process 4-[(pyridine-2-carboxamido) methyl] -tr
Ans-cyclohexane-1-carboxylic acid 1.00 g (3.81 mmol) was dissolved in pyridine 50 ml, 1- (3-aminopropyl) morpholine 0.55 g (3.81 mmol), WSCI.HCl 1.10 g
(5.74 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform.
Chloroform: Recrystallized from n-hexane, colorless needle crystals
0.95 g (2.45 mmol) was obtained (yield 64%). Melting point: 150-153 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.92-1.18 (2H m), 1.35-1.74 (5H m), 1.75-2.10 (5H m),
2.32-2.54 (6H m), 3.21-3.40 (4H m), 3.55-3.74 (4H m),
6.67-6.81 (1H br), 7.39-7.45 (1H m), 7.80-7.89 (1H
m), 8.09-8.23 (1H br), 8.20 (1H d J = 7.9Hz), 8.55 (1H d
J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3328, 2934, 1649, 1699, 1539, 1119

Example 71 N- [2- (1-morpholino) ethyl] -4-[(2,
4,5-Trimethoxybenzamido) methyl] -trans
-Cyclohexane-1-carboxamide

[0243]

[Chemical 83]

Preparation 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.00 g
(2.85 mmol) was dissolved in 50 ml of chloroform, and 1- (2-
Aminoethyl) morpholine 0.37 g (2.84 mmol), WSCI
HCl 0.8 g (4.17 mmol) was added, and the mixture was stirred at room temperature for 2 days.
The reaction mixture was washed with water and 3% aqueous sodium hydrogen carbonate, dried and filtered, and the solvent was evaporated. Silica gel column chromatography (100 g, chloroform: methanol = 50: 1)
And was recrystallized from chloroform: n-hexane to obtain 0.90 g (1.94 mmol) of colorless prism crystals (yield 68
%). Melting point: 179 to 180 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.99-1.20 (2H m), 1.37-1.64 (3H m), 1.91-2.12 (5H m),
3.24-3.42 (4H m), 3.70 (4H t J = 4.6Hz), 3.94 (3H s),
3.96 (3H s), 3.98 (3H s), 5.94-6.10 (1H br), 6.53 (1H
s), 7.76 (1H s), 7.85-8.02 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3190, 2930, 1850, 1636, 1604, 1540, 1510, 1445, 14
00, 1340, 1280, 1208, 1120, 1024, 866

Example 72 N- [2- (4-phenylpiperazino) ethyl] -4-
[(2,4,5-Trimethoxybenzamido) methyl]
-Trans-cyclohexane-1-carboxamide

[0246]

[Chemical 84]

Process N- [2- (4-phenylpiperazino) ethyl] -4-
0.65 g (1.56 mmol) of (aminomethyl) -trans-cyclohexane-1-carboxamide dihydrochloride was added to 40 ml of pyridine.
Dissolve in 2,4,5-trimethoxybenzoic acid 0.36g
(1.70 mmol) and WSCI.HCl 0.90 g (4.69 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. After drying and filtering, the solvent was distilled off and recrystallization from ethanol: n-hexane was performed to obtain 0.50 g (0.93 mmol) of colorless crystals (yield 60%). Melting point: 183-186 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.01-2.31 (16H m), 2.51-2.67 (3H m), 3.14 (2H d J = 10.
6Hz), 3.34 (2H dd J = 5.9Hz, 6.6Hz), 3.44 (2H dd J = 5.3H
z, 5.9Hz), 3.91 (3H s), 3.94 (3H s), 3.96 (3H s), 6.53
(1H s), 6.56 (1H br), 7.19-7.35 (5H m), 7.76 (1H s),
7.95 (1H t J = 5.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measuring method KBr-tab.) 3309, 2931, 2856, 1639, 1609, 1556, 1520, 1468, 14
51, 1440, 1404,1343, 1283, 1215, 1088, 1029

Example 73 N- [2- (4-phenylpiperazino) ethyl] -4-
[(Pyridine-2-carboxamido) methyl] -trans
-Cyclohexane-1-carboxamide

[0249]

[Chemical 85]

Production method N- [2- (4-phenylpiperazino) ethyl] -4-
0.65 g (1.56 mmol) of (aminomethyl) -trans-cyclohexane-1-carboxamide dihydrochloride was added to 40 ml of pyridine.
Dissolved in 0.23 g (1.87 mmol) picolinic acid, WSCI · HCl
0.90 g (4.69 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. After drying and filtering, the solvent was distilled off and the residue was crystallized with ether to give 0.45 g (1.00 mmol) of colorless crystals (yield 64%). Melting point: 182 to 185.5 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.03-1.97 (12H m), 2.03-2.22 (4H m), 2.48-2.58 (3H
m), 3.05 (2H d J = 11.2Hz), 3.33-3.42 (4H m), 6.30 (1H b
r), 7.18-7.34 (5H m), 7.40-7.45 (1H m), 7.82-7.88 (1H
m), 8.15 (1H br), 8.19 (1H d J = 7.9Hz), 8.55 (1H d J = 4.
6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3325, 2927, 2849, 1660, 1642, 1530, 1446, 1436

Example 74 N- [2- (4-phenylpiperazino) ethyl] -4-
[(Pyridin-4-carboxamido) methyl] -trans
-Cyclohexane-1-carboxamide

[0252]

[Chemical 86]

Preparation method 0.23 g (1.87 mmol) of isonicotinic acid was suspended in 15 ml of tetrahydrofuran, 0.20 ml (1.87 mmol) of N-methylmorpholine was added, and further isobutyl chlorocarbonate was added under ice cooling.
24 ml (1.87 mmol) was added dropwise, and N- [2- (4-
Phenylpiperazino) ethyl] -4- (aminomethyl)
-Trans-cyclohexane-1-carboxamide 0.65 g
(1.56 mmol) and N-methylmorpholine (0.34 ml, 3.12 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with 20% sodium hydroxide aqueous solution and ethyl acetate. The extracts were combined, dried and filtered, the solvent was evaporated, and the residue was crystallized from ether to give 0.54 g (1.20 mmol) of colorless crystals (yield 76
%). Melting point: 222-225 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.01-1.99 (13H m), 2.02-2.25 (3H m), 2.48-2.59 (3H
m), 3.03 (2H d J = 11.9Hz), 3.33-3.44 (4H m), 6.29 (1H b
r), 6.39 (1H br), 7.19-7.37 (5H m), 7.63 (2H d J = 5.9H
z), 8.75 (2H d J = 5.9Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3308, 2932, 2850, 1641, 1601, 1545, 1494, 1448, 14
09, 1314, 1207

Example 75 N- [3- (4-phenylpiperazino) propyl] -4
-[(2,4,5-Trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxamide

[0255]

[Chemical 87]

Preparation 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.00 g
(2.85 mmol) was dissolved in 100 ml of pyridine and 0.80 g of 1 .- (3-aminopropyl) -4-phenylpiperidine (2.75
(3.0 mmol) and WSCI.HCl (3.00 g, 15.65 mmol) were added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the mixture was extracted with methylene chloride, dried and filtered, and the solvent was evaporated. Recrystallization from ethanol: n-hexane gave colorless needle crystals (1.03 g, 1.87 mmol) (yield 68%). Melting point: 164.7 to 166.1 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.01-1.16 (2H m), 1.24-2.12 (16H m), 2.52 (2H dd J = 6.
6Hz, 5.9Hz), 3.11 (2H br d J = 11.9Hz), 3.32-3.40 (4H
m), 3.90 (3H s), 3.91 (3H s), 3.94 (3H s), 3.95 (1H b
r), 6.51 (1H s), 7.13-7.34 (6H m), 7.76 (1H s), 7.93 (1
H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3322, 2935, 1644, 1634, 1608, 1552, 1518, 1464, 14
43, 1402, 1282, 1264, 1217, 1038 Mass spectrum FAB M / e 552, 538, 391, 352, 327

Example 76 N- [3- (4-phenylpiperazino) propyl] -4
-[(Pyridine-2-carboxamido) methyl] -tran
s-Cyclohexane-1-carboxamide

[0258]

[Chemical 88]

Process 4-[(tert-butoxycarbonylamino) methyl]-
N- [3- (4-phenylpiperazino) propyl] -tr
ans-cyclohexane-1-carboxamide 0.84 g (1.
84 mmol) was dissolved in 50 ml of ethanol, 50 ml of 4N hydrochloric acid dioxane solution was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in pyridine (150 ml), picolinic acid (0.30 g, 2.44 mmol) and WSCI.HCl (1.00 g, 5.22 mmol) were added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated again under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Ethanol: recrystallized from n-hexane,
0.24 g (0.52 mmol) of colorless needle crystals were obtained (yield 28%). Melting point: 158.6-160.9 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.02-1.17 (2H m), 1.43-2.12 (17H m), 2.51 (2H t J = 5.9
Hz), 2.55 (1H m), 3.10 (2H br d J = 11.9Hz), 3.30-3.42
(4H m), 7.14-7.36 (5H m), 7.41-7.47 (1H m), 7.86 (1H d
t J = 1.3Hz, 7.9Hz), 8.14 (1H br), 8.21 (1H d J = 7.9Hz),
8.55 (1H d J = 4.6Hz) Mass spectrum FAB M / e 463, 358, 327, 302, 273, 245

Example 77 N- [2- (diethylamino) ethyl] -4-[(2,
4,5-Trimethoxybenzamido) methyl] -trans
-Cyclohexane-1-carboxamide

[0261]

[Chemical 89]

Production method 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.50 g
(4.27 mmol) was dissolved in 40 ml of chloroform, and N, N-
Diethylethylenediamine 0.50 g (4.30 mmol), WSCI
HCl (1.06 g, 5.53 mmol) was added, and the mixture was stirred at room temperature for 24 hours.
The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Purified by silica gel column chromatography (100 g, chloroform: methanol = 20: 1), chloroform: n
-Recrystallized with hexane to give colorless prism crystals 1.05g (2.34
Mmol) (yield 55%). Melting point: 149 to 151 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.92-1.20 (8H m), 1.33-2.18 (8H m), 2.48-3.66 (6H m),
3.28-3.36 (4H m), 3.90 (3H s), 3.93 (3H s), 3.96 (3H
s), 6.32-6.51 (1H br), 6.53 (1H s), 7.76 (1H s), 7.86-
8.03 (1H m) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3250, 2820, 1638, 1602, 1560, 1510, 1450, 1278, 12
16

Example 78 4-[(3,4-dimethoxybenzamido) methyl]-
N- [2- (diethylamino) ethyl] -trans-cyclohexane-1-carboxamide

[0264]

[Chemical 90]

Process 4-[(3,4-trimethoxybenzamido) methyl]
-Trans-cyclohexane-1-carboxylic acid 1.00 g (3.
11 mmol) in 50 ml of chloroform, 0.36 g (3.10 mmol) of N, N-diethylethylenediamine, WSCI.HCl
0.78 g (4.07 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Recrystallized with chloroform: ether, colorless prism crystals 0.98g
(2.34 mmol) was obtained (yield 75%). Melting point: 169 ~ 171 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.95-1.16 (8H m), 1.38-1.72 (3H m), 1.765-2.14 (5H
m), 2.47-2.58 (6H m), 3.23-3.34 (4H m), 3.92 (3H s),
3.93 (3H s), 6.16-6.23 (2H br), 6.85 (1H d J = 8.6Hz),
7.24-7.28 (1H m), 7.43 (1H d J = 2.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3270, 2920, 1630, 1600, 1580, 1540, 1500, 1440, 13
06, 1264, 1224, 1200, 1176, 1126, 1018

Example 79 4-[(2,4-dimethoxybenzamido) methyl]-
N- [2- (diethylamino) ethyl] -trans-cyclohexane-1-carboxamide

[0267]

[Chemical Formula 91]

Process 4-[(2,4-trimethoxybenzamido) methyl]
-Trans-cyclohexane-1-carboxylic acid 1.50 g (4.
67 mmol) was dissolved in 70 ml of chloroform, 0.54 g (4.65 mmol) of N, N-diethylethylenediamine, WSCI · HCl 1.
16 g (6.05 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Chloroform: Recrystallized from n-hexane, colorless prism crystals 1.67
g (3.98 mmol) was obtained (yield 85%). Melting point: 117-120 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.83-1.34 (8H m), 1.36-1.81 (4H m), 1.82-2.14 (4H m),
2.15-2.41 (2H m), 2.44-2.59 (4H m), 3.21-3.38 (4H m),
3.85 (3H s), 3.94 (3H s), 6.09-6.24 (1H br), 6.49 (1H
d J = 2.6Hz), 6.60 (1H dd J = 2.0Hz, 8.6Hz), 7.73-7.88 (1H
br), 8.18 (1H d J = 9.2Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3270, 2900, 1620, 1530, 1492, 1440, 1302, 1270, 12
00, 1160, 1110, 1022

Example 80 N- [2- (diethylamino) ethyl] -4-[(3,
4,5-Trimethoxybenzamido) methyl] -trans
-Cyclohexane-1-carboxamide

[0270]

[Chemical Formula 92]

Process 4-[(3,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.50 g
(4.27 mmol) was dissolved in 70 ml of chloroform, 0.48 g (4.13 mmol) of N, N-diethylethylenediamine, WSCI · HC
1.18 g (6.16 mmol) and 1.0 ml of pyridine were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Recrystallization from chloroform: ether gave 1.52 g (3.38 mmol) of colorless prism crystals (yield 82%). Melting point: 181 to 182 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.95-1.18 (8H m), 1.35-2.15 (8H m), 2.44-2.64 (6H m),
3.20-3.40 (4H m), 3.88 (3H s), 3.91 (6H s), 6.12-6.31
(2H m), 7.00 (2H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3270, 2910, 1636, 1580, 1540, 1450, 1410, 1350, 13
36, 1232, 1124

Example 81 4-[(4-amino-5-chloro-2-methoxybenzamido) methyl] -N- [2- (diethylamino) ethyl] -trans-cyclohexane-1-carboxamide

[0273]

[Chemical formula 93]

Preparation Method 4-[(4-Amino-5-chloro-2-methoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.20 g (3.58 mmol) was dissolved in 50 ml of chloroform, and N, N-diethylethylenediamine was added. 0.42 g (3.58 mmol), triethylamine 1.0 ml (7.17 mmol), WSCI · HC
1.03 g (5.38 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Chloroform: Recrystallized from n-hexane to give colorless prism crystals 1.
21 g (2.76 mmol) was obtained (77% yield). Melting point: 144-146 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.95-1.13 (2H m), 1.00 (6H t J = 7.3Hz), 1.38-1.64 (3H
m), 1.86-2.10 (5H m), 2.47-2.55 (6H m), 3.30-3.32 (4H
m), 4.37 (3H s), 4.37 (2H s), 6.15 (1H br), 6.30 (1H
s), 7.72 (1H br), 8.11 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3300, 2940, 1624, 1598, 1474, 1460, 1322, 1234, 12
08

Example 82 N-[(2-Methylpiperidin-1-yl) propyl]
-4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxamide

[0276]

[Chemical 94]

Production method 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.44 g
(4.10 mmol) was dissolved in 50 ml of pyridine, 0.75 g (4.80 mmol) of N- (3-aminopropyl) -2-methylpiperidine and 2.50 g (13.04 mmol) of WSCI.HCl were added, and the mixture was stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, water was added to the residue,
It was extracted with chloroform. After dry filtration, the solvent was distilled off,
Recrystallization from ethanol: n-hexane gave 1.38 g (2.82 mmol) of light brown prism crystals (yield 69%). Melting point: 144-146 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.04-1.13 (5H m), 1.25 (1H m), 1.35-1.53 (5H m), 1.65
-1.76 (6H m), 1.86-2.02 (6H m), 2.37 (1H m), 2.93 (2H
m), 3.24 (1H m), 3.34 (2H t J = 6.3Hz), 3.42 (1H m), 3.9
0 (3H s), 3.94 (3H s), 3.96 (3H s), 6.53 (1H s), 7.37 (1
H br), 7.76 (1H s), 7.93 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3308, 3090, 2927, 2854, 2790, 1937, 1608, 1560, 15
19, 1462, 1404,1342, 1278, 1217, 1208, 1185, 1047,
1025 Mass spectrum FAB M / e 490, 474, 460, 391, 377, 361, 312

Example 83 2,4,5-Trimethoxy-N- [trans- [4- (4
-Methylpiperazine-1-carbonyl) cyclohexan-1-yl] methyl] benzamide

[0279]

[Chemical 95]

Production method 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.50 g
(4.27 mmol) was dissolved in 50 ml of chloroform, 0.43 g (4.29 mmol) of N-methylpiperazine and 0.98 g (5.1 of WSCI.HCl)
(1 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and recrystallized from chloroform: n-hexane to obtain 1.33 g (3.07 mmol) of colorless prism crystals (yield 72%). Melting point: 77-80 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.00-1.18 (2H m), 1.51-1.61 (3H m), 1.78-1.94 (5H m),
2.31 (3H s), 2.39-2.48 (4H m), 3.34 (2H dd J = 5.9Hz, 6.
6Hz), 3.47-3.52 (2H m), 3.58-3.85 (2H m), 3.90 (3H s),
3.94 (3H s), 3.96 (3H s), 6.53 (1H s), 7.76 (1H s), 7.
93 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3360, 2920, 1630, 1600, 1500, 1440, 1280, 1250, 12
05, 1170, 1136, 1020

Example 84 2,4,5-Trimethoxy-N- [trans- [4- (4
-Phenylpiperazine-1-carbonyl) cyclohexane-1-yl] methyl] benzamide

[0282]

[Chemical 96]

Manufacturing method 1.50 g (4.01 mmol) of N- [trans- [4- (4-phenylpiperazine) carbonyl] cyclohexane was dissolved in 50 ml of methylene chloride to prepare 2,4,5-trimethoxybenzoic acid.
0.85 g (4.01 mmol), triethylamine 3.0 ml (21.52 mmol) and WSCI.HCl 1.15 g (6.00 mmol) were added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was washed with water and 5% aqueous sodium hydrogen carbonate, dried and filtered, and the solvent was evaporated. It was purified by silica gel column chromatography (100 g, ethyl acetate: n-hexane = 2: 1) and recrystallized from ethanol: n-hexane to obtain 0.37 g (7.47 mmol) of colorless needle crystals (yield 19
%). Melting point: 156.6-157.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.07-1.13 (2H m), 1.55-1.68 (3H m), 1.80-1.97 (4H m),
2.49 (1H m), 3.17 (4H m), 3.35 (2H dd J = 5.9Hz, 6.6Hz),
3.66 (2H m), 3.78 (2H m), 3.90 (3H s), 3.93 (3H s), 3.
96 (3H s), 6.53 (1H s), 6.91-6.94 (3H m), 7.26-7.31 (2H
m), 7.76 (1H s), 7.93 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3588, 3476, 3384, 2917, 2848, 2812, 1634, 1599, 15
40, 1509, 1441, 1276, 1255 1228 1216 1013 Mass spectrum FAB M / e 496, 270

Example 85 4-amino-5-chloro-2-methoxy-N- [trans
-[4- (4-phenylpiperazine-1-carbonyl)
Cyclohexan-1-yl] methyl] benzamide

[0285]

[Chemical 97]

Production method 2.51 g (6.70 mmol) of N- [trans- [4- (4-phenylpiperazine) carbonyl] cyclohexane was added to pyridine.
200 ml, dissolved in 2 ml of water, 4-amino-5-chloro-2
-Methoxybenzoic acid 1.30 g (6.45 mmol), WSCI.HCl 1.
60 g (8.35 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. Ethanol: recrystallized from n-hexane, colorless needle crystals 0.52
g (1.07 mmol) was obtained (17% yield). Melting point: 204.9-205.3 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.01-1.16 (2H m), 1.54-1.68 (3H m), 1.80-1.93 (4H m),
2.43-2.54 (1H m), 3.16 (4H m), 3.32 (2H dd J = 5.9Hz, 6.
6Hz), 3.65 (2H m), 3.71 (2H m), 3.91 (3H s), 4.38 (2H
s), 6.30 (1H s), 6.88-6.94 (3H m), 7.26-7.31 (2H m),
7.70 (1H br), 8.12 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3472, 3410, 3310, 3202, 2928, 2848, 1635, 1595, 15
40, 1500, 1447, 1416, 1311, 1263, 1249, 1231, 1211,
1176, 1151, 992 Mass spectrum FAB M / e 485, 277

Example 86 2,4,5-Trimethoxy-N- [trans- [4- [4
-(2-Pyridyl) piperazine-1-carbonyl) cyclohexan-1-yl] methyl] benzamide

[0288]

[Chemical 98]

Preparation method 2,4,5-Trimethoxybenzoic acid 0.90 g (4.24 mmol) and triethylamine 0.62 ml (4.45 mmol) were dissolved in tetrahydrofuran 100 ml, and isobutyl chlorocarbonate 0.56 ml (4.32 mmol) was slowly added under ice cooling. Further, under ice cooling, 1- [4- (aminomethyl) cyclohexanecarbonyl] -4- (2-pyridyl) piperazine trihydrochloride 1.66
A suspension of g (4.03 mmol) in 100 ml of methylene chloride and 1.8 ml of triethylamine was added dropwise. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. After drying and filtering, the solvent was distilled off and the residue was recrystallized from ethanol: n-hexane to obtain 1.64 g (3.30 mmol) of colorless needle crystals (yield 82%). Melting point: 205.2 to 205.9 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.08-1.14 (2H m), 1.59-1.69 (3H M), 1.81-1.96 (4H m),
2.50 (1H m), 3.36 (2H dd J = 6.6Hz, 5.9Hz), 3.48 (2H m),
3.61 (4H m), 3.75 (2H m), 3.91 (3H s), 3.94 (3H s), 3.
96 (3H s), 6.53 (1H s), 6.64 (1H dd J = 2.0Hz, 9.2Hz), 6.
67 (1H dd J = 5.3Hz, 7.3Hz), 7.51 (1H dd J = 2.0Hz, 7.3Hz,
9.2Hz), 7.77 (1H s), 7.93 (1H s), 8.21 (1H d J = 5.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3384, 2926, 2844, 1635, 1603, 1515, 1482, 1458, 14
34, 1282, 1264,1243, 1217, 1208, 1030 Mass spectrum FAB M / e 497, 403, 380, 306, 277

Example 87 2,4,5-Trimethoxy-N- [trans- [4- [4
-(2-Pyrimidinyl) piperazine-1-carbonyl]
Cyclohexan-1-yl] methyl] benzamide

[0291]

[Chemical 99]

Preparation 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.00 g
(2.85 mmol) was dissolved in 50 ml of methylene chloride, 0.70 g (4.26 mmol) of N-pyrimidinylpiperazine, 2.0 ml (14.35 mmol) of triethylamine and 1.50 g (7.82 mmol) of WSCI.HCl were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Recrystallization from ethanol: n-hexane gave colorless needle crystals 0.52 g (1.05 mmol) (yield 37%). Melting point: 176.2 to 177.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.08-1.22 (2H m), 1.52-1.65 (3H m), 1.80-1.97 (4H m),
2.45-2.59 (1H m), 3.36 (2H dd J = 5.9Hz, 6.6Hz), 3.56-
3.59 (2H m), 3.68-3.71 (2H m), 3.80-3.87 (4H m), 3.91
(3H s), 3.94 (3H s), 3.97 (3H s), 6.53 (1H s), 6.54 (1H
t J = 4.6Hz), 7.77 (1H s), 7.92 (1H br), 8.33 (2H d J =
4.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3358, 2922, 2858, 1638, 1607, 1589, 1563, 1542, 15
20, 1451, 1278, 1265, 1217, 1025 Mass spectrum FAB M / e 498

Example 88 N- [3- (1-Azabicyclo [3.3.0] octa-
5-yl) propyl] -4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxamide

[0294]

[Chemical 100]

Production method 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 0.35 g
(1.00 mmol) was dissolved in 20 ml of methylene chloride, and 5- (3-
Aminopropyl) -1-azabicyclo [3.3.0] octane 0.16 g (1.04 mmol), triethylamine 0.5 ml (3.
59 mmol) and WSCI.HCl 0.40 g (2.07 mmol) were added, and the mixture was stirred at room temperature for 2 days. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Silica gel column chromatography (100
g, chloroform: methanol: triethylamine = 1
(5: 1: 0.1 → 10: 1: 0.1), colorless needle crystals 0.1
1 g (0.23 mmol) was obtained (23% yield). Melting point: 117.8 to 118.9 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.05-1.13 (2H m), 1.34-1.48 (3H m), 1.63-2.04 (15H
m), 2.79-2.67 (2H m), 3.00-3.06 (2H m), 3.30-3.38 (4H
m), 3.90 (3H s), 3.94 (3H s), 3.96 (3H s), 6.53 (1H s),
7.76 (1H s), 7.95 (1H br), 8.32 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3382, 3346, 2926, 2853, 1643, 1608, 1540, 1516, 14
58, 1268, 1218, 1208, 1026 Mass spectrum FAB M / e 488, 458, 263

Example 89 N- [2- (3-azabicyclo [3.2.2] nona-3
-Yl) ethyl] -4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1
-Carboxamide

[0297]

[Chemical 101]

Production method 4-[(2,4,5-trimethoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.50 g
(4.27 mmol) was dissolved in 50 ml of methylene chloride, and 3- (2-
Aminoethyl) -3-azabicyclo [3.2.2] nonane dihydrochloride 1.00 g (4.15 mmol), triethylamine 1.50
ml (10.76 mmol), WSCI.HCl 1.50 g (7.82 mmol) were added,
Stir at room temperature for 4 days. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Recrystallization from ethanol: n-hexane gave 1.34 g (2.67 mmol) of colorless needle crystals (yield.
64%). Melting point: 161.1-162.6 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.03-1.17 (2H m), 1.39-1.76 (11H m), 1.90-2.08 (7H
m), 2.50 (2H t J = 5.9Hz), 2.54 (2H d J = 4.6Hz), 3.27-3.
37 (4H m), 3.90 (3H s), 3.94 (3H s), 3.96 (3H s), 6.30
(1H br), 6.52 (1H s), 7.76 (1H s), 7.95 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3404, 3266, 2928, 2858, 1651, 1642 , 1607, 1553, 15
19, 1464, 1456, 1438, 1280, 1266, 1219, 1181, 1025 Mass spectrum FAB M / e 502

Example 90 4-[(4-amino-5-chloro-2-methoxybenzamido) methyl] -N- [2- (3-azabicyclo [3.2.2] non-3-yl) ethyl] -Trans-cyclohexane-1-carboxamide

[0300]

[Chemical 102]

Production method 4-[(4-amino-5-chloro-2-methoxybenzamido) methyl] -trans-cyclohexane-1-carboxylic acid 1.82 g (5.34 mmol) was dissolved in pyridine 80 ml and methylene chloride 20 ml to give 3- (2-Aminoethyl) -3-azabicyclo [3.2.2] nonane dihydrochloride 1.30 g (5.39 mmol) and WSCI.HCl 2.00 g (10.43 mmol) were added, and 2 was added at room temperature.
It was stirred for a day. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. After drying and filtering, the solvent was distilled off and recrystallized from ethanol: n-hexane to give colorless needle crystals 1.40.
g (2.85 mmol) was obtained (yield 53%). Melting point: 190.0-192.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.04-1.13 (2H m), 1.42-1.74 (11H m), 1.87-2.07 (7H
m), 2.51-2.58 (6H m), 3.31-3.50 (4H m), 3.91 (3H s),
4.36 (3H s), 6.30 (1H s), 6.31 (1H br), 7.72 (1H br),
8.12 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3410, 3322, 2926, 1638, 1597, 1542, 1503, 1451, 13
14, 1250, 1205

Example 91 N-Benzyl-4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0303]

[Chemical 103]

Process 4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.00 g (2.
(85 mmol) was dissolved in 50 ml of methylene chloride, 2.0 ml (14.35 mmol) of triethylamine, 0.40 g (3.73 mmol) of benzylamine and 1.20 g (6.26 mmol) of WSCI.HCl were added, and the mixture was stirred overnight at room temperature. The reaction mixture was washed with water and 5% aqueous sodium hydrogen carbonate, dried and filtered, and the solvent was evaporated. Ethanol: n-
Recrystallization from hexane gave 0.30 g (0.68 mmol) of colorless needle crystals (yield 24%). Melting point: 188.0-190.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.03-1.17 (2H m), 1.50-1.57 (3H m), 1.89-2.08 (5H m),
3.33 (2H dd J = 5.9Hz, 6.6Hz), 3.90 (3H s), 3.93 (3H
s), 3.95 (3H s), 4.44 (1H d J = 5.3Hz), 5.71 (1H br),
6.52 (1H s), 7.25-7.34 (5H m), 7.75 (1H s), 7.92 (1H b
r) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3306, 2928, 2848, 1638, 1608, 1552, 1522, 1464, 14
57, 1433, 1283, 1218, 1030

Example 92 N-Benzyl-4- (pyridine-2-carboxamidomethyl) -trans-cyclohexane-1-carboxamide

[0306]

[Chemical 104]

Production method 1.75 g (6.19 mmol) of N-benzyl-4- (aminomethyl) -trans-cyclohexane-1-carboxylic acid was dissolved in 50 ml of pyridine, and 0.80 g (6.50 mmol) of picolinic acid was added to WSCI.
-HCl 1.60g (8.35 mmol) was added, and it stirred at room temperature all day and night. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off, and ethanol: n
-Recrystallized from hexane to give pale brown needle crystals 0.75 g (2.13
Mmol) was obtained (yield 34%). Melting point: 163-164 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.06-1.14 (2H m), 1.47-1.57 (3H m), 1.95-2.09 (5H m),
3.34 (2H t J = 6.6Hz), 4.44 (2H d J = 5.9Hz), 5.69 (1H
br), 7.29-7.44 (6H m), 7.84 (1H dd J = 7.9Hz, 5.9Hz),
8.12 (1H br), 8.19 (1H d = 7.9Hz), 8.55 (1H d = 3.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3297, 2920, 2848, 1672, 1658, 1640, 1537

Example 93 N-benzyl-4- (pyridine-4-carboxamidomethyl) -trans-cyclohexane-1-carboxamide

[0309]

[Chemical 105]

Production method 1.44 g (5.09 mmol) of N-benzyl-4- (aminomethyl) -trans-cyclohexane-1-carboxylic acid was dissolved in 100 ml of pyridine, and 0.65 g (5.28 mmol) of isonicotinic acid and 1.10 g of WSCI.HCl. (5.74 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and recrystallized from ethanol: n-hexane to give 0.85 g of colorless needle crystals.
(2.33 mmol) was obtained (yield 46%). Melting point: 222-224 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.05-1.13 (2H m), 1.48-1.63 (3H m), 1.89-2.09 (5H m),
3.35 (2H t J = 6.6Hz), 4.44 (2H d J = 5.9Hz), 5.70 (1H
br), 6.21 (1H br), 7.22-7.36 (5H m), 7.58 (2H dd J ＝
5.9Hz), 8.75 (2H d J = 5.9Hz) Infrared absorption spectrum (cm ^-1 ) (Measuring method KBr-tab.) 3311, 3273, 2933, 1644, 1552

Example 94 N- (3-methylthiopropyl) -4- (2,4,5-
Trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0312]

[Chemical formula 106]

Production method 4- (aminomethyl) -N- (3-methylthiopropyl) -trans-cyclohexane-1-carboxamide hydrochloride 1.13 g (4.03 mmol) was dissolved in pyridine 50 ml, methylene chloride 5 ml, water 1 ml to give 2, 0.95 g (4.24 mmol) of 4,5-trimethoxybenzoic acid and 2.0 g (10.43 mmol) of WSCI.HCl were added, and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After dry filtration
The solvent was distilled off and recrystallized from ethanol: n-hexane,
0.59 g (1.35 mmol) of colorless prism crystals were obtained (yield 33
%). Melting point: 164 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.14 (2H m), 1.40-1.60 (3H m), 1.76-2.08 (7H m),
2.10 (3H s), 2.53 (2H t J = 7.3Hz), 3.33-3.41 (4H m),
3.90 (3H s), 3.94 (3H s), 3.96 (3H s), 5.71 (1H br), 6.
53 (1H s), 7.76 (1H s), 7.94 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3307, 3270, 2927, 2854, 1636, 1607, 1568, 1520, 14
62, 1438, 1277, 1217, 1208, 1025 Mass spectrum FAB M / e 439, 306, 277

Example 95 N- (3-methylthiopropyl) -4- (pyridine-2)
-Carboxamidomethyl) -trans-cyclohexane-
1-carboxamide

[0315]

[Chemical formula 107]

Preparation Method 4- (Aminomethyl) -N- (3-methylthiopropyl) -trans-cyclohexane-1-carboxamide hydrochloride 1.72 g (6.13 mmol) was dissolved in pyridine 50 ml and water 1 ml to give picolinic acid 0.80 g (6.50). Mmol), WSCI · HCl 2.50 g
(13.04 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and the residue was recrystallized from ethanol: n-hexane to obtain 0.50 g (1.43 mmol) of colorless needle crystals (yield).
twenty three%). Melting point: 150-151 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.01-1.14 (2H m), 1.42-2.04 (10H m), 2.10 (3H s), 2.5
3 (2H t J = 7.3Hz), 3.32-3.39 (4H m), 5.67 (1H br), 7.42
(1H ddd J = 1.3Hz, 5.3Hz, 7.9Hz), 7.85 (1H dt J = 1.3Hz, 7.
9Hz), 8.13 (1H br), 8.20 (1H d J = 7.9Hz), 8.55 (1H d J =
5.3Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3287, 2923, 1652, 1537, 1428, 1364, 1205

Example 96 N- (3-methylthiopropyl) -4- (pyridine-4)
-Carboxamidomethyl) -trans-cyclohexane-
1-carboxamide

[0318]

[Chemical 108]

Preparation Method 4- (Aminomethyl) -N- (3-methylthiopropyl) -trans-cyclohexane-1-carboxamide hydrochloride (2.21 g, 7.88 mmol) was dissolved in pyridine (50 ml, water 1 ml) to give isonicotinic acid (1.00 g). 8.12 mmol), WSCI.HCl 1.
90 g (9.96 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off, and the residue was recrystallized from ethanol: n-hexane to obtain 0.77 g (2.20 mmol) of colorless needle crystals (yield 28%). Melting point: 176 to 177 ℃ H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.00-1.13 (2H m), 1.48-2.04 (10H m), 2.10 (3H s), 2.5
2 (2H t J = 7.3Hz), 3.32-3.39 (4H m), 5.74 (1H br), 6.37
(1H br), 7.61 (2H d J = 5.9Hz), 8.74 (2H d J = 5.9Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3306, 2926, 1640, 1556

Example 97 N- (2-Cyanoethyl) -4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0321]

[Chemical 109]

Process 4- (aminomethyl) -N- (2-cyanoethyl) -tr
ans-cyclohexane-1-carboxamide hydrochloride 1.41
g (5.74 mmol) was dissolved in 50 ml of pyridine and 1 ml of water,
4,5-trimethoxybenzoic acid 1.22 g (5.75 mmol), WS
CI-HCl (2.00 g, 10.43 mmol) was added, and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off, and ethanol: n
Recrystallization from -hexane gave 1.56 g (3.87 mmol) of colorless needle crystals (yield 67%). Melting point: 145 to 147 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.99-1.13 (2H m), 1.42-1.65 (3H m), 1.87-2.09 (5H m),
2.64 (2H t J = 5.9Hz), 3.34 (2H t J = 5.9Hz), 3.50 (2H q
J = 5.9Hz), 3.91 (3H s), 3.94 (3H s), 3.96 (3H s), 5.93
(1H br), 6.53 (1H s), 7.76 (1H s), 7.94 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3308, 2932, 2854, 1626, 1608, 1568 , 1520, 1463, 14
39, 1278, 1214, 1025

Example 98 N- (2-Cyanoethyl) -4- (pyridine-2-carboxamidomethyl) -trans-cyclohexane-1-carboxamide

[0324]

[Chemical 110]

Process 4- (aminomethyl) -N- (2-cyanoethyl) -tr
ans-cyclohexane-1-carboxamide hydrochloride 1.19
g (5.05 mmol) was dissolved in 50 ml of pyridine, and picolinic acid was added.
70 g (5.69 mmol) and WSCI.HCl 2.80 g (14.61 mmol) were added, and the mixture was stirred at room temperature for 6 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and the residue was recrystallized from ethanol: n-hexane to obtain 0.58 g (1.84 mmol) of brown needle crystals (yield 39%). Melting point: 161-163 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.06-1.10 (2H m), 1.43-1.51 (3H m), 1.93-2.10 (5H m),
2.63 (2H t J = 6.6Hz), 3.36 (2H t J = 6.6Hz), 3.50 (2H q
J = 6.6Hz), 5.98 (1H br), 7.43 (1H ddd J = 1.3Hz, 4.0Hz, 7.
9Hz), 7.84 (1H dt J = 1.3Hz, 7.9Hz), 8.16 (1H br), 8.20
(1H d J = 7.9Hz), 8.55 (1H d J = 4.0Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3330, 2937, 2853, 1648, 1536, 1444, 1372, 1203

Example 99 N- (3-Ethoxypropyl) -4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0327]

[Chemical 111]

Process 4- (aminomethyl) -N- (3-ethoxypropyl)
-Trans-cyclohexane-1-carboxamide hydrochloride
1.01 g (3.62 mmol) was dissolved in 50 ml of pyridine,
5-Trimethoxybenzoic acid 0.80 g (3.77 mmol), WSCI
1.50 g (7.82 mmol) of HCl was added, and the mixture was stirred at room temperature for 3 days.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. After drying and filtering, the solvent was distilled off, and the residue was recrystallized from ethanol: n-hexane to obtain 1.14 g (2.61 mmol) of brown needle crystals (yield 72%). Melting point: 158.4-159.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.00-1.13 (2H m), 1.18-1.24 (3H m), 1.38-1.54 (3H m),
1.72-1.81 (2H quint. J = 5.9Hz), 1.89-2.06 (5H m), 3.3
3 (2H t J = 5.9Hz), 3.36 (2H q J = 5.9Hz), 3.44-3.55 (4H
m), 3.90 (3H s), 3.94 (3H s), 3.96 (3H s), 6.20 (1H b
r), 6.53 (1H s), 7.76 (1H s), 7.93 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3284, 2931, 2862, 1636, 1606, 1560, 1519 , 1463, 12
80, 1218, 1116 Mass spectrum FAB M / e 437, 423, 391, 306

Example 100 N- [2- (4-hydroxyphenyl) ethyl] -4-
(2,4,5-trimethoxybenzamidomethyl) -tr
ans-cyclohexane-1-carboxamide

[0330]

[Chemical 112]

Preparation Method 4- (Aminomethyl) -N- [2- (4-hydroxyphenyl) ethyl] -trans-cyclohexane-1-carboxamide hydrochloride 0.50 g (1.60 mmol) was added to pyridine 50 ml.
Dissolve it in 1 ml of water and add 2,4,5-trimethoxybenzoic acid.
35 g (1.65 mmol) and WSCI.HCl 1.00 g (5.22 mmol) were added, and the mixture was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and recrystallization from ethanol: n-hexane was performed to obtain 0.44 g (0.94 mmol) of colorless needle crystals (yield 59%). Melting point: 221.3-224.1 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.93-1.09 (2H m), 1.24-1.46 (3H m), 1.68-1.77 (4H m),
2.01 (1H m), 2.57 (2H d J = 6.6Hz), 3.16 (4H m), 3.73 (3
H s), 3.86 (3H s), 3.93 (3H s), 6.66 (2H d J = 7.9Hz),
6.75 (1H s), 6.96 (2H d J = 7.9Hz), 7.43 (1H s), 7.68 (1H
t J = 5.3Hz), 8.04 (1H td J = 5.3Hz, 5.9Hz), 9.11 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3468, 3322, 2929, 2852, 1639, 1610, 1552, 1516, 14
67, 1439, 1404, 1283, 1210, 1182, 1193, 1031 Mass spectrum FAB M / e 471, 457, 369, 351, 334, 306, 277

Example 101 N- [2- (4-hydroxyphenyl) ethyl] -4-
(Pyridine-4-carboxamide methyl) -trans-cyclohexane-1-carboxamide

[0333]

[Chemical 113]

Production method 4- (aminomethyl) -N- [2- (4-hydroxyphenyl) ethyl] -trans-cyclohexane-1-carboxamide hydrochloride 1.10 g (3.52 mmol) was added to pyridine 100 m.
1, dissolved in 1 ml of water, 1.00 g (8.12 mmol) of isonicotinic acid and 4.00 g (20.87 mmol) of WSCI.HCl were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. After drying and filtering, the solvent was distilled off and recrystallized from ethanol: n-hexane to give colorless needle crystals 0.55 g.
(1.44 mmol) was obtained (41% yield). Melting point: 271.7 to 272.0 ℃ H-nuclear magnetic resonance (δ) (solvent DMSO) 0.86-1.09 (2H m), 1.25-1.38 (2H m), 1.52 (1H m), 1.69
-1.80 (4H m), 1.98-2.06 (1H m), 2.58 (2H d J = 7.3Hz),
3.11-3.29 (4H m), 6.65 (2H d J = 7.9Hz), 6.95 (2H d J = 7.
9Hz), 7.67 (1H br), 7.74 (2H d J = 5.9Hz), 8.69 (2H d J =
5.9Hz), 8.70 (1H br), 9.08 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3309, 2932, 1643, 1556, 1515, 1451, 1234 Mass spectrum FAB M / e 382, 369, 277

Example 102 N-piperonyl-4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0336]

[Chemical 114]

Preparation Method 4- (Aminomethyl) -N-piperonyl-trans-cyclohexane-1-carboxamide hydrochloride 1.30 g (3.98 mmol) was dissolved in 100 ml of pyridine and 1.0 ml of water to prepare 2,4,5
-Trimethoxybenzoic acid 0.80 g (3.77 mmol), WSCI ・ HC
1.20 g (6.26 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with chloroform: ethanol = 10: 2, dried and filtered, and the solvent was evaporated.
Ethanol: recrystallized from n-hexane, colorless needle crystals
1.47 g (3.03 mmol) was obtained (yield 76%). Melting point: 224.6-226.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.96-1.16 (2H m), 1.44-1.58 (3H m), 1.88-2.12 (5H m),
3.33 (2H t J = 6.6Hz), 3.90 (3H s), 3.94 (3H s), 3.95 (3
H s), 4.33 (2H d J = 5.3Hz), 5.66 (1H br), 5.94 (2H s),
6.53 (1H s), 6.73-6.75 (3H m), 7.75 (1H s), 7.92 (1H b
r) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3307, 2930, 1640, 1608, 1548, 1520, 1491, 1468, 14
45, 1283, 1253, 1215, 1030 Mass spectrum FAB M / e 485, 461, 437, 369, 277

Example 103 N-piperonyl-4- (pyridine-4-carboxamidomethyl) -trans-cyclohexane-1-carboxamide

[0339]

[Chemical 115]

Preparation Method 4- (Aminomethyl) -N-piperonyl-trans-cyclohexane-1-carboxamide hydrochloride 1.50 g (4.59 mmol) was dissolved in pyridine 100 ml and water 1.0 ml to give isonicotinic acid 0.60 g (4.87 mmol), WSCI / HCl 1.50 g (7.82 mmol)
Was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform: ethanol = 10: 1, dried and filtered, the solvent was distilled off, and recrystallized from ethanol: n-hexane to give 1.46 g of colorless needle crystals ( 3.69 mmol)
Was obtained (yield 80%). Melting point: 221.2-221.3 ° C H-nuclear magnetic resonance (δ) (solvent DMSO) 0.93-0.98 (2H m), 1.34-1.56 (3H m), 1.76-1.83 (4H m),
2.11 (1H m), 3.14 (2H t J = 5.9Hz), 4.15 (2H d J = 5.9H
z), 5.95 (2H s), 6.68 (1H d J = 7.9Hz), 6.75 (1H s), 6.8
9 (1H d J = 7.9Hz), 7.74 (2H d J = 7.9Hz), 8.11 (1H br),
8.67 (1H br) 8.69 (2H d J = 7.9Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3299, 2933, 1641, 1548, 1504, 1491, 1247, 1042 Mass spectrum FAB M / e 396, 277

Example 104 N- [4- (2S-carbamoyl-1-pyrrolidinylcarbonyl) -trans-1-cyclohexyl] methyl-
2,4,5-trimethoxybenzamide

[0342]

[Chemical formula 116]

Process 4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.67 g (4.
75 mmol) was dissolved in 80 ml of pyridine, and L-prolinamide was dissolved.
0.55 g (4.82 mmol) and WSCI.HCl 1.90 g (9.91 mmol) were added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with chloroform, dried and filtered, and the solvent was evaporated. Recrystallization from methanol: ether gave 1.50 g (3.35 mmol) of colorless prism crystals (yield 71%). Melting point: 85-90 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.06-1.18 (3H m), 1.53-2.43 (11H m), 3.35 (2H t J = 6.6
Hz), 3.47-3.60 (2H m), 3.90 (3H s), 3.94 (3H s), 3.96
(3H s), 4.61 (1H d J = 7.9Hz), 5.26 (1H br), 6.53 (1H
s), 7.02 (1H br), 7.94 (1H br), 7.95 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3402, 2934, 2856, 1693, 1639, 1607, 1543 , 1512, 14
39, 1401, 1353, 1264, 1217, 1180, 1025 Mass spectrum FAB M / e 448, 436, 334, 306, 253, 225, 211

Example 105 N ^alpha -[[4- (2S-carbamoyl-1-pyrrolidinylcarbonyl) -trans-1-cyclohexyl] methyl] pyridine-4-carboxamide p-toluenesulfonate

[0345]

[Chemical 117]

Process 1- (aminomethyl) -4- (2S-carbamoyl-1)
-Pyrrolidinyl) -trans-cyclohexane hydrochloride 1.03
g (3.35 mmol) was dissolved in 100 ml of pyridine and 1.0 ml of water,
Isonicotinic acid 0.50 g (4.06 mmol), WSCI · HCl 1.20 g
(6.26 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue and extracted with methylene chloride,
After drying and filtering, the solvent was distilled off. Silica gel column chromatography (200g, ethyl acetate: methanol = 10:
Purified in 1), 0.38 g (1.06 mmol) of a colorless liquid was obtained, which was dissolved in 50 ml of methanol and p-toluenesulfonic acid was added to
197 g (1.06 mmol) was added, and the mixture was stirred for 10 minutes, concentrated under reduced pressure, and recrystallized from ethanol: ether to give colorless needle crystals.
0.42 g (0.79 mmol) was obtained (24% yield). Melting point: 159.6-160.6 ℃ H-nuclear magnetic resonance (δ) (solvent DMSO) 1.00-1.70 (5H m), 1.71-1.94 (7H m), 2.20-2.28 (1H m),
2.29 (3H s), 2.40-2.45 (1H m), 3.14-3.18 (2H m), 3.55
-3.60 (2H m), 4.02-4.26 (5H m), 7.11 (2H d J = 7.9Hz),
7.49 (2H d J = 7.9Hz), 7.93 (2H d J = 5.9Hz), 8.82 (2H d J
= 5.9Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3292, 2928, 2590, 1736, 1676, 1634, 1552, 1504, 14
34, 1308, 1234, 1205, 1180, 1166, 1146, 1122, 1029,
1004, 850, 820, 686

Example 106 N- [2- (1-pyrrolidinylcarbonyl) ethyl]-
4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxamide

[0348]

[Chemical 118]

Preparation method 0.90 g (2.13 mmol) of 3- [4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamido] propionic acid was dissolved in 50 ml of pyridine to give 0.16 g (2.25 mmol of pyrrolidine). ), WSCI ・ HCl 0.
53 g (2.76 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and the residue was recrystallized from chloroform: ether to give 0.88 g (1.85 mmol) of colorless prism crystals (yield 87%). Melting point: 138 to 140 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.95-1.16 (2H m), 1.37-1.72 (3H m), 1.78-2.11 (9H m),
2.39-2.52 (2H m), 3.24-3.63 (8H m), 3.90 (3H s), 3.94
(3H s), 3.96 (3H s), 6.53 (1H s), 6.58-6.69 (1H br),
7.75 (1H s), 7.89-7.99 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3316, 2930, 1637, 1608, 1561, 1519, 1218

Example 107 N- [2-[[2S- (hydroxymethyl) -1-pyrrolidinyl] carbonyl] ethyl] -4- (2,4,5-
Trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0351]

[Chemical formula 119]

Preparation method 3- [4- (2,4,5-Trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamido] propionic acid 0.90 g (2.13 mmol) was dissolved in pyridine 50 ml, and 2S-hydroxypyrrolidine 0.24 g. (2.37 mmol) and WSCI.HCl 0.53 g (2.76 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and the residue was recrystallized from chloroform: ether to give colorless prism crystals (0.78 g).
(1.54 mmol) was obtained (yield 72%). Melting point: 156-159 ° C. H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.14 (2H m), 1.38-1.78 (3H m), 1.79-2.14 (9H m),
2.46-2.58 (2H m), 3.27-3.38 (2H m), 3.38-3.62 (5H m),
3.63-3.76 (1H m), 3.90 (3H s), 3.94 (3H s), 3.96 (3H
s), 4.16-4.28 (1H m), 4.88 (1H br), 6.38-6.48 (1H br),
6.53 (1H s), 7.75 (1H s), 7.88-7.95 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3455, 3334, 3294, 2932, 1639, 1610, 1544, 1519, 14
56, 1220, 1208

Example 108 N- [2-[(2S-carbamoyl-1-pyrrolidinyl] carbonyl] ethyl] -4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0354]

[Chemical 120]

Preparation method 3- [4- (2,4,5-Trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamido] propionic acid 0.90 g (2.13 mmol) was dissolved in pyridine 50 ml to give L-prolinamide 0.27 g. (2.37 mmol), WSCI
-HCl (0.53 g, 2.76 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off and the residue was recrystallized from chloroform: ether to give 0.52 g (1.00 mmol) of colorless prism crystals (yield 47%). Melting point: 236 to 240 ° C. H-nuclear magnetic resonance (δ) (solvent CD ₃ OD) 0.99-1.21 (2H m), 1.39-1.71 (3H m), 1.81-2.24 (9H m),
2.50-2.64 (2H m), 3.38-3.70 (6H m), 3.83 (3H s), 3.93
(3H s), 3.99 (3H s), 4.36-4.44 (1H m), 6.73 (1H s), 7.
56 (1H s) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3407, 3312, 3216, 2933, 2847, 1671, 1655, 1637, 16
09, 1549, 1519, 1437, 1280, 1217, 1206, 1038

Example 109 3- [4- (pyridine-2-carboxamidomethyl)-
trans-cyclohexane-1-carboxamido] propyl = (4-phenylpiperazin-1-yl) glyoxylate

[0357]

[Chemical 121]

Preparation Method 0.47 g (1.09 mmol) of 3- [4- (aminomethyl) -trans-cyclohexane-1-carboxamido] propyl = (4-phenylpiperazin-1-yl) glyoxylate was added to 20 ml of methylene chloride and 10 ml of pyridine. 0.20 g (1.62 mmol) of picolinic acid and 0.50 g (2.61 mmol) of WSCI.HCl were added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying and filtering, the solvent was distilled off, and silica gel column chromatography (200
g, ethyl acetate: n-hexane = 2: 1) to obtain 0.36 g (0.67 mmol) of colorless candy liquid (yield 62%). H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.02-1.15 (2H m), 1.38-1.53 (3H m), 1.62-2.04 (10H
m), 2.29 (1H tt J = 3.3Hz, 12.5Hz), 2.79 (2H dd J = 11.2H
z, 11.9Hz), 3.14 (1H dt J = 2.6Hz, 12.5Hz), 3.37 (4H quin
t. J = 6.6Hz), 4.15 (2H t J = 5.9Hz), 4.69 (1H br.d 1H J =
13.9Hz), 5.13 (1H br.d J = 13.2Hz), 7.19-7.45 (7H m),
7.85 (1H dt J = 1.3Hz, 7.9Hz), 8.14 (1H br), 8.20 (1H d J
= 7.9Hz), 8.54 (1H d J = 4.6Hz) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3399, 3026, 3008, 2939, 2864, 1725, 1674, 1633, 15
30, 1466, 1452, 1266, 1237, 1202, 1177

Example 110 N-Methyl-4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0360]

[Chemical formula 122]

Process 4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.00 g (2.
85 mmol) was dissolved in 50 ml of methylene chloride, and 0.50 g (7.41 mmol) of methylamine hydrochloride and 1.0 ml (7.
17 mmol) and WSCI.HCl (1.00 g, 5.22 mmol) were added, and the mixture was stirred at room temperature for 4 days. The reaction solution was washed with water, dried and filtered, and then the solvent was distilled off. Ethanol: recrystallized from n-hexane,
0.36 g (0.99 mmol) of colorless needle crystals were obtained (yield 35%). Melting point: 193.1-195.2 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 1.03-1.08 (2H m), 1.46-1.60 (3H m), 1.89-2.04 (5H m),
2.80 (3H d J = 4.6Hz), 3.33 (2H dd J = 5.9Hz, 6.6Hz), 3.9
0 (3H s), 3.94 (3H s), 3.96 (3H s), 5.44 (1H br), 6.53
(1H s), 7.76 (1H br), 7.93 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3312, 3263, 2931, 1636, 1570, 1519, 1218, 1025 Mass spectrometry Spectrum FAB M / e 462, 306, 284

Example 111 N-Ethyl-4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0363]

[Chemical 123]

Process 4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.30 g (3.
70 mmol) in 50 ml of methylene chloride, 0.50 g of ethylamine hydrochloride (6.13 mmol) and 0.9 ml of triethylamine (6.
46 mmol) and WSCI.HCl (1.20 g, 6.13 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water and 5% aqueous sodium hydrogen carbonate, dried and filtered, and the solvent was evaporated. ethanol:
Recrystallization from ether gave colorless needle crystals 0.43 g (1.14 mmol) (yield 31%). Melting point: 198.4-198.6 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.98-1.09 (5H m), 1.43-1.61 (3H m), 1.89-2.03 (5H m),
3.23-3.36 (4H m), 3.90 (3H s), 3.94 (3H s), 3.96 (3H
s), 5.39 (1H br), 6.53 (1H s), 7.75 (1H s), 7.93 (1H b
r) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3364, 3316, 1643, 1608, 1539, 1512, 1212 Mass spectrum FAB M / e 379, 306

Example 112 N- (carbamoylmethyl) -4- (2,4,5-trimethoxybenzamidomethyl) -trans-cyclohexane-1-carboxamide

[0366]

[Chemical formula 124]

Process 4- (2,4,5-trimethoxybenzamidomethyl)
-Trans-cyclohexane-1-carboxylic acid 1.00 g (2.
(85 mmol) dissolved in 50 ml of methylene chloride, glycinamide hydrochloride 0.35 g (3.17 mmol), triethylamine 0.8 ml
(5.74 mmol) and WSCI.HCl (1.00 g, 5.22 mmol) were added, and the mixture was stirred at room temperature for 4 days. The reaction solution is washed with water, dried and filtered,
The solvent was distilled off. Recrystallization from ethanol: n-hexane gave 0.22 g (0.54 mmol) of colorless needle crystals (yield 19
%). Melting point: 202.5-203.9 ° C H-nuclear magnetic resonance (δ) (solvent CDCl ₃ ) 0.94-1.00 (2H m), 1.30-1.36 (3H m), 1.75-1.81 (4H m),
2.13 (1H m), 3.17 (2H t J = 5.9Hz), 3.60 (2H d J = 5.9H
z), 3.73 (3H s), 3.86 (3H s), 3.93 (3H s), 6.74 (1H s),
6.96 (1H br), 7.19 (1H br), 7.44 (1H br), 7.82 (1H b
r), 8.04 (1H br) Infrared absorption spectrum (cm ^-1 ) (Measurement method KBr-tab.) 3425, 3310, 1681, 1639, 1608, 1537, 1519, 1218, 12
04, 1032 Mass spectrum FAB M / e 408, 351

The action of promoting gastrointestinal motility of the representative compounds obtained in the above Examples was evaluated by the following method. 6 samples
It was dissolved or suspended in 0.5% CMC at a concentration of mg / ml and orally administered to rats fasted overnight at 30 mg / kg or 10 mg / kg, and 30 minutes later, food mixture (2.5% CM was added).
C, 10% powdered feed (passed through 60 mesh), 0.5
% Evans blue) was administered to each rat in an amount of 2.2 ml,
After a further 30 minutes, the weight (g) of the stomach that has been opened and excised is measured. This was performed on 4 to 5 rats, the average value and standard deviation thereof were calculated, and compared with the control value (g) to calculate the rate of change (%). The results are shown in Tables 1 to 15.

[0369]

[Table 1]

[0370]

[Table 2]

[0371]

[Table 3]

[0372]

[Table 4]

[0373]

[Table 5]

[0374]

[Table 6]

[0375]

[Table 7]

[0376]

[Table 8]

[0377]

[Table 9]

[0378]

[Table 10]

[0379]

[Table 11]

[0380]

[Table 12]

[0380]

[Table 13]

[0382]

[Table 14]

[0383]

[Table 15]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location C07C 255/24 9357-4H 259/08 8318-4H 271/28 7188-4H 323/59 7419-4H C07D 213/40 213/81 401/04 209 8829-4C

Claims (1)

[Claims] 1. A general formula: (In the formula, R ¹ is hydrogen or the formula: (Where m is an integer from 0 to 1, X is -CH ₂ -or -CH = CH-
R ⁵ is hydrogen, phenyl which may have a substituent,
A naphthyl which may have a substituent, a monovalent heterocyclic group which may have a substituent, a lower alkoxy-substituted alkyl or cycloalkyl), and R ² represents hydrogen or R ¹ and R ² together represent homophthaloyl, R ³ is of the formula — (CH ₂ ) _n —R ⁶ (where n is an integer from 1 to 3, R
⁶ is hydrogen, lower alkyl, phenyl which may have a substituent, amino group which may have a lower alkyl substituent, cyano group, thiol which may have a lower alkyl substituent, lower alkoxy, carbamoyl or Formula: (Here, p is an integer of 0 to 1, q is an integer of 0 to 2, and R ⁷ is a monovalent group of a heterocycle which may have a substituent.)
And R ⁴ represents hydrogen, or R ³ and R ⁴ represent a group that forms a 5- or 6-membered ring with the nitrogen to which it is bonded.) 4- (aminomethyl) cyclohexanecarboxamide derivative And acid addition salts thereof.