WO1993016048A1 - Substituted acetamide compound - Google Patents

Abstract

An anticholinergic compound represented by general formula (I), wherein R?1 and R2¿ represent each optionally substituted aryl, R3 represents hydrogen, hydroxy or lower alkyl, R4 represents a group of formula (a), (b), (c) or (d), A?1 and A2¿ represent each lower alkylene, and m and n represent each 0 or 1.

Description

 Specification

Title of invention

 Substituted acetate amide compounds

Technical field

 The present invention relates to a novel substituted acetate amide compound and a pharmaceutically acceptable salt thereof, which has anticholinergic activity, in particular, nervous frequency, neurogenic bladder, nocturnal enuresis, unstable bladder, bladder spasm , Treatment for urinary frequency in diseases such as chronic cystitis and chronic prostatitis, urination disorder such as urinary incontinence; gastric ulcer, duodenal ulcer, hyperacidity, esophageal spasm, gastritis, enteritis, irritable bowel disease, intestine Colic, gallbladder, inflammation, cholangitis, pyloric spasm, pain associated with knee inflammation, 、 inflammation, biliary dyskinesia, sequelae after gallbladder resection, urolithiasis, cystitis, dysmenorrhea, hyperhidrosis, urinary tract Novel substituted acetate amide compounds and pharmaceutically acceptable compounds that are useful for treating convulsions such as convulsions and z or hyperactivity, and are expected to be useful for treating asthma, Parkinson's disease, angina, etc. About salt Things.

Background art

 An object of the present invention is to provide a novel substituted amide compound and a pharmaceutically acceptable salt thereof, which are useful for treating the above-mentioned diseases.

 Another object of the present invention is to provide a formulation useful as a therapeutic agent for the above-mentioned diseases, which contains the substituted acetate amide compound or a pharmaceutically acceptable salt thereof as an active ingredient.

 Disclosure of the invention

The substituted acetate amide compound which is the object compound of the present invention is novel and is represented by the following formula (I).

[Wherein, R ¹ and R ² represent an aryl group which may have a suitable substituent,

R ³ is hydrogen, hydroxyl or a lower alkyl group,

R ⁴ is the formula (i):

(Wherein, R ⁵ represents hydrogen, methyl, ethyl, propyl, isopropyl or imino protecting group),

(ϋ) Formula:

(Wherein, R ⁶ represents a lower alkyl group)

 (iii) Formula:

N A group represented by or

 (iv) Equation:

(Wherein, R ⁷ represents hydrogen, a lower alkyl group or an imino protecting group)

 A group represented by

A ¹ and A ² are lower alkylene groups,

m and n each represent 0 or 1, respectively. (However, (a) when R ¹ and R ² are phenyl groups, R ³ is a hydroxyl group, A ² is a methylene group, m is 0, and n force s 1, R ⁵ is ethyl Not a group,

• (b) When R ′ and R ² are phenyl groups, R ³ is a hydroxyl group, and m and n are 0, R ⁷ is not a methyl group. )]

 The target compound (I) may have an asymmetric carbon atom, and stereoisomers in such a case are also included in the technical scope of the present invention.

 In producing the target compound (I), a compound produced according to a method described in the below-mentioned Production Examples may be used as a starting material, and a compound produced according to a method described in the following Examples also may be used.

Suitable salts of the target compound (I) are conventional non-toxic salts, for example, formate, acetate, trifluoroacetate, maleate, tartaric acid Organic salts such as salts, methanesulfonate, benzenesulfonate, and toluenesulfonate, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate Acid addition salts such as acid salts, or salts with amino acids such as arginine, aspartic acid and glutamic acid, or alkali metal salts such as sodium salts and calcium salts and calcium salts such as Metal salts such as alkaline earth metal salts such as magnesium salts, ammonium salts, such as trimethylamine salts, triethylamino salts, pyridine salts, picolin salts, dicyclohexylamine salts, Organic base salts such as N—N′-dibenzylethylenediamine salt and the like can be mentioned. In the above and following description of this specification, preferred examples and explanations of various definitions included within the scope of the present invention are described in detail below.

 "Lower", unless otherwise indicated, means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

 Suitable examples of the "aryl group" in the "aryl group optionally having substituent (s)" include a phenyl group, a naphthyl group, a pentalenyl group, an anthracenyl group, and the like. Of these, a phenyl group is particularly preferred.

 Examples of “suitable substituents” that can be substituted by the above “aryl group” include, for example, halogen (eg, fluorine, chlorine, bromine, iodine), lower alkyl group (eg, methyl, ethyl, propyl, Isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), lower alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, "b-butoxy, pentyloxy, hexyloxy, etc.)

New paper And the number of substitution by these substituents is 1 or more (preferably 1 to 3).

 Accordingly, a preferred example of the “aryl group optionally having a substituent” is a group having one suitable substituent selected from the group consisting of a halogen, a lower alkyl group and a lower alkoxy group. More preferred examples include a phenyl group having a halogen, a phenyl group having a -C 4) alkyl group, and a phenyl group having a (C, 1C 4) alkoxy group. Examples thereof include a phenyl group having chlorine, a phenyl group having fluorine, a phenyl group having methyl, and a phenyl group having methoxy.

Suitable examples of "lower alkyl" include straight and branched ones such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl. etc. can be mentioned, et al are group, is a preferred example among them, (C, - c ₄₎ alkyl group, and is a further preferred embodiment, a methyl group, Echiru group, blanking opening propyl group, Isopropyl, butyl and t-butyl groups.

Suitable examples of "imino protecting groups" include conventional protecting groups, i.e., substituted or unsubstituted trityl, benzhydryl, benzyl, 4-methoxybenzyl, etc. An alkenyl (lower) alkyl group, a dinitropropyl group, for example, a lower alkoxycarbonyl (lower) alkenyl group such as 1-methoxycarbonyl-1-propene-2-yl, for example, 1-benzoyl1-1-propene-1 2—Aroyl (lower) alkenyl group such as yl, for example, 2—Hydroxy such as hydroxybenzylidene New paper Examples thereof include a xyl (lower) alkylidene group, for example, a silyl compound such as tri (lower) alkylsilyl such as trimethylsilyl, and the following acyl group.

 Preferable examples of the "acyl group" include an aliphatic acyl group, an aromatic acyl group, a heterocyclic acyl group, and an aliphatic acyl group substituted with an aromatic group or a heterocyclic group.

 Examples of the aliphatic acetyl group include a carbamoyl group, for example, a lower alkanoyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, norrelyl, isonoleryl, bivaloyl, and hexanoyl; for example, mesyl and ethanesulfonyl. And lower alkoxysulfonyl groups such as propanesulfonyl and the like, for example, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl, for example, acrylyl, and methanol Lower alkenoyl groups such as lyroyl and crotonyl, for example, (C 3 -C 7) cycloalkanols such as cyclohexanecarbonyl, and the like, amidino groups such as methoxalyl, ethoxyl, and tertiary butoxy Alcoxari, such as A saturated or unsaturated acyclic or cyclic acyl group, such as a protected force such as a propyloxycarbonyl group.

 Examples of the aromatic acyl group include an aroyl group such as benzoyl, toluene, and xyloyl, and an arylene sulfonyl group such as benzenesulfonyl and tosyl.

 Examples of the heterocyclic acyl group include furyl, tenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, morpholinocarbonyl, and the like.

New paper And a heterocyclic carbonyl group.

 Examples of the aliphatic acetyl group substituted with an aromatic group include an alkenyl group such as a phenyl (lower) alkanol group such as phenyl acetyl, phenylpropionyl, and phenylhexanoyl. Alkoxycarbonyl groups such as phenyl (lower) alkoxycarbonyl groups such as benzyloxycarbonyl and phenyloxycarbonyl, and phenoxy (such as phenoxyacetyl and phenoxypropionyl) Lower) alkanoyl groups and the like.

 Aliphatic acryl groups substituted with a heterocyclic group include chenyl acetyl, imidazolyl acetyl, furyl acetyl, tetrazolyl acetyl, thiazolyl acetyl, thiadia azolyl acetyl, chenyl propionyl, and thiadiazolyl. And propionyl.

These acyl groups are further substituted with lower alkyl groups such as carboxy groups such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, and hexyl, such as chlorine, bromine, iodine and fluorine. Halogen, carbamoyl, lower alkanol such as formyl, acetyl, propionyl, etc., alk (lower) alkyl such as benzyl, methyl, ethyl, propyl, isopropyl, butyl, tert. Lower alkyl groups such as tertiary butyl, for example, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and tertiary butoxycarbonyl, for example, alkoxycarbonyl groups such as benzyloxycarbonyl. Groups, such as arylcarbonyl groups such as phenyloxycarbonyl Carboxy (lower) alkyl groups such as carboxymethyl and carboxyethyl, for example new paper Examples thereof include protected carboxy (lower) alkyl groups such as tert-butoxycarbonylmethyl.

 Suitable examples of "lower alkylene group" include straight-chain and branched-chain ones, for example, methylene group, ethylene group, trimethylene group, tetramethylene group, 1,1-dimethylethylene group, pentamethylene group. And hexamethylene groups, among which preferred examples include (C, -C,) alkylene groups, and more preferred examples include methylene group and ethylene group. . In addition, in the target compound (I), either or both of m and n may be 0 in such a case. In this case, such a bond not via a lower alkylene group is formed.

 Various definitions in the present invention are as shown above with typical examples, and these constitute the objective compound (I) under any combination. However, the following combinations are not included in the scope of the present invention.

(a) a combination in which R ¹ and R ² are a phenyl group, R ³ is a hydroxyl group, A ² is a methylene group, m is 0, n is 1, and R ⁵ is an ethyl group

(b) a combination wherein R ¹ and R ^{2 are} phenyl groups, R ³ is a hydroxyl group, m and n forces S 0 and R ⁷ are methyl groups

Among the various definitions in the present invention, particularly preferred are phenyl, fluorine-containing phenyl as R ¹ and R ² , hydrogen, hydroxyl, methyl and m as R ^3. 0 or 1, A ¹ is a methylene group, n is 0 or 1, A ² is a methylene group or an ethylene group, R ⁵ s hydrogen, methyl, ethyl, isopropyl, imino protecting group, R ⁶ is ethyl Group, R ⁷ is hydrogen, methyl, ethyl, isopropyl, etc.

New paper Or an imino protecting group is indicated respectively.

The invention's effect

 The compound (I) of the present invention and salts thereof have anticholinergic activity and are useful for treating urinary dysfunction in humans and animals, and other various diseases described above.

 Compound (I) and salts thereof are characterized in that side effects such as mydriasis are reduced.

 In order to show the usefulness of the compound (I), pharmacological test data of representative compounds of the present invention are shown below.

Exam 1

 Study on suppression of bladder contraction in rat pressure overload model [I] Test method

 Male S.D. lauts weighing 240-450 g were anesthetized with urethane (1.0 g / kg) subcutaneous injection. The bladder was exposed by a midline abdominal incision and the intravesical pressure was recorded as follows. A balloon attached to one end of a stainless steel tube (OD 1.2 mm, length 5 cm) was inserted into the bladder through a small incision in the bladder dome. The other end of the tube was connected to a pressure transducer. The ureter was ligated and cut, and a urinary polyethylene tube was inserted into the cut end on the bladder side to guide urine out.

 Excessive bladder movement (hyperconstrictive movement of the diuretic muscle) was induced by filling the bladder with water. The balloon in the bladder applied a water pressure of about 10 mmHg. Systemic blood pressure and heart rate were monitored from the common carotid artery.

 The test compound was administered intravenously when the bladder contractile response to the water pressure load became constant.

 [Π] Test compound

New paper Test compound (1) _:

 N- (1,2,3,6-tetrahydropyridin-1-yl) methyl 2-hydroxy-2,2-diphenylacetic acid amide

 [m] Test result

ED _{3 for} each test compound. The value (mg / kg) was 0.005 (mg / kg).

 The pharmaceutical composition of the present invention (prophylactic and / or therapeutic regimen for dysuria includes the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and can be administered rectally or pulmonary (nasally or nasally). Suitable for oral inhalation), intranasal administration, ophthalmic administration, topical administration (topical administration), oral administration, parenteral administration (including subcutaneous administration, intravenous administration and intramuscular administration) or inhalation and intravesical administration Used as solid, semi-solid or liquid pharmaceutical preparations together with organic or inorganic carriers or excipients The active ingredient is tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols It is formulated by mixing with, for example, a general-purpose non-toxic and pharmaceutically acceptable carrier for preparing inhalable powders, solutions, emulsions, suspensions, and other various forms suitable for use. If necessary, auxiliaries, stabilizers, extenders, coloring agents, fragrances, etc. may be added, etc. Compound (I) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical preparation of the present invention. Should be contained in an amount sufficient to produce the desired effect on the disease progression or symptoms.

In applying the pharmaceutical preparation of the present invention to humans and animals, methods such as intravenous administration, intramuscular administration, intrapulmonary administration, oral administration and inhalation administration are preferable. The therapeutically effective dose of compound (I) will vary depending on the route of administration, age and symptoms of individual patients, etc. Daily dose of 0.01 to 2 Omg / kg to mice or animals, 0.1 to 20 mg / kg for intramuscular administration, and 0.5 to 50 rag / kg for oral administration. Or it is administered for therapeutic purposes.

 Hereinafter, Production Examples and Examples will be shown to explain the present invention.

Production Example 1

 100 mixture of benzylic acid (5.00g) and phosphorus pentachloride (9.4g). The mixture was stirred with C for 3 'for 5 hours. After cooling, ice water (50 ml) and getyl ether (100 ml) were added to the reaction solution, the organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave a crude product of 2-chloro-2,2-diphenyl acetic chloride (6.16 g). To a solution of this crude product (6.16 g) in anhydrous toluene (50 ml) was added dropwise a solution of 4- (aminomethyl) pyridine (1.97 g) in anhydrous toluene (5 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate (50 ml), and further added with a 1N aqueous sodium hydroxide solution (50 ml). The organic layer was separated, washed with 1N aqueous sodium hydroxide solution (50 ml each, 3 times), and then the solvent was distilled off to obtain N- (pyridine-4-yl) methyl-2-chloro-2,

A crude product of 2-diphenylacetic acid amide (9.06 g) was obtained. A solution of this crude product (9.06 g) in 1 N hydrochloric acid (50 ml) was stirred at 70 C for 2 hours. After cooling, the solution was washed with getyl ether (50 ml).

An aqueous solution of sodium hydroxide was added to make the solution alkaline. The precipitate was collected by filtration to obtain a colorless powder of N- (pyridine-4-yl) methyl-2-hydroxy-1,2,2-diphenylacetic acid amide (6.37 g).

 mp: 148-151 ° C

IR (Nujol): 3330, 1650, 1600, 760, 740, 690cm " ¹ _{NR (DMS0-d 6, δ} ): 4.33 (2H, d, J = 6.3Hz), 6.85 (1H, s),

 7.15-7.18 (2H, ra), 7.25-7.40 (10H, m), 8.42-8, 45 (2H, m), 8.84 (1H, t, J = 6.3Hz)

 MASS (m / z): 183, 105

Production Example 2

 N- (pyridin-41-yl) methyl-2-hydroxy-1,2,2-diphenylacetate amide (80 g) and 4-methoxybenzyl chloride (47.2 g) 65 dimethylformamide (120 ml) solution. The mixture was stirred at C for 1 hour. After cooling, the reaction mixture was diluted with acetone (500 ml) and getyl ether (100 ml), and the mixture was stirred under ice-cooling for 20 minutes. The precipitate was collected by filtration to give a colorless powder of 4 — [(2-Hydroxy-2,2-diphenylacetylamino) methyl] —11- (4-methoxybenzyl) pyridinium chloride (107.57 g) was gotten.

 mp: 205-208 ° C

IR (Nujol): 3250, 3050, 1650, 1610, 750, 700cm- ¹

N Lan _{(DMS0 - d 6, δ)} : 3.76 (3Η, s), 4.55 (2H, d, J = 5.9HZ),

 5.72 (2H, s), 6.99 (2H, d, J = 6.7Hz), 7.00 (1H, s),

7.25-7.40 (10H, m), 7.53 (2H, d, J = 6.7Hz),

 7.87 (2H, d, J = 6.7Hz), 9.13 (2H, d, J = 6.7Hz),

 9.11 (1H, t, J = 5.9Hz)

 MASS (m / z): 183, 93

 Production Example 3

A solution of 4-acetylaminomethylpyridine (7.OOg) and 4-methoxybenzyl chloride (6.8 ml) in acetone (100 ml) was refluxed for 4 hours and then under ice-cooling for 30 hours. Stirring was performed for each minute. Precipitate is collected by filtration. After washing with water, hygroscopic 4-acetylaminomethyl-11- (41-methoxybenzyl) pyridinium chloride (10.88 g) was obtained. This product was used as a starting material in the next step (Production Example 4) without purification.

Production Example 4

 4-Acetylaminomethyl-11- (4-methoxybenzyl) pyridinium chloride (10.88 g) in methanol (200 ml) was added sodium borohydride (5.37 g) little by little under ice-cooling. Was added and the solution was stirred at room temperature for 13 hours. After water (10 ml) was added to the reaction solution, the solvent was distilled off. Ethyl acetate and water were added to the residue, the organic layer was separated, washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was developed on silica gel column chromatography, and purified using a mixture of methylene chloride and methanol (15: 1) as the eluent. A pale yellow oil of 4-acetylaminomethyl-1- (4-methoxybenzyl) was obtained. 1) 1,2,3,6-Tetrahydropyridine (7.27 g) was obtained.

 IR (film): 3300, 1650, 1610, 760cm- '

_{NMR (CDC1 3, δ):} 1.98 (s, 3H), 2.10 (br s, 2H),

 2.56 (t, J = 5.7Hz, 2H), 2.95 (br s, 2H), 3.52 (s, 2H), 3.76 (s, 2H), 3.80 (s, 3H), 5.53 (t, J = 1.5Hz , 1H),

5.95 (br s, 1H), 6.80-6.90 (m, 2H), 7.20-7.30 (m, 2H) ASS (m / z): 274 (M ⁺ ), 215, 121

 Production Example 5

In the same manner as in Production Example 3, 4-acetylaminomethyl-1-propylpyridinium iodide was obtained from 4-acetylmethylpyridine. mp: 135-137 ° C (Acetone washed product)

IR (Nujol): 3250, 1670, 1640, 760, 750 cm— ¹

Negation R (D called _{- d 6, 5): 0.87} (t, J = 7.3Hz, 3H), 1.65-2.00 (m, 2H),

 1.97 (s, 3H), 4.45-4.55 (m, 4H), 7.96 (d, J = 6.8Hz, 2H) 8.67 (t, J = 5.8Hz, 1H), 8.98 (d, J = 6.8Hz, 2H)

MASS (m / z): 193 ( ⁺ ), 149, 107

Production Example 6

 From the compound obtained in Production Example 5 in the same manner as in Production Example 4, 4-acetylaminomethyl-1-propyl-1,1,2,3,6-tetrahydroxypropylidine was obtained.

IR (film): 3300, 3050, 1650, 750cm- ¹

_{NMR (CDC1 3, δ):} 0.91 (t, J = 7.3Hz, 3H),

 1.58 (t, quartet, J = 7.3Hz, J = 5.7Hz, 2H), 1.99 (s, 3H), 2.23 (br s, 2H), 2.30-2.40 (m, 2H), 2.56 (t, J = 5.7 Hz, 2H) 2.95 (d, J = 1.6 Hz, 2H), 3.79 (d, J = 5.4 Hz, 2H),

 5.54-5.57 (m, 1H), 5.66 (br s, 1H)

ASS (m / z): 196 (M ⁺ ), 167, 96

 Production example Ί

 In the same manner as in Production Example 4, an oily 3-acetylamino-1-ethyl 1,2,3,6-tetraethyl lopyridine was obtained from 3-acetylaminomethyl-1-ethylethyl iodide.

 b 150 ° C / 0.08mmHg (kugelrohr)

IR (film): 3270, 1640, 1540cm " ¹

_{NMR (CDC1 3, δ):} 1.15 (3H, t, J = 7Hz, CH 3),

1.99 (3H, s, COCHs) , 2.19 (2H, m, NCH 2 CH 2 CH =),

New paper 2.49 (2H, quartet, J = 7Hz, NCH ₂ CH ₃ ),

2.52 (2H, t, J = 6Hz, CH ₂ CH ₂ N),

2.72 (2H, d, J = 2.5Hz, NCH ₂ C =),

3.78 (2H, d, J = 5.5Hz, CH ₂ N), 5.65 (1H, ra, HC =),

 5.8 (1H, m, NH)

ASS (m / z): 182 (M ⁺ ), 123, HO (base), 108

Production Example 8

In the same manner as in Production Examples 3 and 4, starting from 4-acetylaminomethylpyridine and benzyl bromide, passing through 4-acetylaminomethyl-l-benzylpyridinium bromide to 4-acetylaminomethyl-l N, 1,2,3,6-Tetrahydropyridine was obtained. IR (Film) ： 3250, 1650, 740, 700cm- ¹

_{NR (CDC1 3, δ):} 1.98 (s, 3H), 2.00-2.15 (m, 2Η),

 2.15-2.35 (m, 2H), 2.97 (br s, 2Η), 3.45 (s, 2H),

 3.95-4.00 (m, 2Η), 5.53 (br s, 1H), 5.84 (br s, 1H), 7.20-7.40 (m, 5H)

ASS (m / z): 244 (M ⁺ ), 185, 172

Production Example 9

4-Acetylaminomethyl-11- (4-methoxybenzyl) solution of 1,1,2,3,6-tetrahydropyridine (5.00 g) and 6N sodium hydroxide aqueous solution (16 ml) in methanol (32 ml) Was heated under reflux conditions for 23 hours, and after the reaction was completed, the solvent was distilled off. Ethyl acetate and a 1N aqueous solution of sodium hydroxide were added to the residue. The organic layer was separated, washed with brine and dried over magnesium sulfate, and the solvent was distilled off. The residue is applied to silica gel column chromatography, and methylene chloride and meta When eluted with a mixture of phenols [(10: 1)-(2: 1)], an oily

4-Aminomethyl-11- (4-methoxybenzyl) 1-1,2,3,

6—Tetrahydropyrrolidine (2.31 g) was obtained.

 IR (film): 3370, 1610, 760, 730cm- '

_{NMR (CDC1 3, δ):} 1.84 (br s, 2H), 2.13 (br s, 2H),

 2.57 (t, J = 5.8Hz, 2H), 2.99 (br s, 2H), 3.20 (br s, 2H), '

3.53 (s, 2H), 3.80 (s, 3H), 5.53-5.57 (m, 1H),

 6.80-6.90 (m, 2H), 7.20- 7.30 (m, 2H)

MASS (m / z): 232 ( ⁺ ), 202, 121

Production Example 10

 4-Acetylaminomethyl-1 monopropyl-11,2,3,6—tetrahydropyridin to 4-aminomethyl-1-propyl-1,2,3,6—tetrahydropyridine in the same manner as in Production Example 9 I got bp: 140-150 ° C / 10mmHg (Kugelrohr)

IR (Film): 3270, 1600cm " ¹

_{NR (CDC1 3, δ):} 0.92 (t, J = 7.3Hz, 3H), 1 · 10- 1.70 (br s, 2H),

 1.55 (t, quartet, J = 7.3Hz, J = 5.7Hz, 2H),

 2.14 (d, J = l.6Hz, 2H), 2.30-2.40 (m, 2H),

 2.57 (t, J = 5.7Hz, 2H), 2.96-3.00 (m, 2H), 3.10 (s, 2H),

5.53-5.57 (m, 1H)

MASS (m / z): 154 ( ⁺ ), 125, 96

 Production Example 11

In the same manner as in Production Example 9, 4-acetylaminomethyl-1 benzene 1, 2, 3, 6-tetrahydropyridine was converted to 4-aminomethyl 1 benzene 1, 2,3,6—Get Tetra Hydropyridine New Paper Was.

 IR (Film): 3370, 3270, 1600, 740, 700cm- *

_{NMR (CDC1 3, δ):} 1.61 (s, 2H), 2.13 (br s, 2H),

 2.58 (t, J = 5.8Hz, 2H), 2.95-3.05 (m, 2H), 3.20 (br s, 2H) 3.59 (s, 2H), 5.50-5.55 (m, 1H), 7.20-7.37 (m, 5H)

MASS (m / z): 202 ( ⁺ ), 172, 97

Production Example 12

 In the same manner as in Production Example 9, from 3-acetylaminomethyl-1-ethyl-1,2,3,6—tetrahydropyridine to 3-aminomethyl-1-ethylethyl 1,2,3,6—tetrahydrodropyridine I got

bp: 100-105 ° C / 8.5mraHg (Kugelrohr)

IR (Nujol): 3450, 3370, 3280, 3200cm- ¹

_{NR (CDC1 3, δ):} 1.14 (3H, t, J = 7Hz, CH 3),

1.61 (2H, s, NH ₂ ), 2.21 (2H, m, CH ₂ CH ₂ CH =),

2.7 (2H, quartet, J = 7Hz, NCH ₂ CH ₃ ),

2.49 (2H, t, J = 6Hz, NCH ₂ CH ₂ CH =), 2.93 (2H, m, CH ₂ N),

3.20 (2H, ra, CH ₂ N), 5.62 (1H, m, CH =)

MS (m / z): 140 ( ⁺ ), 123 (base), 110, 108

Production Example 13

A solution of 3-aminomethylviridine (10.0 g) in acetic acid (30 ml) was stirred, and acetic anhydride (17.5 ml) was added thereto at room temperature. The resulting mixed solution was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to obtain crude oily 3-acetylacetylaminopyridine. This product was reacted with iodide chill according to the method of Production Example 3, and the product was crystallized with a mixed solution of n-hexane and ethyl acetate. Light yellow crystalline 3-acetylaminomethyl-new paper 1-Ethylpyridinium iodide was obtained.

mp: 110-111. C

IR (Nujol): 3420, 3260, 1640cm " ¹

NMR (DMS0-d ₆ , δ): 1.54 (3Η, t, J = 7.5 Hz, CH ₃ ),

 1.93 (3H, s, COCHa), 4.44 (2H, d, J = 6Hz, CH2NCO),

4.64 (2H, quartet, J = 7, 5Hz, NCH ₂ CH ₃ ),

 8.12 (1H, t, J = 7.5Hz, pyridinium H),

 8.43 (1H, d, J = 7.5Hz, pyridinium H),

 8.59 (1H, t, J = 6Hz, NH), 9.0 (2H, m, pyridinium H)

MASS (m / z): 135, 107

Production Example 14

 3.3 — Difluoro-2-ethyl propane (4.28 g) mixed with 3 N aqueous sodium hydroxide (28 ml) and ethanol (50 ml) was allowed to stand at room temperature overnight, and then The mixture was stirred at 50 ° C for 2 hours. Ethyl acetate and brine were added to the reaction mixture, and concentrated hydrochloric acid was further added to make it acidic. After the organic layer was separated and dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3,3-diphenyl-2-propenoic acid. mp: 158-161 ° C (washed with ethyl acetate)

IR (Nujol): 1690, 1660, 1610, 720,700cm- ¹

_{NMR (CDC1 3, δ):} 6.32 (s, 1H), 7.10 7.40 (m, 10H)

MASS (m / z): 224 (M ⁺ ), 179, 165

 Example 1

 4-([2-Hydroxy-2,2-diphenylacetylamino) methyl] 1-1— (4-Methoxybenzyl) pyridinium chloride (100 g) in methanol (800 ml) solution in a nitrogen atmosphere 10 Hydrogen at -20 ° C

New paper Sodium boride (32.7 g) was added in small portions. The obtained solution was stirred at room temperature for 1 hour, and the solvent was distilled off. Ethyl acetate (1 · β) and water (500 ml) were added to the residue, and the organic layer was separated. This was washed successively with water (500 ml) and brine (500 ml), dried over magnesium sulfate, and the solvent was distilled off to obtain crude oily N— [1- (4-methoxybenzyl) 1-1,2, 3,6-Tetrahydropyridine-14-yl] methyl-12-hydroxy-2,2-diphenylacetic acid amide was obtained. A mixture of this crude oily substance and 1-chloroethyl carbonate (25 ml) in methylene chloride (700 ml) was heated to reflux for 1 hour, and methanol (350 ml) was added. Then, the solution was heated for 30 minutes. The mixture was refluxed and the solvent was distilled off. The residue was crystallized by treatment with 4 N hydrochloric acid in ethyl acetate, and recrystallized from ethanol to give colorless crystals of N- (1,2,3,6-tetrahydropyridine). Methyl-2-hydroxy-2,2-diphenylacetic acid amide hydrochloride (41. & 4g) was obtained.

mp: 222-224 ° C

IR (Nujol): 3350, 1650, 750, 730, 690cm- ¹

_{NMR (DMS0-d 6, δ} ): 2.15 (2Η, br s), 3.10 (2H, t, J = 5.9Hz),

 3.34 (2H, br s), 3.70 (2H, d, J = 5.5 Hz), 5.41 (1H, br s), 6.82 (1H, s), 7.20-7.45 (10H, m), 8.34 (1H, t, J = 5.5Hz), 9.15 (2H, br s)

MASS (m / z): 322 (M ⁺ ), 183, 95

 Example 2

N — [(1,2,3,6-tetrahydropyridin-141-methyl) methyl] —2—hydroxy-2,2-diphenylacetic acid amide (1.00 g) in 10% palladium on carbon in methanol For hydrogenation. New paper with catalyst removed Thereafter, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give N — [(piperidin-4-yl) methyl] -12-hydroxy-2,2-diphenylacetic acid amide hydrochloride (0.35 g). Obtained.

mp: 251-253 ° C

IR (Nujol): 3360, 2470, 1650, 1600, 750, 730, 700cm— ¹

NMR (DMS0-d ₆ , δ): 1.10-1.40 (m, 2H), 1.50-1.80 (m, 3H),

 2.65-2.90 (m, 2H), 2.90-3.10 (m, 2H), 3.10-3.30 (m, 2H), 6.75 (s, 1H), 7.20-7.45 (m, 10H), 8.28 (br s, 1H) ,

 8.69 (br s, 2H)

MASS (m / z): 324 ( ⁺ ), · 183, 105

Elemental _{analysis: C 2 O H 2, N} 2 0 2 -HCl

 Calculated values C 66.56, H 6.98, N 7.76

 Measured values C 67.04, H 7.09, N 7.76

Example 3

 In the same manner as in Example 2, N — [(1—methyl-1,2,3,6—tetrahydropyridine) methyl] —2—hydroxy 2,2—diphene N-[(1-Methyl-piberidine-4-yl) methyl] -12-hydroxy-2,2-diphenylacetic acid amide hydrochloride was obtained from acetic acid amide.

 mp: 237-239 ° C

IR (Nujol): 3430, 3150, 1670, 790, 770, 710, 700cm- ¹

NMR (DMS0-d6 ₎ δ): 1.20-1.50 (m, 1H), 1.60-1.80 (m, 2H),

 2.20-3.20 (m, 8H), 2.68 (s, 3H), 6.73 (s, 1H),

7.20-7.35 (ra, 10H), 8.30 (br s, 1H), 9.70-9.90 (br s, 1H) MASS (ra / z): 338 (M ⁺ ), 183, 105 New paper 2 Elemental _{analysis: C 2 I H 2 6 N} 2 0 Z -HC1

 Calculated value C 67.28, H 7.26, N 7.47

 Measured value C 67.64, H 7.56, N 7.53

Example 4

 N-[[1- (4-methoxybenzyl) 1-2,3,6-tetrahydropyridin-1-yl] methyl] -12-hydroxy-2,2-diphenylacetamide ( A solution of 1.03 g) and benzyl chlorocarbonate (0.437 g) in 1,2-dichloroethane (10 ml) was stirred at room temperature for 4 hours, diluted with water, and extracted with methylene chloride. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, then developed on silica gel column chromatography, and eluted with a mixed solution of methylene chloride and methanol, to give an oily N — [(1-benzyloxycarboxylate). There was obtained 0.797 g of amide 1,2,3,6-tetrahydropyridin-14-yl) methyl] -12-hydroxy-2,2-diphenylacetate.

IR (f ilm): 3390, 1690, 1670cm ' ¹

_{NMR (CDC1 3, δ):} 1.99 (2Η, br s, = CCH 2 CH 2 N),

3.52 (2H, t, J = 5.5Hz, CH ₂ CH ₂ NC00), 3.76 (1H, s, OH),

3.90 (4H, m, = CHCH ₂ NC00 and C0NCH ₂ ), 5.13 (2H, s, 0CH ₂ ),

5.37 (1H, br s, = CH), 6.49 (1H, m, CONH),

 7.3-7.5 (15H, m, aromatic H)

 ASS (m / z): 183, 105, 91, 77

 Example 5

N-[[1- (4-Methoxybenzyl) 1-1,2,3,6—tetrahydropyridine-14-ylmethyl] -12-hydroxy-2, new paper A 1,2-dichloroethane (55 ml) solution of 2-diphenylacetic acid amide (2.77 g) and 1,1-dichloroethane carbonate (0.75 ml) was heated to reflux for 30 minutes. Methanol (50 ml) was added to the reaction mixture, and the obtained solution was heated under reflux for 1 hour, and then the solvent was distilled off. The residue is developed into a series of gels and gel chromatographs and mixed with methylene chloride and methanol.

(10: 1), then methanol and then a methanol / 28% aqueous ammonia mixture (10: 1) for elution and purification. The solvent was distilled off from the eluate, and the residue was crystallized by treatment with a mixture of 4 N hydrochloric acid and ethyl acetate, and further recrystallized with a mixture of methanol and ethyl acetate.

[(1,2,3,6 -—. Tetrahydropyridin-14-yl) methyl] -12-hydroxy-2,2-diphenylacetic acid amide hydrochloride (1.33 _g ) was obtained.

mp: 223-224 ° C

IR (Nujol): 3350, 1650, 750, 730, 690cm- ¹

NMR (DMS0-d ₆ , δ): 2.15 (br s, 2H), 3.10 (t, J = 5.9Hz, 2H),

 3.34 (br s, 2H), 3.70 (d, J = 5.5Hz, 2H), 5.41 (br s, 1H), 6.82 (s, 1H), 7.20-7.45 (m, 10H), 8.34 (t, J = 5.5HZ, 1H), 9.15 (br s, 2H)

MASS (m / z): 322 (M ⁺ ), 183, 95

 Example 6

 N — [(1 benzyloxycarbonyl 1,2,3,6—tetrahydropyridine-14-yl) methyl] 1-2—hydroxy-2,2-diphenylacetate A solution of amide (186 mg) in a 25% aqueous solution of hydrobromic acid in acetic acid (1.86 ml) was stirred under ice-cooling for 30 minutes, further stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure . Ji Sopro Pill in residue

Sheep paper Ether and water were added to carry out a liquid separation, and an aqueous layer was obtained. The mixture was basified with 1N sodium hydroxide ice ^: solution, and extracted with methylene chloride. The methylene chloride layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was developed by silica gel column chromatography and eluted with a mixture of methylene chloride and methanol to give a colorless powder of N-[(1,2,3,6-tetrahydropyridine-14-yl) methyl] 1-2- Hydroxy-2,2-diphenylacetic acid amide (85 mg) was obtained and recrystallized from ethanol.

rap: 151-153 ° C

Elemental analysis:

 Calculated values C 74.51, H 6.88, N 8.69

 Found C 74.59, H 7.08, N 8.74

IR (Nujol): 3380, 3300, 1670cm " ¹

顏_{(CDC1 3, S): 1.95} (2H, m, = CCH 2 CH 2 NH),

2.85 (2Η, t, J = 5.5Hz, CH ₂ CH ₂ NH),

3.23 (2H, br s, = CHCH ₂ NH), 3.35 (2H, br, = NH and OH), 3.84 (2H, d, J = 5.5Hz, C0NHCH ₂ ), 5.44 (1H, br s, = CH ), 6.70 (1H, t, J = 5.5Hz, CONH),

 7.25-7.5 (10H, m, aromatic H)

MASS (m / z): 322 (M ⁺ ), 183 (base), 105 (base), 96 (base)

 Example 7

 N — [(1,2,3,6-tetrahydropyridin-141-methyl) methyl] To a solution of 12-hydroxy-2,2-diphenylacetic acid amide (6.00 g) in methanol (60 ml), At room temperature, a solution of methanesulfonic acid (1.79 g) in methanol (20 ml) was added. The mixture is concentrated under reduced pressure, and the residue is crystallized.

New ^ After recrystallization with ethanol, colorless crystals of N-[(1,2,3,6-tetrahydropyridin-14-yl) methyl] -12-hydroxy-2,2-diphenyl Amide acetate methanesulfonate (6.66 g) was obtained.

mp: 195-197. C

IR (Nujol): 3400, 1670, 1590, 780, 750, 740, 700cm " ¹

NMR (DMS0-d ₆ , δ): 2.14 (br s, 2H), 2.31 (s, 3H),

 3.14 (t, J = 6.1Hz, 2H), 3.51 (br s, 2H),

 3.71 (d, J = 6.1Hz, 2H), 5,40 (br s, 1H), 6.81 (s, 1H), 7.20-7.41 (m, 1.0H), 8.36 (t, J = 6.1Hz, 1H) ,

 8.65 (br s, 2H)

 MASS (m / z): 323 (M + 1)

Elemental analysis: C _2. H ₂₂ N ₂ 0 ₂ 'CH ₃ S0 ₃ H

 Calculated values C 60.27, H 6.26, N 6.69, S 7.66 Actual values C 60.32, H 6.32, N 6.62, S 7.86

Example 8

 N— (1—Ethoxycarbonylbiperidine-1-4-yl) A solution of 1,2,2-diphenylacetic acid amide (4.00 g) and hydroxide (2.0 g) in methylcellulose sorb (30 ml) The mixture was heated and stirred for an hour. Ethyl acetate (100 ml) and water (300 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (100 ml × 3), combined with the organic layer and the solvent was distilled off under reduced pressure. The residue was treated with a mixture of 4 N hydrochloric acid and ethyl acetate to obtain N- (piperidine-41-yl) -1,2,2-diphenylacetic acid amide hydrochloride.

 mp: 233-235 "C (cleaned with ethyl acetate)

New paper IR (Nujol): 3500, 3300, 1630, 740, 720cm ' ¹

_{NR (DMS0-d 6, δ} ): 1.45- 1.75 (m, 2H), 1.75-2.00 (ra, 2H),

 2.80-3.10 (m, 2H), 3.10-3.25 (in, 2H), 3.70-3.95 (m, 1H) 4.97 (s, 1H), 7.10-7.40 (m, 10H), 8.59 (d, J = 7.4Hz , 1H), 8.86 (br s, 2H)

MASS (m / z): 294 (M ⁺ ), 229, 167, 127

Elemental analysis: C ₁₉ H ₂₂ N ₂ 0'HC1

 Calculated value C 65.41, H 7.22, N 8.03

 Found C 65.67, H 7.32, N 8.12

Example 9

 In the same manner as in Example 8, N (1-ethoxycarbonylbiliverydin-4-yl) -12-hydroxy-2-, 2-diphenylacetic acid amide was converted to N- (piperidin-14-yl) -12- Hydroxy 2,2-diphenylacetic acid amide hydrochloride was obtained.

mp: 193-195 ° C (Acetone-washed product)

IR (Nujol): 3300, 2700, 2600, 2470, 1660, 770, 750, 730, 700 cm " ¹

NMR (D S0-d ₆ , δ): 1.60-2.00 (m, 4H), 2.75-3.05 (ra, 2Η),

 3.05-3.30 (m, 2Η), 3.75-4.00 (m, 1Η), 6.77 (s, 1H), 7.20-7.95, 10H), 8.15 (d, J = 7.7Hz, 1H),

 8.94 (br s, 1H), 9.10 (br s, 1H)

 MASS (m / z): (without M +), 183, 105

Elemental _{analysis: C 19 H 22 N 2 0} 2 'HC1

Calculated value C 64.67, H 6.76, N 7.94, C1 10.05 Actual value C 64.79, H 6.93, N 7.92, C1 9.98 New paper Example 10

 Heat a solution of N- (pyridin-4-yl) methyl-2-hydroxy-2,2-diphenylacetate amide (2.00 g) and methyl iodide (1.6 ml) in acetone (100 ml) for 3 hours The mixture was refluxed and the solvent was distilled off under reduced pressure to obtain crude oily 1-methyl-41-[(2-hydroxy2,2-diphenylphenylcetylamino) methyl] pyridinium iodide. This oil was dissolved in methanol (50 ml), and sodium borohydride (0.95 g) was added. The obtained mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off. Ethyl acetate and a 1N aqueous solution of sodium hydroxide were added to the residue, and the mixture was separated. The organic layer was separated, washed sequentially with water and brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was crystallized by treatment with a mixture of 4 N ethyl acetate hydrochloride and recrystallized from a mixture of propanol and methanol to give N- (1-methyl-1,2,3,6—tetrahydropyridine). (1) Methyl-2-hydroxy-1,2,2-diphenylacetate amide (0.41 g) was obtained.

 mp: 173-174 ° C

IR (Nujol): 3340, 3200, 2550, 1660, 770, 750, 720, 700cm— ¹

_{NMR (DMS0-d 6, δ} ): 2.00-2.50 (2Η, m), 2.80-3.90 (4Η, m),

 2.73 (3Η, s), 3.72 (2Η, d, J = 6.1 Hz), 5.38 (1H, s), 6.82 (1H, s), 7.20-7.40 (10H, m), 8.37 (1H, t, J = 6.1Hz) 10.77 (1H, br s)

 MASS (m / z): 336 (M +), 183, 109

 Example 11

In the same manner as in Example 10, N- (pyridin-4-yl) methyl-2-hydroxy-2,2-diphenylacetamide and iodide chill or a new paper Thus, N- (1-ethylpyridinyl-4-yl) methyl-2-hydroxy-2,2-diphenylacetic acid amide was obtained. mp: 123-124. C

IR (Nujol): 3350, 1650, 780, 740, 720, 700cm " ¹

NMR (DMS0-d ₆ , δ): 1.52 (t, J = 7.2 Hz, 3H), 4.57 (q, J = 7.2 Hz, 2H)

 4.60 (d, J = 6.0Hz, 2H), 7.00 (s, 1H), 7.20-7.50 (m, 10H), 7.85 (d, J = 6.6Hz, 2H), 9.01 (d, J = 6.6Hz, 2H ),

 9.13 (t, J = 6.0Hz, 1H)

 MASS (m / z) ': (without M +), 183, 105

Example 12

 N — [(1,2,3,6—Tetrahydropyridin-14-methyl) methyl] 1-2—Hydroxy-12,2—Diphenylacetic acid amide hydrochloride (0.70 g) and cyanohydrogenation A mixture of sodium boron (0.18 g) dissolved in a mixture of anhydrous methanol (15 ml) and anhydrous acetate (5 ml) was stirred at room temperature for 4 days, and after completion of the reaction, the solvent was distilled off under reduced pressure. Ethyl acetate and a 1N aqueous solution of sodium hydroxide were added to the residue, and the organic layer was separated. After washing with brine and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized by treatment with a mixture of 4 N hydrochloric acid / 1,4-dioxane, yielding N-[(1-isopropyl-1,2,3,6-tetrahydropyridine) -4-yl) Methyl] -12-hydroxy-2,2-difuunylacetic acid amide hydrochloride (0.58 g) was obtained.

 mp: 126-127 ° C (1,4-dioxane washed product)

I (Nujol): 3250, 1660, 760, 700cm- ¹

NMR (DMS0-d ₆ , δ): 1.26 (d, J = 6.6 Hz, 6H), 2.05-2.25 (m, 1H),

2.30-2.60 (m, 1H), 2.75-3.10 (m, 1H), 3.25-3.50 (m, 2H), new] 3.58 (br s, 2H), 3.73 (d, J = 6.0Hz, 2H), 5.42 (s, 1H), 6.83 (br s, 1H), 7.15-7.60 (m, 10H), 8.36 (t, J = 6. OHz, 1H) 10.30 (br s, 1H)

Elemental _{analysis: C 23 H28N 2 0 2 -HC1-1} / 2H 2 0

 Calculated value C 67.39, Η 7.38, Ν 6.83, C1 8.65

 Found C 67.40, H 7.84, N 6.58, CI 8.35

Example 13

 N— (4-Piperidyl) -1 2—Hydroxy 2,2—diphenylacetic acid amide N— (1—Ethylbiberydin—4-yl) 1 2 in the same manner as in Example 12. -Fumarate of hydroxy-2,2-diphenylacetic acid amide was obtained.

mp: 197-199. C (Isopropyl alcohol recrystallized product)

IR (Nujol): 3420, 2350, 1670, 750, 700, 670cm " ¹

_{NMR (DMS0-d 6, δ} ): 1.05 (t, J = 7.2Hz, 3H), 1.45-1.65 (m, 4H),

 2.15-2.40 (m, 2H), 2.54 (q, J = 7.2Hz, 2H),

 2.85-3.05 (m, 2H), 3.55-3.75 (ra, 1H), 6.50 (s, 1H), 7.20-7.40 (m, 11H), 7.96 (d, J = 8. OHz, 1H)

Elemental _{analysis: C 21 H 26 N 2 0-} 1 / 2C, H 4 0 4 - 1 / 2Η 2 0

 Calculated value C 68.13, H 7.21, N 6.91

 Measured C 67.97, H 7.41, 6.67

 Example 14

In the same manner as in Example 12, N— (4-piperidyl) —2,2-diphenylacetic acid amide hydrochloride was converted to N— (1-isopropylpiperidin-1-41-yl) -1,2,2-diphenylacetic acid An amide fumarate was obtained. New paper mp: 175-177 ° C (Acetone washed product)

IR (Nujol): 3200, 2650, 2500, 1660, 790, 770, 740, 700cm " ¹

_{NMR (DMS0-d 6, δ} ): 1.13 (d, J = 6.6Hz, 6H), 1.45-1.75 (m, 2H),

 1.75-2.00 (m, 2H), 2.65-2.90 (m, 2H), 3.00-3.25 (m, 3H),

3.65-3.90 (m, 1H), 4.93 (s, 1H), 6.54 (s, 3H),

 7.10-7.35 (m, 10H), 8.43 (d, J = 7.3Hz, 1H) ''

MASS (ra / z): 336 (M ⁺ ), 321, 167

Elemental _{analysis: C 22 H 2e N 2 0'3} / 2 (C 4 H 4 0 4)

 Calculated value C 65.87, Η 6.71, Ν 5.49

 Measured value C 65.60, H 6.84, N 5.57

Example 15

 In the same manner as in Example 12, N- (4-piperidyl) -12,2-diphenylacetic acid amide hydrochloride to N— (1-ethylbiperidin-14-yl) -12,2-diphenylacetic acid amide The acid salt was obtained.

mp: 179-181 ° C (Acetone washed product)

IR (Nujol): 3250, 1690, 1760, 790, 760, 740cra " ¹

NMR (DMS0-d ₆ , δ): 1.05 (t, J = 7. Hz, 3H), 1.30-1.60 (m, 2H),

 1.70-1.85 (m, 2H), 2.25-2.40 (m, 2H),

 2.55 (q, J = 7.2Hz, 2H), 2.90-3.10 (m, 2H),

 3.40-3.55 (m, 1H), 4.91 (s, 1H), 6.55 (s, 2H),

 7.20-7.30 (m, 10H), 8.34 (d, J = 7.4Hz, 1H)

MASS (m / z): 322 (M ⁺ ), 307, 167, 111

Elemental _{analysis: C 21 H 26 N 2 0} -C 4 H 4 04-1 / 2H 2 0

 Calculated values C 67.10, H 6.98, N 6.26

Observed value C 66.78, Η 6.97, Ν 6.05 Example 16

 A mixture of benzylic acid (2.21 g) and 1,1′-carbonyldiimidazole (1.73 g) in anhydrous methylene chloride (45 ml) was stirred at room temperature for 2.5 hours. To this mixture was added a solution of 4-amino-methyl-1— (4-methoxybenzyl) -11,2,3,6-tetrahydropyridine (2.25 g) in anhydrous methylene chloride (20 ml). Dropping slowly over a period of time. The obtained mixture was stirred at room temperature for 45 minutes, and the solvent was distilled off. Ethyl acetate and 1N aqueous sodium hydroxide solution were added to the residue, the organic layer was separated, washed with water (twice), dried over magnesium sulfate, and the solvent was distilled off. The residue was developed on silica gel column chromatography, and purified with a mixture of methylene chloride and methanol (10: 1) as eluent to give N- [1- (4-methoxybenzyl) as a pale yellow oil. 1,1,2,3,6-Tetrahydroxypyridine-14-methyl)-2-hydroxy-2,2-diphenylacetic acid amide (3.47 g) was obtained.

_{IR (CHC1 3): 3370,} 1660, 1610, 750, 730, 700cm- '

_{NMR (CDC1 3, δ):} 2.02 (br s, 2H), 2, 52 (t, J = 5.8Hz, 2H),

 2.91 (br s, 2H), 3.50 (s, 2H), 3.80 (s, 3H),

 4.10 (br s, 1H), 4.14 (s, 2H), 5.39 (br s, 1H),

 6.39 (br s, 1H), 6.85 (d, J = 12.7Hz, 2H),

 7.20-7.50 (m, 12H)

ASS (m / z): 442 ( ⁺ ), 202, 121

 Example 17

In the same manner as in Example 16, benzylic acid and 1-methyl-14-aminomethyl-1,2,3,6—tetrahydropyridine were converted to N— (1-me Chill 1,2,3,6—tetrahydropyridine (41-yl) methyl 2-hydroxy-2,2-diphenylacetamide oxalate was obtained.

mp: 185-190. C

 IR (Nujol): 1650, 1600, 770, 750, 730, 700cm- '

NMR (D S0-d _B , δ): 2.09 (br s, 2H), 2.50 (s, 3H),

 2.81 (t, J = 5.9 Hz, 2H), 3.19 (br s, 2H),

 3.68 (d, J = 6.0Hz, 2H), 4.98 (br, 2H), 5.37 (s, 1H),

 7.20-7.45 (m, 11H), 8.26 (t, J = 6.0Hz, 1H)

MASS (m / z): 336 (M ⁺ ), 215, 183, 109

Example 18

 In the same manner as in Example 16, benzylic acid and 1-propyl-14-aminomethyl-1,2,3,6—tetrahydropyridine were converted to N— (one-port pill-1 1,2,3,6—tetrahydropyridine. 1-4-yl) Methyl 2- (hydroxy) -2,2-diphenylacetic acid amide hydrochloride was obtained.

rap: 96-98 ° C (recrystallized from a mixture of ethyl acetate methanol / diisopropyl ether)

IR (Nujol): 3250, 1660, 770, 740, 700cm- ¹

_{NMR (DMS0-d 6, δ} ): 0.89 (t, J = 7.3Hz, 3H), 1.60-1.80 (m, 2H),

 2.00-2.55 (m, 2H), 2.90-4.20 (m, 8H), 5.89 (br s, 1H),

6.82 (s, 1H), 7.20-7.45 (m, 10H), 8.37 (t, J = 6.1Hz, 1H),

10.50 (br s, 1H)

ASS (m / z): 364 (M ⁺ ), 335, 183, 137

Elemental _{analysis: C 23 H 2 0 2 '} HC1 new sheet Calculated value C 66.80, Η 7.41, Ν 6.77, C1 8.57 Measured value C 66.77, Η 7.76, Ν 6.44, C1 8.57 Example 19

 In the same manner as in Example 16, benzylic acid and 1-benzyl-4-aminomethyl-1,2,3,6-tetrahydropyridine were used to obtain Ν— (1—benzyl 1,2,3,6—tetrahi Dropiridine (41-yl) methyl 2-hydroxy-2,2-diphenylacetic acid amide hydrochloride was obtained.

mp: 139-141 ° C (recrystallized from a mixture of methanol and ethyl acetate / diisopropyl alcohol)

IR (Nujol): 3450, 3200, 2570, 1660, 750, 710, 680cm " ¹

_{NMR (DMS0-d 6, δ} ): 2.00-2.50 (m, 2H), 2.70-3.50 (m, 2H),

 3.50 (br s, 2H), 3.72 (d, J = 6.0Hz, 2H), 4.30 (s, 2H),

5.38 (s, 1H), 6.81 (s, 1H), 7.25-7.63 (m, 15H),

 8.36 (t, J = 6.0Hz, 1H), 10.92 (br s, 1H)

Elemental _{analysis: C 27 H 2 e N 2} 0 2 'HC1

Calculated (0.8 H ₂ 0 and to) C 69.98, H 6.66, N 6.05, CI 7.65 Found C 69.94, H 6.67, N 5.94 , CI 7.63 Example 20

In the same manner as in Example 16, benzylic acid and 1-ethyl- ₃ , aminomethyl-1,2,3,6—tetrahydropropyridine were converted to N— (1—ethyl 1,2,3,6— Tetrahydroxypyridin-1-yl) methyl-2-hydroxy-2,2-diphenylacetamide amide 1/2 fumarate was obtained.

mp: 185-186. C (recrystallized from isopropyl alcohol) New paper IR (Nujol): 3400, 2750-2600, 1675, 1590cm- ¹

NMR (DMS0-d ₆ , δ): 1.02 (3H, t, J = 7Hz, CH ₃ ),

2.09 (2H, m, = CHCH ₂ CH ₂ ), 2.45-2.65 (4H, m, NCH ₂ X 2), 2.92 (2H, s, = CCH ₂ N), 3.68 (2H, m, C0NCH ₂ ),

 5.52 (1H, br s, = CH), 6.51 (2H, s, fumaric acid = CH),

 7.25-7.4 (10H, m, aromatic H), 8.21 (1H, br s, CONH)

MASS (m / z): 350 (M ⁺ ), 183, 124 (base), 105

Elemental _{analysis: C 22 H 26 N 2 0} 2 '1 / 2C 4 H 4 0 4

 Calculated values C 70.57, H 6.91, N 6.86

 Found C 70,36, H 7.11, N 6.72

Example 21

 Trimethylsilyl cyanide (1.35 ml) was added to a mixture of 4,4'-difluorobenzophenone (2. Og) and zinc iodide (0.1 lg) in anhydrous methylene chloride (15 ml) at room temperature. added. The obtained mixture was stirred at the same temperature for 40 hours, and the solvent was distilled off under reduced pressure. Concentrated hydrochloric acid (30 ml) was added to the residue, and the mixture was stirred at 90 ° C for 14 hours. Ethyl acetate and water were added to the reaction mixture for liquid separation, and the organic layer was separated and concentrated under reduced pressure. To the residue were added diisopropyl ether and a 1 N aqueous solution of sodium hydroxide, and the mixture was separated. The organic layer was separated and washed three times with a 1 N aqueous solution of sodium hydroxide. The aqueous layers were all combined, acidified by adding concentrated hydrochloric acid, and extracted twice with ethyl acetate.

The organic solvent layers were combined, washed successively with water and brine, dried over magnesium sulfate, and evaporated to give crude 4,4'-difluoro mouth benzylic acid (0.80 g). Dissolve this crude product (0.80 g) and N, N'-carbonyldiimidazole (0.6 g) in anhydrous methylene chloride and add 4-aminomethyl-1-ethyl-1,2,3,6-tetrat to this solution. A solution of lahydropyridine (0.60 g) in methylene chloride was slowly added dropwise at room temperature.

 The resulting mixture was stirred at room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate and a 1N aqueous solution of sodium hydroxide were added to the residue to separate the layers. The separated organic layer was washed with water and then with a saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography and then alumina column chromatography, and treated with 4N hydrochloric acid to give N — [(1—ethyl-1,2,3,6—tetrahydropyri. (4-N-methyl) -2-hydroxy-2,2-bis (4-fluorophenyl) acetic acid amide hydrochloride was obtained. rap: 155-157 ° C (diisopropyl ether cleaning product)

IR (Nujol): 3350, 3270 , 2500, 1660, 1600, 820, 770cm "1 NR (DMS0-d 6, δ): 1.24 (t, J = 7.2Hz, 3H), 2.00-2.45 (m, 2H) ,

 2.85-3.80 (m, 6H), 3.09 (quartet, J = 7.2Hz, 2H),

 5.39 (s, 1H), 6.96 (s, 1H), 7.10-7.20 (m, 4H),

7.35-7.45 (m, 4H), 8.46 (br s, 1H), 10.21 (br s, 1H) MASS (m / z): 386 (M ⁺ ), 371, 219, 123, 110

Elemental analysis: C ₂₂ H ₂ 4N ₂ 0 ₂ F ₂ · Η (1.1 / 3H ₂ 0

 Calculated value C 61.61, H 6.03, N 6.53, CI 8.27 Actual value C 61.69, H 6.09, N 6.54, CI 8.27

 Example 22

A solution of 2-chloro-2,2-diphenylacetyl chloride (6.30 g) dissolved in a mixture of benzene (17 ml) and Zn-hexane (11 ml) was stirred at room temperature. A solution of amino-1-azabicyclo [2.2.2] octane in benzene (12 ml) was added dropwise. Use the resulting mixture on new paper The mixture was stirred at room temperature for 30 hours and 30 minutes, and toluene and water were added to carry out a liquid separation. The organic layer was extracted twice with 1 N hydrochloric acid, and the aqueous layers were combined and washed with getyl ether. 7 (After stirring with TC for 1 hour, cool with ice water, add 5% aqueous sodium hydroxide solution to make the solution more viscous, and extract twice with ethyl acetate. The residue was washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.The residue was washed with diisopropyl ether to give a colorless powder (2.90 g), which was salted by a conventional method. This was recrystallized with ethanol to give N- (1-azabicyclo [2.2.2] octane-3-yl) -12-hydroxy-2, .2-difuunyl acetate as a colorless powder. Mid hydrochloride was obtained.

mp: 2 & to 265 ° C (dec.)

IR (Nujol): 3300, 2800-2300, 1660cm " ¹

NR (D S0-d ₆ , δ): 1.6-2.1 (5Η,

3.05-3.6 (6Η, m, N (CH ₂ ) ₃ ), 4.15 (1Η, m, CONHCH),

 6.87 (1Η, S, OH), 7.25-7.45 (10Η, m, aromaticΗ),

 8.59 (1Η, d, J = 7Hz, CONH), 10.36 (1H, br s, HC1)

ASS (m / z): 336 (M ⁺ ), 183 (base), 105

Elemental _{analysis: C 21 H 24 N 2 0} 2 -HC1

 Calculated value C 67.64, H 6.76, N 7.51

 Found C 67.67, Η 7.10, Ν 7.31

 Example 23

In the same manner as in Example 16, 4-amino-11-ethoxycarborubi. From peridine and benzylic acid, N- (4-ethoxycarbonylbiliveridine-4-yl) -12-hydroxy-2,2-diphenylacetic amide was obtained.

mp: 128-131. C (n-hexane washed product)

 IR (Nujol): 3300, 1650, 1620, 760, 740, 720cm- '

_{NMR (CDC1 3, δ):} 1.00-1.41 (m, 2H), 1.23 (t, J = 7.1Hz, 3H),

 1.70-2.00 (m, 2H), 2.75-3.00 (m, 2H), 3.90-4.20 (m, 3H), 4.08 (q, J = 7.1Hz, 2H), 6.67 (d, J = 8.0Hz, 1H) ,

 6.93 (s, 1H), 7.20-7.50 (m, 10H)

MASS (m / z): 382 (M ⁺ ), 370, 216, 183

Example 24

 In the same manner as in Example 16, N— [2— (1—methylbiperidine—4-yl) ethyl] 1-2—hine was prepared from 4— (2-aminoethyl) —1—methylpiperidine and benzylic acid. Droxy 2,2-diphenylacetic acid amide fumarate was obtained. Using silica gel column chromatography, elution was performed with a mixed solution of chloroform and methanol to obtain a white powder. mp: 151-152 "C

IR (Nujol): 3360, 3250 , 3200, 2740-2100, 1700, 1670cm- 1 NMR (D S0-d 6, δ): 1.15-1.45 (5Η, m, CH and CH 2 x 2),

1.7 (2H, m, CH ₂ ), 2.35 (2H, m, CH ₂ ), 2.45 (3H, s, CH ₃ ),

3.0-3.2 (4H, m, CH ₂ x 2), 6.50 (2H, s, HC = CH),

 7.2-7.4 (11H, m, aromatic H and OH),

 8.15 (1H, t, J = 6Hz, NH)

 MASS (m / z): 352 (), 337, 183 (base)

Elemental _{analysis:. C 22 H 28 N 2} 0 2 'C 4 H 4 0 4 new sheet Calculated value C 66.65, Η 6.88, Ν 5.98

 Found C 67.02, Η7.05, Ν5.94

Example 25

 In the same manner as in Example 16, colorless crystals of Ν— (1-ethylpyperidin-3-yl) methyl 2-hydroxy-2,2-diphenylacetate hydrochloride were prepared from 3-aminomethyl-1-ethylbiliveridine and benzylic acid. Obtained.

 Free base

IR (Nujol): 3310, 2800-2300, 1660cm- ¹

_{NR (CDC1 3, δ):} 0.95 (1H, in, piperidine H),

1.00 (3H, t, J = 7Hz, CH 3), 1.5-1.95 (6H, m, piperidine H)

2.30 (2H, quartet, J = 7Hz, NCH ₂ CH ₃ ),

2.7 (2H, m, piperidine H ), 3.1-3.35 (2H, m, CO hidden _2),

4.15 (1H, br, OH), 6.86 (1H, br t, NH),

 7.25-7.53 (10H, m, aromatic H)

MASS (m / z): 352 ( ⁺ ), 337, 183, 105 (base)

 Hydrochloride

 mp: 181-182. C (Isopropyl alcohol recrystallized product)

IR (Nujol): 3360, 3220, 2660, 2570, 1655cm- ¹

NMR (DMS0-d ₆ , δ): 1.05 (1H, m, piperidine H),

1.16 (3H, t, J = 7Hz, CH 3), 1.75 (3H, m, piperidine H), 2.1 (1H, m, piperidine H), 2.45 (1H, m, piperidine H), 2.7 (1H, m, piperidine H),

2.95-3.35 (6H, ra, NCH ₂ CH ₃ , piperidine H, and C0NCH ₂ ), 6.79 (1H, s, OH), 7.2-7.45 (10H, ra, aromatic H), new paper 8.40 (1H, t, J = 6Hz, NH), 10.2 (1H, br, HC1) MASS (m / z): 352 (M ⁺ ), 337, 183, 105 (base)

Elemental _{analysis: C 22 H 2 B N 2} 0 2, HC1

 Calculated value C 67.94, H 7.52, N 7.20

 Measured values C 67.76, H 7.68, N 7.15

Example 26

 In the same manner as in Example 16, 2- (2-aminoethyl) -1 monomethylpyrrolidine and benzylic acid were used to obtain N— [2— (1—methylpyrrolidin-1-2-yl) ethyl-2—hydroxy-2 , 2-Diphenylacetic acid amide hydrochloride was obtained.

mp: 155-157 "C (Ethanol / ethyl acetate mixed solution recrystallized product)

IR (Nujol): 3400, 3180, 2620, 1660, 770cm- ¹

NR (DMS0-d ₆ , δ): 1.40-1.95 (m, 4H), 1.95-2.25 (m, 2H),

 2.64 (s, 3H), 2.75-3.10 (m, 2Η), 3.10-3.25 (m, 2H), 3.35-3.55 (m, 1Η), 6.76 (s, 1H), 7.20-7.50 (m, 10H), 8.38 (br s, 1H), 10.36 (br s, 1H)

MASS (m / z): 338 (M ⁺ ), 323, 183, 155, 84

Elemental analysis: C ₂₁ H _3. N ₂ 0 ₂ 'HC1

 Calculated values C 67.28, H 7.26, N 7.47, C1 9.46

 Found C 67.29, H 7.53, N 7.46, C1 9.44

 Example 27

In the same manner as in Example 16, 4-amino 1-ethoxycarbodiperidine and 2,2-diphenylacetic acid were converted to N— (1—ethoxycarbodirubiperidin-1-41) 1-2,2-diphenylacetic acid I got it. New paper mp: 163-165 ° C (n-hexane washed product)

IR (Nujol): 3300, 1650, 770, 750, 730, 700cm- ¹

NMR (CDcl ₃ , δ): 1.10-1.35 (ra, 5H), 1.80-2.00 (m, 2H),

 2.80-2.95 (m, 2H), 3.90-4.15 (m, 5H), 4.90 (s, 1H),

 5.52 (d, J = 7.5Hz, 1H), 7.20-7.40 (m, 10H)

ASS (m / z): 366 ( ⁺ ), 199

Example 28

 In the same manner as in Example 16, 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine and 3,3-diphenylpropionic acid were converted to N- (1-ethyl-1,2,3). , 6-Tetrahydropyridin-4-yl) Methyl-3,3-diphenylpropionate amide oxalate was obtained.

mp: 133-134 ° C (isopropyl alcohol diisopropyl ether mixed liquid recrystallized product)

IR (Nujol): 3330, 2600, 1720, 1640, 1600, 750, 710cm- ¹

NMR (DMS0-d ₆ , δ): 1.18 (t, J = 7.2Hz, 3H), 1.95 (br s, 2H),

 2.89 (d, J = 8.2Hz, 2H), 3.01 (q, J = 7.2Hz, 2H),

 2.95-3.10 (m, 2H), 3.39 (br s, 2H), 3.54 (br s, 2H), 4.47 (t, J = 8.2Hz, 1H), 4.88 (s, 1H), 7.10-7.30 (in, 10H), 8.13 (br s, 1H)

MASS (m / z): 348 (M ⁺ ), 333, 167, 123

Elemental _{analysis: C 23 H 28 N 2 0'C} 2 H 2 0 4

 Calculated value C 68.47, Η 6.90, Ν 6.39

 Measured values C 68.46, H 6.97, N 6.31

Example 29 New paper In the same manner as in Example 16, 4-aminomethyl-1 monoethyl-1, 2,3,6—tetrahydropyridine and 3,3 diphenylpropenoic acid: ^ et N— (1—ethyl-1 , 2,3,6-Tetrahid 4-yl) Methyl-3,3-diphenylpropenoic acid amide oxalate was obtained.

mp: 163-164. C (Isopropyl alcohol Z Ethyl acetate mixed methanol recrystallized product)

IR (Nujol): 3330, 2720, 1720, 1640, 770, 700cm— ¹

NMR (DMS0-d ₆ , δ): 1.20 (t, J = 7.3 Hz, 3H), 2.11 (br s, 2H),

 3.08 (q, J = 7.3Hz, 2H), 3.00-3.20 (m, 2H), 3.51 (br s, 2H) 3.55-3.70 (m, 2H), 4.40 (br s, 2H), 5.22 (s, 1H ),

 6.50 (s, 1H), 7.10-7.40 (m, 10H), 8.15-8.20 (m, 1H)

ASS (m / z): 346 (M ⁺ ), 207, 123

Elemental _{analysis: C 23 H 26 N 2 0} -C 2 H 2 0 4

 Calculated values C 68.79, H 6.47, N 6.42

 Measured value C 69.21, H 6.53, N 6.40

Example 30

 In the same manner as in Example 16, 4-aminomethyl-1-ethyl-1, 2 ', 3,6-tetrahydropyridine and 5-hydroxy-5H-10,11-dihydroxybenzene [a, d] Cycloheptene-5—Hydroboric acid to N- (1-ethyl-1,2,3,6—tetrahydropyridin-1 4—yl) methyl-2—hydroxy 2— (5—hydroxy 5 H—10 , 11-dihydrobenzo [a, d] cycloheptene-15-yl) acetic acid amide hydrochloride was obtained.

 Free base: colorless crystals

IR (Nujol): 3460, 3390, 2740, 1640cm- ¹ New paper NR (D S0-d ₆ , δ): 0.98 (3H, t, J = 7Hz, CH ₃ ),

 1.86 (2H, brs, CH2CH2N),

2.25-2.45 (4H, m, CH ₂ CH _Z NCH ₂ CH ₃ ),

2.75-2.9 (4H, m, = CHCH ₂ N and cycloheptene CH ₂ ),

3.3-3.45 (2H, m, cycloheptene CH ₂ ),

 3.54 (2H, d, J = 6Hz, CONCH2), 5.29 (1H, s, = CH),

 6.81 (1H, s, OH), 7.05-7.25 (6H, m, aromatic H),

 7.46 (1H, t, J = 6Hz, NH), 7.75-7.85 (2H, m, aromatic H)

MASS (m / z): 376 ( ⁺ ), 209, 123 (base), 110

 Hydrochloride: colorless crystals ·

rap: 158-159.5 ° C (Ethyl acetate crystal product)

IR (Nujol): 3420, 3330, 2730-2000, 1655cm- ¹

NMR (DMS0-d ₆ , δ): 1.23 (3H, t, J = 7Hz, CH ₃ ),

1.95-2.45 (2H, m, CH ₂ CH ₂ N),

2.75-3.15 (5H, ra, NCH2CH3, cycloheptene CH ₂ , and .yridine H), 3.3-3.45 (4H, m, pyridine HX 2 and cycloheptene CH ₂ ),

3.35-3.65 (3H, m, C0NCH ₂ and pyridine Hx 2),

 5.30 (1H, br s, = CH), 6.89 (1H, s, OH),

 7.05-7.25 (6H, ra, aromatic H),

 7.75-7.85 (3H, m, NH and aromatic Hx 2),

 10.5 (1H, br, HC1)

ASS (m / z): 376 (M ⁺ ), 209 (base), 123, 110

Elemental analysis: C ₂₄ H ₂₉ N ₂ 0 ₂ C1'3 / 2H ₂ 0

Calculated value C 65.52, Η 7.27, Ν 6.37 C1 8.06 New ^ paper 1

 42 Actual value C 65.68, Η 7.27, Ν 6.38, C1 8.06

Example 31

A solution of 2,2-diphenylpropionic acid (0, 70 g) dissolved in thionyl chloride (2.3 ml) was heated under reflux for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. Toluene (10 ml) was added to the residue, and the solvent was again distilled off under reduced pressure. The residue obtained by dissolving the residue in anhydrous methylene chloride (10 ml) is treated with 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (0.43 g) and triethylamine (1.5 ml) in anhydrous chloride. A methylene (10 ml) solution was added at room temperature. The resulting mixture was stirred at room temperature for 3 hours, and methylechloride and water were added to the reaction mixture. The organic layer was separated, washed with water (3 times), a 1N aqueous solution of sodium hydroxide, and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was developed on silica gel column chromatography, and a mixture of methylene chloride and methanol (20: 1) eluted was treated with a mixture of 4 N hydrochloric acid and ethyl acetate, followed by isopropyl alcohol and diisopropyl alcohol. When recrystallized with a tel mixture, N- (1-ethyl- 1,2,3,6-tetrahydropyridin-14-yl) methyl-2,2-diphenylpropionate amide hydrochloride (0.10 _g ) was gotten.

 mp: 93-94 ° C

IR (Nujol): 3450, 3350, 2670, 2600, 1630, 760, 740cm— ¹

_{NMR (DMS0-d 6, δ} ): 1.24 (t, J = 7.2Hz, 3H), 1.89 (s, 3H),

2.00-3.70 (m, 8H), 3.06 (q, J = 7.2Hz, 2H), 5.31 (br s, 1H) 7.10-7.40 (m, 10H), 7.64 (br s, 1H), 10.08 (br s, 1H) elemental _{analysis: C 23 H 28 N 2 0} -HC1

Calculated value C 68.56, Η 7.75, Ν 6.95, C1 8.80 New paper Measured value C 68.82, Η 7.95, Ν 6.89, C1 8.95

Example 32

 In the same manner as in Example 31, 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine and 2,2-difluoroacetic acid chloride were used to prepare Ν— (1-ethyl-1,2,3,6-tetraethyl). (Trahydropyridine 4-yl) methyl-2,2-diphenylacetic acid amide hydrochloride was obtained. rap: 205-207 ° C (Ethanol Z diisoprovir ale mixture recrystallization

IR (Nujol): 3270, 3070, 2670, 2550, 2470, 1640, 750, 700cm ' ¹

NR (DMS0-d ₆ , δ): l, 23 (t, J = 7.2Hz, 3H), 2.00-2.40 (ra, 2H),

 2.80-3.00 (m, 4H), 3.04 (q, J = 7.2Hz, 2H),

 3.60-3.80 (m, 2H), 5.06 (s, 1H), 5.39 (s, 1H),

 7.10-7.35 (m, 10H), 8.67 (t, J = 5.7Hz, 1H),

 10.43 (br s, 1H)

MASS (m / z): 334 (M ⁺ ), 167, 123

Elemental _{analysis: C 22 H 26 N 2 0} -HC1

 Calculated values C 71.24, H 7.34, N 7.55, CI 9.56

 Found C 71.30, H 7.62, N 7.52, CI 9.73

Example 33

A mixture of 2-chloro-2,2-diphenylacetic acid chloride (0.80 g) and 4-diethylaminomethylbiperidine (0.51 g) was stirred for a while at room temperature, and diluted with methylene chloride (10 ml). . The obtained mixture was stirred at the same temperature for 1 hour, and thereto were added ethyl acetate and water, and the mixture was separated. The vinegar liquid ethyl layer was washed with an aqueous sodium hydroxide solution and then with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Residual dioxane New paper (7.4 ml) and IN hydrochloric acid (3.7 ml). The solution was stirred at 90 ° C. for 1 hour and 30 minutes, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydroxide solution and then with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was developed on silica gel column chromatography and eluted with chromatographic form and methanol to give an oily 1- (2,2-diphenyl-2-hydroxyacetyl) -4-4-ethylethylmethylbiperidine (0.33). g) was obtained. This product was converted to the hydrochloride (0.20 g) by a conventional method.

 Free base

_{NR (CDC1 3, δ):} 0.93 (6H, t, J = 7Hz, CH 3 2),

0.95-1.95 (5H, m, piperidine CH ₂ CHCH ₂ ),

 2.06 (2H, d, J = 6.5Hz, CHCHaN),

2.43 (4H, quartet, J = 7Hz, N (CH ₂ CH ₃ ) ₂ ),

 2.68 (2H, m, CONCH x 2), 3.59 (1H, m, CONCH),

 4.74 (1H, m, CONCH), 6.2 (1H, s, OH),

 7.4 (10H, m, aromatic H)

MASS (m / z): 380 (M ⁺ ), 183, 86 (base)

 Hydrochloride

 mp: 175-176 ° C

IR (Nujol): 3400, 3160, 2760-2300, 1610cm " ¹

NR (DMS0-d ₆ , δ): 0.7 (1H, ra, piperidine CH),

1.05 (1H, m, piperidine CH), 1.18 (6H, t, J = 7Hz, CH ₃ x 2) 1.45 (1H, m, piperidine CH), 1.9 (2H, m, piperidine CH), 2.65 (2H, m , CONCH x 2), 2.8 (2H, m, CHCH ₂ N),

3.05 (4H, m, N (CH ₂ CH ₃ ) ₂ ), 4.15 (1H, m, CONCH), new paper 4.4 (1H, m, CONCH), 6.92 (1H, s, OH),

 7.3 (10H, m, aromatic H), 9.9 (1H, br, HC1)

MASS (m / z): 380 (M ⁺ ), 183, 86 (base)

Elemental analysis: C ₂ -H ₃₂ N ₂ 0 ₂ 'HC1'1 / 2H ₂ 0

 Calculated value C 67.67, H 8.04, N 6.58, CI 8.32

 Found C 67.62, H 8.08, N 6.51, CI 8.32

Example 34

 (4) One Promote 2,2-Divinylbutyric acid (1.5 g) and a solution of thionyl chloride (1.37 ml) in anhydrous chloroform (20 ml) were heated under reflux for 4 hours, and then the solvent was distilled off under reduced pressure. A crude product of 2,2-diphenylbutyric acid chloride was obtained.

Preparation of a solution of 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (0.73 g) and triethylamine (2.6 ml) in methylene chloride (15 ml). A solution of the crude 4-promo 2,2-diphenylbutyric acid chloride in methylene chloride (15 ml) was added at room temperature, and the resulting mixture was stirred overnight. The solvent was distilled off under reduced pressure, and ethyl acetate and a 1N aqueous solution of sodium hydroxide were added to the residue to separate the layers. The organic layer was separated, washed sequentially with water (three times) and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was developed on silica gel column chromatography and eluted with methylene chloride / methanol (15: 1 mixture), and further developed on alumina column chromatography and eluted with n-hexane ethyl acetate (20: 1) mixture. The resulting free base was treated with fumaric acid (229 mg) according to a conventional method to give 1-ethyl 4-[(3,3-diphenyl-2-oxopyrrolidine-11-yl) methyl] -1, 2, 3, 6—Tetrahydropyridine fumaric acid New paper The salt (0.54 g) was obtained.

mp: 90 ° C ~ (decomposition) (washed with n-hexane)

IR (Nujol): 2500, 1680, 800, 770, 750, 700cm " ¹

_{NMR (DMS0d 6, δ):} 1.11 (t, J = 7.2Hz, 3H), 2.17 (br s, 2H),

 2.73 (q, J = 7.2Hz, 2H), 2.80-2.90 (m, 4H), 3.24 (br s, 2H) 3.86 (s, 2H), 4.11 (t, J = 6.4Hz, 2H), 5.53 (s , 1H),

 6.52 (s, 2H), 7.10-7.40 (m, 10H)

MASS (m / z): 360 (M ⁺ ), 238, 165, 123

New paper

Claims

The scope of the claims

1. —general formula

R ¹

R ² one C one (A ¹⁾ _m one _{^{CONH - (A 2) n -}} R 4 (I) R 3

[Wherein, R ¹ and R ² are an aryl group which may have a suitable substituent,

R ³ is hydrogen, a hydroxyl group or a lower alkyl group,

R ⁴ is the formula (i):

(Wherein, R ⁵ represents hydrogen, methyl, ethyl, propyl, isopropyl or imino protecting group),

(ii) Formula:

(Wherein represents a lower alkyl group)

New paper (iii) Formula:

A group represented by or

 (iv) Equation:

(Wherein, R ⁷ represents hydrogen, a lower alkyl group or an imino protecting group)

 A group represented by

A ¹ and A ² are lower alkylene groups,

m and n each represent 0 or 1, respectively. (However, (a) when R ¹ and R ² are phenyl groups, R ³ is a hydroxyl group, A ² is a methylene group, m is 0, and n force is 1, R ⁵ is an ethyl group But also

(b) When R ¹ and R ² are a phenyl group, R ³ is a hydroxyl group, and m and n are 0, R ⁷ is not a methyl group. )]

And a pharmaceutically acceptable salt thereof.

2. A prophylactic and / or therapeutic agent for dysuria comprising the substituted acetate amide compound according to claim 1 as an active ingredient.

New ^闲; paper