HK1059082A - 2,2-diphenylbutanamide derivatives and medicines containing the same - Google Patents

Description

2, 2-diphenylbutanamide derivatives and drugs containing the same

Technical Field

The present invention relates to 2, 2-diphenylbutanamide derivatives or their salts exhibiting excellent peripheral analgesic activity and analgesic activity against neuropathic pain; and a medicament containing the derivative or salt.

Background

Known analgesic drugs include centrally acting opioid analgesics, such as morphine; non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin; and local analgesic drugs such as lidocaine (The journal Medicinal Chemistry, vol.42, No.9, p.1481, 1999, incorporated herein by reference).

However, morphine exhibits adverse side effects of central action, thus limiting the use of morphine. Meanwhile, the existing non-steroidal anti-inflammatory drugs and local analgesic drugs show insufficient analgesic activity for some pains. Therefore, there is a need for a drug exhibiting safety and high analgesic activity as compared with the above drugs.

In recent years, The presence of mu-receptors in peripheral organs has been reported, and analgesic activity represented by these receptors is now being elucidated (The Journal of pharmacological and experimental Therapeutics, Vol.248, No.3, p.1269, 1989; The Journal of Investigative Dermatology, Vol.111, p.297, 1988; and Drug Therapy, Vol.323, p.1685, 1995).

Japanese patent application publication (kokai) No.47-173 discloses diarylpiperidinobutyramide compounds. Among these compounds, loperamide, developed as an antidiarrheal, is now under development as a peripheral analgesic (Anesthesiology, Vol.90, p.225, 1999; and the journal of Pharmacology and Experimental Therapeutics, Vol.289, p.494, 1999).

However, loperamide does not necessarily exhibit satisfactory peripheral analgesic activity.

Neuropathic pain is caused by, or induced by, a primary injury to the nervous system or a dysfunction of that system. Examples of neuropathic pain include herpes zoster pain, diabetic pain, chronic pain after surgery or trauma, pain after dental treatment, and pain after bone marrow damage/cerebral stroke. The level of neuropathic pain is significantly higher than would be expected from a noxious stimulus applied to a body part suffering from neuropathic pain.

The analgesic drug has low analgesic activity on neuropathic pain. For example, NSAIDs that block the formation of pain producing substances do not relieve acute pain.

Accordingly, an object of the present invention is to provide a compound exhibiting excellent peripheral analgesic activity and excellent analgesic activity against neuropathic pain.

Disclosure of the invention

In view of the foregoing, the inventors have conducted extensive studies in order to produce the above-mentioned compound exhibiting excellent analgesic activity, and found that a 2, 2-diphenylbutanamide derivative represented by the following formula (1), which exhibits remarkably excellent peripheral analgesic activity and neuropathic pain relieving activity as compared with the above-mentioned loperamide, can be used as a medicament. The present invention has been completed based on this finding.

Accordingly, the present invention provides a 2, 2-diphenylbutanamide derivative represented by the following formula (1):

[ wherein A represents- (CH)₂)_n- (n is 1 or 2) or methine (CH); when A is-CH₂-when B represents a methine group or a nitrogen atom, wherein a and B form a single bond; when A is- (CH)₂)₂-when B represents a nitrogen atom, wherein a and B form a single bond; and when a is methine, B represents a quaternary carbon atom, wherein a and B form a double bond;

R¹and R²Are each the sameOr different, represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group; or R¹And R²May form a heterocyclic ring together with the adjacent nitrogen atom; and Ar represents a phenyl group, a bicyclic aromatic ring, a monocyclic heterocyclic ring, a bicyclic heterocyclic ring, or a fluorenyl group, which may have a substituent represented by the following group:

(wherein R is³Represents a hydrogen atom, a halogen atom, phenyl, lower alkyl, or-O-R⁴(wherein R is⁴Represents a hydrogen atom, a lower alkyl group, or- (CR)⁵R⁶)_m-Y (wherein R⁵And R⁶Each represents a hydrogen atom or a lower alkyl group; y represents-COOR⁷，-OR⁸，-OCOR⁹or-CONR¹⁰R¹¹(wherein R is⁷、R⁸And R⁹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group; and R¹⁰And R¹¹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹⁰And R¹¹May form a heterocyclic ring together with the adjacent nitrogen atom); and m is 1-6)))](ii) a Or a salt of the derivative.

The present invention also provides a medicament comprising the 2, 2-diphenylbutanamide derivative (1) or a salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition comprising the 2, 2-diphenylbutanamide derivative (1) or a salt thereof and a pharmaceutically acceptable carrier.

The present invention also provides a method for treating peripheral pain or neuropathic pain, comprising administering 2, 2-diphenylbutanamide derivative (1) or a salt thereof.

The invention also provides application of the 2, 2-diphenyl butanamide derivative (1) or a salt thereof in preparing a peripheral analgesic drug or a neuropathic pain relieving drug.

Brief Description of Drawings

FIG. 1 shows the time to onset of pain response measured for each drug used in test example 2.

Best Mode for Carrying Out The Invention

In the 2, 2-diphenylbutanamide derivative (1) of the present invention, when n of a in formula (1) is 1, the ring is assumed to be a piperazine ring, and when n is 2, the ring is assumed to be a homopiperazine ring. Among these, a piperazine ring is preferable (n ═ 1).

With R¹And R²Examples of lower alkyl groups represented include C1-C6 linear or branched alkyl groups. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Preferred examples of cycloalkyl groups include C3-C8 cycloalkyl groups. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Among these, R¹And R²Particularly preferred are a hydrogen atom and a C1-C6 alkyl group, respectively.

Is formed by R¹And R²The number of atoms of the heterocyclic ring formed together with the adjacent nitrogen atom is preferably 3 to 6. Examples of the heterocyclic ring include aziridine ring, pyrrolidine ring, piperidine ring, piperazine ring, and morpholine ring. Pyrrolidine rings are particularly preferred.

Examples of the group represented by Ar include bicyclic aromatic rings such as naphthalene rings; monocyclic heterocycles such as pyridine ring, pyrimidine ring, pyrazine ring, and thiazole ring; and bicyclic heterocycles such as quinoline and isoquinoline rings.

Ar is preferably phenyl which may have a substituent. From R³Examples of the halogen atom represented are a fluorine atom and a chlorine atom. Examples of lower alkyl groups include C1-C6 linear or branched alkyl groups. Specific examples include alkyl groups as described above.

substituent-O-R⁴R of (A) to (B)⁴Represents a hydrogen atom, a lower alkyl group, or- (CR)⁵R⁶)_m-Y. From R⁵Or R⁶Examples of lower alkyl radicals represented by the lines C1-C6A linear or branched alkyl group. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. R⁵And R⁶Each is preferably a hydrogen atom. In- (CR)⁵R⁶)_min-Y, m is 1 to 6, preferably 1 to 3.

In the group-COOR represented by Y⁷，-OR⁸，-OCOR⁹or-CONR¹⁰R¹¹In the formula (II) is represented by R⁷、R⁸、R⁹、R¹⁰Or R¹¹The lower alkyl groups represented are C1-C6 linear or branched alkyl groups. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Preferred examples of cycloalkyl groups include C3-C8 cycloalkyl groups. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Preferably, R⁷Is a hydrogen atom or an ethyl group; r⁸Is a hydrogen atom or a methyl group; and R⁹Is methyl.

Is formed by R¹⁰And R¹¹The number of atoms of the heterocyclic ring formed together with the adjacent nitrogen atom is preferably 3 to 6. Examples of the heterocyclic ring include aziridine ring, pyrrolidine ring, piperidine ring, piperazine ring, and morpholine ring.

Preferred examples of the phenyl group which may have a substituent include a phenyl group and a phenyl group having a substituent at an ortho position. Preferred examples of the substituent include a methyl group, a chlorine atom, a fluorine atom, a hydroxyl group, and a methoxy group.

There is no particular limitation on the salts of the 2, 2-diphenylbutanamide derivative of the present invention, as long as the salts are pharmacologically acceptable. Examples of the salts include addition salts of inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid; and addition salts of organic acids such as formic acid, acetic acid, fumaric acid, maleic acid, and tartaric acid. The compounds of the present invention include solvates, such as hydrates, as well as polybasic acid salts.

The compounds of the present invention are obtained by using the following formulae (1-1), (1-2) and (1-3)Represents:

[ wherein R¹、R²And n have the same meaning as described above; and Ar' represents a phenyl group, a bicyclic aromatic ring, a monocyclic heterocyclic ring, a bicyclic heterocyclic ring, or a fluorenyl group, which may have a substituent represented by the following group:

(wherein R is^3’Represents a hydrogen atom, a halogen atom, phenyl, lower alkyl, or-O-R⁴(wherein R is⁴Represents a hydrogen atom, a lower alkyl group, or- (CR)⁵R⁶)_m-Y (wherein R⁵And R⁶Each represents a hydrogen atom or a lower alkyl group; and Y represents-COOR⁷，-OR⁸or-OCOR⁹(wherein R is⁷、R⁸And R⁹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group), m is 1 to 6)))]；

(wherein R is¹And R²Have the same meaning as described above; and R^3”Represents a hydrogen atom, a halogen atom, phenyl, lower alkyl, or-O-R⁴(wherein R is⁴Represents a hydrogen atom, a lower alkyl group, or- (CR)⁵R⁶)_m-Y (wherein R⁵And R⁶Each represents a hydrogen atom or a lower alkyl group; and Y represents-COOR⁷，-OR⁸，-OCOR⁹or-CONR¹⁰R¹¹(wherein R is⁷、R⁸And R⁹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group; and R¹⁰And R¹¹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹⁰And R¹¹May form a heterocyclic ring together with the adjacent nitrogen atom), m is 1 to 6)))](ii) a And

(wherein R is¹、R²And R^3”Having the same meaning as described above).

The 2, 2-diphenylbutanamide derivatives and their salts of the present invention can be produced, for example, by the following methods a to L.

Production of a compound represented by the formula (1-1):

(method A)

(in the above formula, X represents a halogen atom, and R¹、R²N and Ar have the same meanings as described above).

Specifically, furylideneammonium compound (2) is reacted with compound (3) to obtain compound (1a) of the present invention. The reaction is carried out in the presence of a base (generally 2 to 5 equivalents, preferably 3 equivalents) at 40 to 140 deg.C (preferably 80 to 120 deg.C) for 1 to 18 hours. The reaction can be carried out in an anhydrous solvent such as benzene, toluene, xylene, tetrahydrofuran or dimethylformamide. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide; and organic bases such as triethylamine.

Compound (2) can be synthesized by a known method [ r.a. stokbrokx et al, j.med.chem., 16, 782(1973) ].

Compound (3) can be synthesized by the following method, or can be commercially available.

1) The compound (3) represented by the following formula (3-1) is commercially available.(in the above formula, n and R^3’Have the same meaning as described above. ) Examples of commercially available compounds include N- (2-methoxyphenyl) piperazine (N ═ 1, R^3’＝2-OCH₃)。

2) The following compound (3-2) was synthesized by the following method.

Compound (3-2) can be synthesized in hydrobromic acid under heating. In addition, the compound (3-2) can be produced by a synthesis method using boron tribromide, or a method using ethanethiol and aluminum chloride.

3) The following active halides of heterocyclic compounds can be synthesized by nucleophilic substitution reaction of piperazine or homopiperazine and an active halide in a solvent under heating.

(in the above formula, Z represents a leaving group, and n and Ar have the same meanings as described above.)

The reaction does not necessarily require a solvent. Specific examples of the solvent that can be used include toluene, xylene, and pseudocumene. The reaction temperature is suitably 100 ℃ and 170 ℃. The reaction time is preferably 4 to 24 hours.

The following commercially available products can also be used.

4) Compound (3) can be synthesized by the method described in the following publications.

1) S.L. Buchward et al, Angew.chem.int.Ed.Engl.34, 1348 (1995).

2) J.P.Wolfe et al, Acc.chem.Res., 31, 805-818 (1998).

(in the above formula, n and Ar have the same meanings as described above.)

Preferably, bis (tri-o-tolylphosphine) palladium (II) dichloride [ PdCl ] is used₂(P (o-tolyl)₃)₂]As a catalyst; using the bromide of the halogen compound as a leaving group; and potassium tert-butoxide in an amount of 1 to 2 equivalents is used as the base. Preferred examples of the solvent used include toluene, xylene, and pseudocumene. Reaction temperatureThe degree is approximately 100-170 ℃. The amount of catalyst is 0.5 to 10 mol%, preferably 5 mol%. The reaction time is preferably 4 to 24 hours.

(method B)

(in the above formula, m is 1-6; R¹、R²、n、R⁵、R⁶And Y has the same meaning as described above; and Z represents a halogen atom, methanesulfonate, toluenesulfonate, or trifluoromethanesulfonate. )

Specifically, the compound (1b) is reacted with the compound (4), thereby obtaining the compound (1c) of the present invention. The reaction is carried out in the presence of a base (preferably 1 to 3 equivalents, preferably 1 to 1.5 equivalents) at 20 to 100 deg.C (preferably 20 to 60 deg.C) for 2 to 36 hours. The reaction can be carried out in an anhydrous solvent such as acetone, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. Examples of the base include inorganic bases such as sodium carbonate, sodium hydroxide, and sodium hydride; and organic bases such as triethylamine. The base may be used in combination with potassium iodide.

Compound (4) is conveniently available as a commercial reagent, or can be synthesized by known methods.

(method C)

(in the above formula, R¹、R²N and m have the same meanings as described above. )

Specifically, compound (1d) (i.e., wherein R is⁵And R⁶Compound (1c)) which is H and Y is OAc, to obtain compound (1e) of the present invention.

(in the above formula, R¹、R²N and m have the same meanings as described above. )

Compound (1f) synthesized by Process B (i.e., ProcessWherein R is⁵And R⁶Compound (1c)) wherein H and Y are COOEt is hydrolyzed to obtain compound (1g) of the present invention.

The above reaction is carried out in the presence of a base (generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents) at 20 to 40 deg.C (preferably 20 to 25 deg.C) for 1 to 5 hours. The above reaction may be carried out in a solvent capable of being mixed with water, such as methanol, ethanol, dioxane or tetrahydrofuran. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide and sodium carbonate.

Preparation of a Compound represented by the formula (1-2):

(method D)

(in the above formula, X represents a halogen atom; R¹And R²Have the same meaning as described above; and R^3-1Represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group. )

Specifically, furylideneammonium compound (2) is reacted with compound (5) to obtain compound (1-2a) of the present invention. The reaction is carried out in the presence of a base (generally 2 to 5 equivalents, preferably 3 equivalents) at 40 to 100 deg.C (preferably 50 to 60 deg.C) for 1 to 18 hours. The reaction can be carried out in an anhydrous solvent such as benzene, toluene, xylene, tetrahydrofuran or dimethylformamide. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as triethylamine. The above-mentioned compound (2) can be synthesized by a known method [ r.a. stokbrokx et al, j.med.chem., 16, 782(1973) ]. The method for synthesizing the above compound (5) will be described below in reference examples.

(method E)

(in the above formula, R¹、R²、R⁵、R⁶N and Y have the same meanings as described above; and X represents a halogen atom, methanesulfonate, toluenesulfonate, or triflateAn alkylsulfonate. )

Specifically, the compound (1-2b) is reacted with the compound (6), thereby obtaining the compound (1-2c) of the present invention. The reaction is carried out in the presence of a base (generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents) at 20 to 100 deg.C (preferably 20 to 60 deg.C) for 1 to 36 hours. The reaction can be carried out in an anhydrous solvent such as acetone, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. Examples of the base include inorganic bases such as sodium carbonate, sodium hydroxide and sodium hydride; and organic bases such as triethylamine. The base may be used in combination with potassium iodide. The above-mentioned compound (6) can be conveniently obtained as a commercial reagent, or can be synthesized by a known method.

(method F)

(in the above formula, R¹、R²、R⁵、R⁶、R⁹And n has the same meaning as described above. )

The compounds (1-2e) of the present invention can be produced by hydrolysis of the compounds (1-2 d). Specifically, the compound (1-2d) is hydrolyzed in the presence of a base (1-3 equivalents, preferably 1-1.5 equivalents) at 20-40 deg.C (preferably 20-25 deg.C) for 1-5 hours. The reaction may be carried out in a solvent capable of being mixed with water, such as methanol, ethanol, dioxane or tetrahydrofuran. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and sodium carbonate.

(method G)

(in the above formula, R¹、R²、R⁵、R⁶、R⁷And n has the same meaning as described above. )

Specifically, the compound (1-2f) is hydrolyzed to obtain the compound (1-2g) of the present invention. The reaction is carried out in the presence of a base (generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents) at 20 to 40 deg.C (preferably 20 to 25 deg.C) for 1 to 5 hours. The reaction may be carried out in a solvent capable of being mixed with water, such as methanol, ethanol, dioxane or tetrahydrofuran. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and sodium carbonate.

Preparation of a Compound represented by the formula (1-3):

(method H)

(in the above formula, R¹And R²Have the same meaning as described above. )

Compound (8) is produced from furylideneammonium compound (2) and compound (7) in a similar manner to (method a), and compound (8) is dehydrated, thereby obtaining compound (1-3a) of the present invention. The dehydration reaction is carried out by adding an excess of acid to the compound (8), and then refluxing the resulting mixture under heating for several hours. The reaction may be carried out by using a solvent such as alcohol, tetrahydrofuran or dioxane. Examples of acids that may be used include hydrochloric acid and sulfuric acid.

(method I)

(in the above formula, R¹、R²、R⁵、R⁶N and Y have the same meanings as described above; and X represents a halogen atom, methanesulfonate, toluenesulfonate, or trifluoromethanesulfonate. )

The above reaction is carried out in a similar manner to (method E).

(method J)

(in the above formula, R¹、R²、R⁵、R⁶、R⁹And n has the same meaning as described above. )

The above reaction is carried out in a similar manner to (method F). Specifically, the compounds (1 to 3c) are hydrolyzed to obtain the compounds (1 to 3d) of the present invention.

(method K)

(in the above formula, R¹、R²、R⁵、R⁶、R⁷And n has the same meaning as described above. )

The above reaction is carried out in a similar manner to (method G). Specifically, the compounds (1 to 3e) are hydrolyzed to obtain the compounds (1 to 3f) of the present invention. (method L)

(in the above formula, R¹、R²And R³Have the same meaning as described above. )

The compound (1-3) is reduced to obtain the compound (1-2) of the present invention. The reduction reaction is carried out in a hydrogen atmosphere in the presence of a catalyst such as palladium, palladium/carbon, rhodium or platinum black (1 to 50% by weight based on the whole of the compound (1 to 3)) at room temperature to elevated temperature and under ambient pressure or with the application of pressure for 1 to 10 hours. Preferred solvents include ethanol, methanol and aqueous alcohols. If desired, small amounts of acid may be added.

The salt of the 2, 2-diphenylbutanamide derivative of the present invention is obtained, for example, by reacting compound (1) with an acid (1 to 3 equivalents, preferably 1 equivalent) in an anhydrous solvent at 0 to 30 ℃ for 0.1 to 0.5 hours. Examples of the solvent include anhydrous ether, anhydrous tetrahydrofuran, anhydrous chloroform, anhydrous dioxane, and anhydrous acetone. Examples of the acid include the above-mentioned acids.

The 2, 2-diphenylbutanamide derivatives of the present invention or their salts thus obtained can be purified by a combination of column chromatography and recrystallization.

As described in the test examples below, the 2, 2-diphenylbutanamide derivatives or their salts of the present invention exhibit excellent mu-opioid agonist activity and analgesic activity against fenvalerate-induced pain, and thus can be used as drugs, such as neuropathic pain relief drugs and peripheral analgesic drugs for mammals (including humans) and other animals. The peripheral analgesic drug of the present invention can be used for preventing or alleviating pain caused by various diseases such as cancer and inflammatory diseases, surgery, injury, fracture and burn.

Pharmaceutical compositions of various forms can be produced from the 2, 2-diphenylbutanamide derivatives or their salts of the present invention by a conventional method. The mode of administration is not particularly limited, and may be appropriately selected depending on the purpose of treatment. For example, the composition may assume any configuration such as oral medication, injection, suppository, ointment or patch. These shaped products can be produced by the usual methods, which are known to the person skilled in the art.

The oral solid medicine is prepared as follows. The 2, 2-diphenylbutanamide derivative or a salt thereof of the present invention is mixed with excipients (and, if necessary, additives such as a binder, a disintegrant, a lubricant, a coloring agent, a sweetener or a flavoring agent), and the resulting mixture is processed by a conventional method to form a product such as a tablet, a coated tablet, a granule, a powder or a capsule.

Oral liquid medicine is prepared as follows. The 2, 2-diphenylbutanamide derivative or its salt of the present invention is mixed with additives such as a sweetener, a buffer, a stabilizer or a flavoring agent, if necessary, and the resulting mixture is processed by a conventional method to obtain a product such as an internal liquid medicine.

Injections were prepared as follows. The 2, 2-diphenylbutanamide derivative or its salt of the present invention is mixed with an additive such as a pH adjuster, a buffer, a stabilizer, an isotonic agent or a local anesthetic, and the resulting mixture is processed by a conventional method to obtain an injection such as subcutaneous injection, intramuscular injection or intravenous injection.

Suppositories are prepared as follows. The 2, 2-diphenylbutanamide derivative or its salt of the present invention is mixed with a known carrier for the production of pharmaceuticals, such as polyethylene glycol, lanolin, coconut oil or fatty acid triglyceride (and if necessary additives such as surfactants), and the resulting mixture is further processed by a conventional method to obtain suppositories.

The ointment was prepared as follows. The 2, 2-diphenylbutanamide derivative or its salt of the present invention is mixed with a conventional base, stabilizer, wetting agent or preservative if necessary, and the resulting mixture is further processed by a conventional method to obtain an ointment.

The patch is prepared by applying the above ointment, cream, gel or paste to a common carrier by a conventional method.

The amount of the 2, 2-diphenylbutanamide derivative or its salt of the present invention to be incorporated into a unit of physical form varies depending on the health condition of a patient in need of treatment or the physical form of the drug. Preferably, the amount of derivative or salt introduced into a physical unit is from about 0.25 to about 100mg in the case of oral drugs, from about 0.05 to about 20mg in the case of injections, and from about 0.1 to about 50mg in the case of suppositories. The daily dose of the medicine having the above-described configuration varies depending on the health condition, body weight, age and sex of the patient. The daily dosage of the drug for adults is usually about 0.005 to about 2mg/kg, preferably about 0.01 to about 0.1 mg/kg. The medicament is preferably administered once daily or about 2-4 times daily separately. Examples

The present invention is described in detail below by way of examples, which should not be construed as limiting the invention.

Reference example 1

4-bromo-2, 2-diphenylbutyric acid (23g, 72mmol) was suspended in chloroform (150 mL). Thionyl chloride (20mL, 270mmol) was added dropwise at room temperature. DMF (0.2mL) was then added and the mixture was heated and refluxed for 4 hours. Thereafter, the solvent was evaporated under reduced pressure, whereby 23g of 4-bromo-2, 2-diphenylbutyryl chloride was obtained (yield 94.7%).

A50% aqueous dimethylamine solution (8g, 90mmol) and sodium carbonate (18g, 170mmol) were suspended in water (100mL) and the suspension was cooled to a temperature between 0 and 5 ℃. To the cooled suspension was added dropwise 4-bromo-2, 2-diphenylbutanoyl chloride (23g, 68mmol) prepared above dissolved in toluene (100 mL). The mixture was stirred for 2 hours, after which the aqueous layer was washed with toluene, followed by extraction with chloroform, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was crystallized from methyl isobutyl ketone to obtain 11g of dimethyl (tetrahydro-3, 3-diphenyl-2-furylidene) ammonium bromide (yield 46.8%).

¹H-NMR(CDCl₃)δ(ppm)：2.96(3H，s)，3.47(2H，t)，3.83(3H，s)，4.85(2H，t)，7.40-7.60(10H，m)

Reference example 2

The procedure of reference example 1 was repeated except for using pyrrolidine instead of the 50% aqueous dimethylamine solution, to obtain a (tetrahydro-3, 3-diphenyl-2-furylidene) pyrrolidinium bromide (yield 53.6%).

¹H-NMR(CDCl₃)δ(ppm)：1.80-2.30(4H，m)，2.88(2H，t)，3.50(2H，t)，4.37(2H，t)，4.88(2H，t)，7.25-7.70(10H，m)

Reference example 3

Piperazine (610mg, 7.08mmol), 2-bromonaphthalene (1.04g, 5.02mmol), sodium tert-butoxide (680mg, 7.08mmol) and bis (tri-o-tolylphosphine) dichloro palladium (II) [ PdCl [ -PdCl [ ]₂(P (o-tolyl)₃)₂](200mg, 0.247mmol) was added to pseudocumene (bp 169 ℃ C.; 20mL) and the mixture was stirred under reflux for 24 hours. Subsequently, the reaction mixture was diluted by adding tetrahydrofuran, and the diluted solution was filtered with celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and 7% MeOH/CHCl₃The eluate was concentrated under reduced pressure, whereby 546mg of 1- (2-naphthyl) piperazine, an interesting product, was obtained as a pale yellow solid (yield 51.5%). MS (EI) m/z: 212 (M)⁺)

¹H-NMR(CDCl₃)δ(ppm)：1.99(1H，s)，3.05-3.15(4H，m)，3.21-3.32(4H，m)，7.13(1H，d，J＝1.9Hz)，7.20-7.35(2H，m)，7.35-7.50(1H，m)，7.60-7.80(3H，m)

Reference example 4

Piperazine (610mg, 7.08mmol) and 4-chloroquinoline (820mg, 5.01mmol) were added to pseudocumene (20mL) and the mixture was refluxed for 8 hours. Subsequently, the solvent contained in the reaction mixture was evaporated under reduced pressure. A1N aqueous sodium hydroxide solution was added to the residue. Thereafter, the resulting mixture was extracted with chloroform, followed by drying over dehydrated magnesium sulfate and concentration under reduced pressure. Subjecting the residue to silica gel column chromatography, and subjecting to AcOEt, MeOH and Et₃The eluate, N85: 15: 1, was concentrated under reduced pressure. Thus, 738mg of 1- (4-quinolyl) piperazine (yield 69.0%) as a pale yellow solid, which is an interesting product, was obtained.

MS(EI)m/z：213(M⁺)

¹H-NMR(CDCl₃)δ(ppm)：1.73-1.96(1H，br)，3.05-3.36(8H，m)，6.77-6.88(1H，m)，7.40-7.54(1H，m)，7.58-7.70(1H，m)，7.96-8.10(2H，m)，8.67-8.76(1H，m)

Reference example 5

1- (3-methoxyphenyl) piperazine (3.0g, 15.6mmol) was added to 48% hydrobromic acid (25mL) and the mixture was heated at 140 ℃ for 5 hours. After cooling, the pH of the mixture was adjusted to 9 with 3N aqueous sodium hydroxide solution. Subsequently, the resultant mixture was extracted with chloroform, followed by drying over anhydrous magnesium sulfate. After concentration under reduced pressure, ether (50mL) was added to the residue, and the light red precipitate was collected by filtration to obtain 2.2g of 1- (3-hydroxyphenyl) piperazine as an interesting product (yield 79.1%).

MS(FAB)m/z：179(M+H)⁺

¹H-NMR(DMSO)δ(ppm)：2.70-2.85(4H，m)，2.90-3.00(4H，m)，6.18(1H，dd，J＝2.0，7.8Hz)，6.27(1H，s)，6.33(1H，d，J＝7.8Hz)，6.96(1H，t，J＝7.8Hz)，9.00(1H，br)

Example 1

Dimethyl (tetrahydro-3, 3-diphenyl-2-furylidene) ammonium bromide (350mg, 1.01mmol) and 1-phenylpiperazine (150mg, 0.899mmol) were dissolved in anhydrous dimethylformamide (20 mL). Sodium carbonate (200mg, 1.89mmol) was added and the mixture was stirred at 110 ℃ for 4 h. Subsequently, the solvent was evaporated from the reaction mixture under reduced pressure. The resulting residue was dissolved in ethyl acetate, followed by washing with water, drying over anhydrous magnesium sulfate, and concentration under reduced pressure. The residue was purified by silica gel column chromatography. The 5% MeOH/AcOEt eluate was concentrated under reduced pressure, whereby 373mg of 4- (4-phenylpiperazin-1-yl) -N, N-dimethyl-2, 2-diphenylbutanamide (compound No.1) which was a pale yellow oil of interest was obtained (yield 97.1%).

The thus-obtained meaningful compound is converted into amorphous powder of hydrochloride salt by the following procedure to enhance water solubility and facilitate pharmacological tests. Further, compound nos.2 to 51 obtained as described below were similarly processed to obtain amorphous powders of hydrochloride salts, which were then subjected to pharmacological tests.

(preparation of hydrochloride salt)

The above meaningful product (compound No.1, 360mg, 0.834mmol) was dissolved in anhydrous ether (30 mL). Under ice-cooling, a 1N hydrochloric acid-ether solution (0.9mL) was added to crystallize. The precipitated white precipitate was collected by filtration, followed by washing with ether and drying, to obtain 330mg of the hydrochloride of the above-mentioned interesting product (i.e., the hydrochloride of compound No.1) (yield 84.5%).

Examples 2 to 41, 46 and 47

A procedure similar to example 1 was carried out to obtain compound Nos.2-41, 46 and 47 shown in the following relevant tables.

Example 42

4- [4- (2-hydroxyphenyl) piperazin-1-yl 1-N, N-dimethyl-2, 2-diphenylbutanamide (Compound No.36) (1.1g, 2.5mmol) was dissolved in anhydrous dimethylformamide (20 mL). 2-bromoethyl acetate (0.5g, 3.0mmol) and potassium carbonate (0.4g, 3.0mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added to water, followed by extraction with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.7g of ethyl 2- [2- [4- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperazin-1-yl ] phenoxy ] acetate (compound No.42) (yield 51.0%).

Examples 44, 48 and 50

A procedure similar to example 42 was carried out, whereby compound nos.44, 48 and 50 shown in the following relevant tables were obtained.

Example 43

Ethyl 2- [2- [4- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperazin-1-yl ] phenoxy ] acetate (compound No.42) (560mg, 1.0mmol) was dissolved in methanol (5 mL). A1N aqueous solution of sodium hydroxide (5mL) was added, and the mixture was stirred at 50 ℃ for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform, washing with water, and drying with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography, whereby 440mg of 4- [4- [2- (2-hydroxyethoxy) phenyl ] piperazin-1-yl ] -N, N-dimethyl-2, 2-diphenylbutanamide (compound No.43) was obtained (yield 85.9%).

Examples 45, 49 and 51

The procedure was carried out in analogy to example 43, so as to obtain the compounds nos.45, 49 and 51 shown in the relevant tables below.

Example 52

4- [4- (2-hydroxyphenyl) piperazin-1-yl]-N, N-dimethyl-2, 2-diphenylbutanamide (Compound No.36) (1.24g, 2.80mmol), ethyl α -bromoisobutyrate (6.00g, 30.8mmol), and anhydrous potassium carbonate (2.00g, 14.5mmol) were added to anhydrous dimethylformamide (20mL), and the mixture was stirred at an external temperature of 50 ℃ for 16 hours. At the completion of the reactionAfter that, dimethylformamide was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting mixture was washed with water and dried over anhydrous sodium sulfate. Subsequently, ethyl acetate was evaporated under reduced pressure, and the residual oily substance was subjected to column chromatography using silica gel (60 g). 2% MeOH/CHCl₃The eluate was concentrated under reduced pressure, whereby 820mg of 2- [2- [4- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] interesting product was obtained as a pale yellow oil]Piperazin-1-yl]Phenoxy radical]Ethyl 2-methylpropionate (Compound No.52) (yield 52.6%).

Example 53

2- [2- [4- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl]Piperazin-1-yl]Phenoxy radical]Ethyl-2-methylpropionate (compound No.52) (660mg, 1.18mmol) was dissolved in a solvent mixture of 1N aqueous sodium hydroxide solution (10mL), methanol (10mL) and 1, 4-dioxane (10 mL). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was added to water. The resulting mixture was neutralized to pH7 with dilute hydrochloric acid, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Chloroform was evaporated under reduced pressure, and the residual oily substance was crystallized from ether, whereby 356mg of the interesting product 2- [2- [4- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl group was obtained as colorless crystals]Piperazin-1-yl]Phenoxy radical]2-Methylpropionic acid (Compound No.53) (yield 57.1%). TABLE 1TABLE 2TABLE 3

Compound No.	R3	Yield (%)	Performance of	Melting point (decomposition)
					28	2-CH3	99.8	Light yellow oil
29	3-CH3	93.0	Light yellow oil
					30	4-CH3	95.0	Light yellow oil
31	2-F	97.8	Light yellow oil
					32	4-F	97.8	Light yellow oil
33	2-Cl	96.4	Light yellow oil
					34	3-Cl	96.4	Light yellow oil
35	4-Cl	98.6	Light yellow oil
					36	2-OH	98.9	Light yellow oil
37	3-OH	93.6	Light yellow oil
					38	4-OH	92.5	Light yellow oil
39	2-OCH3	97.4	Light yellow oil
					40	3-OCH3	89.2	Light yellow oil
41	4-OCH3	89.8	Colorless crystal	139-140
					42	2-O(CH2)2OCOCH3	50.9	Light yellow oil
43	2-O(CH2)2OH	85.9	Light yellow oil
					44	2-OCH2COOC2H5	74.3	Light yellow oil
45	2-OCH2COOH	51.2	Colorless crystal	125-126
					52	2-OC(CH3)2COOEt	52.6	Light yellow oil
53	2-OC(CH3)2COOH	57.1	Colorless crystal	173-174

TABLE 4

Compound No.	R3	Yield (%)	Performance of	Melting point (decomposition)
					46	H	98.5	Light yellow oil
47	2-OH	95.9	Light yellow oil
					48	2-O(CH2)2OCOCH3	60.0	Colorless crystal	158-159
49	2-O(CH2)2OH	68.5	Light yellow oil
					50	2-OCH2COOC2H5	73.1	Light yellow oil
51	2-OCH2COOH	46.4	Colorless crystal	150-151

TABLE 5

Compound No.	Mass(EI：M+)	1H-NMRδ：ppm(CDCl3)
			1	427	2.07-2.18(2H，m)，2.22-2.42(3H，br)，2.42-2.58(6H，m)，2.86-3.06(3H，br)，3.10(4H，t，J＝5.0Hz)，6.80(1H，t，J＝7.2Hz)，6.87(2H，d，J＝8.0Hz)，7.16-7.32(4H，m)，7.32-7.47(8H，m).
2	477	2.12-2.25(2H，m)，2.25-2.46(3H，br)，2.46-2.58(2H，m)，2.58-2.78(4H，br)，2.86-3.20(7H，m)，7.03(1H，dd，J＝7.4，1.1Hz)，7.22-7.56(14H，m)，7.74-7.84(1H，m)，8.08-8.18(1H，m).
			3	477	2.09-2.22(2H，m)，2.24-2.44(3H，br)，2.44-2.70(6H，m)，2.87-3.14(3H，br)，3.14-3.34(4H，br)，7.05(1H，s)，7.10-7.55(13H，m)，7.55-7.76(3H，m).
4	503	2.07-2.20(2H，m)，2.20-2.43(3H，br)，2.43-2.60(6H，m)，2.82-3.10(3H，br)，3.10-3.22(4H，m)，6.93(2H，d，J＝8.8Hz)，7.24-7.58(17H，m).
			5	515	2.04-2.20(2H，m)，2.20-2.42(3H，br)，2.42-2.62(6H，m)，2.84-3.08(3H，br)，3.08-3.24(4H，br)，3.81(2H，s)，6.90(1H，d，J＝8.5Hz)，7.06(1H，s)，7.13-7.22(1H，m)，7.22-7.50(12H，m)，7.56-7.68(2H，m).
6	434	2.06-2.17(2H，m)，2.22-2.41(3H，br)，2.41-2.54(6H，m)，2.88-3.08(3H，br)，3.39(4H，t，J＝5.1Hz)，6.52(1H，d，J＝3.7Hz)，7.16(1H，d，J＝3.7Hz)，7.23-7.33(2H，m)，7.33-7.46(8H，m).
			7	428	2.04-2.18(2H，m)，2.20-2.41(3H，br)，2.41-2.56(6H，m)，2.84-3.10(3H，br)，3.44(4H，t，J＝5.1Hz)，6.52-6.62(2H，m)，7.22-7.48(11H，m)，8.11-8.17(1H，m).
8	428	2.07-2.17(2H，m)，2.20-2.41(3H，br)，2.41-2.56(6H，m)，2.80-3.07(3H，br)，3.13(4H，t，J＝5.0Hz)，7.11(1H，d，J＝3.0Hz)，7.12(1H，d，J＝3.0Hz)，7.33-7.47(8H，m)，8.05(1H，t，J＝3.0Hz)，8.25(1H，s).
			9	428	2.06-2.16(2H，m)，2.22-2.41(3H，br)，2.41-2.52(6H，m)，2.88-3.10(3H，br)，3.23(4H，t，J＝5.0Hz)，6.59(2H，d，J＝6.8Hz)，7.22-7.47(10H，m)，8.22(2H，d，J＝6.8Hz).
10	429	2.06-2.17(2H，m)，2.24-2.43(3H，br)，2.38(4H，t，J＝5.0Hz)，2.44-2.53(2H，m)，2.86-3.10(3H，br)，3.72(4H，t，J＝5.0Hz)，6.43(1H，t，J＝4.9Hz)，7.22-7.32(2H，m)，7.33-7.46(8H，m)，8.26(2H，d，J＝4.9Hz).

TABLE 6

Compound No.	Mass(EI：M+)	1H-NMRδ：ppm(CDCl3)
			11	429	2.08-2.18(2H，m)，2.22-2.40(3H，br)，2.40-2.60(6H，m)，2.86-3.12(3H，br)，3.12-3.24(4H，m)，7.24-7.34(2H，m)，7.34-7.47(8H，m)，8.30(2H，d，J＝2.9Hz)，8.65(1H，d，J＝2.9Hz).
12	429	2.06-2.19(2H，m)，2.22-2.40(3H，br)，2.40-2.53(6H，m)，2.86-3.08(3H，br)，3.50(4H，t，J＝5.0Hz)，7.24-7.33(2H，m)，7.33-7.46(8H，m)，7.80(1H，d，J＝2.6Hz)，8.02(1H，dd，J＝2.6，1.5Hz)，8.07(1H，d，J＝1.5Hz).
			13	478	2.07-2.19(2H，m)，2.20-2.43(3H，br)，2.43-2.57(6H，m)，2.90-3.12(3H，br)，3.66(4H，t，J＝5.1Hz)，6.91(1H，d，J＝9.2Hz)，7.18(1H，t，J＝7.7Hz)，7.22-7.32(2H，m)，7.32-7.46(8H，m)，7.49(1H，t，J＝7.7Hz)，7.55(1H，d，J＝7.7Hz)，7.66(1H，d，J＝7.7Hz)，7.83(1H，d，J＝9.2Hz).
14	478	2.14-2.26(2H，m)，2.26-2.46(3H，br)，2.46-2.56(2H，m)，2.60-2.72(4H，br)，2.84-3.10(3H，br)，3.10-3.24(4H，br)，6.77(1H，d，J＝5.0Hz)，7.24-7.34(3H，m)，7.24-7.34(8H，m)，7.63(1H，t，J＝8.5Hz)，7.97(1H，d，J＝8.5Hz)，8.02(1H，d，J＝8.5Hz)，8.69(1H，d，J＝5.0Hz).
			15	478	2.14-2.26(2H，m)，2.26-2.46(3H，br)，2.46-2.58(2H，m)，2.58-2.78(4H，br)，2.82-3.08(3H，br)，3.08-3.22(4H，br)，7.23-7.34(2H，m)，7.34-7.50(8H，m)，7.56(1H，t，J＝8.0Hz)，7.65(1H，t，J＝8.0Hz)，7.92(1H，d，J＝8.0Hz)，8.05(1H，d，J＝8.0Hz)，8.14(1H，s)，8.93(1H，s).
16	441	1.78-1.96(2H，m)，2.14-2.48(7H，m)，2.48-2.60(2H，m)，2.63-2.76(2H，m)，2.84-3.08(3H，br)，2.32-3.50(4H，m)，6.56-6.68(3H，m)，7.10-7.22(2H，m)，7.22-7.46(10H，m).
			17	491	2.08-2.46(5H，m)，2.60-2.80(4H，m)，2.90-3.10(3H，br)，3.10-3.62(8H，m)，7.13(1H，d，J＝7.4Hz)，7.16-7.52(13H，m)，7.56(1H，d，J＝8.0Hz)，7.74-7.86(1H，m)，8.08-8.18(1H，m).
18	491	1.94-2.40(7H，m)，2.48-2.70(2H，m)，2.80-3.12(7H，m)，3.30-3.90(4H，m)，7.00-7.56(15H，m)，7.56-7.76(2H，m).
			19	517	2.10-2.40(5H，m)，2.40-2.66(4H，m)，2.70-3.14(7H，m)，3.48(2H，t，J＝6.2Hz)，3.56-3.84(2H，m)，6.70(2H，d，J＝8.8Hz)，7.20-7.43(13H，m)，7.46(2H，d，J＝8.8Hz)，7.53(2H，d，J＝8.8Hz).

TABLE 7

Compound No.	Mass(EI：M+)	1H-NMRδ：ppm(CDCl3)
			20	529	1.95-2.17(2H，br)，2,19-2.60(7H，m)，2.64-3.10(7H，m)，3.49(2H，t，J＝6.3Hz)，3.54-3.70(2H，br)，3.80(2H，s)，6.65(1H，dd，J＝10.5，2.2Hz)，6.82(1H，d，J＝2.2Hz)，7.15(1H，t，J＝8.2Hz)，7.21-7.49(12H，m)，7.57(1H，d，J＝8.2Hz)，7.60(1H，d，J＝8.2Hz).
21	448	1.76-1.92(2H，m)，2.08-2.46(7H，m)，2.48-2.63(2H，m)，2.63-2.74(2H，m)，2.84-3.04(3H，br)，3.40-3.64(4H，m)，6.41(1H，d，J＝4.1Hz)，7.13(1H，d，J＝4.1Hz)，7.23-7.32(2H，m)，7.32-7.43(8H，m).
			22	442	1.78-1.91(2H，m)，2.14-2.48(7H，m)，2.48-2.60(2H，m)，2.60-2.72(2H，m)，2.82-3.10(3H，br)，3.49-3.59(2H，m)，3.59-3.68(2H，m)，6.40(1H，d，J＝8.8Hz)，6.43-6.50(1H，m)，7.18-7.44(11H，m)，8.05-8.12(1H，m)，
23	443	1.72-1.91(2H，m)，2.16-2.46(7H，m)，2.48-2.58(2H，m)，2.60-2.70(2H，m)，2.84-3.06(3H，br)，3.62-3.80(4H，m)，6.40(1H，t，J＝4.7Hz)，7.22-7.30(2H，m)，7.30-7.44(8H，m)，8.25(2H，d，J＝4.7Hz).
			24	443	1.80-2.00(2H，br)，2.14-2.54(7H，m)，2.54-2.68(2H，br)，2.70-2.83(2H，br)，2.88-3.10(3H，br)，3.34-3.56(4H，m)，7.20-7.44(10H，m)，8.10(2H，d，J＝2.4Hz)，8.51(1H，d，J＝2.4Hz).
25	492	1.82-2.00(2H，br)，2.15-2.37(5H，m)，2.37-2.48(2H，m)，2.48-2.64(2H，br)，2.64-2.84(2H，br)，2.84-3.05(3H，br)，3.74(2H，t，J＝6.3Hz)，3.76-3.88(2H，br)，6.79(1H，d，J＝9.2Hz)，7.10-7.19(1H，m)，7.19-7.29(2H，m)，7.29-7.43(8H，m)，7.43-7.52(1H，m)，7.54(1H，d，J＝8.0Hz)，7.62(1H，d，J＝8.0Hz)，7.80(1H，d，J＝9.2Hz)
			26	492	1.86-2.02(2H，m)，2.10-2.50(7H，m)，2.50-2.68(2H，m)，2.70-3.20(5H，m)，3.46-3.66(4H，m)，7.02(1H，d，J＝2.5Hz)，7.18-7.50(12H，m)，7.50-7.62(1H，m)，7.86-7.96(1H，m)，8.58(1H，d，J＝2.5Hz).
27	492	1.84-2.01(2H，m)，2.20-2.44(5H，m)，2.44-2.56(2H，m)，2.72-2.91(4H，m)，2.91-3.14(3H，br)，3.35(4H，t，J＝5.9Hz)，7.20-7.33(2H，m)，7.33-7.50(8H，m)，7.52-7.59(1H，m)，7.60-7.68(1H，m)，7.91(1H，d，J＝7.5Hz)，8.08(1H，d，J＝7.5Hz)，8.18(1H，s)，8.88(1H，s).

TABLE 8

Compound No.	Mass(FAB：(M+H)+)	1H-NMRδ：ppm(CDCl3)
			28	442	2.10-2.18(2H，m)，2.23(3H，s)，2.26-2.40(3H，br)，2.43-2.58(6H，m)，2.85(4H，t，J＝4.6Hz)，2.91-3.05(3H，br)，6.90-6.99(2H，m)，7.07-7.15(2H，m)，7.24-7.30(2H，m)，7.33-7.46(8H，m).
29	442	2.07-2.16(2H，m)，2.23-2.40(3H，br)，2.28(3H，s)，2.42-2.55(6H，m)，2.88-3.13(7H，m)，6.60-6.71(3H，m)，7.10(1H，t，J＝7.8Hz)，7.23-7.45(10H，m).
			30	442	2.08-2.16(2H，m)，2.23(3H，s)，2.26-2.38(3H，br)，2.43-2.55(6H，m)，2.90-3.10(7H，m)，6.78(2H，d，J＝8.8Hz)，7.02(2H，d，J＝8.8Hz)，7.23-7.29(2H，m)，7.32-7.46(8H，m).
31	446	2.10-2.18(2H，m)，2.28-2.39(3H，br)，2.43-2.58(6H，m)，2.92-3.07(7H，m)，7.24-7.31(2H，m)，7.34-7.45(8H，m).
			32	446	2.08-2.17(2H，m)，2.28-2.39(3H，br)，2.42-2.57(6H，m)，2.90-3.10(7H，m)，6.78-6.85(2H，m)，6.87-6.96(2H，m)，7.24-7.31(2H，m)，7.33-7.46(8H，m).
33	462	2.10-2.19(2H，m)，2.26-2.40(3H，br)，2.45-2.61(6H，m)，2.88-3.07(4H，m)，6.91(1H，t，J＝8.0Hz)，6.99(1H，d，J＝8.0Hz)，7.17(1H，t，J＝8.0Hz)，7.23-7.46(11H，m).
			34	462	2.06-2.16(2H，m)，2.24-2.39(3H，br)，2.41-2.52(6H，m)，2.88-3.02(3H，br)，3.05-3.12(4H，m)，6.70(1H，d，J＝8.5Hz)，6.73(1H，d，J＝8.5Hz)，6.79(1H，s)，7.10(1H，t，J＝8.5Hz)，7.23-7.30(2H，m)，7.32-7.46(8H，m).
35	462	2.07-2.16(2H，m)，2.23-2.40(3H，br)，2.41-2.54(6H，m)，2.88-3.10(7H，m)，6.76(4H，d，J＝9.0Hz)，7.13(4H，d，J＝9.0 Hz)，7.22-7.30(2H，m)，7.31-7.45(8H，m).
			36	444	2.09-2.17(2H，m)，2.27-2.39(3H，br)，2.43-2.58(6H，m)，2.81(4H，t，J＝4.4Hz)，2.93-3.05(3H，br)，6.81(1H，dt，J＝7.8，1.2Hz)，6.89(1H，dd，J＝7.8，1.2Hz)，7.02(1H，dt，J＝7.8，1.2Hz)，7.11(1H，dd，J＝7.8，1.2Hz)，7.25-7.32(2H，m)，7.34-7.46(8H，m).

TABLE 9

Compound No.	Mass(FAB：(M+H)+)	1H-NMRδ：ppm(CDCl3)
			37	444	2.09-2.18(2H，m)，2.27-2.37(3H，br)，2.43-2.54(6H，m)，2.91-3.06(7H，m)，6.17-6.25(2H，m)，6.34(1H，d，J＝8.0Hz)，6.97(1H，t，J＝8.0Hz)，7.21-7.43(10H，m).
38	444	2.08-2.17(2H，m)，2.28-2.36(3H，br)，2.45-2.56(6H，m)，2.93-3.02(7H，br)，6.72(4H，dd，J＝9.3，4.9Hz)，7.24-7.30(2H，m)，7.33-7.42(8H，m).
			39	458	2.10-2.19(2H，m)，2.27-2.39(3H，br)，2.44-2.60(6H，m)，2.90-3.09(7H，m)，3.80(3H，s)，6.81(1H，d，J＝8.3Hz)，6.84-6.90(2H，m)，6.91-6.98(1H，m)，7.22-7.30(2H，m)，7.32-7.45(8H，m).
40	458	2.08-2.14(2H，m)，2.28-2.37(3H，br)，2.43-2.52(6H，m)，2.93-3.02(3H，br)，3.10(4H，t，J＝4.9Hz)，3.76(3H，s)，6.37(1H，dd，J＝7.8，2.0Hz)，6.40(1H，t，J＝2.0Hz)，6.47(1H，dd，J＝7.8，2.0Hz)，7.12(1H，t，J＝7.8Hz)，7.24-7.30(2H，m)，7.33-7.45(8H，m).
			41	458	2.08-2.15(2H，m)，2.28-2.38(3H，br)，2.43-2.55(6H，m)，2.93-3.04(7H，m)，3.74(3H，s)，6.80(2H，d，J＝2.4Hz)，6.84(2H，d，J＝2.4Hz)，7.24-7.30(2H，m)，7.33-7.45(8H，m).
42	530	2.05(3H，s)，2.10-2.18(2H，m)，2.27-2.40(3H，br)，2.43-2.58(6H，m)，2.88-3.10(7H，m)，4.17(2H，t，J＝4.8Hz)，4.40(3H，t，J＝4.8Hz)，6.78-6.95(4H，m)，7.24-7.30(2H，m)，7.33-7.46(8H，m).
			43	488	2.06-2.16(2H，m)，2.23-2.40(3H，br)，2.41-2.61(6H，m)，2.88-3.10(7H，m)，3.54-3.63(2H，m)，4.13(2H，t，J＝4.6Hz)，4.77-4.90(1H，m)，6.93-7.04(4H，m)，7.22-7.30(2H，m)，7.32-7.45(8H，m).
44	530	1.28(3H，t，J＝7.3Hz)，2.08-2.18(2H，m)，2.24-2.40(3H，br)，2.42-2.60(6H，m)，2.87-3.13(7H，m)，4.23(2H，q，J＝7.3Hz)，4.63(2H，s)，6.75-6.80(1H，m)，6.87-6.97(3H，m)，7.23-7.30(2H，m)，7.32-7.45(8H，m).
			45	502	2.29(3H，s)，2.52-2.71(4H，m)，2.90-3.19(7H，m)，3.21-3.38(4H，m)，4.53(2H，s)，6.80-6.99(4H，m)，7.22-7.44(10H，m).

Watch 10

Compound No.	Mass(FAB：(M+H)+)	1H-NMRδ：ppm(CDCl3)
			46	454	1.52(2H，dt，J＝6.5，6.5Hz)，1.66(2H，dt，J＝6.5，6.5Hz)，2.14-2.22(2H，m)，2.42-2.58(8H，m)，3.12(4H，t，J＝5.1Hz)，3.59(2H，t，J＝6.5Hz)，3.59(2H，t，J＝6.5Hz)，6.80(1H，t，J＝7.6Hz)，6.86(2H，d，J＝7.6Hz)，7.17-7.42(12H，m).
47	470	1.53(2H，dt，J＝6.5，6.5Hz)，1.67(2H，dt，J＝6.5，6.5Hz)，2.15-2.22(2H，m)，2.42-2.62(8H，m)，2.82(4H，t，J＝4.9Hz)，3.54-3.63(2H，m)，6.82(1H，dt，J＝7.8，1.5Hz)，6.90(1H，dd，J＝7.8，1.5Hz)，7.03(2H，dt，J＝7.8，1.5Hz)，7.12(1H，dd，J＝7.8，1.5Hz)，7.24-7.42(10H，m).
			48	556	1.52(2H，dt，J＝6.5，6.5Hz)，1.67(2H，dt，J＝6.5，6.5Hz)，2.05(3H，s)，2.15-2.24(2H，m)，2.43-2.61(8H，m)，2.95-3.11(4H，m)，3.59(2H，t，J＝6.5Hz)，4.14-4.21(2H，m)，4.37-4.44(2H，m)，6.79-6.83(1H，m)，6.87-6.96(3H，m)，7.23-7.42(10H，m).
49	514	1.52(2H，dt，J＝6.8，6.8Hz)，1.67(2H，dt，J＝6.8，6.8Hz)，2.13-2.25(2H，m)，2.40-2.69(8H，m)，2.93-3.13(4H，m)，3.54-3.65(4H，m)，6.92-7.04(4H，m，)，7.22-7.42(10H，m).
			50	556	1.28(3H，t，J＝6.8Hz)，1.52(2H，dt，J＝6.5，6.5Hz)，1.67(2H，dt，J＝6.5，6.5Hz)，2.16-2.26(2H，m)，2.43-2.63(8H，m)，2.96-3.14(4H，m)，3.59(2H，t，J＝6.5Hz)，4.23(2H，q，J＝6.8Hz)，4.63(2H，s)，6.76-6.80(1H，m)，6.87-7.00(3H，m)，7.23-7.43(10H，m).
51	528	1.53(2H，dt，J＝6.8，6.8Hz)，1.68(2H，dt，J＝6.8，6.8Hz)，2.40(2H，t，J＝6.8Hz)，2.53-2.70(4H，m)，2.84-3.33(8H，m)，3.57(2H，t，J＝6.8Hz)，4.50(2H，s)，6.73-6.87(4H，m)，7.20-7.44(10H，m).
			52	558	1.23(3H，t，J＝7.0Hz)，1.53(6H，s)，2.05-2.16(2H，m)，2.24-2.42(3H，br)，2.43-2.62(6H，m)，2.86-3.15(7H，m)，4.21(2H，q，J＝7.0Hz)，6.77-6.84(2H，m)，6.86(1H，dd，J＝7.8，1.5Hz)，6.90-6.96(1H，m)，7.24-7.32(2H，m)，7.32-7.46(8H，m).
53	530	1.21-1.40(1H，m)，1.48(3H，m)，1.56-1.73(1H，m)，1.89(3H，s)，2.02-2.20(2H，m)，2.29(3H，s)，2.38-2.51(1H，m)，2.51-2.72(2H，m)，2.72-2.90(1H，m)，2.90-3.22(2H，m)，2.99(3H，s)，3.32-3.48(1H，m)，3.52-3.72(1H，m)，6.21(1H，t，J＝7.8Hz)，6.32(1H，t，J＝7.8Hz)，6.57(1H，t，J＝7.8Hz)，6.93-7.10(2H，m)，7.10-7.70(9H，m)，7.90-8.70(1H，br).

Reference example 6

4-bromo-2, 2-diphenylbutyric acid (23g, 72mmol) was suspended in chloroform (150 mL). Thionyl chloride (20mL, 270mmol) was added dropwise at room temperature. Subsequently, dimethylformamide (DMF; 0.2mL) was added and the mixture was heated and refluxed for 4 hours. Thereafter, the solvent was evaporated under reduced pressure, thereby obtaining 23g of 4-bromo-2, 2-diphenylbutyryl chloride (yield 94.7%).

A50% aqueous dimethylamine solution (8g, 90mmol) and sodium carbonate (18g, 170mmol) were suspended in water (100mL) and the suspension was cooled to a temperature between 0 and 5 ℃. To the cooled suspension was added dropwise 4-bromo-2, 2-diphenylbutanoyl chloride (23g, 68mmol) prepared above dissolved in toluene (100 mL). The mixture was stirred for 2 hours, after which the aqueous layer was washed with toluene, followed by extraction with chloroform, washing with water, and drying. The solvent was evaporated under reduced pressure and the residue was crystallized from methyl isobutyl ketone to obtain 11g of dimethyl (tetrahydro-3, 3-diphenyl-2-furylidene) ammonium bromide (yield 46.8%).

¹H-NMR(CDCl₃)δ(ppm)：2.96(3H，s)，3.47(2H，t，J＝6.4Hz)，3.83(3H，s)，4.85(2H，t，J＝6.4Hz)，7.40-7.60(10H，m)

The procedure of reference example 6 was repeated except for using pyrrolidine instead of the 50% aqueous dimethylamine solution to obtain a (tetrahydro-3, 3-diphenyl-2-furylidene) pyrrolidinium bromide (yield 53.6%).

¹H-NMR(CDCl₃)δ(ppm)：1.96(2H，quintet，J＝6.4Hz)，2.13(2H，quintet，J＝7.4Hz)，2.89(2H，t，J＝6.8Hz)，3.50(2H，t，J＝6.4Hz)，4.37(2H，t，J＝7.3Hz)，4.87(2H，t，J＝6.4Hz)，7.40-7.55(10H，m)

Reference example 7

Magnesium powder (240mg, 10mmol) was added to anhydrous tetrahydrofuran (2 mL). Separately, 2-methoxybromobenzene (1.9g, 10.7mmol) was dissolved in anhydrous tetrahydrofuran (10mL) and an aliquot of the resulting mixture (1/5 amount) was added. Thereafter, 1, 2-dibromoethane (0.1mL) and a small amount of iodine were added thereto, and the mixture was heated to 40 ℃. After the reaction started, the remaining portion of the solution of 2-methoxybromobenzene in anhydrous tetrahydrofuran was added dropwise and the mixture was heated and refluxed for 30 minutes.

1-benzyl-4-piperidone (1.89g, 10mmol) was dissolved in anhydrous tetrahydrofuran (30mL) at room temperature, and the mixture was added dropwise to the resulting solution of Grignard reagent in anhydrous tetrahydrofuran. Subsequently, the resulting mixture was heated and refluxed for 30 minutes, and then a saturated aqueous solution of ammonium chloride (10mL) was added dropwise. The solvent was then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ether, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 1.84g of 1-benzyl-4- (2-methoxyphenyl) -4-piperidinol (yield 61.8%).

¹H-NMR(CDCl₃)δ(ppm)：1.50-1.90(2H，m)，2.52(2H，dt，J＝12.8Hz，4.8Hz)，2.80-3.25(3H，m)，3.25-3.50(2H，m)，3.87(3H，s)，6.91(1H，dd，J＝1.1Hz)，7.03(1H，s)，7.10-7.40(1H，m)，7.40-7.60(1H，m)

Reference example 8

1-benzyl-4- (2-methoxyphenyl) -4-piperidinol (2.08g, 7.0mmol) was dissolved in dioxane (10 mL). Subsequently, 6N hydrochloric acid (20mL) was added thereto, and the mixture was heated and refluxed for 3 hours. After completion of the reaction, the pH of the mixture was adjusted to 9 with 1N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 1.50g of 1-benzyl-4- (2-methoxyphenyl) -1, 2, 3, 6-tetrahydropyridine (yield 77.0%).

¹H-NMR(CDCl₃)δ(ppm)：2.50-2.58(2H，m)，2.67(2H，t，J＝5.9Hz)，3.15-3.19(2H，m)，3.65(2H，s)，3.80(3H，s)，5.75-5.78(1H，m)，6.85(1H，d，J＝8.3Hz)，6.89(1H，dt，J＝8.3Hz，1.0Hz)，7.15-7.42(7H，m)

Reference example 9

1-benzyl-4- (2-methoxyphenyl) -1, 2, 3, 6-tetrahydropyridine (1.5g, 5.4mmol) was dissolved in ethanol (30 mL). Subsequently, 10% palladium on carbon (0.6g) was added thereto, and the mixture was subjected to catalytic reduction at room temperature and 1 atmosphere for 6 hours. After the completion of the reaction, the catalyst was filtered, and the filtrate was concentrated under reduced pressure, thereby obtaining 0.88g of 4- (2-methoxyphenyl) piperidine (yield 85.7%).

¹H-NMR(CDCl₃)δ(ppm)：1.95-2.05(2H，m)，2.10-2.23(2H，m)，3.04(2H，t，J＝10.2Hz)，3.15-3.25(1H，m)，3.60-3.68(2H，m)，3.84(3H，s)，6.87(1H，d，J＝8.3Hz)，6.94(1H，t，J＝6.4Hz)，7.17-7.25(2H，m)

Reference example 10

4- (2-methoxyphenyl) piperidine (530mg, 2.3mmol) was added to 48% hydrobromic acid (10mL), and the mixture was heated and stirred at 140 ℃ for 17 hours. After cooling, a 3N aqueous sodium hydroxide solution was added to the reaction mixture to adjust the pH of the mixture to 9, followed by extraction with chloroform, drying over anhydrous magnesium sulfate, and concentration under reduced pressure to obtain 4- (2-hydroxyphenyl) piperidine (280mg, 68.0%) as a residue in the form of powder.

¹H-NMR(CDCl₃)δ(ppm)：1.70-1.93(4H，m)，2.70-2.90(2H，m)，2.95-3.10(1H，m)，3.10-3.32(2H，m)，4.00-5.20(2H，br)，6.70(1H，dd，J＝7.7Hz，1.4Hz)，6.84(1H，dt，J＝7.7Hz，1.4Hz)，7.04(1H，dt，J＝7.7Hz，1.4Hz)，7.14(1H，dd，J＝7.7Hz，1.4Hz)。

Reference example 11

Dimethyl (tetrahydro-3, 3-diphenyl-2-furylidene) ammonium bromide (3.5g, 10mmol) and 4- (2-hydroxyphenyl) -4-piperidinol (1.93g, 10mmol) were dissolved in anhydrous dimethylformamide (20mL) in the presence of sodium carbonate (3.2g, 30mmol), and the mixture was stirred at 100 ℃ for 3 hours. The reaction mixture was added to water, followed by extraction with ethyl acetate, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 3.6g of 4- [4- (2-hydroxyphenyl) -4-hydroxypiperidin-1-yl ] -2, 2-diphenyl-N, N-dimethylbutanamide (yield 78.6%).

Reference example 12

Brominated (tetrahydro-3, 3-diphenyl-2-furylidene) pyrrolidinium salt (10.75g, 29mmol) and 4- (2-hydroxyphenyl) -4-piperidinol (6.20g, 32mmol) were dissolved in anhydrous dimethylformamide (200mL) in the presence of sodium carbonate (8.5g, 80mmol), and the mixture was stirred at 100 ℃ for 3 hours. The reaction mixture was added to water, followed by extraction with ethyl acetate, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 13.9g of 4- [4- (2-hydroxyphenyl) -4-hydroxypiperidin-1-yl ] -2, 2-diphenyl-1- (1-pyrrolidinyl) -1-butanone (yield 99.0%).

Example 54

Dimethyl (tetrahydro-3, 3-diphenyl-2-furylidene) ammonium bromide (500mg, 1.4mmol) and 4- (2-methoxyphenyl) piperidine (300mg, 1.6mmol) were dissolved in anhydrous dimethylformamide (20 mL). Subsequently, sodium carbonate (500mg, 5mmol) was added and the mixture was stirred at 100 ℃ for 3 hours. The reaction mixture was added to water, followed by extraction with ethyl acetate, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 440mg of 4- [4- (2-methoxyphenyl) piperidin-1-yl ] -N, N-dimethyl-2, 2-diphenylbutanamide (compound No.54) (yield 66.9%).

Examples 55 to 64

The procedure was carried out analogously to example 1, giving the compounds Nos.55 to 64.

Example 65

4- [4- (2-hydroxyphenyl) piperidin-1-yl ] -N, N-dimethyl-2, 2-diphenylbutanamide (Compound No.57) (580mg, 1.3mmol) was dissolved in anhydrous dimethylformamide (12mL), and 100mg of potassium hydroxide (powder) was added thereto. Ethyl chloroacetate (180mg, 1.5mmol) was added dropwise at 0 deg.C and the resulting mixture was stirred at room temperature for an additional 12 hours. The reaction mixture was added to water, followed by extraction with ethyl acetate, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 395mg of ethyl [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] acetate (compound No.65) (yield 57.0%).

Example 66

4- [4- (2-hydroxyphenyl) piperidin-1-yl ] -N, N-dimethyl-2, 2-diphenylbutanamide (Compound No.57) (1,500mg, 3.4mmol) was dissolved in anhydrous dimethylformamide (20 mL). 2-bromoethyl acetate (600mg, 3.6mmol), potassium carbonate (600mg, 4.5mmol) and a small amount of potassium iodide were then added, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was added to water, followed by extraction with ethyl acetate, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 390mg of ethyl 2- [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] acetate (compound No.66) (yield 21.6%).

Examples 67 and 68

A procedure similar to example 66 was carried out, whereby compound nos.67 and 68 were obtained.

Example 69

Ethyl 2- [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] acetate (compound No.66) (360mg, 0.68mmol) was dissolved in methanol (5 mL). Subsequently, a 1N aqueous solution of sodium hydroxide (1mL) was added, and the mixture was stirred at 50 ℃ for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 203mg of 4- [4- [2- (2-hydroxyethoxy) phenyl ] piperidin-1-yl ] -N, N-dimethyl-2, 2-diphenylbutanamide (compound No.69) (yield 61.3%).

Examples 70 and 71

A procedure similar to example 69 was carried out, whereby compound nos.70 and 71 were obtained.

Example 72

Ethyl [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] acetate (compound No.65) (360mg, 0.7mmol) was dissolved in methanol (5 mL). Subsequently, a 1N aqueous solution of sodium hydroxide (5mL) was added, and the mixture was stirred at 50 ℃ for 1 hour. After completion of the reaction, the reaction mixture was added to water, and the pH of the mixture was adjusted to 4 to 5 with 1N HCl, followed by extraction with chloroform, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 320mg of [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] acetic acid (compound No.72) (yield 94.0%).

Example 73

4- [4- (2-hydroxyphenyl) -4-hydroxypiperidin-1-yl ] -2, 2-diphenyl-N, N-dimethylbutanamide (1.40g, 3.1mmol) was dissolved in a solvent mixture of dioxane (7mL) and 6N hydrochloric acid (14mL), and the mixture was heated and refluxed for 3 hours. After completion of the reaction, the pH of the mixture was adjusted to 11 with 1N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography, whereby 1.24g of 4- [4- (2-hydroxyphenyl) -1, 2, 3, 6-tetrahydropyridin-1-yl ] -N, N-dimethyl-2, 2-diphenylbutanamide (compound No.73) was obtained (yield 92.3%).

Example 74

The procedure of example 65 was repeated using 4- (4- (2-hydroxyphenyl) -1, 2, 3, 6-tetrahydropyridin-1-yl) -N, N-dimethyl-2, 2-diphenylbutanamide (compound No.73), thereby obtaining ethyl [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] -1, 2, 3, 6-tetrahydropyridin-4-yl ] phenoxy ] acetate (compound No. 74).

Example 75

The procedure of example 66 was repeated by using the compound No.73, and the procedure similar to example 69 was carried out without isolating the obtained product, thereby obtaining 4- [4- [2- (2-hydroxyethoxy) phenyl ] -1, 2, 3, 6-tetrahydropyridin-1-yl ] -N, N-dimethyl-2, 2-diphenylbutanamide (compound No. 75).

Example 76

The procedure of example 72 was repeated using ethyl [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] -1, 2, 3, 6-tetrahydropyridin-4-yl ] phenoxy ] acetate (compound No.74), thereby obtaining [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] -1, 2, 3, 6-tetrahydropyridin-4-yl ] phenoxy ] acetic acid (compound No. 76).

Example 77

4- [4- (2-hydroxyphenyl) -4-hydroxypiperidin-1-yl ] -2, 2-diphenyl-1- (1-pyrrolidinyl) -1-butanone (4.20g, 8.7mmol) was dissolved in a solvent mixture of dioxane (20mL) and 6N hydrochloric acid (40mL), and the mixture was heated and refluxed for 3 hours. After completion of the reaction, the pH of the mixture was adjusted to 11 with 1N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate, washing with water, and drying. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 3.45g of 4- [4- (2-hydroxyphenyl) -1, 2, 3, 6-tetrahydropyridin-1-yl ] -2, 2-diphenyl-1- (1-pyrrolidinyl) -1-butanone (compound No.77) (yield 85.3%).

Example 78

4- [4- (2-hydroxyphenyl) -1, 2, 3, 6-tetrahydropyridin-1-yl ] -2, 2-diphenyl-1- (1-pyrrolidinyl) -1-butanone (compound No.77) (2.50g, 5.36mmol) was dissolved in ethanol (80mL), and 10% palladium on carbon (0.80g) was further added. The mixture was subjected to catalytic reduction at room temperature and 1 atmosphere pressure for 12 hours under a hydrogen atmosphere. After the completion of the reaction, the catalyst was filtered, and the filtrate was concentrated under reduced pressure, whereby 1.45g of 4- [4- (2-hydroxyphenyl) piperidin-1-yl ] -2, 2-diphenyl-1- (1-pyrrolidinyl) -1-butanone (compound No.78) (yield 60.3%) was obtained.

Example 79

The procedure of example 65 was repeated using 4- [4- (2-hydroxyphenyl) piperidin-1-yl ] -2, 2-diphenyl-1- (1-pyrrolidinyl) -1-butanone (compound No.78), whereby ethyl [2- [1- [4- (1-pyrrolidinyl) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] acetate (compound No.79) was obtained.

Example 80

The procedure of example 66 was repeated using 4- [4- (2-hydroxyphenyl) piperidin-1-yl ] -2, 2-diphenyl-1- (1-pyrrolidinyl) -1-butanone (compound No.78), thereby obtaining ethyl 2- [2- [1- [3, 3-diphenyl-4-oxo-4- (1-pyrrolidinyl) butyl ] piperidin-4-yl ] phenoxy ] acetate (compound No. 80).

Example 81

The procedure of example 69 was repeated using ethyl 2- [2- [1- [3, 3-diphenyl-4-oxo-4- (1-pyrrolidinyl) butyl ] piperidin-4-yl ] phenoxy ] acetate (compound No.80) to obtain 4- [4- [2- (2-hydroxyethoxy) phenyl ] piperidin-1-yl ] -2, 2-diphenyl-1- (1-pyrrolidinyl) -1-butanone (compound No. 81).

Example 82

The procedure of example 72 was repeated using ethyl [2- [1- [4- (1-pyrrolidinyl) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] acetate (compound No.79) to obtain [2- [1- [4- (1-pyrrolidinyl) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] acetic acid (compound No. 82).

Example 83

4- [4- (2-hydroxyphenyl) piperidin-1-yl group]-N, N-dimethyl-2, 2-diphenylbutanamide (Compound No.57) (400mg, 0.905mmol), ethyl α -bromoisobutyrate (2.00g, 10.3mmol) and anhydrous potassium carbonate (700mg, 5.06mmol) were added to anhydrous dimethylformamide (10mL), and the mixture was stirred at an external temperature of 50 ℃ for 15 hours. After completion of the reaction, dimethylformamide was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, followed by washing with water and drying over anhydrous magnesium sulfate. Subsequently, ethyl acetate was evaporated under reduced pressure, and the residual oily substance was subjected to column chromatography using silica gel (60 g). 3% MeOH/CHCl₃The eluate was concentrated under reduced pressure, whereby 181mg of 2- [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] interesting product as a pale yellow oil was obtained]Piperidin-4-yl radical]Phenoxy radical]Ethyl 2-methylpropionate (Compound No.83) (yield 36.0%).

Example 84

Ethyl 2- [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] -2-methylpropionate (compound No.83) (240mg, 0.432mmol) was dissolved in a solvent mixture of 1N aqueous sodium hydroxide solution (5mL), methanol (5mL) and 1, 4-dioxane (5mL), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was added to water, and the resulting mixture was neutralized to pH7 with dilute hydrochloric acid, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Chloroform was evaporated under reduced pressure, and the precipitated crystals were pulverized in the presence of ether, thereby obtaining 169mg of 2- [2- [1- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl ] piperidin-4-yl ] phenoxy ] -2-methylpropanoic acid (compound No.84) as a meaningful product as colorless crystals (yield 74.1%).

Tables 11 to 14 show the yield, properties and melting point of the compounds No.54 to 84, and tables 15 to 17 show the NMR data of the compounds. TABLE 11

Compound No.	R3	Yield (%)	Performance of	Melting point (decomposition)
					54	2-OCH3	66.9	Light yellow oil
55	3-OCH3	79.1	Light yellow oil
					56	4-OCH3	58.5	Light orange oil
57	2-OH	74.6	Light yellow oil
					58	3-OH	57.0	Colorless crystal	110
59	4-OH	73.6	Light yellow crystal	104
					60	2-CH3	56.2	Light yellow oil
61	3-CH3	67.2	Light yellow oil
					62	4-CH3	61.2	Light orange oil
63	3-F	40.0	Light yellow oil
					64	4-F	46.2	Light orange oil
65	2-OCH2CO2C2H5	57.0	Light yellow oil
					66	2-O(CH2)2OCOCH3	21.6	Light yellow oil
67	3-O(CH2)2OCOCH3	70.3	Light yellow oil
					68	4-O(CH2)2OCOCH3	54.4	Light orange oil
69	2-O(CH2)2OH	61.3	Colorless amorphous crystal
					70	3-O(CH2)2OH	77.5	Light yellow oil
71	4-O(CH2)2OH	69.7	Light orange oil
					72	2-OCH2CO2H	94.0	Colorless crystal	202
83	2-OC(CH3)2COOEt	36.0	Light yellow oil
					84	2-OC(CH3)2COOH	74.1	Colorless crystal	156-158

TABLE 12

Compound No.	R3	Yield (%)	Performance of	Melting point (decomposition)
					73	2-OH	92.3	Light yellow oil
74	2-OCH2CO2C2H5	60.0	Colorless crystal	147
					75	2-O(CH2)2OH	98.5	Light yellow oil
76	2-OCH2CO2H	89.1	Colorless crystal	135

Watch 13

Compound No.	R3	Yield (%)	Performance of	Melting point (decomposition)
					77	2-OH	85.3	Light yellow oil

TABLE 14

Compound No.	R3	Yield (%)	Performance of	Melting point (decomposition)
					78	2-OH	60.3	Light yellow oil
79	2-OCH2CO2C2H5	54.0	Light yellow oil
					80	2-O(CH2)2OCOCH3	57.3	Light yellow oil
81	2-O(CH2)2OH	72.2	Light yellow oil
					82	2-OCH2CO2H	87.6	Colorless crystal	239

Watch 15

Compound No.	Mass(FAB：(M+H)+)	1H-NMRδ：ppm(CDCl3)
			54	457	1.58-1.80(4H，m)，1.94-2.20(4H，m)，2.24-2.39(3H，br)，2.44-2.58(2H，m)，2.80-3.06(6H，m)，3.78(3H，s)，6.78-6.92(2H，m)，7.12-7.19(2H，m)，7.24-7.44(10H，m).
55	457	1.63-1.80(4H，m)，1.90-2.05(3H，br)，2.08-2.17(2H，m)，24-2.42(4H，m)，2.47-2.55(2H，m)，2.88-3.08(3H，m)，3.76(3H，s)，6.68-6.74(2H，m)，6.77(1H，d，J＝7.8Hz)，7.17(1H，t，J＝7.8Hz)，7.25-7.45(10H，m).
			56	457	1.62-1.77(4H，m)，1.77-1.93(2H，m)，1.93-2.07(2H，m)，2.07-2.20(2H，m)，2.25-2.42(3H，m)，2.46-2.57(2H，m)，2.90-3.10(4H，m)，3.76(3H，s)，6.81(2H，d，J＝8.8Hz)，7.10(2H，d，J＝8.8Hz)，7.25-7.30(2H，m)，7.34-7.45(8H，m).
57	443	1.77-1.88(2H，m)，2.06-2.22(2H，m)，2.31(3H，s)，2.52-2.79(6H，m)，2.90-3.04(1H，m)，3.01(3H，s)，3.24-3.37(2H，m)，6.72-6.78(1H，m)，6.88-6.97(2H，m)，7.03-7.08(1H，m)，7.26-7.43(10H，m).
			58	443	1.48-1.69(4H，m)，1.84-1.97(2H，m)，2.02-2.16(2H，m)2.20-2.38(4H，m)，2.42-2.53(2H，m)，2.80-3.08(5H，m)，6.52-6.63(3H，m)，7.05(1H，t，J＝7.8Hz)，7.21-7.40(10H，m).
59	443	1.62-1.73(4H，m)，1.92-2.07(2H，m)2.08-2.20(2H，m)，2.20-2.38(4H，m)，2.47-2.54(2H，m)，2.87-3.07(5H，m)，6.71(2H，d，J＝8.8Hz)，6.98(2H，d，J＝8.8Hz)，7.22-7.29(2H，m)，7.31-7.43(8H，m).
			60	441	1.62-1.84(4H，m)，1.97-2.20(4H，m)，2.26-2.42(3H，br)，2.27(3H，s)，2.46-2.68(3H，m)，2.84-3.09(5H，m)，7.02-7.16(3H，m)，7.18-7.22(1H，m)，7.24-7.46(10H，m).
61	441	1.57-1.80(4H，m)，1.89-2.18(4H，m)，2.26-2.57(5H，m)，2.74-3.08(6H，m)，6.81-6.97(3H，m)，7.17-7.44(11H，m).
			62	441	1.50-1.85(8H，m)，1.95-2.47(5H，m)，2.29(3H，s)，2.48-2.63(2H，m)，2.90-3.15(4H，m)，7.08(4H，s)，7.20-7.30(2H，m)，7.30-7.45(8H，m).
63	445	1.63-1.80(4H，m)，1.85-2.20(4H，m)，2.24-2.58(6H，m)，2.86-3.10(5H，m)，6.95-7.02(3H，m)，7.15(1H，t，J＝7.3Hz)，7.24-7.45(10H，m).
			64	445	1.60-1.74(4H，m)，1.74-1.90(2H，m)，1.90-2.06(2H，m)，2.06-2.18(2H，m)，2.22-2.43(3H，m)，2.43-2.53(2H，m)，2.85-3.10(4H，m)，6.93(2H，t，J＝8.8Hz)，7.11(1H，d，J＝8.8Hz)，7.13(1H，d，J＝8.8Hz)，7.20-7.30(2H，m)，7.30-7.43(8H，m).
65	529	1.27(3H，t，J＝7.3Hz)，1.64-1.85(4H，m)，2.00-2.23(4H，m)，2.27-2.42(3H，br)，2.46-2.60(2H，m)，2.86-3.09(6H，m)，4.23(2H，q，J＝7.3Hz)，4.59(2H，s)，6.68(1 H，d，J＝7.8Hz)，6.93(1H，t，J＝7.3Hz)，7.10(1H，t，J＝7.8Hz)，7.20(1H，d，J＝7.3Hz)，7.23-7.46(10H，m).

TABLE 16

66	529	1.55-1.85(5H，m)，1.90-2.20(3H，m)，2.06(3H，s)，2.25-2.40(3H，s)，2.45-2.60(2H，m)，2.80-3.10(6H，m)，4.13(2H，t，J＝4.9Hz)，4.41(2H，t，J＝4.9Hz)，6.79(1H，t，J＝7.8Hz)，6.92(1 H，t，J＝7.3Hz)，7.13(1H，dt，J＝7.8Hz，1.5Hz)，7.18(1H，d，J＝6.4Hz)，7.25-7.30(2H，m)，7.30-7.45(8H，m).
			67	529	1.64-1.80(4H，m)，1.94-2.17(5H，m)，2.08(3H，br)，2.23-2.55(6H，m)，2.84-3.09(4H，m)，4.13(2H，t，J＝4.8Hz)，4.39(2H，t，J＝4.8Hz)，6.69-6.82(3H，m)，7.17(1H，t，J＝7.8Hz)，7.23-7.46(10H，m).
68	529	1.62-1.77(4H，m)，1.77-2.03(4H，m)，2.03-2.17(2H，m)，2.08(3H，s)，2.23-2.42(3H，m)，2.43-2.53(2H，m)，2.87-3.07(4H，m)，4.12(2H，t，J＝4.9Hz)，4.39(2H，t，J＝4.9Hz)，6.81(2H，d，J＝8.9Hz)，7.09(2H，d，J＝8.9Hz)，7.25-7.30(2H，m)，7.30-7.40(8H，m).
			69	487	1.60-1.75(2H，m)，1.85-2.00(2H，m)，2.00-2.10(2H，m)，2.33(3H，br.s)，2.40-2.50(2H，m)，2.65-2.75(1H，m)，2.85-3.15(7H，m)，3.39(1H，br.s)，3.90-4.00(2H，m)，4.02(2H，t，J＝4.0Hz)，6.82(1H，d，J＝9.0Hz)，6.88(1H，ddd，J＝8.3Hz，8.3Hz，1.0Hz)，7.10-7.20(1H，m)，7.20-7.50(11H，m).
70	487	1.62-1.78(4H，m)，1.91-2.04(2H，m)，2.08-2.17(2H，m)，2.24-2.42(4H，m)，2.45-2.55(2H，m)，2.86-3.09(5H，m)，3.91(2H，t，J＝4.5Hz)，4.03(2H，t，J＝4.5Hz)，6.68-6.81(3H，m)，7.16(1H，t，J＝7.8Hz)，7.23-7.46(10H，m).
			71	487	1.60-1.85(4H，m)，1.90-2.25(4H，m)，2.25-2.45(3H，m)，2.47-2.60(2H，m)，2.90-3.10(6H，m)，3.92(2H，t，J＝4.4Hz)，4.04(2H，t，J＝4.4Hz)，6.82(2H，d，J＝8.3Hz)，7.10(2H，d，J＝8.8Hz)，7.22-7.30(2H，m)，7.33-7.45(8H，m).
72	501	1.72-2.03(4H，m)，2.28(3H，s)，2.35-2.69(7H，m)，2.95-3.08(1H，m)，2.97(3H，s)，3.21-3.40(1H，m)，4.40(2H，s)，6.63-6.95(4H，m)，7.24-7.42(10H，m).
			73	441	2.15-2.24(2H，m)，2.27-2.42(5H，m)，2.45-2.54(2H，m)，2.58-2.68(2H，m)，2.87-3.08(5H，m)，5.71(1H，s)，6.78-6.87(2H，m)，6.97-7.02(1H，m)，7.05-7.12(1H，m)7.24-7.44(10H，m).
74	527	1.26(3H，t，J＝7.3Hz)，2.13-2.23(2H，m)，2.27-2.42(3H，br)，2.47-3.12(5H，m)，4.22(2H，q，J＝7.3Hz)，5.74(2H，s)，6.71(1H，d，J＝8.3Hz)，6.92(1H，t，J＝7.3Hz)，7.11-7.18(2H，m)，7.23-7.46(10H，m).
			75	485	2.31(3H，s)，2.70-2.84(4H，m)，2.89-3.04(2H，m)，3.01(3H，s)，3.07-3.20(2H，m)，3.49-3.68(2H，m)，3.88-4.03(4H，m)，5.56(1H，s)，6.80-6.92(2H，m)，7.05(1H，d，J＝7.5Hz)，7.22(1H，t，J＝7.5Hz)，7.27-7.46(10H，m).

TABLE 17

76	499	2.29(3H，s)，2.71-3.10(7H，m)，2.99(3H，s)，3.38-3.55(2H，m)，3.89-4.04(1H，m)，4.54(2H，m)，5.64(1H，s)，6.76(1H，d，J＝7.8Hz)，6.93(1H，t，J＝7.8Hz)，7.10-7.22(2H，m)，7.26-7.46(10H，m).
			77	467	1.47-1.58(2H，m)，1.62-1.72(2H，m)，2.21-2.30(2H，m)，2.33-2.57(4H，m)，2.60-2.68(2H，m)，3.04(2H，d，J＝2.9Hz)，3.60(2H，t，J＝7.0Hz)，5.70(1H，s)，6.76-6.85(2H，m)，6.99(1H，d，J＝7.3Hz)，7.08(1H，t，J＝7.3Hz)，7.25-7.42(10H，m).
78	469	1.46-1.57(2H，m)，1.60-1.82(6H，m)，2.00-2.26(4H，m)，2.42-2.59(4H，m)，2.77-3.02(2H，m)，3.54-3.65(2H，m)，6.67(1H，d，J＝7.8Hz)，6.76(1H，t，J＝7.3Hz)，6.96(1H，t，J＝7.8Hz)，7.06(1H，d，J＝7.3Hz)，7.20-7.38(10H，m).
			79	555	1.26(3H，dt，J＝7.3，2.2Hz)，1.47-1.58(2H，m)，1.61-1.85(6H，m)，2.03-2.32(4H，m)，2.42-2.63(4H，m)，2.92-3.10(3H，m)，3.52-3.66(2H，m)，2.4.23(2H，dq，J＝7.3，2.2Hz)，4.60(2H，s)，6.68(1H，d，J＝7.8Hz)，6.93(1H，t，J＝7.8Hz)，7.10(1H，t，J＝7.8Hz)，7.20(1H，d，J＝7.8Hz)，7.23-7.45(10H，m).
80	555	1.48-1.58(2H，m)，1.61-1.85(6H，m)，2.06(3H，s)，2.08-2.37(4H，m)，2.42-2.65(4H，m)，2.85-3.14(3H，m)，3.54-3.63(2H，m)，4.08-4.15(2H，m)，4.36-4.44(2H，m)，6.79(1H，d，J＝7.5Hz)，6.92(1H，t，J＝7.5Hz)，7.09-7.21(2H，m)，7.23-7.42(10H，m).
			81	513	1.46-1.58(2H，m)，1.60-1.72(4H，m)，1.80-2.30(6H，m)，2.40-2.60(4H，m)，2.65-2.78(1H，m)，2.89-3.08(2H，m)，3.52-3.62(2H，m)，3.88-4.05(4H，m)，6.77-6.91(2H，m)，7.07-7.16(2H，m)，7.22-7.40(10H，m).
82	527	1.47-1.58(2H，m)，1.61-1.72(2H，m)，1.75-2.06(6H，m)，2.32-2.53(4H，m)，2.57-2.73(3H，m)，2.97-3.10(1H，m)，3.26-3.42(1H，m)，3.50-3.60(2H，m)，4.41(2H，s)，6.63-6.93(4H，m)，7.23-7.41(10H，m).
			83	557	1.20(3H，t，J＝7.1Hz)，1.56(6H，s)，1.56-1.94(6H，m)，1.94-2.25(2H，m)，2.25-2.45(3H，br)，2.45-2.64(2H，br)，2.80-3.20(6H，m)，4.20(2H，q，J＝7.1Hz)，6.61(1H，dd，J＝7.8，1.0Hz)，6.90(1H，dt，J＝7.8，1.0Hz)，7.01(1H，dt，J＝7.8，1.0Hz)，7.17(1H，dd，J＝7.8，1.0Hz)，7.25-7.32(2H，m)，7.32-7.47(8H，m).
84	529	1.46(6H，s)，1.67-1.96(4H，m)，2.20-2.36(3H，br)，2.36-2.51(2H，m)，2.51-2.63(2H，m)，2.63-2.76(2H，m)，2.88-3.06(5H，m)，3.28-3.42(1H，m)，6.59-6.69(1H，m)，6.72-6.85(1H，m)，7.27-7.35(2H，m)，7.35-7.45(10H，m).

Test example 1 (Effect demonstrated by an ileal sample taken from a guinea pig)

Hartley male guinea pigs (body weight: about 500g) were used. Ileum (15-30cm) was taken from the ileocecum of each guinea pig, to thereby prepare a longitudinal muscle sample having an enteromuscular plexus. The opioid receptor activity of the test drugs was measured by the method proposed by Oka et al (eur.j. pharmacol., 77; 137-141, 1982). Agonist activity is expressed by potency relative to the activity of DAMGO (which is a selective mu-opioid agonist) ([ D-Ala ]²，N-MePhe⁴，Gly⁵-ol]-enkephalin). The fact that the test drug is in fact an opioid agonist has been demonstrated by antagonism with naloxone.

The results are given in the following table.

Watch 18

Compound No.	Relative potency
		36	10
39	20
		43	20
45	20
		69	10
DAMGO	1.0
		Morphine (morphine)	0.14
Loperamide	4.3

Test example 2

Fenvalerate induced pain in ICR male mice (5 weeks old) in order to evaluate the analgesic effect of various drugs. Specifically fenvalerate (Na)⁺Channel activator, 1 μ g/site) was administered locally subcutaneously to the footpad of mice and the duration of the pain response (whipping or puncturing the footpad) so induced was observed. Wherein the total time of occurrence of a pain response during the course of 30 minutes after administration is used as an index for evaluating the analgesic effect. Each test drug was topically administered to the same site 15 minutes prior to the administration of fenvalerate. Using [2- [4- [4- (dimethylamino) -3, 3-diphenyl-4-oxobutyl group]Piperazin-1-yl]The monohydrochloride salt of phenoxyacetic acid (example 45) is used as the drug of the present invention. Loperamide and morphine, which exhibit mu-opioid agonist activity, are known to be used as comparative drugs, and a solvent (10% DMSO) is used as a control. Results(average of 10 mice per group) is given in figure 1.

As can be seen from fig. 1, the neuropathic pain relief drug of the present invention was demonstrated to exhibit a statistically significant analgesic effect on the pain response induced by fenvalerate.

Industrial applicability

The 2, 2-diphenylbutanamide derivatives or their salts of the present invention exhibit excellent mu-opioid agonistic effects and analgesic activity against neuropathic pain, and thus can be used as peripheral analgesics, neuropathic pain relieving drugs, or the like.

Claims (10)

1. A2, 2-diphenylbutanamide derivative represented by the following formula (1):

[ wherein A represents- (CH)₂)_n- (n is 1 or 2) or methine (CH); when A is-CH₂-when B represents a methine group or a nitrogen atom, wherein a and B form a single bond; when A is- (CH)₂)₂-when B represents a nitrogen atom, wherein a and B form a single bond; and when a is methine, B represents a quaternary carbon atom, wherein a and B form a double bond;

R¹and R²Each, which is the same or different, represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹And R²May form a heterocyclic ring together with the adjacent nitrogen atom; and Ar represents a phenyl group, a bicyclic aromatic ring, a monocyclic heterocyclic ring, a bicyclic heterocyclic ring, or a fluorenyl group, which may have a substituent represented by the following group:

(wherein R is³Represents a hydrogen atom, a halogen atom, phenyl, lower alkyl, or-O-R⁴(wherein R is⁴Represents a hydrogen atom, a lower alkyl group, or- (CR)⁵R⁶)_m-Y (wherein R⁵And R⁶Each represents a hydrogen atom or a lower alkyl group; y represents-COOR⁷，-OR⁸，-OCOR⁹or-CONR¹⁰R¹¹(wherein R is⁷、R⁸And R⁹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group; and R¹⁰And R¹¹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹⁰And R¹¹May form a heterocyclic ring together with the adjacent nitrogen atom); and m is 1-6)))](ii) a Or a salt of the derivative.

2. A2, 2-diphenylbutanamide derivative represented by the following formula (1-1):

[R¹and R²Each, which is the same or different, represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹And R²May form a heterocyclic ring together with the adjacent nitrogen atom; n is 1 or 2; and Ar' represents a phenyl group, a bicyclic aromatic ring, a monocyclic heterocyclic ring, a bicyclic heterocyclic ring, or a fluorenyl group, which may have a substituent represented by the following group:

(wherein R is^3’Represents a hydrogen atom, a halogen atom, phenyl, lower alkyl, or-O-R⁴(wherein R is⁴Represents a hydrogen atom, a lower alkyl group, or- (CR)⁵R⁶)_m-Y (wherein R⁵And R⁶Each represents a hydrogen atom or a lower alkyl group; y represents-COOR⁷，-OR⁸or-OCOR⁹(wherein R is⁷、R⁸And R⁹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group; and m is 1-6)))](ii) a Or a salt of the derivative.

3. A2, 2-diphenylbutanamide derivative represented by the following formula (1-2):

[ wherein R¹And R²Each, which is the same or different, represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹And R²May form a heterocyclic ring together with the adjacent nitrogen atom; and R^3”Represents a hydrogen atom, a halogen atom, a lower alkyl group, or-O-R⁴(wherein R is⁴Represents a hydrogen atom, a lower alkyl group, or- (CR)⁵R⁶)_m-Y (wherein R⁵And R⁶Each represents a hydrogen atom or a lower alkyl group; y represents-COOR⁷，-OR⁸，-OCOR⁹or-CONR¹⁰R¹¹(wherein R is⁷、R⁸And R⁹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group; and R¹⁰And R¹¹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹⁰And R¹¹May form a heterocyclic ring together with the adjacent nitrogen atom); and m is 1-6))](ii) a And salts of the derivatives.

4. A2, 2-diphenylbutanamide derivative represented by the following formula (1-3):

[ wherein R¹And R²Each, which is the same or different, represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹And R²May form a heterocyclic ring together with the adjacent nitrogen atom; and R^3”Represents a hydrogen atom, a halogen atom, a lower alkyl group, or-O-R⁴(wherein R is⁴Represents hydrogenAtom, lower alkyl, or- (CR)⁵R⁶)_m-Y (wherein R⁵And R⁶Each represents a hydrogen atom or a lower alkyl group; y represents-COOR⁷，-OR⁸，-OCOR⁹or-CONR¹⁰R¹¹(wherein R is⁷、R⁸And R⁹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group; and R¹⁰And R¹¹Each represents a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R¹⁰And R¹¹May form a heterocyclic ring together with the adjacent nitrogen atom); and m is 1-6))](ii) a Or a salt of the derivative.

5. A medicament comprising the 2, 2-diphenylbutanamide derivative or its salt according to any one of claims 1 to 4 as an active ingredient.

6. A medicament according to claim 5 which is a peripheral analgesic.

7. The medicament according to claim 5, which is a neuropathic pain relieving medicament.

8. A pharmaceutical composition comprising the 2, 2-diphenylbutanamide derivative or salt thereof according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

9. A method for treating peripheral pain or neuropathic pain, comprising administering the 2, 2-diphenylbutanamide derivative or salt thereof according to any one of claims 1 to 4.

10. Use of the 2, 2-diphenylbutanamide derivative or a salt thereof according to any one of claims 1 to 4 for the preparation of a peripheral analgesic drug or a neuropathic pain relieving drug.