WO2006101245A1 - N-substituted-n-(4-piperidinyl) amide derivative - Google Patents

Abstract

A compound represented by the general formula (I) below or a salt thereof is used as an analgesic. (I) (In the formula, R1 represents an alkyl group having 1-6 carbon atoms, an optionally substituted 5- or 6-membered heterocyclic group or the like; R2 represents an acylamino group having 1-6 carbon atoms, an alkyl(thiocarbonyl)amino group having 2-6 carbon atoms, an ureide group, a thioureide group or the like, and the substitution position of R2 is an ortho- or meta-position; R3 represents a hydrogen atom or an alkoxycarbonyl group having 2-8 carbon atoms or the like; R4 represents an optionally substituted phenyl group or a 5- or 6-membered heterocyclic group; R5 represents a hydrogen atom or the like; R6 represents a hydrogen atom or the like; R7 represents a hydrogen atom or a methyl group; and m represents 1 or 2.)

Description

 N—Substituted N— (4-Piperidinyl) amide derivative

Technical field

 The present invention relates to an N-substituted mono-N- (4-piperidinyl) amide derivative or a salt thereof, and an analgesic agent containing this as an active ingredient. Light

Background art

 Rice field

 N-substituted mono-N- (4-piberidinyl) amide derivatives are disclosed in Japanese Patent Laid-Open Nos. 51-115 478 (Patent Document 1) and Japanese Patent Laid-Open No. 53-14998 2), Japanese Patent Laid-Open No. 2-2 9 2 2 7 9 (Patent Document 3), Japanese Laid-Open Patent Publication No. 2-300 1 6 7 (Patent Document 4), or Z hongguo Yaoke Daxue X uebao 1 9 9 3 Many compounds have been reported in 24, p 2 5 7-2 6 3 (Non-patent Document 1), and are known to have analgesic and anesthetic effects.

 For example, Patent Document 1 includes the following formulas (A),-

Patent Document 4 includes the following formula (B),

 N-substituted mono-N- (4-piperidinyl) amide derivatives represented by B are described as drugs having analgesic activity. On the other hand, Non-Patent Document 1 includes the following formula (C),

The N-substituted-N- (4-piperidinyl) amide derivative represented by the formula is described as having been studied for anesthetic action.

 In addition, fentanyl, a representative compound of N-substituted mono-N- (4-piperidinyl) amide derivatives, is clinically used as an anesthetic aid and analgesic. The analgesic action of these N-substituted mono-N_ (4-piberidinyl) amide derivatives is thought to be due to the agonistic action on the μ-receptor, one of the opioid receptors. , Fentanyl, etc. Ν—Substitution 1 Ν— (4—Pipe

2 In addition to amide derivatives, morphine is well known. However, these drugs have side effects such as dependence, bradycardia, respiratory depression, and gastrointestinal motility suppression, and there is a need to provide new analgesics with reduced side effects. On the other hand, the analgesic action via t-receptor was thought to be central, but recently, it has been reported that μ-receptor also exists at peripheral sensory nerve endings, and there is an analgesic mechanism through this. (C. S tein, An est h. An a 1 g., 1 9 9 3 years, 7 6, ρ 1 8 2- 1 9 1 (non-patent document 2), C. S tein, T he N ew England J ournalof Me dicine, 1 995, 3 3 2, pl 6 8 5— 1 6 9 0 (Non-patent Document 3), A. Herz, Progressin B rain R es., 1 9 9 6 years, 1 1 0, p 9 5 — 1 04 (Non-Patent Document 4)). Therefore, the present inventors have the possibility that a drug having an analgesic action by selectively acting on a peripheral / i-receptor may become an analgesic having no side effect based on a central action such as dependence. First, the following general formula (D),

(In the formula, represents an alkyl group having 1 to 6 carbon atoms, R ₂ and R ₄ represent a phenyl group which may have a substituent, R ₃ represents a hydrogen atom, and 2 to 8 carbon atoms. R ₅ represents an amino acid residue such as glycine, alanine, leucine, or phenylalanine, and m represents 1 or an alkyloxycarbonyl group, or a methyl group substituted with an alkoxy group having 1 to 6 carbon atoms. 2)

Patent for N-phenol N- (4-piperidinyl) amide derivatives represented by I am applying. (WO 0 3/0 8 28 1 9 (Patent Document 5)) As a result of further intensive research on the N-phenol N- (4-piperidinyl) amide derivatives, the present inventors It was found that the present compound of the present invention alleviated side effects based on the central action and had a good analgesic action, thereby completing the present invention.

In addition, as a compound structurally similar to the compound of the present invention, the following formula (E),

A compound represented by the following formula (F)

(Bioorganic & Medicinal C hemistry 2 00 2 years, 1 0, pl 0 0 9— 1 0 1 8 (Non-patent Document 5)), the following formula (G)

 (G) o u r n a 1 o f P h a r m a c y a n d P h 1 98 8 years, 40, p 6 05-6 08 (Non-patent document 6)

 And compounds represented by (H) (TetrahedroonLetters, 1 987, 28, p40 1-404 (Non-patent Document 7)). In Non-Patent Document 5, the compound represented by (E) is only described as a synthetic intermediate, and there is no description of pharmacological action, and the compound represented by (F) is not described. Although there is a description that it shows affinity for a receptor and has an analgesic action, there is no description of whether the analgesic action is peripheral or not.

Further, the non-patent document 6 describes that the compound represented by the above (G) showed almost no analgesic action in the rat tai 1-withdrawa 1 test. . Furthermore, Non-Patent Document 7 only describes that the compound represented by (H) exhibits an affinity for fentanyl to about 1/4 receptors. Accordingly, these compounds do not describe the compounds of the present invention. Disclosure of the invention

 An object of the present invention is to provide a novel N-substituted mono-N_ (4-piperidinyl) amide derivative or a salt thereof having analgesic action.

That is, the present invention provides the following general formula (I)

(In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 members, or an alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, or substituted. The group may have 1 to 3 halogen atoms, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. Represents a 5- or 6-membered heterocyclic group,

R ² is an acylamino group having 1 to 6 carbon atoms, N— (an acyl having 1 to 6 carbon atoms) 1 N— (alkyl having 1 to 6 carbon atoms) amino group, alkyl having 2 to 6 carbon atoms (thiocarbonyl) ) Represents an amino group, a ureido group, a thiolide group, an alkoxycarbonyllumino group having 2 to 6 carbon atoms, or an alkylsulfonylamino group having 1 to 6 carbon atoms, wherein the substitution position of R ² is ortho or meta. And

R ³ represents a hydrogen atom, an alkoxycarbonyl group having 2 to 8 carbon atoms, or a methyl group substituted with an alkoxy group having 1 to 6 carbon atoms,

R ⁴ is a halogen atom as a substituent, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, a nitro group, a cyan group, or amino Represents a phenyl group which may have 1 to 3 groups or a 5- or 6-membered heterocyclic group,

R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a halogen atom,

R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ⁷ represents a hydrogen atom or a methyl group,

 M represents 1 or 2. )

Or a salt thereof.

 The present invention also relates to an analgesic containing the compound represented by the above general formula (I) or a salt thereof as an active ingredient. · Best mode for carrying out the invention

 Next, the present invention will be described in detail.

In the above general formula (I), R ¹ may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, or a pentyl group having 1 to 6 carbon atoms. 3- to 7-membered cycloalkyl groups (preferably cyclopropyl groups) such as alkyl groups (preferably ethyl groups), cyclopropyl groups, cyclopentyl pentyl groups, or cyclohexyl groups, methoxy groups, ethoxy groups , A propyloxy group, an isopropyloxy group, a ptyloxy group, an i-butyloxy group, a t-butyloxy group, a methyl group substituted with an alkoxy group having 1 to 6 carbon atoms such as a pentyloxy group, an ethyl group, a propyl group, an isopropyl Group, butyl group, i-butyl group, t-butyl group, or alkyl group having 1 to 6 carbon atoms such as pentyl group (for example, An ethoxyethyl group or a methoxymethyl group, preferably a methoxymethyl group), or a substituent such as a chlorine atom, a bromine atom or a fluorine atom, a rogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, i 1-butyl group, t-butyl group, or alkyl group having 1 to 6 carbon atoms such as pentyl group, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, i-butyloxy group, t-butyloxy group Group, or an alkoxy group having 1 to 6 carbon atoms such as a pentyloxy group, or a methyl group substituted with a halogen atom such as a chlorine atom, a bromine atom or a fluorine atom, an ethyl group, a propyl group, an isopropyl group, a butyl group, i Alkyl having 1 to 6 carbon atoms such as 1-ptyl group, t-butyl group, or pentyl group Have a group 1 to 3 or even include 5- or 6-membered heterocyclic ring group of good such as a furyl group or a thienyl group.

As R ² , N— (a C 1-6 acyl) such as a formylamino group, a acetylamino group or a propionylamino group having 1 to 6 carbon atoms, a acetylmethylamino group or the like — N — ( An alkyl group having 1 to 6 carbon atoms) amino group, methyl (thiocarbonyl) amino group or ethyl (thiocarbonyl) amino group such as an aralkyl (thiocarbonyl) amino group, ureido group, thioureido group, etc. A methoxycarbonenoleamino group, an ethoxycarboenoleamino group, a propyloxy group, a ruponylamino group, a butoxycarbonylamino group, or a t-butoxycarbonylamino group, etc. Charcoal such as sulfonylamino group, ethylsulfo-lumino group or propylsulfonylamino group Examples thereof include an alkylsulfonylamino group having a prime number of 1 to 6.

R ³ includes a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group, or an alkoxycarbonyl group having 2 to 8 carbon atoms (preferably, a methoxycarbonyl group) such as a propenoreoxycarbonyl group, or a methoxy group. A methyl group substituted with an alkoxy group having 1 to 6 carbon atoms such as ethoxy group, propyloxy group, isopropyloxy group, ptyloxy group, i-butyloxy group, t-butyloxy group, pentyl group oxy, etc. And the like. Examples of R ⁴ include a 5- or 6-membered heterocyclic group such as a phenyl group or a cheenyl group, a pyrazolyl group, or a pyridyl group, which may have 1 to 3 substituents. Examples of such substituents include halogen atoms such as fluorine atom, chlorine atom or bromine atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t_butyl group, or pentyl group. Such as alkyl groups having 1 to 6 carbon atoms, such as alkyl groups having 1 to 6 carbon atoms, methoxy groups, ethoxy groups, propyloxy groups, isopropyloxy groups, ptyloxy groups, i-butyloxy groups, tert-butyloxy groups, or pentyloxy groups. Alkoxy group, methyl group substituted with 1 to 3 fluorine atoms, halogen atom such as bromine atom or chlorine atom, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-pentyl group , Or an alkyl group having 1 to 6 carbon atoms such as a pentyl group (for example, trifanololometinole group, chloromethyl group, Ethyl group, 2-bromoethyl group, 2-fluoroethyl group, etc.), nitro group, cyan group, or amino group.

As R ⁵ , a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, or an alkyl group having 1 to 6 carbon atoms such as a pentyl group, a hydroxyl group Or halogen atoms, such as a fluorine atom, a chlorine atom, or a bromine atom, are mentioned, Preferably it is a hydrogen atom.

R ⁶ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, or an alkyl group having 1 to 6 carbon atoms such as a pentyl group, preferably hydrogen. An atom, a methyl group or an ethyl group, more preferably a hydrogen atom.

R ⁷ represents a hydrogen atom or a methyl group, preferably a hydrogen atom, and m represents 1 or 2, preferably 1.

(1) Further, as the compound of the present invention, R ² is an acylamino group having 1 to 6 carbon atoms, an alkyl (thiocarbonyl) amino group having ² to 6 carbon atoms, a ureido group or a thiolide group. A compound represented by I) or a salt thereof is preferred. (2) The compound of the present invention is preferably a compound represented by the above general formula (I) or a salt thereof, wherein R ² is an acetylylamino group or a ureido group. .

(3) Further, as the compound of the present invention, a compound represented by the above general formula (I) in which the substitution position of R ² is a meta position, a compound described in the above (1) or (2), or a salt thereof is included. preferable.

 (4) The compound of the present invention is preferably a compound represented by the above general formula (I) wherein m is 1, or a compound or a salt thereof according to any one of the above (1) to (3). Les.

(5) The compound of the present invention is preferably a compound represented by the above general formula (I), wherein R ⁷ is a hydrogen atom, or a compound or salt thereof described in any one of (1) to (4) above. .

(6) Moreover, as this invention compound, the compound represented by the said general formula (I) whose R < ³ > is a hydrogen atom or a C2-C6 alkoxycarbonyl group, or said (1)-

The compound or a salt thereof according to any one of (5) is preferred.

(7) Further, as the compound of the present invention, a compound represented by the above general formula (I) wherein R ³ is a hydrogen atom, or a compound or a salt thereof according to any one of the above (1) to (5) preferable.

(8) Further, as the compound of the present invention, a compound represented by the above general formula (I), wherein R ³ is an alkoxy group having 2 to 6 carbon atoms, or a group represented by the above (1) to (5) Any of the compounds or salts thereof are preferred.

(9) As the present invention compounds, the compound represented by the general formula R ¹ is a cycloalkyl group alkyl or 3-8 membered ring of one to 6 carbon (I), or the

The compound according to any one of (1) to (8) or a salt thereof is preferable.

(10) Further, as the compound of the present invention, a compound represented by the above general formula (I), wherein R ¹ is a furyl group or a chenyl group, or any one of the above (1) to (8) A compound or a salt thereof is preferred.

(11) Further, as the compound of the present invention, R ⁴ may have a substituent. Or a compound represented by the above general formula (I) in which the heterocyclic group is a chenyl group, a pyrazolyl group, or a pyridyl group in a 6-membered heterocyclic group, or the above (1.) to (10) Or a salt thereof is preferred.

(1 2) Further, as the compound of the present invention, a compound represented by the above general formula (I) wherein R ⁴ is a phenyl group which may have a substituent, or the above (1) to (1 The compound described in any of 0) or a salt thereof is preferable.

(1 3) As the present invention compounds, the compound represented by the general formula R ⁵ is a hydrogen atom (I), or the (1) according to any of - (1 2) compound or its The salt of is preferred.

(14) Further, as the compound of the present invention, a compound represented by the above general formula (I), wherein R ⁶ is a hydrogen atom, or a compound according to any one of the above (1) to (13) Or its salts are preferred.

(15) In the present invention, an analgesic containing as an active ingredient the compound represented by the general formula (I), the compound according to any one of (1) to (14) or a salt thereof is an analgesic. It is preferred that the action is peripheral. The compound of the present invention represented by the above general formula (I) may have geometric isomers, diastereomers, optical isomers and the like, and these isomers are also included in the present invention. Furthermore, the compounds of the present invention include pharmaceutically acceptable salts such as inorganic acids such as hydrochloric acid or sulfuric acid, or salts with organic acids such as oxalic acid, citrate or tartaric acid. Next, a method for producing the compound represented by the above general formula (I) as the compound of the present invention will be described. The inventive compound of the above general formula (I) is produced by the following Method A, Method B or Method C. <Method A>

 (a)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and m are the same as described above.) The compound of the present invention represented by the above general formula (I) is a starting material ( It can be obtained by subjecting a) to an acylation reaction. 'The acylation reaction is carried out in the general formula (b) in the starting material (a) in the presence of a base such as triethylamine or N-methylmorpholine in a solvent that does not participate in the reaction such as dichloromethane, chloroform, and toluene. It is carried out by reacting the acid chloride represented. In this case, the reaction temperature is preferably 0 ° C. to the reflux temperature of the solvent. In addition, the acylation reaction of the starting material (a) is carried out using an acid anhydride represented by the general formula (c) in the presence or absence of a solvent not involved in the reaction such as toluene at room temperature to 150 ° C. It can also be performed at a temperature of ° C. The starting material (a) is prepared by a known method (P. G. H. Van D ae 1 eeta 1., Arzneu m. — Forsch. Drug R es-1 9 76

, 26, 1 5 2 1 M. W. L o b b e z o o, a n d W. S o u d i j n,

J. Me d. C hem., 1 9 8 1, 24, 7 7 7, A. M nt te r o e t a 1,, B i o r g. Me d. C hem, 20 0 2, 1 0 1 0 0 9 etc.

), And can be synthesized by a method according to them. <Method B>

(In the formula, Z represents a leaving group such as chlorine atom, bromine atom, iodine atom, mesyloxy group, or tosyloxy group, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ′, R ⁷ and m are the same as above.) The compound of the present invention represented by the above general formula (I) is obtained by reacting the starting material (d) with the compound represented by the general formula (e). .

The reaction is carried out at room temperature to 100 ° C. in the presence of a base such as sodium carbonate or potassium carbonate in a solvent that does not participate in the reaction such as acetonitrile, 4-methyl-2-pentanone, N, N-dimethylformamide. In the compound represented by the general formula (e), when Z is a chlorine atom or a bromine atom, it is preferable to coexist sodium iodide or rhodium iodide. The starting material (d) is prepared by a known method (PGH V an D aeleeta 1., Arzne um. — Forsc h. Drug R es., 1 9 7 6, 26, 1 5 2 1, P. L. F e 1 dmanand M. F. J. B raekeen, J-Org. C he m., 1 990, 5 5, 420 7, N. Laiindeeta 1., J. Med d. C he m , 1 990, 3 3, 2 8 7 6, etc.), and similar methods. C¾>

(First step)

 (b)

 (g)

 (Second process)

(g)

(3rd process)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , ⁷ and m are the same as above.) 1) 1st process

The acylation reaction of the starting material (f) with the compound represented by the general formula (b) or the compound represented by the general formula (c.) Can be carried out in the same manner as described in the method A above. . The starting material (f) is obtained by a known method (P.G.H-VanDae 1eeta 1., Arzneum.-For s c h.Dru g R es-1 9 7 6

, 2 6, 1 5 2 1, M. W. L o b b e z o o J a 11 d W. S o u d i j n

, J. Med. Chem., 1 98 1, 24, 7 7 7, A. Monteroeta 1., B ioorg. Med. Chem 2 00 2, 1 0 1 0 0 9 etc.), and It can be synthesized by a method according to them.

2) Second process

 Conversion from the compound represented by the general formula (g) to the compound represented by the general formula (h) is performed in a solvent that does not participate in the reaction such as methanol, ethanol, water, acetic acid, zinc, iron, tin chloride (Π ) And the like, reduction with a thio compound such as hydrosulfite sodium, or catalytic hydrogenation using palladium-carbon and platinum (IV) oxide as a catalyst. The reaction temperature varies depending on the type of reducing agent used, but is from room temperature to the reflux temperature of the solvent.

3) 3rd process

Conversion from the compound represented by the general formula (h) to the compound of the present invention represented by the general formula (I) is performed as follows depending on the type of R ² .

(1) When R ² is an acylamine group having 1 to 6 carbon atoms: The compound represented by the general formula (h) is reacted with an acid halide or an acid anhydride.

(2) When R ² is an alkyl (thiocarbonyl) amino group having 1 to 6 carbon atoms: After converting the amino group of the compound represented by the general formula (h) to an acylamine group having 1 to 6 carbon atoms, Lawesson 's drugs (T etrahedron, 1 9 8 ο, 4 1, 5 0 6 1 etc.) etc. are allowed to react. (3) When R ² is a ureido group: sodium cyanate or the like is reacted with the compound represented by the general formula (h) under acidic conditions. .

(4) When R ² is a thiolide group: sodium thiocyanate or the like is reacted with the compound represented by the general formula (h) under acidic conditions.

(5) When R ² is an alkoxycarbonylamino group having 1 to 6 carbon atoms: A compound represented by the general formula (h) is reacted with a black carbonate or the like.

(6) When R ² is an alkylsulfonylamino group having 1 to 6 carbon atoms: the compound represented by the general formula (h) is reacted with an alkylsulfonyl chloride.

 The compound represented by the compound (h), which is an intermediate raw material of the compound of the present invention, can also be produced by the following method D.

<Method D>

: 1st step) Introduction of protecting groups

(Second step) 0

 R'-C-CI

 (b)

(3rd process)

 (h)

Wherein W represents a protecting group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a trityl group, and R ¹ R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and m are the same as above. )

1) 1st process

 Introduction of the protecting group into the primary amino group of the starting material (i) can be carried out by a usual method. For example, when the protecting group is a tert-butoxycarbonyl group, it can be obtained by reacting di-tert-butyl dicarbonate in the presence of a base such as triethylamine using a mixed solvent of tetrahydrofuran or water. . When the protecting group is a trityl group, it can be obtained by reacting trityl chloride in a solvent such as chloroform in the presence of a base such as triethylamine. The starting material (i) can be synthesized by reducing the starting material (ί) of Method C.

2) Second process

The acylation reaction of the compound represented by the general formula (j) with the compound represented by the general formula (b) or the compound represented by the general formula (c) is performed in the same manner as described in the above-mentioned method A. be able to. 3) 3rd process

Removal of the protecting group (W) of the amino group of the compound represented by the general formula (k) can be carried out by a usual method. For example, when the protecting group is a tert-butoxycarbonyl group or a trityl group, the compound of the general formula (h) can be obtained by acid treatment using trifluoroacetic acid or the like. Further, among the compounds of the present invention, compounds represented by the following general formulas (q) and (r) wherein R ⁶ is a hydrogen atom, m is 1, and R ⁵ is a hydroxyl group or a halogen atom are Each can be manufactured by the following E method and F method.

<Method E>

 (m) (O)

 (

(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁷ are the same as above.)

1) 1st process

The reaction of the starting material (m) and the epoxide (n) is carried out at 50 to 120 ° C. in the presence or absence of a solvent that does not participate in the reaction. The starting material (m) is a known method (Z hi — Xian Wangeta 1., J. Med. Chem., 1 9 9 5, 3 8, 3 6 5 2, etc.), and those It can synthesize | combine by the method according to. -

2) Second process

The acylation reaction of the compound represented by the general formula (o) with the compound represented by the general formula (b) can be carried out in the same manner as described in the method A.

3) 3rd process

Hydrolysis of the compound represented by the general formula (P) to the compound of the present invention represented by the general formula (q) is carried out in a mixed solvent of water and an organic solvent (methanol, ethanol or tetrahydrofuran). It is carried out by reacting a base such as potassium carbonate or sodium hydroxide at room temperature to 60 ° C. <F method>

 (r)

(Wherein R ⁸ represents a halogen atom, and R ¹ , R ² , R ³ , R ⁴ and R ⁷ are the same as above.) Reaction of the compound represented by the general formula (q) with a halogenating reagent Depending on the type of R ⁸ halogen atom. For example, when R ⁸ is a fluorine atom, the general formula can be obtained by reacting with jethylamino sulfur trifluoride in a solvent such as dichloromethane.

The compound of the present invention represented by (r) can be produced. Representative examples of the compounds of the present invention thus obtained are shown below. ,

 (1) The compound of the present invention represented by the following general formula.

(In the formula, R ¹ , R ² , R ¹¹ and m are as described in Tables 1 and 2) 【table 1】

2

[Table 2]

No R ¹ R ² R ¹¹ m

11 2 Furyl Honoleminoreamino H 1

12 2—Frinoleacetylamino H 1

13 2 -furyl acetylamino 3- N0 ₂ 1

14 2-Frill Ureido H 1

15 2 -Ruffled 3-NH ₂ 1

16 2-furyl methoxycarbonylamino H 1

17 3—Frinoleacylamino H 1

18 2-Chenyl Acetylamino H

 19 2-Chelley Road H 1

20 5 -isoxazolyl acetylamino H 1 (2) The compound of the present invention represented by the following general formula.

And R ¹¹ is as shown in Tables 3-5)

[Table 3]

[Table 4]

[Table 5]

(3) Compound of the present invention represented by the following general formula

(Wherein R ¹ , R ² , R ⁵ and R ⁶ are as described in Table 6)

[Table 6]

 (4) The compound of the present invention represented by the following general formula

(Where R ¹ , R ² , R ⁵ and R ⁶ are as described in Table 7)

[Table 7]

 The compound of the present invention represented by the following general formula.

(Where R ¹ , R ² and R ⁴ are as described in Table 8) [Table 8]

 The compound of the present invention represented by the following general formula.

(Where R ¹ , R ² and R ⁴ are as described in Tables 9 and 10)

[Table 9]

[Table 1 0]

(7) The compound of the present invention represented by the following general formula

(Where R ¹ R ² , R ³ , R ⁷ , R ¹¹ and m are as described in Table 11)

[Table 1 1]

(8) The compound of the present invention represented by the following general formula

(Wherein I ¹ , R ² , R ³ , R ⁷ , R ¹¹ and m are as described in Tables 12 to 14)

[Table 1 2]

[Table 1 3]

 [Table 14]

The compound of the present invention represented by the following general formula.

And R ^{7 as} described in Table 15)

[Table 15]

 (10) The compound of the present invention represented by the following general formula.

(Where R ¹ , R ² , R ³ , R ⁴ and R ⁷ are as described in Tables 16 and 17) [Table 1 6]

[Table 1 7]

^ Describes pharmacological experiments of the present invention. The compound of the present invention was subjected to a binding experiment using [ ³ H] DAMGO / a pharmacological experiment on affinity for a receptor and analgesic action by an acetic acid rising test. As described in Example 32 below, the present invention The compound was found to have excellent binding affinity for one receptor as well as excellent analgesic activity. (See Tables 18 and 19)

 In addition, the analgesic effect of the compound of the present invention described in Examples 2, 19 and 30 described later was confirmed by conducting an antagonistic test using peripheral and central (systemic) sex / monoiobide receptor antagonists for the analgesic effect by the acetic acid rising test. Was found to be peripheral. (Table 20)

 Therefore, the compound of the present invention represented by the above general formula (I) has an excellent analgesic action and is therefore useful as an analgesic.

 In particular, among the compounds of the present invention, peripheral drugs; i drugs that selectively act on one receptor are expected as analgesics without side effects (dependence, etc.) based on central effects. The compound of the present invention can be administered to humans by oral administration or parenteral administration.

 In order to formulate, it can be produced into a dosage form such as a tablet, capsule, powder, injection, suppository, or transdermal preparation in the technical field of preparation.

 The dosage is usually about 0.0 lmg to: LOO Omg per day in the case of an oral preparation of the compound of the present invention, and about 0.0 OO lmg to LO Omg in the case of an injection. Can be increased or decreased depending on age, symptoms, etc. Next, the present invention will be described in more detail with reference examples and examples, but the present invention is not limited thereto.

Examples Reference Examples 1. 4--(2-Aminophenyl) -amino 1-phenethylenobiperidine

 4-(2-2-Trophenyl) amino 1-Phenethylbiperidine (2.24 g, 6.88 mm o 1) in ethanol (15OmL) in 10% palladium on carbon (224 mg) was added, and catalytic hydrogenation was performed at room temperature and 1 atm for 20 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol: = 30 Z1) to obtain 1.74 g (yield 86%) of the title compound. It was.

¹ H NMR (CD C 1 ₃ , 400 MH ζ) δ: 1.5— 1. 6 (2 Η, m), 2.0-2.2 (2H, m), 2. 22 (2 H, dt , J = 2, 1 2 H z), 2.5— 2. 7 (2 H, m), 2. 7— 2. 9 (2 H, m), 2. 9 _ 3. 0 (2 H, m), 3.1-3.4 (4 H, m), 6. 6-6. 9 (4H, m), 7.1-7.4 (5 H, m) Reference Example 2

 4- (3-acetylaminophenyl) amino 1-phenethinoleviperidin

 1-phenethylo-4 monopiperidone (1.00 g, 4.92 2 mm o 1) and 3, —aminoacetolide (85 500 mg, 5.66 mm o 1) in toluene (1 0 ml) p-Toluenesulfonic acid monohydrate (10 mg) was added to the solution, and the mixture was heated to reflux overnight using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (1 OmL), sodium borohydride (2 14 mg, 5.66 mm o 1) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into sodium bicarbonate water, extracted with black mouth form, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 96/4) to obtain 48 9 mg (yield 29%) of the title compound.

¹ H NMR (CD C 1 3.400MH ζ) δ: 1. 4-1. 6 (2 H, m), 2.0 — 2.3 (4H, m), 2. 1 5 (3 H, s ), 2.5-2. 7 (2 H, m), 2. 7− 2. 9 (2 H, m), 2. 9− 3.0 (2 H, m), 3. 2− 3. 4 (1 H, m), 3.5—3.7 (1 H, br), 6. 3 5 (1 H, brd , J = 8 H z), 6. 54 (1 H, brd, J = 7 H z), 7.0-7. 4 (8 H, m) Reference Example 3

 4 1 — (2 -acetylenoaminophenyl) amino 1-phenethylenobiperidine

 The title compound was obtained as white crystals in the same manner as in Example 2 using 1-phenethyl-4-piperidone and 2, -aminoacetanilide.

¹ H NMR (CDC 1 3, 400 MHz) δ: 1. 4— 1. 6 (2 Η, m), 1. 8 7 (1. 2 H, s), 2. 0— 2. 1 (2 Η, m), 2.1-2.3 (2 H, m), 2.20 (1.8 H, s), 2.5-2 · 7 (2 I- I, m), 2. 7 1 2. 9 (2 H, m), 2. 9 1 3.0 (2 H, m), 3.2 — 3.4 (1 H, m), 3. 8 — 4.1 (1 H , br), 6. 6— 6. 9 (2.4H, m), 7.0-7.4 (7.6 H, m) Reference Example 4

 4-(2 1-forminoreaminophenyl) amino 1-phenethinoleviperidine

 9 1- (3-Dimethylaminopropyl) — 3 _ethylcarbodiimide hydrochloride (55) in 8% formic acid (2700 mg, 5.75 mmol) in dichloromethane (6 mL) under ice-cooling 2 mg, 2.8 8 mmo 1) was added, and the mixture was stirred at 5 ° C for 15 minutes. To this mixture was added N-methylol morpholine (0.32 mL, 2.91 1 mm o 1) and 4- (2-aminophenyl) amino-1 _phenethylbiperidine (2 1 3 mg, 0 7 2 1 mm o 1) was added. After stirring at 5 ° C for 4 hours, ethyl acetate and aqueous sodium carbonate solution were added to the reaction mixture, and the organic layer was separated and washed with brine. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (black mouth form / methanol = 25Z1) to obtain a crude product of the title compound. This was recrystallized from ethyl hexane acetate to obtain 175 mg (yield 75%) of the title compound as light brown crystals.

¹ H NMR (CD C 1 3, 400MH ζ) δ: 1.5— 1. 7 (2 H, m), 2.0 — 2. 1 (2 H, m), 2. 1— 2.3 ( 2 H, m), 2.5—2.7 ( 2 H, m), 2. 7— 2. 9 (2 H, m), 2. 9— 3. 0 (2 H, m), 3. 2— 3.4 (1 H, m), 3. 5 2 (0. 3 H, brs), 3. 6 9 (0. 7 H, brd, J = 7 H z), 6. 7— 6. 9 (2 H, m), 7. 0— 7. 4 (7.7 H, m), 7. 4 8 (0.3 H, d, J = 8 H z), 8. 3 3 (0.7 H, d, J = 1 2 H z), 8 4 3 (0. 3 H, d, J = 2 H z). Reference Example 5

 1-Phenethyl 4-41 (2-propionylaminophenyl) Aminobiperidine 4-1- (2-Aminophenyl) amino- 1-Phenethylbiperidine (6 2 mg, 0.2 1 mm o 1) of toluene obtained in Reference Example 1 To the (0.5 mL) solution, propionic anhydride (26 mg, 0.20 mm o 1) was added. After stirring at room temperature, 1N aqueous sodium hydroxide solution and ether were added to the reaction mixture under ice-cooling, and the precipitated crystals were collected by filtration and washed with water and ether. After drying under reduced pressure, the title compound was obtained as pale brown crystals (38 mg, yield 51%).

 1 H NMR (CDC 1 3 4 0 OMH z) δ: 1. 0 7 (0.9 H,, b r t

), 1.28 (2. 1 Η, t J = 7 H z), 1. 4—1.7 (2 H, m), 1

'9— 2.3 (4.6 Η, m), 2.4 3 (1.4 H, q, J = 7 H z), 2.

5-2. 7 (2 mm, m), 2-7-2. 9 (2 H, m) 2. 9-3 • 0 (2 H m), 3.2-3.4 (1 H m) , 3.5 7 (0. 7 H, brs), 3.

9 8 (0.3 H, b rs) 6.5 5 (0.3 H, b rs), 6.6 6.

9 (2 H, m), 7.0-7 4 (7 H, m), 7.4 1 (o. 7 H, d, J =

8 H z) Reference Example 6

 4-1 (3-acetylaminophenyl) aminobiperidine

 (1) 4- (3-Acetylaminophenyl) Amino 1-benzylpiperidine 1 benzyl 1 4-piperidone and 3'-aminoacetamide were used to give the title compound in the same manner as in Reference Example 2. Obtained.

¹ H NMR (CD C 1., 40 OMH z) δ: 1. 4— 1. 6 (2 Η, m), 1. 9 1 2. 2 (41-1, m), 2. 17 (3 H, s), 2. 7-2. 9 (2 H, m), 3.2-3.4 (1 H , m), 3.4 — 3. 8 (1 H, br), 3.5 2 (2 H, s), 6. 3 3 (1 H, d, J = 8 Hz), 6.5 4 ( 1 H, d, J = 8 H z), 7.0-7.4 (8 H, m).

(2) 4-(3 -Acetylaminophenyl) aminopiperidine

To the above solution of 4_ (3-acetylaminophenyl) amino-1-benzylpiperidine (600 mg, 1.86 mm o 1) in methanol (6 mL), 10% paradium carbon (120 mg) ) And catalytic hydrogenation at 60 ° C. overnight. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain 326 _mg (yield 99%) of the title compound. ¹ H NMR (CD C 1 3, 40 OMH z) 5: 1. 2—1.4 (2 H, m),

2. 0— 2. 2 (2 Η, m), 2. 1 4 (3 Η, s), 2 · 7 1 (2 Η, dt, J = 2, 1 2 Η ζ), 3. 1 0 ( 2 Η, dt, J = 2, 1 3 Η ζ), 3.2—3.4 (1 Η, m), 3.5—3.8 (1 Η, br), 6.34 (1 Η, brd, J = 7 H z), 6. 54 (1 H, brd, J = 7 H z), 7.0 — 7, 2 (

3 H, m). Reference Example 7

 4 1 (2-acetylaminophenol) Amino biperidine

 (1) 4- (2-acetylaminophenyl) Amino 1-benzylpiperidine 1-benz ^ / 1-piperidone and 2,1aminoacetamide were used to prepare the title compound in the same manner as in Reference Example 2. Obtained as brown crystals.

¹ H NMR (CD C 1 a, 40 OMH z) δ: 1. 4— 1. 6 (2 Η, m), 1. 86 (1.2 Η, s), 1. 9— 2. 1 (2 Η , m), 2.1 — 2.3 (2 Η, m), 2.20 (1.8 Η, s), 2.7 — 2.9 (2 Η, m), 3.2 — 3.4 (1 Η, m), 3.5 2 (2 Η, s), 3. 6 1 (0. 6 Η, brs), 3. 96 (0. 4H, brd, J = 8 H z), 6.5 5 (0. 4 H, brs), 6. 6— 6. 8 (2 H, m), 7. 0— 7.4 (7. 6 H, m). (2) 4-1-2-acetylaminophenyl) aminobiperidine

 The title compound was obtained as pale brown crystals in the same manner as in Reference Example 6 (2) using the above 4-1- (2-acetylaminophenyl) amino-11-benzylpiperidine.

1 H NMR (CDC 1 3, 400 MHz) δ: 1. 2— 1. 8 (3 Η, m), 1. 8 7 (1.2 H, s), 1. 9 1 2. 1 (2 H , m), 2. 2 1 (1. 8 H, s), 2.6-2. 8 (2H, m), 3.0-3.2 (2 H, m), 3.2-3. 5 (1 H, m), 3.62 (0.6 H, brs), 3.96 (0.4H, brd, J = 8 Hz), 6.5—6.9 (2.4 H , m), 7. 0—7.4 (2.6 H, m).

Reference Example 8

 4-1 (3-cetinoleaminophenenole) amino 1-methinole _ 1-phenetinorepiperidine

 (1) 4 1 (3 -acetylaminophenol) 1 amino 1 1 benzyl 1 3 -methyl piperidine

 The title compound was obtained in the same manner as in Reference Example 2 using 1-benzyl-1-3-methyl-4-piperidone and 3'-aminoacetanilide. The cis and trans isomers were separated by silica gel column chromatography (ethyl acetate Z methanol = 25 Z 1) and obtained as yellow oils.

 C I S:

¹ H NMR (CDC 1 3, 400 MHz) δ: 0.97 (3 H, d, J = 7 H ζ), 1. 6— 1. 9 (2 H, m), 2.0 1 2 2 (1 H, m), 2. 1 4 (

3Η, s), 2.2—2.4 (3 H, m), 2.4 1 2 • 6 (1 H, m), 3.

2- 3.6 (2 H, b r), 3.4 6 (1 H, d, J = 1 3 H z), 3.5 2 (

1 Η, d, J = 1 3 H z), 6. 3 5 (1 H, b r d J J = 8 H z), 6.5

5 (1 H, b r d, J = 8 H z), 7. 07 (1 H, t, J = 8 H z) J 7.

1-7.4 (7 H, m). trans:

¹ H NMR (CDC 1 3, 400 MHz) δ: 0.94 (3 H,. D, J = 7 H z), 1.3 — 1.5 (l H, m), 1.5 — 1 7 (1 H, m), 1. 8 1 (1 H, t, J = 1 1 H z), 2. 0— 2. 2 (2 H, m), 2. 1 3 (3 H, s ), 2.8—3.0 (3H, m), 3.2—3.6 (1H, br), 3.50 (2H, s), 6.3 1 (1H, brd) , J = 8 H z), 6. 50 (1 H, brd, J = 8 H z), 7.0 — 7. 2 (3 H, m), 7.2 — 7.4 (5 H, m

4_ _ (3-Acetylaminophenyl) amino-3-methylpiperidine The cis and trans isomers of the above 4-1- (3-acetylaminophenyl) amino-1 ^ The title compound was obtained in the same manner as in Reference Example 6 (2).

 C I S:

¹ H NMR (CDC 1 3, 40 OMH z) δ: 0-94 (3 H, d, J = 7 H z), 1.5 4 (1 H, brs), 1.6 1 1. 7 ( 2 H, m), 2.0-2

2 (1 H, m), 2. 15 (3 H, s), 2.7 ― 2.8 (2 H m), 2.

8 5 (1 H, d d, J = 4, 1 3 H z), 2.9 8 (1 H, d t, J = 1, 3, 5

H z)-, 3.5-3. 6 (1 H, m), 3. 6-3 • 8 (1 H, b r), 6.3

5 (l H, b r d, J = 8 H z), 6.5 2 (1 H b r d, J = 8 H z)

, 7.0-7.2 (3 H, m).

 t r a n s:

¹ H NMR (CD C 1 a, 40 OMH z) δ: 0 • 9 7 (3 H, d, J = 6 H z), 1.1 — 1. 3 (1 H, m), 1.4 — 1.5 (1H, m), 1.58 (

1 H, b rs), 2. 0- 2. 2 (1 H, m), 2 • 1 4 (3 H s), 2.

38 (1 H, d d, J = 1 1, 1 3 H z), 2.67 (1 H, d t, J = 2, 1

3 H z), 2. 9—3.2 (3 H, m), 3.46 (1 H, b r d), 6.3

3 (1 H, b r d, J = 8 H z), 6.5 1 (1 H b r d, J = 8 H z)

7. 0-7.2 (3 H, m). (3) 4— (3-Acetylaminophenyl) Amino 3-methyl 1 1 1-phenethyl norpiperidine

 In the above solution of cis-4- (3-acetylaminophenyl) amino-1-methylpiperidine (2 7 2mg, 1.10 mm o 1) in acetonitrile (6 mL), (2-promoethyl) benzene (20 3 mg, 1.10 mm o 1), sodium carbonate (46 7 mg, 4.49 mmol) and sodium oxalate (30 mg, 0.2 Ommo 1) were added, and the mixture was heated to reflux. After cooling to room temperature, the reaction mixture was poured into water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel force ram chromatography (ethyl acetate / methanol monool = 20X 1), and the cis isomer of the title compound as a white crystal, 3 19 mg (yield 83% ) Obtained.

 In the same manner, the trans isomer of the title compound was obtained as a pale yellow oil from trans-4 (3-acetylaminophenyl) amino-3-methylpiperidine (14 3 mg) (15 8 mg, yield 7). 8%).

c i s:

¹ H NMR (CD C 1 3, 40 OMH z) δ: 0.97 (3H, d, J = 7 H z), 1. 7-1.9 (2 H, m), 2. 1 1 2 3 (1 H, m), 2. 1 3 (

3 H J s), 2. 3 1 2. 7 (6 H, m), 2.7-2. 9 (2 H, m), 3.

4 1 3.6 (1 H, m), 3.7 2 (1 H, brs), 6. 35 (1 H, brd J = 8 H z), 6.5 3 (1 H, brd, J = 8 H z), 7. 0 6 (1

H, t, J = 8 H z),. 1-7.4 (7 H, m). T r a n s:

¹ H NMR (CD C 1 3, 40 OMH z) δ: 1.00 (3 H, d, J = 6 H z) 1. 3— 1.5 (1 H, m), 1. 6 ― 1. 8 (1 H, m), 1-8 7 (

1 H t, J = 1 1 H z), 2. 0-2. 2 (2 H, m) J 2. 1 4 (3 H, s

), 2.5-2. 7 (2 H, m), 2. 7-2.8 (2 H m), 2. 8 1 3.

1 (3 H, m), 3.2 1 3.7 (1 H, br), 6. 3 3 (1 H, brd, J = 8 H z), 6.5 1 (1 H, brd, J = 8 H z), 7.0-7.4 H, m) Reference Example 9

c i s-4-(2 -acetylenoaminophenyl) amino 3 -methyl 1 1 -phenethylpiperidine

 (1) c i s— 1 benzenore _ 3— methinore 1 4 _ (2— nitroenol) amino piperidine and tr a n s— 1 — penzino ree 3 one methinore 4 1 (2—2 trophenyl) aminopiperidine

 4_Amino-1—Benzenole 1—Methinorepiperidine (6 4 6 mg, 3. 16 mm o 1) n—Propanole (1 6 mL) 669 mg, 4.74 mm o 1), sodium carbonate (670 mg) and potassium iodide (15 mg) were added. After heating at reflux for 30 hours, the reaction mixture was concentrated and water was added. Extraction with ethyl acetate was performed, and the extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/3), and the cis-isomer of the title compound as an orange oil 4 7 3 mg (yield 4 6%)-, 2 4 1 mg (yield 23%) of the trans isomer was obtained as an orange oil.

 C I S

¹ H NMR (CD C 1 3, 4 0 0 MHz) δ • 1 0 0 (3 H, d, J = 7 Hz), 1.8 — 2. 0 (2 H, m), 2. 1 — 2 • 6 (5 H, m), 3.4 8 (

1 H, d, J = 1 3 H z), 3 • 5 4 (1 H, d, J = 1 3 H z), 3. 7-3

8 (1 H, m), 6.6 0 (1 H, d d d, J 1 '7, 9 H 2), 6. 8 7

(1 H, d, J = 9 H z), • 2-7.5 (6 f [ϊ m), 8.] 8 (1 H, dd, J = 1, 8 H z) '8. 3 5 (1 H, brd J = 8 H z)

 t r a n s:

¹ H NMR (CD C 1 3, 400 MHz) δ-0 9 7 (3 H, d, J = 6 Hz), 1.5 1 1.7 (1 H, m), 1.8- 2 • 0 (2 H, m), 2. 0-2

2 (2 H, m), 2.8 1 3 0 (2 H, m) 3 .1 1 3. ^ (1 H, m) , 3.5 3 (2 H, s), 6. 59 (1 H, ddd, J = 1, 7, 8 H z)

8 5 (1 H, d, J = 8 H z), 7. 2— 7.5 (6 H, m),. 8. 09 H, brd, J = 8 H z), 8. 1 7 ( 1 H, dd, J = 1, 9 H z).

(2) s— 4— _ (2-Aminophenol) 3-amino-piperidine

1 in 1 ethanol (1 2 mL) solution of cis _ 1-benjirou 3-methinole 4- (2-nitrophene) aminopiperidine (47 3 mg, 1. 45 mm o 1) 0% palladium on carbon (4 7 mg) was added, and catalytic hydrogenation was performed at room temperature and 1 atm for 4.5 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (black mouth form / methanol = 30/1) to give the title compound as a brown oil. 9 5 mg (yield 69%) was obtained.

¹ H NMR (CD C 1 a, 400 MHz) δ: 1. 0 1 (3 H, d, J = 7 H z), 1. 7-1.9 (2 H, m), 2.1-2 2 (1 H, m), 2.2-2 • 5 (3 H, m), 2.5-2. 7 (1 H, m), 3. 29 (3 H, brs), 3.4 5 (1 H, d, J = 14 Hz), 3.4 — 3.5 (1 H, m), 3.5 3 (1 H, d, J = 14 Hz), 6. 6— 6. 9 (4 H, m), 7.2-7. 4 (5 H, m).

(3) c i s— 4-(2-Acetylaminophenyl) Amino 1 —Benzyl-3-methylinoleviperidine

Acetic anhydride (94 L, 1) in a toluene (3 mL) solution of the above cis-4- (2-aminophenol) amino-1-benzinoreyl 3-methinorepiperidine (29 5 mg, 1.0 mm o 1) 0 mm o 1) and stirred at room temperature for 25 hours. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with toluene, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the title compound was obtained as pale brown crystals in 3 2 3 mg (yield 96%). _{^{1 H NMR (CD C 1 3}} , 40 OMH z) 6: 0. 94 (1. 2 H, d, J = 7 H z), 1. 0 1 (1. 8 H, d, J = 7 H z ), 1.6-1.9 (2H, m), 1.88 (1.2 H, s), 2.1-2.5 (4 H, m), 2.20 (1. 8 H, s), 2.5—2.7 (1 H, m), 3.4 — 3.6 (3 H, m), 3 8 1 (0.6 H, brs), 4.0 8 (0, 4 H, brd, J. = 8 H z), 6.5 7 (0. 4 H, brs), 6. 6— 6. 8 (2 H, m), 7. 0— 7. 4 (7.6 H, m).

(4) c i s— 4-(2-acetylamino nophenyl) amino-3-methyl-1-monophenethylpiperidine

Using the above cis-4- (2-acetylenylaminophenyl) amino-1-pentinoleyl 3-methylbiperidine, a debenzylation reaction was carried out in the same manner as in Reference Example 6 (2), followed by Reference Example 8 (3 The alkylation reaction with (2-bromoethyl) benzene was carried out in the same manner as above. The reaction mixture thus obtained was purified by silica gel column chromatography to obtain the title compound as a pale yellow oil. ¹ H NMR (CD C 1 a, 4 0 0 MH ζ) δ: 0.95 (1.2 H, d, J = 7 H z), 1.0 2 (1.8 H, d, J = 7 H z), 1. 6— 1. 9 (2 H, m), 1. 8 9 (1. 2 H, s), 2.1-2.3 (1 H, m), 2. 2 1 ( 1. 8 H, s), 2.3-2. 7 (6 H, m), 2. 7-2. 9 (2 H, m), 3.4-3.6 (1 H, m), 3. 7—4.2 (l H 'br), 6. 6— 6. 8 (2.4 H, m), 7.0—7.3 (7.6 H, m) Reference Example 1 0

 t r a n s— 4— (2-Acetylaminophenyl) Amino 3-methyl 1-phenethylpiperidine

Using the trans-1- 1-benzyl-3-methyl-4- (2-nitrate fununyl) aminobiperidine obtained in Reference Example 9 (1), the title compound was prepared according to the method described in Reference Examples 9 (2) to (4). Obtained as light purple crystals.

 t r a n s:

¹ H NMR (CD C 1 ₃ , 40 OMH z) δ: 0.97 (1.2 H, d, J = 6 H z), 1.04 (1.8 H, d, J = 7 H z), 1. 3— 1.5 (1 H, m), 1.6 — 1. 8 (1 H, m), 1 .. 8 — 1.9 (0. 6 H, m), 1 . 8 7 (1. 2 II, s), 2.0-2.2 (2.4 H, m), 2. 1 8 (1.8 H, 2.5-2. 7 (2 I- I, m) , 2. 7— 2. 9 (2 H, m), 2. 2. 9 —

L (3 H, m), 3.54 (0. 6 H, brs), 3. 8 8 (0.4 H, d, J = 9 H z), 6. 6— 6. 8 (2 H, m ), 6. 84 (0.4 H, s), 7.0—7.4 (7.6 H, m) Reference Example 1 1

 4-one- (3-acetylaminophenyl) amino-1-one phenethylpiperidine 4-methyl carboxylate

 (1) 1-Benzenoyl 4-1 (3-2 Trophenyl) Aminopiperidine 1 4

 3—2-troanilin (1.28 g, 9.27 mm o 1) in acetic acid (8 mL) solution 1 1 benzil 4 1 piperidone (1.59 mL, 8.5 8 mm o 1) was added, and the mixture was stirred at room temperature for 1 hour. Further, trimethylsilyl cyanide (1.16 mL, 8.70 mm o 1) was added dropwise while maintaining the internal temperature at 35 ° C. or lower, and the mixture was stirred at room temperature. The reaction mixture was neutralized with an aqueous solution of potassium carbonate, added with jetyl ether and stirred overnight. The precipitated yellow crystals were collected by filtration and washed with water and n-hexane Z ethyl acetate (3Z1). The title compound was dried under reduced pressure at 50 ° C. overnight to obtain 2.22 g (yield: 7 7%) as yellow crystals.

¹ H NMR (CDC 1 3, 400 MHz) δ: 1. 9— 2. 0 (2 Η, m), 2. 40 (2 H, dt, J = 2, 1 3 H z), 2.4 − 2. 6 (2 H, m), 2.8-2. 9 (2H, m), 3.5 5 7 (2 H, s), 4.0 9 (1 H, s), 7. 19 ( 1 H, dd, J = 2, 8 H z), 7.2-7.4 (5 H, m), 7. 3 8 (1 H, t, J = 8 H z), 7. 6— 7 7 (2 H, m).

(2) 1 Benjirou 4— (3—2 Trophenyl) Aminobiperidine 1 4 1 Carbonic acid amide

Under ice-cold conditions, 97% sulfuric acid (5.4 mL) in 1 benzil 4-(3-trophenyl) aminopiperidine 1-4-strength linole (2.22 g, 6. 60 mm o 1) The The mixture was gradually added and stirred at room temperature. The reaction mixture was added to ice water and neutralized with potassium carbonate. The precipitate was collected by filtration and washed with warm water to remove inorganic salts. Air-drying at room temperature gave 1.95 g (yield 83%) of the title compound as yellow crystals.

¹ H NMR (CD C 1 3, 400 MHz) 5: 1. 9 2 (2 H, d, J = 1 3

H z), 2. 1 1 2 · 2 (2 H, m), 2.3-2.4 (2 H, m), 2. 7-

2. 8 (2 H, m), 3.5 50 (2 H, s), 4.3 6 (1 H, s), 5. 4 7

(1 H, brs), 6. 6 5 (1 H, brs), 6. 8 9 (1 H, dd, J = 2, 8 H z), 7.2-7. 4 (6 H, m) 7.4-7.5 (1 H, m), 7. 6 2 (1 H, dd, J = 2, 8 H z).

(3) 1-Benzenoleol 4 1 (3 -2 Trophenyl) aminobiperidine _ 4-Power Norevonic acid

1-Penzinore 4- (3-nitrophenyl) aminopiperidine mono-reacted norbonamide (1.95 g, 5.5 1 mm o 1) with concentrated hydrochloric acid (10 mL) and water (3 mL) was added and the mixture was heated to reflux for 2.5 hours. Subsequently, 6N sodium hydroxide aqueous solution (l l mL) was added dropwise so that the internal temperature was kept below 40 ° C under ice cooling. The reaction mixture was cooled to room temperature, and the precipitate was collected by filtration and washed thoroughly with water. Drying under reduced pressure at 60 ° C. gave 1.39 g (yield: 71%) of the title compound as yellow crystals.

1 H NMR (CD a OD, 400 MH ζ) δ 2.0-3. 8 (4 Η, m), 3.2-3.6 (4 Η, m), 4.3 7 (2H, s), 7. 0 1 (1 H, d, J = 8 H z), 7. 34 (1 H, t, J = 8 H z), 7.5—7.6 (7H, m)

(4) 1-Benzenoyl 4- (3-Nitrophenyl) aminobiperidine 4-methyl carbonate

Under ice-cooling, methanolyl (4 mL) was added dropwise with thionyl chloride (0 · 4 1 mL, 5.6 mm o 1) over 0.5 h, and 1-benzyl-4- (3-nitrate) was added to the resulting solution. Mouthphenyl) Aminobiperidine monostrength rubonic acid (5 17 mg, 1.45 mm o 1) was added. 5. After refluxing for 5 hours, the mixture was stirred overnight at room temperature. To the reaction mixture An aqueous potassium carbonate solution was added and the mixture was extracted with black mouth form. The extract was washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the title compound was obtained as a brown oil in the form of 53 2 mg (yield 99%).

¹ H NMR (CDC 13, 400 MHz) δ: 2. 0— 2. 1 (2 Η, m), 2. 2-2.4 (4 H, m), 2. 6— 2. 7 (2 H , m), 3.5 2 (2 H, s), 3. 7 2 (3 H, s), 4.1 9 (1 H, s), 6. 8 1 (1 H, dd, J = 2 , 8 H z), 7.2-7. 3 (6 H, m), 7.40 (1 H, t, J = 2 H z), 7.5 6 (1 H, dd,] = 2, 8 H z).

(5) 4 — _ (3 _aminomino 2) Amino acid 1

1-benzyl mono 4- (3-nitrophenyl) aminopiperidine mono 4-methyl oleate (60 mg, 1.62 mm o 1) of methanol monole (6 mL) 10% palladium on carbon (60 mg) was added, and catalytic hydrogenation was performed at room temperature and 1 atm for 4.5 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (black mouth form Z methanol = 9 7Z 3) to give the title compound 5 3 8 mg (yield 9 8%). -

¹ H NMR (CD C 13, 400 MHz) δ: 1. 9— 2. 1 (2 H, m),

2. 1—2.3 (2H, m), 2.3—2.5 (2H, m), 2.5—2.7 (2H, m), 3.49 (2H, s ), 3.5 2 (2 H, brs), 3. 6 8 (

3 H, s), 3. 7 7 (1 H, brs), 5.90 (1 H, t, J = 2 H z), 5. 9 9 (1 H, dd, J = 2, 8 H z), 6. 0 9 (1 H, dd, J = 2, 8 H z), 6. 9 1 (1 H, t, J = 8 H z), 7. 2— 7.4 (5 H, m).

(6) 4 1 (3-acetylaminophenol) Amino 1-Benzylpiperidine 1 4

A solution of 4- (3-aminophenyl) amino 1-benzylpiperidine 1-4 methyl norbornate (5 3 2 mg, 1.5 7 mm o 1) in toluene (5 mL) and anhydrous acetic acid (0. 1 5 mL, 1.5 7 mm.o 1) and stirred at room temperature. Reaction mixture The compound was poured into sodium bicarbonate water, extracted with Kokuguchi Form, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroformmethanol = 97 Z3) to obtain 491 mg (yield 82%) of the title compound.

¹ H NMR (CD C 1 3, 400MH ζ) δ: 1. 9— 2. 1 (2 H, m), 2. 1 4 (3 H, s), 2. 1— 2.3 (2 H, m), 2.3—2.5 (2 H, m), 2.5—2.7 (2 H, m), 3.5 0 (2 H, s), 3.69 (3 H, s), 3.93 (1H, brs), 6.28 (1H, brd, J = 8Hz), 6.67 (1H, brd, J = 8Hz), 6. 9—7.1 (3 H, m), 7.2-7.4 (5 H, m).

(7) 4 1 (3 -acetylenoaminophenyl) amino piperidine 1 4

 In the above solution of 4- (3-acetylaminophenyl) amino-1-benzylpiperidine mono-methyl norevonate (4 8 2 mg, 1. 26 mm o 1) in methanol (15 mL), 10% Palladium-carbon (240 mg) was added, and catalytic hydrogenation was performed for 2 hours while heating under reflux. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain 358 mg (yield 97%) of the title compound.

¹ H NMR (CD C 1 3, 400MH ζ) δ: .1.8-2. 0 (2 H, m), 2. 1 4 (3 H, s), 2.0-2.2 (2 H , m), 2. 8—3.0 (4 H, m), 3.70 (3 H, s), 3.99 9 (1 H, brs), 6. 3 1 (1 H, dd, J = 2, 8 H z), 6. 6 8 (1 H, brd, J = 8 H z), 7.0-7.2 (3 H, m).

(8) 4 1 (3-Acetylaminophenyl) Amino 1-Phenethylbiperidine 1 4 1-Methylole of canoleponate

In the above solution of 4- (3-aceti ^ / aminophenyl) aminobiperidine 4-4-methylolanolate (1 7 5 mg, 0.60 1 mm o 1) in acetonitrile (4 mL) (2-Promoethylol) ) Benzene (122 mg, 0.66 1 mm o 1), sodium carbonate Lithium (2 5 5 mg, 2.40 mm o 1) and sodium iodide (18 mg, 0.120 mm o 1) were added, and the mixture was heated to reflux. The reaction mixture was poured into water, extracted with chloroform, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (chromium form / methanol = 94/6) to obtain 189 mg (yield 79%) of the title compound.

1 H NMR (CD C 1 3, 400MH ζ) δ: 2. 0— 2. 1 (2 H, m), 2. 1 4 (3 H, s), 2. 2-2.4 (2 H, m), 2.4-2. 9 (8 H, m), 3. 70 (3 H, s), 3. 94 (1 H, brs), 6. 3 1 (1 H, brd, J = 8 H z), 6. 6 7 (1 H, brd, J = 8 H z), 6. 9-7.1 (3 H, m), 7.1-7.4 (5 H, m).

Example 1

 N- (2-acetylenylaminophenyl) — N— (1-phenethylenobiperidine mono-4-yl) propionate amid oxalate

(1) N- (2 -acetylaminophenyl) -N- (1 _Phenethylpiperidine — ₄ yl) propionic acid amide- ₄ -1 (2-acetylaminoaminophenyl) obtained in Reference Example 3 ) Amino 1-1 phenethylpiperidine (8 5'mg, 0.25 mm o 1) and triethylamine (0.21 mL) in dichloromethane (3 mL) under ice-cooling, propionyl chloride (1 0 5 mg, 1.1 3 mmo 1) was added. After stirring at room temperature for 17 hours, triethylamine (0.28 mL) and propioninochloride (140 mg, 1.5 1 mm o 1) were further added under ice cooling, and the mixture was stirred at 5 ° C for 2 hours. did. The reaction mixture was poured into sodium bicarbonate water, extracted with black mouth form, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10-1) to obtain a crude product of the title compound. This was recrystallized from ethyl hexane acetate to obtain 29 mg (yield 29 ° / ₀ ) of the title compound as white crystals.

1 H NMR (CD C 1 ₃ , 400 MHz) 6: 1. 03 (3 H, t, J = 7 Η ζ), 1. 3 8 (1 Η, dq, J = 4, 1 2 Η ζ), 1. 5— 1. 8 (2 Η, m ), 1. 8— 2. 1 (3 H, m), 2. 0— 2. 2 (2 H m), 2. 1 7 (3 H, s), 2. 4-2. 6 (2 H , m), 2.6-2. 8 (2 H, m), 2.9 1 3.1 (2H, m), 4.5-4. 7 (1 H, m), 7 0-7. 5 (9 H, m), 8.4-8. 6 (1 H, br).

(2) N- (2-acetylenylaminophenyl) _N— (1-phenethylbiperidine — 4-yl) propionic acid amid oxalate

 Methanol of N- (2-acetylaminophenyl) 1N- (1-phenethylbiveridine-1-4-yl) propionate (29 mg, 0.0 74 mmol) To the (1 mL) solution, oxalic acid (7 mg, 0.078 mm o 1) was added. The solvent was distilled off under reduced pressure, and the residue was dissolved in isopropanol (0.5 mL) and stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed with isopropanol, and dried to give 28 mg (yield 79%) of the title compound as a white powder.

¹ H NMR (CD ₃ OD, 40 OMH z) δ-1. 0 1 (3 H, t, J = 7 H z), 1.5 — 1. 7 (1 H, m), 1 • 9 2. 1 (2 H, m), 1.98 (

2 H, q, J = 7 H z), 2.1-2.3 (1 H, m), 2.1 8 (3 H, s)

2.9-3.0 (2 H, m), 3.0 1 3 • 2 ■ (2H, m), 3.2-3.4

(2 H, m), 3.5 1 3.8 (2 H, m) y 4.5-4.7 (1 H, m), 7

2 1 7.4 (7 H, m), 7. 45 (1 H t, J = 8 H z), 7. 94 (1

H, d, J = 8 H z) •

IR (cm ¹ , KB r): 3 348, 2 9 7 8, 294 1, 1 6 9 3, 1 6 5

3, 1 5 87, 1 5 2 2, 1 448, 1 3 9 2 1 3 7 3, 1 2 9 2, 1 26 7

, 1 40, 1 0 90, 64, 700 Example 2

 N— (3-acetinoreaminophenyl) 1 N— (1-phenethyleperidine 1- 4-yl) propionate amid oxalate

 (1) N- (3 -acetylaminophenyl) 1 N— (1-phenethylbiperidine

—4—yl) propionic acid amide Propionic anhydride (0.38 mL) was added to 4- (3-acetylaminophenyl) amino 1-phenethylpiperidine (lOO mg, 0.296 mg o 1) obtained in Reference Example 2. The mixture was stirred at 1 35 ° C. for 30 minutes. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with chloroform, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (black mouth form / methanoylol = 96/4) to obtain 22 mg (yield 19%) of the title compound. It was.

1 H NMR (CDC 1 ₃ , 4 0 0 MH ζ) δ: 1.0 2 (3 Η, t, J = 7 H z), 1.3-1.6 (2 H, m), 1.7 — 1. 9 (2 H, m), 1.9 — 2.1 (2 H, m), 2.1-2.3 (2 H, m), 2. 1 9 (3 H, s), 2.5-2.6 (2 H, m), 2.6-2. 8 (2 H, m), 2. 9-3.1 (2 H, m), 4.6-4. 8 ( 1 H, m), 6.8 3 (1 H, d, J = 8 H z), 7.1 — 7.5 (8 H, m), 7.8 — 8.0 (1 H, m) .

(2) N- (3 -Acetylaminophenyl) -N- (1-phenethylpiperidine 1- 4-yl) propionate amid oxalate

 Using the above N- (3-acetinoreaminophenol- 1) N- (1-phenethylrebiperidine 1-yl) propionic acid amide, in the same manner as in Example 1 (2). The title compound was obtained as a white powder.

¹ H NMR (CD ₃ OD, 400 MHz ζ) δ: 1. 0 1 (3 H, t, J = 7 H z), 1. 6— 1. 9 (2 H, br), 2. 0 3 (2 H, q, J = 7 H z), 2.0-2.2 (2 H, m), 2. 1 4 (3 H, s), 2.9—3.0 (2 H, m ), 3.15 (2H, brt), 3.2—3.4 (2H, m), 3.64 (2H, brd), 4.7—4.9 (1H, m ), 6. 9-7.0 (1 H, m), 7.2-7.5 (7 H, m), 7. 6 7 (1 H, brs).

IR (cm— ¹ , KB r): 3 3 9 8, 3 0 3 0, 1 6 5 5, 1 6 0 1, 1 5 5 1, 1 4 8 9, 1 4 3 7, 1 3 8 7, 1 3 0 6, 1 2 7 7, 1 0 4 9, 8 0 8, 7 5 4, 7 0 2. Example 3 N- _ (2-acetylaminophenyl) -N- (1-phenethylpiperidine monoyl) cyclopropanecarboxamide oxalate

 4-1 (2-acetylaminophenolinole) amino 1-phenethylbiperidine (50 mg, 0.14 8 mm o 1) and tretinoleamine (4 2 / x L, 0.2 To a solution of 9 6 mmol 1) in dichloromethane (2. OmL) was added ice-cold propane strength norbornyl chloride (19 mg, 0.185 mmol) under ice-cooling and stirred for 1 hour. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with black mouth form. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl hexane acetate to give the free base of the title compound as white crystals. This was dissolved in ethyl acetate, and a solution of oxalic acid (10.5 mg, 0.11 6 mm o 1) in oxalic acid was added. The obtained crystals were collected by filtration and dried to obtain 44 mg (yield 60%) of the title compound as white crystals.

m p: 1 54-1 5 7 ° C

¹ H NMR (CD ₃ OD, 400 MHz) δ: 0.6—0.7 (2 H, m),

0. 8— 0. 9 (1 H, m), 0.9. 1.1 — 1 (1 H, m), 1.1 — 1. 2 (1 H, m), 1.5 — 1. 7 ( 1 H, m), 1.9 1 2. 1 (2H, m), 2. 1 9 (3 H, s), 2.2-2.3 (1 H, m); 0 (2 H, m)

, 3. 0— 3. 2 (2 H, m) '. 3. 2— 3.4 (2 H, m), 3.5— 3.7 (2H, m), 4.5— 4.6 (1 H, m), 7.2-7.4 (7 H, m), 7.4-7.5 (1 H, m), 7. 95 (1 H, d, J = 8 H z ).

1 R (cm ~ ¹ , KB r): 3 3 9 8, 3 3 58, 1 6 9 5, 1 64 5, 1 5 8 9, 1 5 2 2, 14 5 0, 14 1 0, 1 2 94 , 1 2 6 7, 9 64, 75 8, 7 0 2.Example 4

 N— (3-acetylaminophenyl) 1 N— (1-phenethylbiperidine 1-41) cyclopropanecarboxamido oxalate

4- (3-Acetyl ^ / aminophenol Λ ^) Using amino-11 monopheny ^ / piperidine, the title compound was obtained as white crystals in the same manner as in Example 3. mp: 1 7 3-1 8 1 ° C

¹ H NMR (CD ₃ OD, 40 OMH z) δ: 0.6—0.7 (2H, m), 0.8—1.0 (2H, m), 1.2—1.3 ( 1 H, m), 1. 7— 1. 9 (

2 H, br), 2 · 0-2.2 (2 H, m), 2. 14 (31-1, s), 2. 9-3.0 (2 H, m), 3.1- 3.2 (2 H, m), 3.2-3.4 (2 H, m

), 3. 64 (2 H, b r d), 4.7 — 4. 9 (1 H, m), 7.0 3 (1

H, d, J = 7 H z), 7.2-7.4 (5 H, m), 7.4—7.5 (2 H, m), 7. 7 1 (1 H, s).

IR (cm— ¹ , KBr): 3 3 9 8 3 3 23, 1 6 9 7, 1 6 5 1 1 6 0

1 1 5 5 2, 1 4 9 1, 1 4 1 6 1 3 6 9, 1 3 1 3 1 2 6 9, 1 2 0 3

1 1 34, 1 0 5 7, 1 0 2 8 9 5 7, 8 9 5 8 0 2, 5 2, 7 0 2 Example 5

 N— (3-acetylenylaminophenyl) 1 N— (1-phenethylbiperidine 1-41) Furan 1-strength rubonic acid amid succinate

 (1) N- (3-acetylaminophenyl) -N- (1-phenethylpiperidine _4 yl) furan 2 _strength norlevonic acid amide

 4 (3-acetylaminophenyl) amino 1-phenethylbiperidine (100 mg, 0.26 6 mm o 1) of clotted form (1 mL) 0.08 mL) and 2-fluoroinochloride (35 L, 0.356 mm o 1) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into sodium bicarbonate water, extracted with black mouth form, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (black mouth form methanol = 9 7/3) to give 85 mg (yield 66%) of the title compound as pale yellow crystals. Obtained.

1 H NMR (CDC 1 ₃ , 40 OMH ζ) δ: 1. 4— 1. 6 (2Η, m), 1. 6— 2. 0 (2 H, m), 2. 0— 2.3 (2 H, m), 2. 23 (3 H, s), 2.4-2.6 (2H, m), 2.6-2.8 (2H, m), 2.9-3.1 (2 H, m), 4.6-4. 8 (1 H, m), 5.5 3 (1 H, brs), 6. 14 (1 H, dd, J = 1, 3 H z) , 6. 90 (1 H, d, J = 8 H z ), 7. 0-7. 7. 9 2 (1 H, d, J = 7 H z), 8.3

4, (1 H, b r

(2) N— (3-acetylaminophenyl) 1 N_ (1 — phenethylrepiperidine — 4 1 yl) furan _ 2 — strong rubonic acid amide oxalate

N— (3-acetylenylaminophenyl) 1 N— (1—Phenetyl ^^ piperidine—4-yl) Furan 2-carboxylic acid amide (8 5 mg, 0.19) 7 mm o 1) Ethyl acetate (l mL) —Methanol (0.5 mL) solution was added oxalic acid (19 mg, 0.2 1 mm o 1) in ethyl acetate (0.8 mL) . After stirring at room temperature for a while, the precipitated crystals were collected by filtration and washed successively with ethyl acetate and ether. Drying under reduced pressure gave 79 mg (yield: 77%) of the title compound as white crystals.

m p: 2 0 7-2 1 0 ° C

¹ H NMR (CD a OD, 400 MHz) δ: 1.8 1 2,. 0 (2 H,: m),

2. 17 (3 H, s), 2. 25 (2 H, rd), 2 • 9 1 3.1 (2 H, m), 3.2-3.4 (4 H, m), 3. 7 3 (2 H, brd), 4. 9 1 5

0, (1 H, m), 5.8 5 (1 H, d, J = 3 H z) 6.3 3 (1 H d d

,} = 2, 3 H z), 7.05 (1 H, b r d,. J = 8 H ζ), 7.2-7.

4 (5H, m), 7.48 (1H, t, J = 8Hz), 7-5 3 (1H, d, J

= 2 H z), 7. 6 1 (1 Η ·, b r d, J = 8 H z) f 7.7 2 (1 H b rs „,).

IR (cm— ¹ , KB r): 1 7 2 8, 1 6 8 4, 1 6 2 4:, ¹ 6 0 3, 1 5 6

0, 1 4 9 1, 1 4 7 1, 1 4 1 9, 1 4 0 0, 1 3 6 9, 1 3 2 3, 1 2 3 6

, 1 1 8 6, 1 1 3 2, 1 0 3 8, 9 4 5, 8 8 3, 5 6, 7 3 1, 7 0 2,

5 9 4, 5 3 8, 4 6 5.Example 6

 N- (2—acetylaminophenyl) 1 N— (1 phenethylbiperidine — 4 1 yl) Furan 2 1 rubonic acid amido oxalate

 ,,

(1) N— (2-acetylaminophenol) 1 N— (1 phenethyl pipette V 1) 1) Furan 2-carboxylic acid amide

 Using 4- (2-acetylaminophenyl) amino-11-phenethylbiperidine, light yellow crystals were obtained in the same manner as in Example 5 (1).

 1 H NMR (C D C 13, 400 MHz) δ: 1.49 (1 H, d q, J

1 2 Η ζ), 1. 7 3 (1 Η, d q, J = 4, 1 2 H z), 1. 8-1.

1 Η, m), 2. 0— 2. 1 (1 H, m), 2. 1 6 (3 H, s), 2.1

3 (2 H, m), 2.5-2.6 (2 H, m), 2. 7 1 2.8 (2 H,

2. 9-3.1 (2H, m), 4. 70 (1 H, t t, J = 4, 1 2 H z

5.57 (1 H, b r s), 6. 1 7 (1 H, d d, J = 1, 3 H z),

0—7.3 (8H, m), 7.44 (1H, dt, J = 2, 8Hz), 7.80 (1H, brs), 8.46 (1H, d, J = 8 H z).

(2) N— (2 -acetylenophenyl) -N- (1-phenethylpiperidine -4-yl) furan 2-2-norebonic acid amidoxalate

 N- (2-acetylaminophenyl) 1N- (1-phenethylbiperidine-4-yl) furan 2-carponic acid amide was used in the same manner as in Example 1 (2). To give the title compound as white crystals.

m p: 1 7 7-1 8 2 ° C (decomposition)

¹ H NMR (CD ₃ OD, 40 OMH z) 6: 1. 7— 1. 9 (1 H, m), 2.0 — 2.2 (2H, m), 2. 1 3 (3 H, s ), 2.3-2.4 (1 H, m), 2.9-3.1 (2H, m), 3.1-3.4 (4H, m), 3.6-3.8 ( 2H, m), 4.6—4.8 (1 H, m), 5.91 (1 H, d, J = 3 Hz), 6.30 (1 H, dd, J = 1, 3 H z), 7.2-7. 4 (7H, m), 7.4 1 7. 6 (2 H, m), 7. 9 7 (1 H, d, J = 8 H z).

IR (cm— ¹ , KB r): 34 1 7, 3 2 3 0, 3 0 3 2, 2 9 6 2, 1 75 3, 1 6 8 6, 1 6 5 3, 1 6 24, 1 5 9 3, 1 5 5 6, 1 5 2 5, 1 468, 1 4 5 2, 1 400, 1 3 7 3, 1 34 2, 1 2 9 6, 1 1 90, 1 1 1 7, 1 0 8 8 , 1 0 3 8, 94 1, 7 54, 704, 5 94. Example 7

 N— (2-acetylaminophenyl) 1 N— (1-phenethyl leviperidine 1-4-1) furan 1-strength rubonic acid amidoxalate

 The title compound was obtained as white crystals in the same manner as in Example 3 using 4- (2-acetylaminophenyl) amino 1-phenethylbiperidine and 3-furoyl chloride.

m p: 1 7 9-1 8 8 ° C

¹ H NMR (CD 3 OD, 400 MHz) δ: 1 • 7-1.9 (1 H, m),

2. 0— 2. 2 (2 H, m), 2. 1 2 (3 Η, s), 2. 3 1 2.4 (1 H, m), 2. 9— 3.0 (2 H m ), 3.0-3.2 (2H, m), 3.2-3

4 (2 H, m), 3.6-3.8 (2 Η, m), 4.6-4. 9 (1 H, m)

, 6. 1 9 (1 H, d, J = 1 H z), 6. 7 7 (1 H, b r s), 7.2-

7.4 (8 H, m), 7. 4 1 7.5 (1 H, m), 7. 96 (1 H, d, J =

8 H z).

IR (cm ¹ , KB r): 3 408, 3 3 34, 1 7 34, 1 6 9 3, 1 6 1

8, 1 5 60, 1 5 2 2, 1 4 48, 1 3 9 8, 1 3 7 3, 1 34 4, 1 29 2

, 1 244, 1 200, 1 1 6 1, 1 0 1 4, 8.7 6, 8 1 6, 5 0, 700

5 9 6. Example 8

 N— (3-acetylaminophenyl) 1 N— (1 phenethylpiperidine 1 4-yl) furan 3 3-carboxylic acid amid oxalate

 The title compound was obtained as white crystals in the same manner as in Example 3, using 4- (3-acetylaminophenyl) amino-1-phenethylbiperidine and 3-furoyl chloride.

m p: 2 0 2-20 5 ° C

¹ H NMR (CD 3 OD, 40 OMH z) δ 1. 8—2.0 (2 H, m), 2. 1 2 (3 H, s), 2. 20 (2H, brd), 2.9 — 3. 1 (2 H, m), 3.1 — 3.4 (4H, m), .3. 6 8 (2 H, brd), 4. 8— 5 0 (1 H, m), 6. 1 7 (1 H, d J 1 H z), 6. 8 7 (1 H s

, 7. 0 0 (1 H, d, J 8 H z) 7 • 2 ― 7 • 4 (6 H, m) 7 • 4

(1 H, t, J = 8 H z) 7.5 5 5 (1 H d ί J = 8 H z) ί 7 6 7 (

H, s) •

 I R (-1

 c m, KB r) '340 8 ί 3 2 6 5 ϊ 1 6 8 9, 1 6 0 1 1 5

0, 1 4 9 1, 1 40 6, 1 404, 1 3 7 7 1 3 4 6, 1 3 1 7, 1 2 5

, 1 1 9 8, 1 1 5 5, 1 0 80, 1 0 4 9 1 0 1 4, 9 8 7 8 7 6 7

0, 70 2, 6 0 0. Example 9

 N— (2-acetylaminophenyl) 1 N— (1-phenethylbiperidine 1- 4-yl) thiophene 2-strong rubonic acid amidoxalate

 The title compound was obtained as white crystals in the same manner as in Example 3, using 4- (2-acetylaminophenyl) amino-1-phenethylpiperidine and 2-thiophenecarbol chloride.

m p: 20 9-2 1 1 ° c

¹ H NMR (CD ₃ OD, 40 OMH z) δ: 1. 7-1.9 (1 H, m),

2. 0-2. 2 (2 H, m), 2. 1 1 (3 Η, s), 2. 3-2. 4 (1 H, m), 2. 9-3.1 (2 Η, m), 3.1 1 3.4 (4 H, m), 3.6 1 3

8 (2 H, m), 4.7-4. 8 (1 H, m), 6. 7 7 (1 H, d d, J =

1, 4 H z), 6. 8 3 (1 Η, d d, J = 4, 5 H z), Ί. 2-1. 4 (7

H, m), 7.4-7.6 (2H, m), 7.98 (1H, d, J = 8Hz).

IR (cm— ¹ , KB r): 340 8, 3 3 04, 1 76 5;, 1 6 9 7, 1 6 1

4, 1 5 9 3, 1 5 2 7, 1 45 2, 1 4 1 7, 1 3 8 5, 1 3 1 3, 1 2 94

, 1 2 3 8, 1 1 1 9, 1 0 1 6, 9 5 8, 8 5 4, 72 5, 704, 60 2. Example 1 0

Ν— (3-cetinoleaminophenyl) 1 N- (1 — phenethylbiperidine 1-41 inore) thiophene 2 — force norebonic acid amide, oxalate The title compound was obtained as white crystals in the same manner as in Example 3 using 4-mono (3-acetinoreaminophenol) and amino-1-monopirepiperidine and 2-thiophenecarbol chloride.

m p: 1 74 1 1 7 7 ° C (decomposition point)

¹ H NMR (CD a 0D, 4 0 0 MHz) δ: 1. 8— 2. 0 (2 H, m),

2. 1 2 (3 H, s), 2. 2 4 (2 H brd), 2.9-3.0 (2 H, m), 3.1 1 3.4 (4 H, m), 3 • 6 8 (2 H, brd), 4. 8— 5

0 (1 H, m), 6. 8—6.9 (2 H m), 7.0 4 (1 H, d, J == 8

H z),. 2-7.4 (5 H, m), 7 • 4 3 (1 H, t, J = 8 H z), 7

4 8 (1H, dd, J = 1, 5Hz) 7.55 (1H, d, J = 8Hz),

7. 7 2 (1 H, s).

 I R (c m_ 1

 ί KB r): 3 4 0 6, 1 6 8 6, 1 5 9 7, 1 5 5 2, 1 4 8

9, 1 4 2 1, 1 3 7 3, 1 3 1 3, 1 2 5 4, 1 2 0 7, 1 1 1 5, 1 0 4 3

, 4 2, 70 2 Example 1 1

 N- (2-acetinoreaminophenol) 1 N— (1-phenethylrepiperidine 1- 4-yl) isoxazol 5-carponic acid amide oxalate

 Using 4- (2-acetylaminophenyl) amino-1-phenethylbiperidine and isoxazole-5-carbonyl chloride, the title compound was obtained as white crystals in the same manner as in Example 3.

mp: 1 4 5-1 4 8 ° C (decomposition point)

1 H NMR (CD ₃ OD, 40 OMH z) 6: 1 • 7 1 1.9 (1 H, m),

2 • 0-2. 2 (2 H, m), 2. 15 (3 H, s) '2-3-2. 4 (1 H, m), 2. 9-3.1 (2 H, m), 3.1-3.4 (4 H, m), 3.6 1

• 8 (2H, m), 4.6-4.8 (1H, m), 5.91 (1H, s), 7.

2 ― 7.4 (7 H, m), 7.4-7.5 (1 H, m), 7.9 1 (1 H, d,

J: 8 H z), 8.2 2 (1 H, s).

^{IR (cm- 1, KB r)} :. 3 5 8 9, 3 2 9 8, 1 6 8 6:, 1 6 3 5, 1 5 9 1, 1 5 6 6, 1 5 2 5, 1 4 8 5, 1 4 5 2, 1 3 9 4, 1 37 1, 1 3 2 9, 1 294, 1 20 5, 1 1 6 3, 1 1 1 7, 1 0 5 1, 9 8 7, 9 5 3, 9 2 0, 8 1 2, 7 5 8, 7 1 0, 5 9 6. Example 1 2

 N- (3-acetinoreaminophenolinole) -N- (1-phenethinorebiperidine 1- 4-yl) isoxazol 5-strength rubonic acid amide oxalate

 The title compound was obtained as white crystals in the same manner as in Example 3, using 4- (3-acetylaminophenyl) amino-11-phenethylolepiperidine and isoxazole-5-stryl chloride.

¹ H NMR (CD ₃ 0D, 40 OMH z) δ: 1. 8— 2. 0 (1 H, m), 2. 0— 2.3 (3 I- I, m), 2. 1 2 ( 3 H, s), 2.9—3.1 (2 H, m), 3.1—3.4 (4H, m), 3.6—3.8 (2H, m), 4.8 — 5.0 (1 H, m), 5.93 (1 H, s), 7.01 (1 H, d, J = 7 Hz), 7.2—7.4 (5 H, m), 7.40 (1 H, t, J = 8 Hz), 7.5 0 (1 H, d, J = 8 Hz), 7.71 (1 H, s), 8. 2 1 (1 H, s) Example 1 3

 N— (2—acetylaminophenyl) 1 N— (1—phenethyl leviperidine 1—41) acetate oxalate

 4 1 (2-Acetylaminophenyl) Using amino-1-phenethylbiperidine and hydrochloride acetyl as in Example 3 (but using pyridine as the base) to give the title compound as white crystals Obtained.

m p: 1 8 0-1 8 3 ° C

¹ H NMR (CD ₃ OD, 400 MHz) 6: 1. 5— 1. 7 (1 H, m), 1. 78 (3 H, s), 1. 9— 2. 1 (2H, m) , 2.1 — 2.3 (1 H, m), 2. 19 (3 H, s), 2. 9 1 3.0 (2H, m), 3.0 — 3.2 (2 H, m), 3.2-3.4 (2 H, m), 3.5-3.7 (2 H, m), 4.5 -4. 7 (1 H, m), 7.2-7 , 4 (7H, m), 7.4—7.5 (1 H , m), 7. 9 2 (1 H, d, J = 8 H z).

IR (cm " ¹ , KB r): 340 8, 3 3 5 6, 1 6 9 3, 1 6.4 9, 1 5 8

9, 1 5 24, 1 450, 1 3 8 9, 1 2 94, 1 2 3 6, 1 1 1 9, 9 5 7, 76 0, 70 0, 6 1 5. Example 1 4

 N— (1—Phenethylbiperidine 4-yl) 1 N— (2_propioninoleaminofuel) Furan 2-2-rubonic acid amid oxalate

 (1) N- (1-phenethylenobibiperidine 4-yl) 1 N- (2-propionylaminophenyl) furan 2 _carboxylic acid amide

Using the 1-phenethyl 4- (2-propionylaminophenyl) aminobiperidine obtained in Reference Example 5, the title compound was obtained as white crystals in the same manner as in Example 5 (1).

¹ H NMR (CDC 13, 400 MHz) δ: 1. 1 6 (3 Η, t, J = 7 H z), 1.5 1 (1 H, dq, J = 4, 1 2 H z), 1. 6— 1.9 (2 H, m), 2.0 — 2.1 (1 H, m), 2.1 — 2.3 (2 H, m), 2. 34 (2 H, q , J = 7 H z), 2.5— 2. 6 (2H, lii), 2. 7-2. 8 (2 H, m), 2.9— 3.1 (2 H, m), 4 72 (1 H, tt, J = 4, 1 2 Hz), 5.6 3 (1 H, d, J = 3 Hz), 6. 1 8 (1 H, dd, J = l, 3 H z), 7.0-7.4 (8 H, m), 7.4-7.5 (2 H, m), 8.4 6 (1 H, d, J = 8 H z).

 (2) N- (1-phenethyl leviper 'gin 4-yl) -N- (2-propionylaminophenol) Furan 2-strong uronic acid amide oxalate

 Using N- (1-phenethylbiperidine 1-yl) 1-N- (2-propionyl ruaminophenyl) furan 2-strong rubonic acid amide as described in Example 1 (2) above. To give the title compound as white crystals.

¹ H NMR (CD ₃ OD, 40 OMH z) 5: 1. 1 3 (3 H, t, J = 7 H z), 1. 7— 1. 9 (1 H, m), 2.0 — 2 2 (2 H, m), 2.3-2.5 (3 H, m), 2. 9-3.1 (2 H, m), 3.1-3.3 (2 H, m) , 3. 6− 3. 8 (2 H, m) 8 (1 H m), 5 • 8 9 (1 H

, d, J = 3 H z), 6. 30 (1 H, d d, J = 1 3 H z), 7 2 1 7.

4 (7 H m) 7. 4 1 7 6 (2 H, m), • 8 9 (1 H, d J = 8 H z „So-

I R (c m-1

 , KB r); 3 3 0 0, 2 9 6 6, 1 7 5 7, 1 6 9 1, 1 6 2

8, 1 5 8 9, 1 56 0, 1 5 2 2, 1 4 7 1, 1 4 5 0, 1 4 0 0 J 1 348

, 1 2 9 0, 1 1 88, 1 1 1 9, 1 0 74, 1 0 4 9 J 1 0 3 0 9 5 5, 8

5 6, 7 5 2, 7 2 9, 6 9 8 Example 1 5

 N-_ (1-phenethylbiperidine 4-41 1) -Ν -_ ^ 3--propioninoleaminophenyl) furan 2-carboxylic acid amid oxalate

 (1) N— (3—2 Trophenyl) -N— (1—Phenethylpiperidine 4-yl) Furan 2--Strong rubonic acid amide

 The title compound was obtained in the same manner as in Example 5 (1) using 4- (3-nitrophenyl) amino-1-phenethylbiperidine.

¹ H NMR (CD C 1 3, 400 MHz) 6: 1.5 1 (2 H, dq, J = 4, 8 H z), 1. 9-2.0 (2 H, m), 2.2 3 (2 H, dt, J = 2, 1 2 H z), 2.5-2. 6 (2 H, m), 2. 7— 2. 8 (2H, m), 3. 0 — 3. 1 (2 H, m), 4.7-4. 9 (1 H, m), 6.2-6. 3 (2 H, m), 7.1-7. 3 (6 H, m), 7. 4— 7. 6 (1 H, m), 7.5 8 (1 H, t, J = 8 H z), 8.0 5 (1 H, t, J = 2 H z), 8. 2—8.3 (1 H, m).

(2) N— (3-Aminophenyl) 1 N_ (1-phenethylbiperidine 1- 4-yl) Furan 2-2-carboxylic acid amide

N- (3-Nitrophenol-Nole) 1-N- (1-Phenetinorepiperidine 4-Ninole) Furan 2-Canoleponic acid amide (6 1 4 mg, 1. 46 mm o 1) methanol (10 mL) Add 10% paradium-carbon (6 1 mg) to the solution and add 1 atmosphere at room temperature. Catalytic hydrogenation overnight at pressure. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure and recrystallized from ethyl acetate monohexane to obtain 4 94 mg (yield: 87%) of the title compound as white crystals.

¹ H NMR (CDC 1 ₃ , 40 OMH z) δ: 1.5 1 1.7 (2 H, m),

1.8-2. 0 (2 H, m), 2.1-2.3 (2 H, m), 2.5-2.6 (

2 H, m), 2. 7-2. 8 (2 H, m), 2. 9-3 1 (2 H, m), 3.

7 3 (2 H, s), 4. 7— 4. 9 (1 Η, m), 5.5 6 (1 H, d, J = 3

H z), 6. 16 (1 H, d d, J = 1, 3 H z), 6 4 6 (1 H, t, J =

2 H z), 6.5 6 (1 H, b r d, J = 8 H z), 6-7 1 (1 H, d d,

] = 2, 8 H z), 7. 1 — 7. 3 (6 H, m), 7. 3 7 (1 H, d, J = 1

H z).

(3) N— (1-phenethinorebiperidine 4-ynole) -N- (3-propionylaminophenol) Furan 2-strength rubonic acid amide

N- (3-Aminophenolinole) 1 N- (1-phenethylrebiperidine 4-yl) Furan 1-Carboxylic acid compound (l OO mg, 0.2 5 7 mm o 1) Add triethylamine- (0.08 ml) and propionyl chloride (2 7 / x L, 0.308 mmo 1) to a solution of black form (1.5 ml) at room temperature. Stir for 2 hours. The reaction mixture was poured into sodium bicarbonate water, extracted with chloroform, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from ethyl hexane acetate to obtain 10 O mg (yield 87%) of the title compound as white crystals.

¹ H NMR (CD C 1 ₃ , 400 MHz) δ: 1. 2 6 (3 H, t, J = 7 H z), 1.4 — 1. 7 (2 H, m), 1. 8—2.0 (2 H, m), 2.1-2.3 (2 H, m), 2. 4 2 (2 H, q, J = 7 H z), 2.5-2.6 (2 H, m), 2.7 — 2. 8 (2 H, m), 2.9 — 3. l (2 H, m), 4.7-4.9 (l H, m), 5 6 1 (1 H, d, J = 1 H z), 6. 1 5 (1 H, dd, J = 1, 3 H z), 6. 90 (1 H, brd, J = 8 H z ), 7.1-7.4 (9H, m), 7.67 (1H, brd, J = 8Hz). (4) N _ — (1-phenethylbiperidine 4-yl) — N—— (3-propionylaminophenyl) _furan 2-strong rubonic acid amid oxalate

Using the above N- (1_phenethylbiperidine monoyl) 1-N- (3-propioaminoaminofuryl) furan 2-strong rubonic acid amide in the same manner as in Example 5 (2). To give the title compound as white crystals.

m p: 2 0 2-2 0 6 ° C

¹ H NMR (CD ₃ OD, 40 OMH z) δ: 1.2 3 (3 H, t J = 7 H ζ), 1. 8 1 2. 0 (2 H m), 2. 2 5 (2 H, brd) 2 • 44 (

2 H, q, J = 7 H z), 2 • 9-3-1 (2 H, m), 3.1 1 3 3 • 4 (4 H

, M), 3.73 (2H, brd), 4.8 15.0 (1H, m) 5.85

(1 H, d, J = 3 H z), 6.3 3 (1 H, d d, J = 1, 3 H z) 7.0

4 (1 H, d d, J = 1, 8 H z), 7.2 ― 7.4 (5 H, m) 7-4 7 (

1 H, t, J = 8 H z), 7 • 5 3 (1 H, d, J = 1 H z), 7-6 2 (1 H

, D d, J = 1, 8 H z) 7 • 74 (1 H b r s) •

IR (cm— ¹ , Br)-3 2 6 9, 2 9 7 8, 1 6 8 0, 1 6 2 0 1 6 0

5, 1 5 6 0, 1 4 7 1, 1 4 3 9, 1 4 0 6, 1 3 4 6, 1 3 2 1 1 2 2 7

, 1 1 9 0, 1 1 3 0, 1 0 3 2, 9 4 7, 7 5 ϋ, 2 3, 7 0 6 5 9 2. Example 1 6

 N— (2-forminoreaminophenyl) -N- (1-phenethylrepiperidin 4-yl) Furan 2-strong rubonic acid amidoxalate

 (1) N- (2-forminoreaminophenol) 1 N— (1-phenethylbiperidine 1- 4-yl) Furan 1- canoleponic acid amide

 Triethylamine (5) was added to a solution of 4- (2-formylaminophenyl) amino-1 monophenethylpiperidine (5 8 mg, 0.18 mm o 1) obtained in Reference Example 4 in toluene (3 mL). 0 μL) and 2-Furoyl chloride (33 mg, 0.25 mm o)

1) was added and stirred at room temperature for 19 hours. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was analyzed by silica gel column chromatography (chloroform methanolate = 30/1). Purification gave 37 mg (yield 50%) of the title compound as pale tan crystals.

1 H NMR (CD C 1 a, 4 0 0 MH ζ) δ: 1.2-1. 5. (1 H, m), 1.6-2. 0 (2 H, m), 2.0-2 3 (3 H, m), 2.4 1 2 · 6 (2 H, m), 2.6 — 2. 8 (2 H, m), 2. 9 — 3.1 (2 H, m) , 4. 6-4. 8 (1 H, m), 5.4 0 (0.8 H, d, J = 3 H z), 5. 93 (0.2 H, brs), 6.1 0 (0. 8 H, dd, J = 1, 3 H z), 6. 2 1 (0. 2 H, brs), 7.0 — 7.5 (9 H, m), 7. 7 8 ( 0.2 H, brd, J = 8 H z), 8.5—8.7 (2 H, m), 9. 1 8 (0. 8 H, brs).

(2) N— (2—Honoreminoreaminophenole) -N- (1 —Phenetinoleviperidin — 4 yl) Furan 1 _Carboxylic acid amid oxalate

Using N- (2-forminoreaminophenyl) 1 N- (1-phenethylbiperidine- ₄ ^) furan 2_carboxylic acid amide as described in Example 1 (2) The title compound was obtained as white crystals.

m p: 1 2 6-1 3 3 ° C

¹ H NMR (CD a OD, 400 MHz) δ: 1. 6 ― 1-9 (1 H, m),

1. 9 2 .2 (2 H, m),, 2.3-2.5 (1 H, m), 2. 9 1 3. 1

(2 H, m), 3.1 1 3.4 (4 H, m), 3.6 ― 3-8 (2 H, m), 4

7—4.9 (1 H, m), 5., 9 1 (0.8 H, b r s), 6.0 0 (0.

2 H, b rs), 6.3 1 6., 4 (1 H, m), 2-7.4 (7 H, m)

, 7.4-7.6 (2 H, m),, 8. 2 8 (0. 8 H s) 8. 3 7 (1 H, d, J = 8 H z), 8.5 5 (0 2 H, s).

IR (cm ^-1 , KB r): 3 4 0 8, 3 0 3 0, 1 6 9 3, 1 6 3 7, 1 5 9 3, 1 5 6 0, 1 5 2 5, 1 4 5 4, 1 3 9 8, 1 3 4 2, 1 2 9 6, 1 2 3 4, 1 1 8 8, 1 1 3 2, 7 5 4, 7 0 2

Example 1 7 N —— (3-Acetinolemethinoreaminopheninole) —One N— (1-phenethinorebiperidine)

-4-inole) Furan 2—Strong rubonic acid salt oxalate

 (1) N- (3-acetylenomethinoreaminophenyl) — N— (1-phenethylepiperidine monoyl) 4-furan 2-carboxylic acid amide

 N- (3-acetylaminoamino) -N- (1-1 phenethylpiperidine-1 4 _yl) furan 2-2-rubonic acid amide (1 0 7 mg) obtained in Example 5 (1) , 0.248 mm o 1) in anhydrous DMF (2 mL) solution at 60 ° C. Sodium hydride (12 mg, 0.30 mm o 1) was added, and the mixture was stirred at room temperature for 15 minutes. To the resulting mixture was added methyl iodide (30 °, 0.48 mm o 1) and stirred at room temperature for 2 hours, followed by cold water and extraction with ethyl acetate, and the extract was washed with water and brine. And dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (Kokuguchi Form / Methanol = 30/1) to give 34 mg (yield 31%) of the title compound as a yellow oil. .

¹ H NMR (CD C 1 3, 400 0MH ζ) δ: 1. 4— 1. 7 (2 H, m), 1. 8 1 (3 H, brs), 1. 8— 2. 0 (2 H , m), 2.4 3 (2 H, dt, J = 2, 1 2 H z), 2.5— 2 · 7 (2 H, m), 2. 7— 2. 8 (2 H, m ), 3.0-3.1 (2 H, m), 3.25 (3 H, s), 4. 8 1 (1

H, tt, J = 4, 1 2 H z), 6. 0 0 (1 H, brs), 6. 20 (1 H, dd, J = 2, 3 H z), 6. 9 8 (1 H , Brs), 7.1—7.3 (8H, m), 7.46 (1H, t, J = 8Hz).

(2) N— (3 -acetylenomethinoreaminophenyl) 1 N— (1—phenethylepiperidine 1 4-yl) furan 1 2-carboxylic acid amid oxalate

 The above N- (3-acetylmethylmethylaminophenyl) 1 N- (1-phenethylbiperidine 1-yl) furan-2-strong rubonic acid amide was used in the same manner as in Example 1 (2). The title compound was obtained as pale yellow crystals.

¹ H NMR (CD a OD, 40 0MH ζ) δ: 1. 7— 2. 0 (2 H, m),

I. 8 1 (3 H, brs), 2.1 — 2.3 (2 H, m), 2. 9 — 3.1 (2 H, m), 3.1 — 3.5 (7 H, m), 3.6-3. 8 (2H, m), 4. 8 1 5 0 (1 H, m), 6.0 9 (1 H, brs) 6-3 3 (1 H, brs) 7.2-7. 7 (1 0 H, m)

IR (cm- ¹ , KB r): 34 1 9, 30 1 6 2 9 6 6 1 6 5 1, 1 6 4

5, 1 5 9 5, 1 5 5 6, 1 4 8 9, 1 46 8 1 4 2 1, 1 3 9 8, 1 340

, 1 3 1 7, 1 2 6 5, 1 1 8 8, 1 1 28 1 0 8 2 1 0 4 9, 1 0 3 0,

96 6 9 4 7, 8 8 5, 8 4 9, 7 6 8, 7 5 0 7 2 5 7 0 6, 6 2 3. Example 1 8

 N—— (1—Phenine Repiperidine 4-Nyl) —N— _ (2-Uray Dofenenole) Furan 2--Strong Rubonic Acid Amid Oxalate

 (1) 1-phenethyl 4- (2-ureidophenyl) aminopiperidine 4-1- (2-aminophenyl) amino-1-phenethylbiperidine (80 mg, 0.27mmo 1) obtained in Reference Example 1 To a solution of acetic acid (0.5 mL) —water (1 mL), add a solution of sodium sianate (35 mg, 0.54 mm o 1) in water (lmL) and stir at 35 ° C for 15 minutes. did. The reaction mixture was poured into aqueous sodium hydrogen carbonate, extracted with black mouth form, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (black mouth form Z methanol = 92Z8) to obtain 83 mg (yield 91%) of the title compound as white crystals.

1 H NMR (CD C 1, 400 MH ζ) δ: 1.5—1.7 (2 H, m), 2.0 — 2.2 (2 H, m), 2.2 1 (2H, brt ), 2.5-2. 7 (2 H, m), 2.7-2. 9 (2H, m), 2.9-3.0 (2 H, m), 3.2-3.4 (1 H, m), 4.0 — 4.4 (1 H, br), 4. 83 (2 H, brs), 6. 3 6 (1 H, brs), 6. 6 7 (1 H, dt, J = 1, 7 H z), 6. 7 1 (1 H, d, J = 7 H z), 7.1-7. 4 (7 H, m).

(2) N— (1—Phenethylbiperidine 4-yl) -N- (2-Ureidophenyl) Furan 2-Carboxylic acid amide

The title compound was obtained in the same manner as in Example 5 (1) using the above 1-phenethyl 1-41 (2-ureidophenyl) aminobiperidine. ¹ H NMR (CDC 1 3, 400 MHz) δ: 1. 3— 1.5 (1 H, m),

1. 7-1. 9 (1 H, m), 2.0 — 2.3 (4 H, m), 2.5 — 2.6 (2 H, m), 2. 7-2. 8 ( 2 H, m), 2. 9 1 3. 1 (2 H, m), 4.4 1 4. 8 (1 H, br), 5.0-6.0 (2 H, br), 5. 3 0 (1 H, brs), 6.0 6 (1 H, brs), 6. 9-7. 3 (8 H, m), 7.4-7.5 (1 H, m), 8. 5— 8. 7 (2 H, m).

(3) N- (1—Phenethylbiperidine 4-yl) 1 N— (2-ureidophenyl) Furan 2_Carboxylic acid amidoxalate

Using the above N— (1-phenethylleviperidin-4-yl-N- (2-ureidophenyl) furan-2-strong rubonic acid amide in the same manner as in Example 5 (2) The compound was obtained as white crystals.

m p: 2 0 3-2 0 7 ° C

¹ H NMR (CD ₃ OD, 40 OMH z) δ: 1.5 — 1. 7 (1 H, m),

1. 8— 2. 0 (1 H, m), 2. 0 7 (1 H, brd), 2. 2 9 (1 H, brd), 2. 7-3.1 (6 H, m), 3. 4− 3. 6 (2 H, m), 4 · 6— 5. 0 (1 H, m), 5. 8 2 (1 H, br-s), 6. 3 2 (1 H, dd , J = 1, 3 Hz), 7.0—7.4 (7 H, m), 7.4—7.5 (1 H, m), 7.5 1 (1 H, d, J = l H z), 8.13 (1 H, d, J = 8 H z).

IR (cm ^-1 , KB r): 3 4 2 9, 3 3 4 8, 1 7 0 5, 1 5 8 9, 1 5 5 8, 1 5 2 5, 1 4 7 0, 1 4 5 2, 1 4 0 4, 1 3 3 8, 1 3 0 2, 1 2 3 2, 1 1 8 8, 1 1 3 4, 1 1 1 7, 1 0 8 8, 1 0 3 2, 1 0 1 4, 9 5 8, 9 4 3, 7 6 2, 7 2 3, 7 0 0, 5 9 4, 4 4 7.Example 1 9

 N- (1-phenethylrebiperidine 1 4 _l) 1 N— (3-ureidophenol) Furan 1-carboxylic acid amid oxalate

(1) N- (1 —Phenetinorebiperidine 4-quinole) -N- (3-ureidophenyl) furan 2-carboxylic acid amide. Example 1 N- (3-Aminophenyl) 1 N— (1-phenethylbiperidine 1-yl) obtained in (2) Example 1 8 (1) To give the title compound.

¹ H NMR (CDC 1 3, 400 MHz) δ: 1. 3-2. 0 (4 Η, m), 1. 8— 2. 0 (2 H, m), 2.4 1 2.6 (2 Η, m), 2. 6— 2. 8 (2 Η, m), 2. 8— 3. 1 (2 Η, m), 4. 6— 4. 8 (1 Η, m), 5 0 6 (2 Η, s), 5.5 1 (1 Η, brs), 6. 1 4 (1 Η, dd, J = 1, 3 H z), 6. 6 6 (1 Η, brs) , 6. 8 2 (1 H, dd, J = 1, 8 H z), 7. 1—7.4 (7 H, m), 7-9 1 (1 H, d, J = 8 H z) , 8. 08 (1 H, brs).

(2) N— (1-Phenine Repiperidine 4- 4-Nole) — N— (3-Ureidophenyl) Furan 2 _Carboxylic acid salt oxalate

Using the above N- (1-phenethylrepiperidine-41-yl) -N- (3-ureidophenyl) furan-2-strong rubonic acid amide in the same manner as in Example 5 (2) The compound was obtained as white crystals.

m p: 200-202 ° C

¹ H NMR (CD ₃ OD, 40 OMH z) 5: 1. 8-2. 0 (2 H, m),

2. 1 7 (2 H, brd), 2.9 1 3.1 (2 H, m), 3-20 (2 H, brt), 3.2-3.4 (2 H, m) , 3. 6 8 (2 H, brd), 4.

8— 5. 0 (1 H, m), 5.8 0 (1 H, d, J = 3 H z) 6 • 3 0 (1 H

, D d, 1 = 2, 3Hz), 6. 8-7. 0 (1 H, m), 7 • 2 ― 7.4 (7

H, m), 7.5 1 (1 H, d, J = 2 H z), 7.5 6 (1 H b rs).

IR (cm ¹ , KB r): 34 27, 3 3 3 6, 2 9 70, 1 7 3 6, 1 68

0, 1 64 5, 1 6 20, 1 5 8 7, 1 5 5 6, 1 4 9 1, 1 4 6 6, 1 427

, 1 40 8, 1 3 7 1, 1 3 2 1, 1 2 6 9, 1 1 8 6, 1 1 3 0 1 0 30,

94 7, 90 6, 76 2, 7 48, 72 5, 6 9 8, 5 94, 4 7 6 Example 20 N- [2— (Methoxycarbonylamino) phenyl] -N- (1-phenethylbiperidine _ 4 yl) furan 2-carboxylic acid amid oxalate

 (1) 4 1 [2— (Methoxycarbonylamino) phenyl] Amino 1-phene chinolepiperidine

In a solution of 4- (2-aminophenyl) amino-1-phenethylbiperidine (80 mg, 0.27 mmol) obtained in Reference Example 1 in dichloromethane (l mL) -triethylamine (0. lmL), add ice. Under cooling, methyl methyl carbonate (23 L, 0.30 mm o 1) was added, and the mixture was stirred at the same temperature for 1 hour and then stirred at room temperature for a while. The reaction mixture was poured into sodium bicarbonate water, extracted with black mouth form, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate Z methanol = 95/5) to obtain 2 l mg (yield 22%) of the title compound. ¹ H NMR (CD C 1 3, 400 MHz) δ: 1.5 — 1. 7 (2 H, m), 2.0-2.1 (2 I- I, m), 2. 20 (2 H , brt), 2.5-2. 7 (2H, m), 2. 7-2. 9 (2 H, m), 2. 9-3.1 (2 H, m), 3.2-3 4 (1 H, m), 3.4-3. 8 (1 H, br), 3.7 7 (3 H, s), 6.2-6.5 (1 H, br), 6. 7—6.8 (2H, m), 7.08 (1H, brt), 7.1—7.4 (6H, m):

(2) N- “2— (Methoxycarbonylamino) furol” — N— (1-phenethylpiperidine di-4-yl) furan 2-carboxylic acid amide

The title compound was obtained in the same manner as in Example 5 (1) using the above 4- [2- (methoxycarbonylamamino) phenyl] amino-1-phenethylpiperidine.

1 H NMR (CD C 1 3, 400MH ζ) δ: 1. 4— 1. 6 (1 H, m), 1. 6— 1. 8 (1 Η, m), 1. 8— 1. 9 ( 1 H, m), 2.0 — 2. 1 (1 H, m), 2.1-2.3 (2 H, m), 2.5 — 2.6 (2 H, m), 2. 7-2.8 (2H, m), 2.9—3.1 (2H, m), 3.73 (3H, s), 4.6—4.8 (1H, m), 5. 6 4 (1 H, d, J = 3 H z), 6. 1 8 (1 H, dd, J = 1, 3 H z), 6. 9 1 (1 H, s), 7.0 — 7 5 (9 H, m), 8.2 3 (1 H, d, J = .8 H z). (3) N- [2-—Methoxycarbonylamino] phenyl] -N- (1-1phenethylpiperidine _4-ynole) furan 2-strong rubonic acid amidoxalate

Using the above N— [21- (methoxycarbonylamino) phenol] -N- (1_phenethylpiperidine-1-4-ΛΛ) furan-2-strong rubonic acid, Example 5 ( The title compound was obtained as white crystals in the same manner as 2).

¹ H NMR (CD ₃ OD, 400 MH ζ) δ: 1.5—1.7 (1 Η, m), 1.19 1 2. 2 (2 H, m), 2.3 _ 2. 5 (1 H, m), 2.9 _ 3.4 (6 H, m), 3.5 — 3. 8 (2 Η, m), 3.7 2 (3 H, s), 4.6 -5.0 (1 H, m), 5.90 (1 H, d, J = 3 H z), 6. 30 (1 H, dd, J = 1, 3 H z), 7.0 -7. 6 (9 H, m), 8.0 6 (1 H, d, J = 8 Hz). Example 2 1

 N— (3-Methanesulfonylaminophenol) 1 N— (1 Monophenylbiveridine _ 4—yl) furan 2—Strong rubonic acid amid oxalate

Example 1 N— (3-Aminophenyl) _N_ (1—phenethylpiperidine 1-4-ynole) obtained in 5 (2) Furan 2—force norevonamide (5 3 mg, 0.14 mm o 1) And triethylamine (29 / _i L, 0.20 mm o 1) in dichloromethane (1 mL) at 0 ° C under nitrogen atmosphere at 0 ° C. 4 mm o 1) was added and stirred at room temperature for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with black mouth form. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and an ethanol solution of oxalic acid (3 mg, 0.033 mm o 1) was added to the resulting white powder. The precipitated crystals were collected by filtration, washed with ethanol, and dried to give the title compound as white crystals (5 mg, yield 7%).

¹ H NMR (CD ₃ OD, 400 MHz) 5: 1. 7— 1. 9 (1. 3 H, m), 1. 9— 2. 0 (0. 7 H, m),. 2. 1— 2. 2 (1. 3 H, m), 2. 2—2.4 (0.7 Hm), 2.8—3.0 (: m), 2.94 (3Hs), 3.0—3.2 (2H, m), 3. 2-3. (4 H, m)., 4. 7—. 0 (1 H, m), 5 8-5. 9 (1 H, m), 3 1 (1 H, dd, J 2, 3 H z), 7. 0-7. 1 (1 H, m), 7.-7. 4 (7 H, m),. 4-7.5 (2 H, a) .Example 2 2

 N— (2-acetylaminophenyl) -N- [1— [2-(2-Chenyl) ethyl I piperidine 4-yl] furan 2-carboxylic acid amide — oxalate

 (1) 4— (2 — Acetylaminophenyl) Amino 1 — [2 — (2 — Chenyl) Ethinole] Piperidine

To a solution of 4-mono (2-acetylaminophenyl) aminopiperidine (140 mg, 0.60 mm o 1) obtained in Reference Example 7 to acetonitol (4 mL), methane sulphonic acid 2— (2— Chael) ethyl ester (13 Omg, 0.63 mm o 1), sodium carbonate (25 55 mg, 2.4 1 mm o 1) and sodium oxalate (18 mg, 0.12 mm) o 1) was added and heated to reflux. After cooling to room temperature, water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with water and hexane. After drying under reduced pressure, 163 mg (yield 79%) of the title compound was obtained as pale brown crystals.

1 H NMR (CD C 1 ₃ , 400 0MH ζ) δ: 1. 4— 1. 7 (2 H, m), 1. 8 8 (1.2 H, s), 2. 0— 2. 1 ( 2 H, m), 2.1—2.3 (2 H, m), 2.21 (1.8 H, s), 2.6—2.7 (2H, m), 2.8 — 3. 0 (2 H, m), 3. 0— 3.1 (2 H, m), 3.2 — 3.4 (1 H, m), 3.6 3 (0.6 H, brs ), 3. 9 7 (0. 4H, brd, J = 8 H z), 6.5-7. 3 (6.4 H, m), 7. 3 7 (0. 6 H, d, J = 7 H z).

(2) N- (2-Acetylaminophenyl) 1 N— [1— “2— (2-Cenyl) ethyl” Piperidine 1 4-yl フ ラ ン Furan _ 2— Power rubonic acid amide

Above 4— (2-acetylaminophenyl) amino 1 1 [2— (2 The title compound was obtained as pale yellow crystals in the same manner as in Example 5 (1) using ethethyl] piperidine.

 H NMR (CD C 1 4 0 0 MHz) δ 1 • 4 9 (1 H, d q, J = 4

, 1 2 H z), 1. 7 3 (1 H, d q, J = 4 1 2 H z), 1. 8 — 1. 9 (

1 H, m), 2.0 1 2.1 (1 H, m), 2 • 1 6 (3 H, s) 2. 1 1 2 •

3 (2 H, m), 2 • 5 1 2.7 (2 H, m) 2 9 — 3.1 (4 H, m)

4. 6 8 (1 H, t t J = 4, 1 2 H z) 5 • 5 9 (1 H, b r s) 6

• 1 7 (1 H, d d J = 1, 3 H z), 6-7 8 (1 H, d, J = 3 H z)

6.8 9 (1 H, d d J = 3, 5 H z), 7-0 ― 7.2 (3 H, m), 7 •

2 9 (1 H, b rs),. 4 4 (1 H, d t J = 2, 8 H z), 7. 7 9

(1 H, b r s) 8.4 5 (1 H, d, J 2 8 H z)-

(3) N— (2-acetylaminophenyl) -N- [1-[2-(2-Cenyl) ethyl] piperidine monoyl] furan mono 2-strong rubonic acid amidoxalic acid Salts N— (2-acetylaminophenyl) — N— [1 — [2-(2-Cheyl) echinole] Piperidine — 4-yl] Furan 1-strength rubonic acid amide In the same manner as in Example 1 (2), the title compound was obtained as white crystals.

m p: 1 8 5-1 9 1 ° C (decomposition)

¹ H NMR (CD ΟΌ / Ό O 1 0/1, 4 00 MHz) δ; 1.6 7 (

1 H, d q., J = 4, 1 3 H z), 1 • 9-2. 1 (2 H, m) 2-1 4 (3

H, s),. 2-2.3 (1 H, m), 2.8 1 3.0 (2 H m), 3.0

-3.3 (4 H, m), 3.4 1 3 • 6 (2 H, m), 4.6-4 • 7 (1 H, m), 5.8 3 (1 H, brs), 6.3 1 (1 H, dd, J 1 3 H z)

, 6. 9-7.0 (2 H, m),-2 1 7.4 (3 H, m), 7 • 4 8 (1 H

, D, J = 1 H z), 7.5 2 (1 H d t, J = 1, 8 H z) 7 • 9 2 (1

H, d, J = 8 H z).

IR (cm ¹ , KB r): 3 4 0 8 3 3 1 7 2 9 6 2, 1 6 7 6, 1 6 2

4, 1 5 9 3, 1 5 5 8, 1 5 2 5 1 4 6 8, 1 4 5 2, 1 4 0 0 1 3 7 1

, 1 3 3 5, 1 2 9 6, 1 2 3 8, 1 1 8 8, 1 1 1 5, 1 0 3 6 1 0 1 4, 9 6 2, 94 3, 754, 700, 6 1 5, 5 9 6. Example 2 3

 N— (3-acetylaminophenol) -N- [1-[2— (2-Chenyl) ethyl] piperidin 4-resin] furan 2-canoleponic acid amid oxalic acid salt

 (1) 4 1 (3-acetylaminophenyl) Amino 1 1 [2— (2-Chenyl) ethynole] Piperidine

 The reaction was carried out in the same manner as in Example 2 2 (1) using 41 (3-acetylaminophenol) aminobiperidine obtained in Reference Example 6, and column chromatography (ethyl acetate Z methanol = 20 / Purification by 1) gave the title compound as a pale yellow oil.

¹ H NMR (CDC 1 a, 400 0 MH ζ) δ: 1.4 1 1. 6 (2 Η, m), 1. 9-2.3 (4 H, m), 2. 1 3 (3 H , s), 2.6-2. 7 (2 H, m), 2.8-3. 0 (2 H, m), 3.0-3.1 (2 Η, m), 3.2- 3.4 (1 Η, m), 3.2-3.6 (1 Η, br), 6.34 (1 Η, brd, J = 8 H z), 6.5 8 (1 H, brd, J = 8 H z), 6. 8 2 (1 H, d, J = 3 H z), 6. 9 2 (1 H, dd, J = 3, 5 H z), 7. 0— 7.2 (3 H, m), 7.3-7.5 (1 H, br).

(2) N- (3-Acetinoreaminophenol) 1 N— [1— [2— (2-Chenyl) ethinore] Piperidine 1-yl] Furan 1— Power norlevonic acid amide

 Using the above 4- (3-acetylaminophenyl) amino-1- [2- (2-phenyl) ethyl] piperidine, the title compound was converted into white crystals in the same manner as in Example 5 (1). Obtained.

¹ H NMR (CD C 1 3, 400 MHz) δ: 1.5 2 (2Η, dq, J = 4, 1 2 H z), 1. 7— 1. 9 (2 H, m), 2.1 — 2.3 (2H, m), 2.22 (3H, s), 2.5-2.7 (2H, m), 2.9—3.1 (4H, m), 4. 7 3 (1 H, tt, J = 4, 1 2 H z), 5.5 6 (1 H, d, J = 3 H z), 6. 1 5 (1 H, dd, J = 1, 3H z), 6. 78 (1 H, dd, J = 1, 3 H z), 6. 8— 7. 0 (2 H, m), 7. 1 0 (1 H, dd, J = l, 5 H z), 7. 1 6 (1 H, brs ), 7. 3 1 (1 H, d,. J = 1 H z), 7. 3 6 (1 H, t, J = 8 H z), 7. 7—7.9 (2H, m).

(3) N— (3-acetylaminophenyl) — N— [1— [2— (2-Chenyl) ethinole] piperidine mono 4-quinole] furan 2- force olevic acid amid oxalate N — (3 -Acetylaminophenyl) -N- [1-[2 — (2-Chel) ethyl] piperidine 4-yl] furan 2-carboxylic acid amide Example 1 (2) To give the title compound as white crystals.

mp: 1 9 8-20 1 ° C (decomposition)

¹ H NMR (CD OD, 40 OMH z) δ: 1 • 8 1 2. 0 (2 H, m),

2. 1 3 (3 H, s), 2 • 1-2.3 (2 H, m) 3.1-3 • 4 (6 H, m) 3. 6-3. 8 (2 H, m) , 4.8 1 5-0 (1 Η, m) 5. 8 1 1

1 H d, J = 3 H z), 6 • 2 9 (1 H, d d J 1, 3 H z) 6. 9-

7. 1 (3 H, m), 7. 2 8 (1 H, d d, J 2 15 ζ ζ) 7 • 4 3 (1

H, t, J = 8 H z), 7 • 4 8 (1 H, b r s) ί 7.5 6 (1 H, b r d, J = 8 H z), 7. 6 7 (1 H, b r s)-

IR (cm ^-1 , KB r) '· 3 047, 3 0 2 2 1 74 1, 1 6 8 0, 1 64

9, 1 6 0 5, 1 5 6 8, 1 4 90, 1 4 6 6, 1 4 0 6, 1 3 7 9, 1 3 2 1

, 1 2 6 7, 1 2 34, 1 1 8 8, 1 1 4 9, 1 1 2 4 1 0 8 2 1 0 3 2,

9 8 7, 9 6 6, 94 5, 9 2 6, 90 4, 8 8 7 8 5 4, 7 9 6 7 64,

7 2 3, 7 6 9.Example 24

 N— (3-acetylaminophenyl) 1 N— [1 1 (1 1 methyl 1 2 1 phenylethyl) piperidine 1 4 —yl] furan 2 — strong rubonic acid amid oxalate

(1) 4-1 (3-acetylaminophenyl) 1-1 (1-methyl-2-phenylethyl) piperidine

4 1 (3-acetylamino minophenyl) aminobiperidine (150) obtained in Reference Example 6 m ○ g, 0. 64 3 mmo l) in acetonitrile (3 mL) solution of 2-bromo _ 1 monophenol- 1 (1 4 1 mg, 0.707 mm o 1), sodium carbonate (2 7 2 mg, 2.57 mm o 1) and sodium iodide (19 mg, 0.12 9 mmo 1) were added, and the mixture was heated to reflux for 24 hours. The reaction mixture was poured into water, extracted with black mouth form, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chlorophonolem Z methanol = 94 Z 6) to obtain 55 _mg (yield 24%) of the title compound. .

¹ H NMR (CD C 1 3, 400 MH ζ) δ: 0.97 (3 H, d, J = 6 H z), 1.4-1.6 (2 H, m), 1.9 — 2 2 (4H, m), 2.15 (3H, s), 2.4—3.8 (7H, m), 6.34 (1H, brd, J = 7Hz), 6. 54 (1 H, brd, J = 7 H z), 7.0 — 7.4 (8 H, m)-

(2) N— (3-acetylaminophenyl) 1 N— “1 _ (1-methyl-2-phenylenopiethyl) piperidine 4-41] furan 2- 2-canoleponic acid amide 3-Acetylaminophenyl) Amino compound 11 (11-methyl-2-phenylethyl) Piperidine was used to obtain the title compound in the same manner as in Example 5 (1).

¹ H NMR (CDC 1 3, 40 OMH z) δ • 0.90 (3 H, d, J = 7 H z), 1.4-1.6 (2 H, m), 1.7 ― 2 • 0 (2 H, m), 2 • 2 3 (

3 H, s), 2.3 5 (1 H, d d, J = 1 0 1 3 H z), 2.4-2.6 (

2 H, m), 2.7-3.0 (3 H, m), 2 • 9 4 (1 H, d d, J 2 4, 1

3 H z), 4.6-4. 8 (1 H, m), 5 5 4 (1 H, b rs), 6.1

4 (1 H, d d, J = 2, 3 H z), 6.90 (1 H, d, J = 8 H z), •

4 (8 H, m), 7. 9 1 (1 H, d J = 8 H z), 8.1 9 (1 H

, B r s).

(3) N— (3-acetylene nophenyl) N “1 1 (1-methinole 2 1-phenenole etinore) Piperidine 1- 4 yl] Furan 1 2 rubonic acid amide Acid salt

N_ (3-acetylaminophenyl) — N— [1 — (1 — methyryl 2-phenenoleethyl) piperidine 1- 4-inole] furan 2 _ canoleponic acid amide In the same manner as in Example 5 (2), the title compound was obtained as white crystals.

¹ H NMR (CD 3 OD, 4 0 0 ΜΗ ζ) δ: 1 2 2 (3 H, d, J = 7 H ζ), 1. 9 1 2. 1 (2 H m), 2. 1 6 ( 3 H s), 2. 2-2.4 (

2 H, m), 2. 75 (1 H, t, J = 1 3 H z) J 3.2 5 (1 H, d d, J

= 3, 1 3 Η z), 3.3-3.5 (2 H, m), 3 5-3.7 (3 H, m)

, 4.9-5.1 (1 H, m), 5.8 6 (1 H, d J = 3 H z), 6.3 3

(1 Η, d d, J = 2, 3 Hz), 7.07 (1 H j d d, J = 1, 8 Hz),

7. 2-7.4 (5 H, m) 7. 4 8 (1 H, t f J = 8 H z), • 5 2 (

1 Η, d, J = 2 Hz), 7 59 (1 H, d d, J = 1, 8 Hz), 7.7 4

(1st floor, b r s).

IR (cm— ¹ , KBr): 3 2 6 7, 1 6 8 6, 1 6 0 1, 1 5 5 6 1 4 7

0, 1 4 3 7, 1 4 0 4, 1 3 0 2, 1 1 9 0, 1 0 3 2, 7 5 4, 2 7, 7

0 4.Example 2 5

 N- _ (3-acetylaminophenyl) -N- [1- (2-Funoleo _ 2--Fenole Norole) Piperidine 4-41] Furan 1 -Carboxylic acid oxalate

(1) N-(3 -acetylaminophenyl) 1 N— [1 1 [2— (2 -furoyl

) Oxy-2 monophenethyl] biperidine 1 4-inole] furan-2 — carponamide

4_ (3-acetylaminoamino) aminobiperidine (1 5 7 mg, 0.67 3 mm o 1) obtained in Reference Example 6 was added to styreneoxide (0.08 mL, 0.74 0 mmo). 1) was added and stirred at 90 ° C. The reaction mixture was purified by silica gel column chromatography (ethyl acetate methanol = 9 1), and 4- (3-hydroxy-aminophenyl) amino 1- 1 (2-hydroxy 2-phenyl ether) pipet 1 85 mg of lysine was obtained as a mixture. This mixture was mixed with black mouth form (2 mL ), Triethylamine (0.3 mL) and 2-furoyl chloride (0.1 2 mL, 1.2 6 mm o 1) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with black mouth form, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 92 mg (yield 25%) of the title compound.

¹ H NMR (CDC 1 3, 40 OMH z) δ: 1. 3 ― 1-5 (2 H, m),

1. 6— 1. 8 (2 H, m), 2.1-2.4 (2 Η, m) 2. 2 1 (3 H, s), 2. 6 5 (1 H, dd, J = 3, 1 4 H z), 2 • 9 5 (1 H, dd, J

= 9, 1 4 Η ζ), 2. 7— 3. 1 (2 H, m), 4. 6 4 • 8 (1 H, m)

, 5.5 1 (1 Η, b r d, J = 2 H z), 6. 0 9 (1 H, d d, J = 3,

9 Η ζ), 6. 1 2 (1 Η, d d, 1 = 2, 3 ζ ζ), 6 • 4 8 (1 H, d d,

J = 2, 3 Η ζ), 6. 85 (1 H, d, J = 8 Η ζ) 6 • 9 9 (1 H, brs), 7. 15 (1 Η, d, J = 3 H z), 7.2-7 • 4 (8 H, m), 7

5 4 (1 Η, d, J = 2 Η z), 7. 9 4 (1 Η, b r d, J = 7 H z),

8. 1 0 (1 Η, b r s)

(2) N— (3-acetylaminophenol) 1N2 [1— (2-hydroxy-2-monophenol 4 ^) piperidine-4-amino] furan 2-streptolamide N— (3-acetylaminophenol) 1 N— [1 — [2— (2-Furoyl) oxy-2-phenolinoreethino] piperidine 1- 4-inole] furan 2—power norebon acid To a solution of amide (91 mg, 0.168 mm o 1) in ethanol (1 mL) was added 1 N aqueous sodium hydroxide solution (0.20 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with black mouth form, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 75 mg (yield: 100%) of the title compound.

¹ H NMR (CD C 1 3, 40 OMH z) δ: 1. 4— 1. 7 (2 Η, m), 1. 7— 1. 9 (2 Η, m), 2. 1— 2. 3 (1 Η, m), 2. 2 1 (3 Η, s), 2. 3 9 (1 Η, dd, J = 1 0, 1 2 Η ζ), 2.3-2. 6 (1 Η , m), 2. 4 8 (1 Η, dd, J = 3,. 1 2 Η ζ), 2. 7— 2, 9 (1 Η, b rd), 3.0-3.2 (1 H, brd), 4.6 3 (1 H, dd, J = 3, 1 0 Hz), 4.6-4. 8 (1 H, m) , 5.5 9 (1 H, d, J = 3 H z), 6. 16 (1 H, dd, J = 2, 3 H z), 6. 9 1 (1 H, d, J = 8 H z), 7.2-7.5 (8 H, m), 7. 80 (1 H, brd, J = 8 H z), 7. 8 6 (1 H, brs).

(3) N- (3 -acetylenoaminophenol) 1 N— [1 — (2 -Fluoro 2 — phenenoreethinole) Piperidine 4 yl] Furan 1 _ force norebonic acid amide

 N- (3-acetyl ether in a nitrogen stream in a solution of diethylaminosulfur trifluoride (DAST) (49 μL ·, 0.37 1 mm o 1) in dichloromethane (0.5 mL) Nophenyl) -N- [1 (2-Hydroxy 2 _phenyl) Piperidine 1 4-Inole] Furan 2—Strength norebonamide (8 3 mg, 0.1 8 5 mm o A dichloroethane (lm L) solution of 1) was added dropwise and stirred at the same temperature for 30 minutes. The reaction mixture was poured into aqueous sodium bicarbonate and extracted with black mouth form, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel force ram chromatography (black mouth honolem / methanol = 9 7/3 and hexane / ethyl acetate = 1 3) and the title compound was purified. 16 mg (yield 19%) was obtained.

¹ H NMR (CD C 13, 400 MHz) 6: 1.4-2. 0 (4 Η, m):,

2. 1-2. 3 (2 H, m)? 2. 2 3 (3 H, s), 2.5 6 (1 H, d d d

, J = 2, 1 4, 3 5 Hz) 2. 8 6 (1 H, ddd, J = 9, 1 4, 1 7 Hz), 2. 9 1 3.1 (2 H m) '4 6— 4. 8 (1 H, m), 5.5 4 (

1 H, b rs), 5.5 6 (1 H, d d d, J = 2, 9, 4 9 H z), 6 • 1

4 (1 Η, d d, J = 2, 3 H z), 6.90 (1 H, d, J = 8 H z), 7-

1 1 (1 Η, brs), 7-2— 7.4 (7 H, m), 7. 8 9 (1 H, brd, J = 8 H z), 8. 1 9 (1 H, brs) .

(4) N- (3-acetylene nophenyl) 1 N_ "1 1 (2-funoleoro 2 phenolinoyl) piperidine 4-yl] furan 2-carboxylic acid amide Oxalate

Using the N- (3-acetylaminophenyl) -N- [1- (2.-fluoro-2-phenenoleethyl) piperidine-4-ynole] furan 2-force nolevonic acid amide obtained above, Example 5 The title compound was obtained as a white powder in the same manner as (2).

1 H NMR (CD ₃ OD, 400 MHz ζ) δ: 1. 8— 2. 1 (2 H, m),

2. 1 3 (3 H, s), 2.1-2.4 (2 H, m), 3.2-3.5 (3 H, m), 3.5-3. 9 (3 H, m), 4.8—5.0 (1 H, m), 5.8 2 (1 H, d, J = 3 H z), 5. 96 (1 H, dd, J = 9, 4 9 H z), 6. 29 (1 H, dd, J = 2, 3 H z), 7.03 (1 H, d, J = 8 H z), 7.

3—7.6 (8 H, m), 7.70 (1 H, b rs). Example 26

c i s -N- (2-Acetinoreaminophenol) 1 N— (3-Methinole 1-Phenyl thiopiperidine 4-41) Furan 2—Strong rubonic acid amid oxalate

 (1) c i s -N- (2-acetylaminophenol) -N- (3-methinole 1-phenethylpiperidine 1- 4-inole) Furan 1

 The title compound was obtained as pale yellow crystals in the same manner as in Example 5 (1) using cis-4 1 (2-acetylaminophenyl) amino 1-methyl 1-phenethylpipe V gin obtained in Reference Example 9. Got as

¹ H NMR (CD C 1, 40 OMH z) δ: 1.15 (1.2 H, d, J =

7 H z), 1. 2 0 (1. 8 Η, d, J = 7 H z), 1 • 1 1 1. 3 (1 H, m

), 1, 5— 1. 7 (1 H ί m), 1. 9-2. 2 (1 H, m), 2. 1 3 (1

8 H, s), 2. 1 8 (1.2 Η, s), 2. 2 1 2 4 (1 H, m), 2.

4-2. 6 (2 H, m), 2.6-3.1 (5 Η, m) 4. 1 9 (0.4 H, tt, J = 4, 1 2 H z) 4.5 3 (0. 6 Η, tt J = 4, 1 2 H z),

5. 4 4 (0. 6 H, d, J = 3 Η ζ), 6. 0 7 (0 4 H, d, J = 3 H z

), 6. 1 4 (0. 6 H, d d, J = 1, 3 Η ζ), 6 2 1 (0. 4 H, d d

'J = 1, 3 H z), 6. 9-7.5 (9.6 Η, m) 7.9 0 (0. 4 H, brs), 8. 2 2 (0 6 Η, d,. J = 8 Η ζ), 8.4 3 (0. 4 H, d J = 8 H z)

(2) cis -N- (2-Acetylaminophenyl) — N— (3-Methyl-11-one phenethylbiperidine-41-yl) Furan 2-2-Lubonic acid amid oxalate Cis-N- (2-acetylaminophenyl) — N— (3-methyl-1-monopiperidine _41-yl) Furan-2-carboxylic acid amide Example 1 ( The title compound was obtained as white crystals in the same manner as 2).

m p: 1 4 9-1 5 3 ° C

¹ H NMR (CD ₃ OD, 40 OMH z) 5: 1. 3 1 (0. 6 H, d 7 H z), 1. 34 (2.4 H, d, J = 8 H z), 1. 6—2.1 (2), 2.04 (2.4H, s), 2.18 (0.6 H, s), 2.7—3 7 H, m), 3.5—3 7 (2H, m), 4.0—4.1 (0.2 H, 4.74 (0.8 H, tt, J = 4, 13 Hz), 5.84 (0.8 H, = 3 H z), 6.0 3 (0. 2H, d, J = 4H z) '6. 27 (0. 8 d, J = 2, 3 H z), 6. 3 1 (0. 2 H , dd, J = 2, 4 H z),-7.5 (9. 8 H, m), 7. 8 3 (0. 2 H, brd, J = 8 H z IR (cm ^-1 , KB r ): 343 3, 3 2 6 9; 2 9 6 8, 1 7 6 3, 9, 1 6 26, 1 5 8 9, 1 560, 1 5 2 7, 1470, 1 45 2, 1, 1 3 6 9, 1 2 9 2, 1 2 3 2, 1 1 84, 1 1 4 7, 1 1 1 7, 1 0 1 0 3 9, 1 00 9, 8 8 5, 84 9, 7 7 7, 7 5 2, 7 1 9, 7 00 Example 2 7

 trans -N- (2—acetylaminophenol) 1 N— (3—methynole 1 enethylpiperidine 1 4 _yl) furan 2—strong rubonic acid amid oxalate (1) trans—N— (2-acetylaminophenyl) 1 N— (3-methisole 1 1-phenethylbiperidine 1 4-yl) furan 1-carboxylic acid amide

Reference Example 10 Using the trans-4- (2-acetylaminophenyl) amino-3-methyl-1- 1-phenethylbiperidine obtained in 0, the title compound was prepared in the same manner as in Example 5 (1). Obtained as white crystals. . ¹ H NMR (CD C 1 3, 40 OMH z) δ: 1. 1 1 (3 H, d, J = 6 H z), 1.4 — 1. 7 (0. 8 H, m) 1. 8 — 2. 3 (4.2 H, m), 2. 1 0 (0. 6 H, s), 2. 1 1 (2 4 H, s), 2.5-2.6 (2 H, m ), 2. 7-2. 8 (2 H, m), 2 9 1 3. 1 (2 H, m) 4. 3—4.6 (0. 2 H, br), 4. 6— 4. 9 (0. 8 H, br), 5.47 (0. 8 H, brs), 5. 6 9 (0. 2 H, brs), 6. 1 4 (0. 8 H, brs), 6. 20 (0. 2H, brs), 7. 1-7.5 (9.2 H, m), 7. 76 (0. 8 H, brs), 8.3— 8.5 (1 H, m) .

(2) t r a n s -N- (2-acetylenylaminophenyl) — N— (3-Methylolene-phenethylrepiperidine-1-4-inole) —Furan 2—Norebon acid amide — oxalate

 Example 1 (2) using the above trans-N- (2-acetylaminophenyl) —N— (3-methinole-1 4-phenethylpiperidine-4-yl) furan-2-carboxylic acid amide ) To give the title compound as white crystals.

m p: 1 43-1 46 ° C

¹ H NMR (CD 3 OD, 40 OMH z) δ: ϊ. 1 7 (0.9 H, d, J =

6 H z), 1. 20 (2. 1 H, d, J = 6 H z), 1. 4— 1. 9 (0. 3 H, br), 2. 0— 2.5 (1. 7 H, br),. 2. 1 0 (2 · 1 H, s), 2. 1 3 (0.9 H, s), 2. 7-3.2 (4 H, m), 3.2- 3.4 (3H, m), 3.5—3.8 (2H, m), 4.7—5.2 (1H, br), 5.7—6.0 (1H, m ), 6.2-6.4 (1 H, m), 7.2-7. 7 (9.3 H, m), 7. 9 3 (0.7 H, brd, J = 7 H z) .

IR (cm— ¹ , KB r): 34 2 3, 3 3 04, 2 9 70, 1 6 9 1, 1 6 3 2, 1 5 8 9, 1 5 5 8, 1 5 24, 1 46 8, 145 0, 1 3 9 8, 1 3 3 5, 1 2 9 2, 1 2 3 8, 1 1 9 1, 1 1 3 6, 1 09 2, 1 0 3 9, 1 0 1 1,

7 5 6, 70 2. 'Example 2 8 cis — N— _ (3 -acetylaminophenyl) — N— (3 -methyl 1-1 -phenethylpiperidine 1-4 yl) furan 2 -strength rubonic acid amide

 (1) c i s -N- (3-acetylenominophenyl) 1 N— (3-methyl-1-phenethylpiperidine 1-4-yl) furan 2-carboxylic acid amide

 The title compound was obtained in the same manner as in Example 5 (1) using cis-4- (3-acetylaminophenyl) amino-3-methyl-11 monobibiperidine obtained in Reference Example 8 (3). Obtained as white crystals.

¹ H NMR (CD C 1 3 / CD ₃ OD = l 0/1, 400 MHz) δ: 1.2 1 (3 H, d, J = 7 H z), 1.2—1.4 (1 H, m), 1. 6 5 (1 H, dq, J = 4, 1 3 H z), 2.0 − 2.2 (1 H, m), 2. 1 5 (3 H, s ), 2.37 (1 H, dd, J = 3, 1 1 Hz), 2.4 1 2.6 (2 H, m), 2.6-3.0 (5 H, m), 4. 5 3 (1 H, tt, J = 4, 1 3 H z), 5. 6 4 (1 H, brs), 6. 1 7 (1 H, dd, J = l, 3 H z), 6. 6—7.5 (9 H, m), 7. 6—7.9 (1 H, br).

(2) c i s -N- (3 -acetylenoamino phenyl) —N— (3 -methylolene 1 -1 phenethylbiperidine 1 -4 yl) furan 1 2 -strength rubonic acid amid oxalate is -N- (3-acetinoreaminophenol-nor) 1 N- (3-methinole 1 1-phenethylrebiperidine 1-4-1 yl) Furan 2 2-force norebonic acid amide, In the same manner as in Example 5 (2), the title compound was obtained as a pale yellow powder.

¹ H NMR (CD 3 OD, 40 OMH z) 5: 1. 3 2 (3 H, d, J = 7 H z), 1. 6 — 1. 9 (1 H, br), 1. 9 2.2 (1 H, br), 2.1

3 (3 H, s), 2. 9—3.4 (7 H, m), 3.5 — 3. 7 (2, m)

4. 7-4. 9 (1 H, m), 5.8 0 (1 H, d, J = 3 H z) r 6. 2 9 (

1 H, d d, J = 1, 3 H z) J 6. 9-7. 6 (9 H, m), 7 '6 1 8.0

(1 H, b r).

IR (cm ^-1 , KB r): 3 4 2 5, 2 9 7 3, 1 7 3 6, 1 6 8 5, 1 6 3

7, 1 5 9 7, 1 5 6 0, 1 4 7 0, 1 4 3 7, 1 3 9 4, 1 3 7 1, 1 3 1 5

, 1 2 4 6, 1 1 8 4, 1 1 2 8, 1.0 3 1, 8 8 5, 5 4, 7 2 3, 7 0 2 Phenethylpiperidine-4-ynole) furan 2-carboxylic acid amino acid-oxalate

(1) t r a n s — N— (3-cetylaminophenyl) — N— (3-methylolene 1-phenethylrepiperidine 1-4-inore) furan 1-casreponic acid amide

 The title was obtained in the same manner as in Example 5 (1) using trans-4- (3-acetylenaminophenyl) amino 3-methyl-1-phenethylbiperidine obtained in Reference Example 8 (3). The compound was obtained as a pale yellow oil.

¹ H NMR (CDC 1 3, 4 0 0 MH ζ) δ: 1. 0 7 (3 H, d, J = 5 Η ζ), 1.4-2.3 (5 Η, m), 2. 2 0 (3 Η, s), 2.4 1 2. 6 (2 Η, m), 2.6-2. 8 (2 Η, m), 2. 9 1 3. 1 (2 Η, m), 4 5-4. 8 (1 Η, br), 5.57 (1 Η, brs), 6. 15 (1 H, brs), 6. 8-8. 2 (1 1 H, m).

(2) t r a n s — N— (3-acetylaminophenol) 1 N— (3-methinole L—phenethylepiperidine 1 4-inore) furan 2 _ canoleponic acid amine

'Trans-N- (3-acetylenoaminophenol-nor) 1-N- (3-methinole 1-one piperidine 1- 4-furan 1-canoleponic acid amide as described in Example 1 The title compound was obtained as white crystals in the same manner as (2).

1 H NMR (CD ₃ OD, 40 OMH z) 5: 1. 2 1 (3 H, d, J = 6 H z), 1. 6-2. 0 (1 H, br), 2.0 — 2.3 (1 H, br), 2. 1 3 (3 H, s), 2. 8—3.4 (7 H, m), 3. 6—3.8 (2 H, m), 4 9—5.1 (1H, br), 5.85 (1H, brs), 6.30 (1H, dd, J = 2, 3Hz), 6.9 (1 H, br), 7.2-7. 6 (8 H, m), 7. 6-7. 9 (1 H, br).

IR (cm ^-1 , KB r): 3 3 9 8, · 3 3 0 4, 3 2 7 0, 3 1 3 8, 2 9 6 4, 1 7 3 8, 1 6 8 6, 1 6 5 1, 1 6 20, 1 6 0 1, 1 5 5 8, 1 4 70

'1 4 3 5, 1 3 9 8, 1 3 7 1, 1 3 1 9, 1 28 6, 1 242, 1 1 8 6,

1 1 34, 1 0 90, 1 0 3 6, 9 7 6, 9 3 7, 8 8 5, 7 54, 7 2 7, 7

04. Example 3 0

c i s -N- (3—Methinole 1-Phenetinorepiperidine 1 4-Inole) -N- (3 —Ureidophenyl) Furan _ 2—Strong rubonic acid amid oxalate

 (1) c i s-4-(3-Aminophenyl) amino 1-Methyl-1-phenone Noripeperidine

Ethanol (4 mL) of cis-4- (3-acetylaminophenyl) amino-3-methylenolebiperidine (2 1 1 mg, 0.60 mm o 1) obtained in Reference Example 8 (3) ) To the solution were added 85% potassium hydroxide (2 3 8 mg, 3. 62 mm o 1) and water (l mL), and the mixture was heated to reflux for 51 hours. After cooling to room temperature, the reaction mixture was poured into water, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography .1 (black form / methanol = 20 1) to obtain 15.5 mg (yield 83%) of the title compound as a brown oil. It was. .

¹ H NMR (CD C 1 ₃ , 400MH ζ) δ: 0.97 (3 H, d, J = 7 H z), '1. 6— 1. 9 (2 H, m), 2.1 — 2. 2 (1 H, m), 2.2-2.7 (6 H, m), 2. 7—2.9 (2 H, m), 3.4-3.5 (1 H, m ), 3.2-3. 7 (3 H, br), 5. 95 (1 H, t, J = 2H z), 6.0-6.1 (2 H, m), 6. 94 ( 1 H, t, J = 8 H z), 7.1-7.3 (5 H, m).

(2). 1 8−4− [3− (6! ”1 —Putoxycanoleponylamino) Pheninole Ί Amino-3-methyl 1 1 1 Phenethylbiperidine

Tetrahydrofuran (3mL) of the above cis-4- (3-aminophenol) amino-3-methyl-1-phenethylinolebiperidine (73mg, 0.24mm o 1) ) —To a water (lmL) solution were added triethylamine (0.1 OmL) and di-tert-butyl dicarbonate (63 mg, 0.29 mm o 1), and the mixture was stirred at room temperature. The reaction mixture was poured into an aqueous sodium carbonate solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform formethanol: = 3 OZ l), and the title compound was obtained as a pale yellow oil, 97 mg (yield 100%). ) Obtained.

¹ H NMR (CD C 1 3, 400MH ζ) δ: 0.9. 6 (3 H, d, J = 7 H z), 1.5 1 (9 H, s), 1. 7-1. 9 (2 H, m), 2. 1— 2. 2 (1 H, m), 2. 2— 2. 7 (6 H, m), 2. 7— 2. 9 (2 H, m), 3.5 — 3.6 (1 H, m), 3.69 (1 H, brs), 6. 28 (1 H, dd, J = 2, 8 H z), 6.4-6.5 (2 H , m), 6.93 (1 H, brs), 7.03 (1 H, t, J = 8 Hz), 7.1-7. 3 (5 H, m).

(3) cis— N— [3— (tert-Butoxycanoleponinoleamino) fenenore] — N— (3-Methanole 1-Phenetinoleviperidin _4-inole) Furan 2—Powered oleonic acid

 In the same manner as in Example 5 (1), the title compound was prepared using the above cis-4- [3- (tert-ptoxycarbonylamino) phenyl] amino-3-methyl-11-phenylbiperidine. Obtained as a yellow oil.

_{^{1 H NMR (CD C 1 3}} , 400MH ζ) δ: 1. 1 9 (3 H, d, J = 7 Η ζ), 1. 2- 1. 3 (1 Η, m), 1. 5 1 ( 9Η, s), 1.6-1.7 (1Η, m), 2. 0— 2. 1 (1Η, m), 2.3—2.4 (1Η, m), 2.4 2.6 (2H, m), 2.6-2.9 (5 H, m), 4.5 3 (1 H, tt, J = 4, 1 3 Hz), 5.64 (1 H , d, J = 2 H z), 6. 1 6 (1 H, dd, J = 2, 4 H z), 6. 6 6 (1 H, brs), 6. 7-7. 3 (9 H , m), 7. 4 8 (1 H, brd, J = 8 H z).

(4) c N—— (3-Aminophenyl) -N- (3-Methyl-1, 4-Rubiperidine, 4-yl) Furan 2 r-force ruponic acid amide Cis— N— [3— (tert-ptoxycanoleponylamino) phenyl] — N— (3 -methyl-1 phenethylbiperidine 1 4-1 yl) furan 1 2-carbonic acid amide ( 1 05 mg, 0.208 mm o 1) was added with 4 mo 1 ZL hydrogen chloride / dioxane (1 mL) and stirred at room temperature for 3 hours. To the reaction mixture was added aqueous sodium carbonate solution, extracted with ethyl acetate, and washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as pale yellow orange crystals, 8 l mg (yield 9 7%) Obtained.

¹ H NMR (CD C 1 3, 400MH ζ) δ: 1. 1 9 (3 H, d, J = 7 H z), 1. 3—1.4 (1 H, m), 1. 7 2 ( 1 H, d,] = 4, 1 3 H z), 2.0-2.2 (1 H, m), 2.3 8 (1 H, dd, J = 3, 1 2 H z), 2 4-2. 6 (2 H, m), 2.6-3.0 (5 H, m), 3 · 8 5 (2 H, brs), 4.5 1 (1 H, tt, J = 4, 1 3 H z), 5. 6 3 (1 H, d, J = 3 H z), 6. 17 (1 H, dd, J = l, 3 H z), 6.3— 6. 8 (2 H, br), 6. 6 8 (1 H, dd, J = 1, 8 H z), 7.0-7. 3 (6 H, m), 7. 34 (1 H, d, J = 1 H z).

(5) c i s— N— (3-methizole 1-phenethinorepiperidine 1- 4-inole) 1 N 1 (3-ureidophenyl) furan 2-2-carboxylic acid amide

 Example 1 8 Using the above ci s -N- (3-Aminophenol-Nole) 1 N- (3-Methyl-1-phenethyl piperidine 1 4 _yl) furan 2-carboxylic acid amide

The title compound was obtained as white crystals in the same manner as (1).

1 H NMR (CDC 1 a / CD ₃ ΟΌ = 1/1 0, 40 ΟΜΗ ζ) δ: 1. 2 3 (3 Η, d, J = 7 Η ζ), 1.4-1. 6 (1 Η , m), 1. 7— 1. 9 (1 Η, m), 2. 2— 2. 4 (1 Η, m), 2.4— 3. 1 (8 Η, m), 4.5— 4. 6 (1 Η, m), 5. 6 9 (1 Η, d, J = 3 H z), 6. 25 (1 H, dd, J = 1, 3 H z), 6. 6— 7. 8 (1 0 H, m).

(6) cis -N- (3-Methylolone 1.-Phenethylbiperidine 4-Ninore) 1 N -(3-Ureidophenyl) Furan 2-Strength rubonic acid amid oxalate. is -N- (3-Methinole 1-Phenetinorebiperidine 4- 4-Nole) 1 N- (3-ureidophenyl) Furan 2-Carboxylic acid amide, as in Example 1 (2) The title compound was obtained as pale yellow crystals.

¹ Η NMR (CD ₃ OD / D ₂ 0 = 1 0/1, 40 OMH z) δ: 1. 2 9 (3 Η, d, J = 6 H z), 1. 6-1. 8 (1 Η, m), 1. 8— 2. 1 (1 H 'm), 2.6-3.5 (9 H, m), 4.6-4. 7. (1 H, m), 5. 7 3 (1 H, brs), 6. 30 (1 H, dd, J = 2, 3 Η ζ), 6. 6—7.4 (8 H, m), 7. 50 (1 H, d , J = 2 H z), 7.5-7. 9 (1 Η, br).

Example 3

 4— “N— (3—acetylaminophenol} _ one N— (2-furoyl) amino” one

1-Phenethyl Piperidine 1-4 Methylol sulfonic acid oxalate

 (1) 4— [N— (3-acetylaminophenol) 1 N— (2-furoyl) amino] 1 1-phenethylbiperidine 1 4 1-methyl canoleponate

Reference Example 11 The title compound was obtained in the same manner as in Example 5 (1) using 4- (3-acetylaminophenyl) amino-1-phenethylpiperidine-IV. Obtained.

¹ H NMR (CDC 1 3.400 MHz) 6: 1. 6— 1. 9 (2 H, m), 2. 1 9 (3 H, s), 2.3 — 2. 7 (6 Η, m ), 2. 7— 2. 9 (4 Η, m), 3. 7 8 (3 Η, s), 5.44 (1 Η, d, J = 3 Η ζ), 6.1-6.2 (1 Η, m), 7.0—7.5 (9 Η, m), 7.8—8.0 (2 Η, m)

(2) 4-[Ν— (3-acetylylaminophenyl) monosaccharide— (2-furoyl) amino] 1-phenethylbiperidine _ 4-carboxylic acid methinoside oxalate

The above 4— [(-(3-acetylene.minophenyl) 1 一 — (2-furoyl) Mino] 1-phenethylbiperidine 1-methyl 4-carboxylate Example 5 (

The title compound was obtained as white crystals in the same manner as 2).

¹ H NMR (CD 3 OD, 400 MHz) δ: 2. 0— 2 • 2 (2 H, m),

2. 1 4 (3 H, s), 2. 6 1 (2 H, brd), 2. 9 1 3 • 1 (2H, m), 3.2 — 3.7 (6 H, m), 3 8 5 (3 Η, s) ί 5 • 6 3 (1 H, d, J = 3 H z), 6. 29 (1 H, dd, J = 1, 3 Η ζ), 7 • 1 8 (1 H

, B r d, J = 8 H z), 7.2-7.4 (5Η, m), 7 4 8 (1 H, t

, J = 8 H z), 7.5 1 (1 H, d J = 1 Η ζ), 7. 64 (1 H, brd, J = 8 H z), 7. 84 (1 H, brs) .

IR (cm— ¹ , KB r): 3 3 8 1 3 0 3 2, 1 740 1 6 8 6, 1 6 3

7, 1 5 9 7, 1 5 5 2, 1 46 8, 1 4 3 3, 1 3 9 6, 1 3 5 6, 1 3 3 2

, 1 2 79, 1 2 3 6, 1 2 1 3, 1 1 8 4, 1 14 2, 1 0 9 2, 1 034,

9 9 9, 9 54, 9 1 6, 8 8 5, 8 0 2, 7 58, 7 1 2

Example 3 2

 (Pharmacological experiment) ·

 I. Measuring method

 (1) Binding to human μ opioid receptor; affinity

The binding test for μ-obioid receptor was performed using a membrane marker of human iobioreceptor (GenBank Accession No. L 2 5 1 1 9) expressed in C HO— Κ 1 cells by gene transfer. (RECEPTORBIOLO GY IN C.). “ ³ H” DA MG O was used as the radioligand.

In the presence of the test substance, add a membrane preparation and a final concentration of 5 nM “ ³ H” D AMG O 2 2. Incubate at C for 2.5 hours. The reaction was stopped by suction filtration with a GF / B filter using a cell harvester, and washed with Tris-HC 1 buffer. The radioactivity remaining on the membrane was measured with a liquid scintillation counter. The specific binding amount of “ ³ H” D AM.GO is the same as the total binding amount. It was calculated as the difference in the amount of binding in the presence of radioactive naloxone 100 nM.

Calculate the binding rate in the presence of each concentration of the test substance for the specific binding of Γ ³ H ”DAMGO, and IC _{5 using} Graph Pad Prism. The value was determined.

(2) Analgesic action (acetic acid rising method)

ICR male mice were used as 8 mice per group. A test substance was subcutaneously administered 30 minutes later, and a 0.6% acetic acid aqueous solution (0.1 mL / L O g body weight) was intraperitoneally administered. Thereafter, the number of rising that occurred in 20 minutes was counted. ED ₅ from the suppression rate for the number of expression in the control group. The value was calculated.

(3) Peripheral and central (systemic) sex; treatment with opioid receptor antagonist

ICR male mice were used as 8 mice per group. Peripheral administration of 5 mg Zk g of naloxone methioxide, a peripheral _μ _ obioid receptor antagonist that does not cross the blood-brain barrier, or naloxone hydrochloride, an integral μ-obioid receptor antagonist, 1 The test substance was administered subcutaneously after 0 minutes. Twenty minutes later, a 0.6% acetic acid aqueous solution was intraperitoneally administered (0.1 mLZ l O g body weight), and the number of rising that occurred in the subsequent 20 minutes was counted. We compared the rise rate of the test substance alone group with that of the naloxone methoidide or naloxone hydrochloride pretreatment group.

I I. Test results

 Test results

(1) μ — Binding experiment to receptor [Table 18]

(2) Analgesic effect [Table 19]

(3) Peripheral and central (systemic) sex / X-opioid receptor antagonistic antagonist studies

[Table 2 0

From the above Tables 18 and 19, it was revealed that the compound of the present invention has an excellent binding affinity for the μ-receptor and an excellent analgesic action. Further, from Table 20, it was clarified that the analgesic action of the compound of the present invention is almost completely antagonized by the peripheral mu-obioid receptor antagonist (the analgesic action is almost eliminated). In the above antagonistic test (3), the analgesic effect of funnintanil was not affected by the pretreatment of peripheral antagonist, but disappeared completely by the pretreatment of systemic antagonist. On the other hand, the analgesic action of oral peramide was almost completely antagonized by peripheral antagonists. From the above results, it was confirmed that the analgesic action of fentanyl is not caused by peripheral -obioid receptors but is expressed through central / -opiopoid receptors. It was also confirmed that the analgesic action of oral peramide was expressed through peripheral μ-obioid receptors.

Claims

 The following general formula (I),

Word

of

Surrounding

(In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 members, or an alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, or a substituent. May have 1 to 3 halogen atoms, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. Or a 6-membered heterocyclic group,

R ² is an acylamine group having 1 to 6 carbon atoms, Ν— (an acyl having 1 to 6 carbon atoms) — Ν— (an alkyl having 1 to 6 carbon atoms) an amino group, an alkyl group having ² to 6 carbon atoms (thiocarbon) Represents an amino group, a ureido group, a thioureido group, an alkoxycarbonylamino group having 2 to 6 carbon atoms, or an alkylsulfonylamino group having 1 to 6 carbon atoms, wherein R ² is substituted at the ortho or meta position. Yes,

R ³ represents a hydrogen atom, an alkoxycarbonyl group having 2 to 8 carbon atoms, or a methyl group substituted with an alkoxy group having 1 to 6 carbon atoms,

R ⁴ is a halogen atom as a substituent, an alkyl group having 16 carbon atoms, 1-6 carbon atoms An alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom, a nitro group, a cyano group, or a phenyl group which may have 1 to 3 amino groups, or a 5- or 6-membered ring Represents a heterocyclic group of

R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a halogen atom,

R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ⁷ represents a hydrogen atom or a methyl group,

 M represents 1 or 2. )

 Or a salt thereof.

2 R ² is an acylamine group having 1 to 6 carbon atoms, an alkynole (thiocarbon) amino group, ureido group or thioureido group having 2 to 6 carbon atoms, or a compound or a salt thereof according to claim 1 .

3. The compound or a salt thereof according to claim 1, wherein R ² is an acetylamino group or a urea group.

4. The compound or a salt thereof according to any one of claims 1 to 3, wherein the substitution position of R ² is the meta position. ,

 The compound or a salt thereof according to any one of claims 1 to 4, wherein 5 m is 1.

The compound or a salt thereof according to any one of claims 1 to 5, wherein 6 R is a hydrogen atom.

7. The compound or a salt thereof according to any one of claims 1 to 6, wherein R ³ is a hydrogen atom or an alkoxycarbonyl group having 2 to 6 carbon atoms.

The compound or salt thereof according to any one of claims 1 to 6, wherein 8 R ³ is a hydrogen atom.

9 The compound or salt thereof according to any one of claims 1 to 6, wherein R ³ is an alkoxycarbonyl group having 2 to 6 carbon atoms.

10. The compound or a salt thereof according to any one of claims 1 to 9, wherein 10 R ¹ is an alkyl group having 1 to 6 carbon atoms or a 3- to 8-membered cycloanolalkyl group.

The compound or a salt thereof according to any one of claims 1 to 9, wherein 1 1 R ¹ is a furyl group or a chael group. . Any one of claims 1 to 11, wherein the heterocyclic group in the 5- or 6-membered heterocyclic group optionally having a substituent of 1 2 R ⁴ is a chenyl group, a pyrazolyl group, or a pyridyl group The compound or its salt as described in the said term.

The compound or a salt thereof according to any one of claims 1 to 11, wherein 1 3 R ⁴ is a phenyl group which may have a substituent.

The compound or a salt thereof according to any one of claims 1 to 13, wherein 14 R ⁵ is a hydrogen atom.

1 5 R ⁶ is a compound or salt thereof according to any one of claim first to 1-4, wherein the claims are hydrogen atoms.

 1 6 An analgesic comprising the compound or salt thereof according to any one of claims 1 to 15 as an active ingredient.

 1 7 The analgesic according to claim 16 wherein the analgesic action is peripheral