JPH0140820B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel phenoxyalkylamine derivative, more specifically, it has the following general formula: In the formula, R ₁ and R ₂ each independently represent a lower alkyl group, or R ₁ and R ₂ together with the nitrogen atom to which they are bonded may be further substituted with a lower alkyl group. Forms a good 5- to 7-membered nitrogen-containing heterocycle; R ₃ represents a hydrogen atom or a lower alkyl group; m is 3 or 4; n is an integer of 1 to 3; Z is the following formula -COY ₁ , ―SO ₃ Y ₂ , ―PO(OY ₃ ) ₂ ,

[Formula] and represents a monovalent group selected from the group consisting of, where Y ₁ is a tridecyl group, a substituted lower alkyl group [here, the substituent is a halogen atom, a phenyl group, a nitrophenyl group, a benzoyl phenyl group,
carboxy group, lower alkoxycarbonyl group, lower alkanoyl group or 1-(4-methylphenyl)isoquinolin-5-yl group], styrine group, cyclohexyl group, naphthyl group, substituted phenyl group [wherein the substituent is lower alkyl group, lower alkoxy group, cyano group, carboxy group, lower alkanoyloxy group or dimethylamino group], lower alkoxy group, benzyloxy group, amino group, di-lower alkylamino group, pyridyl group, furanyl group, quinolyl group or a thienyl group; Y ₂ and Y ₃ each represent a hydrogen atom or a lower alkyl group; Y ₄ , Y ₅ and Y ₆ each independently represent a lower alkyl group; Y ₇ represents a hydrogen atom, and Y ₈ represents a lower alkyl group substituted with lower alkoxy, or Y ₇ and
Y ₈ together represent a trimethylene group or a tetramethylene group; R ₁ , R ₂ , R ₃ , m and n have the above meanings; The compound of the above formula () and its salts exhibit an excellent and long-lasting suppressive effect on gastric acid secretion, and are useful as active ingredients of anti-ulcer agents. By the way, one of the major causes of ulcers in the stomach or duodenum is the secretion of abnormally large amounts of gastric acid, and the conventional anti-ulcer drugs to deal with this are those that have the effect of neutralizing gastric acid and those that have anticholinergic effects. It is broadly divided into those with . However, the type that neutralizes gastric acid is short-lasting and weakly effective, and the type that has anticholinergic effects has strong side effects and is undesirable. On the other hand, it is already known that gastric acid secretion is stimulated via histamine _H2 receptors, and recently,
A new type of gastric acid secretion inhibitor that has this histamine H ₂ receptor antagonistic effect has been developed, and several proposals have been made [for example, Japanese Patent Publication No. 53-24422, Japanese Patent Application Laid-open No. 18557-1982, Showa 53-149936
Publication No. 109963, Japanese Patent Application Laid-Open No. 1983-109963,
115860, JP-A-56-8352, etc.]. The compound of the above formula () provided by the present invention is a novel compound that has not been described in conventional literature, and has an excellent gastric acid secretion suppressing effect based on histamine H ₂ receptor antagonism and its long-lasting effect, It is a useful compound as a new type of anti-ulcer agent. The term "lower" as used herein means that the compound or group to which this term is attached has no more than 6 carbon atoms, preferably no more than 4 carbon atoms. Thus, a "lower alkyl group" can be either linear or branched, for example methyl, ethyl, n-propyl, isopropyl, n-
Butyl, isobutyl, sec-butyl, tert-butyl groups, etc. are included, and examples of "lower alkoxy groups" include methoxy, ethoxy, n-propoxy,
Examples include isopropoxy, n-butoxy, isobutoxy groups, and the like. Also, "lower alkanoyl group"
Examples include acetyl, propionyl, butyryl, isobutyryl, valeryl groups, etc.
Examples of the "halogen atom" include fluorine, chlorine, and bromine. In the above formula (), specific examples of the "substituted lower alkyl group" represented by _Y1 include the following: chloropropyl, bromopropyl, carboxyethyl, methoxycarbonylethyl, ethoxycarbonylhexyl, phenylmethyl, phenylpropyl, p-nitrophenylmethyl, p-nitrophenylpropyl, m-benzoyl phenylethyl group, etc. Further, specific examples of the "substituted phenyl group" represented by Y ₁ include the following: 2-methoxyphenyl, 2-carboxyphenyl, 4-
Methylphenyl, 4-cyanophenyl, 4-dimethylaminophenyl, 2-acetoxyphenyl,
3,4,5-trimethoxyphenyl group, etc. In the above formula (), the "5- to 7-membered nitrogen-containing heterocycle" that can be formed by R ₁ and R ₂ together with the nitrogen atom to which they are bonded refers to a "5- to 7-membered nitrogen-containing heterocycle" that contains a heteroatom other than the nitrogen atom. It is desirable that there be no ring, and it is preferable that the ring is saturated. Specific examples of such heterocyclic groups include l-pyrrolidinyl group

[Formula] l-piperidinyl group

[Formula] and l-perhydroazepinyl basis

[Formula] is mentioned. These nitrogen-containing heterocyclic groups may be further substituted (preferably mono-substituted) with a lower furkyl group, and specific examples of such substituted nitrogen-containing heterocyclic groups include:

【formula】

[Formula] is included. The group in the above formula ()

Groups suitable as [Formula] include:

【formula】

【formula】

[Formula] etc. are included, and among these, especially is suitable. Further, as the group R ₃ , a hydrogen atom, a methyl group and an ethyl group are preferable. However, atomic groups

Especially suitable as [Formula] are:

【formula】

[Formula] is mentioned. In addition, in the above formula (), m is preferably 3, and n is preferably l. As the compound of the formula () provided by the present invention, in addition to those listed in the examples below, the following can be cited as representative examples: N-[3-[3-(1-pyrrolidinyl)ethyl]phenoxy ]propyl]-4-chlorobutyryloxyacetamide, N-[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]methylglutaryloxyacetamide, N-[3-[3-[1-(1-pyrrolidinyl)
Ethyl]phenoxy]propyl]phenylacetoxyacetamide, N-[4-[3-(1-piperidinylmethyl)
Phenoxy]butyl]phenylacetoxyacetamide, N-[3-[3-(1-perhydroazepinylmethyl)phenoxy]propyl]cinnamoyloxyacetamide, N-[3-[3-[1-(1-) hyperidinyl)
ethyl]phenoxy]propyl]cyclohexanecarbonyloxyacetamide, N-[3-[3-[1(1-perhydroazepinylmethyl)ethyl]phenoxy]propyl]-
2-methoxybenzoyloxyacetamide, N-[3-[3-(4-methyl-1-piperidinylmethyl)phenoxy]propyl]-2-carboxybenzoyloxyacetamide, N-[3-[3-(1- piperidinylmethyl)
phenoxy]propyl]-4-cyanobenzoyloxyacetamide, N-[3-[3-[1-(1-pyrrolidinyl)
ethyl]phenoxy]propyl]-3,4,5-
Trimethoxybenzoyloxyacetamide, N-[3-[3-(1-piperidinylmethyl)
Phenoxy]propyl]methoxycarbonyloxyacetamide, N-[4-[3-(1-piperidinylmethyl)
Phenoxy]butyl]isopropyloxycarbonyloxyacetamide, N-[3-[3-(2-methyl-1-piperidinylmethyl)phenoxy]propyl]ethoxycarbonyloxyacetamide, N-[3-[3-(1-) piperidinylmethyl)
phenoxy]propyl]-3-methoxycarbonyloxypropionamide, N-[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]-4-benzyloxycarbonyloxybutanamide, N-[3-(3-dimethylaminomethylphenoxy)propyl]carbamoyloxyacetamide, N-[3-[3-(1-pyrrolidinyl)propyl] phenoxy]propyl]-2-pyridinecarbonyloxyacetamide, N-[3-[3-(1-piperidinylmethyl)
Phenoxy]propyl]isonicotinoyloxyacetamide, N-[3-[3-[1-(1-pyrrolidinyl)]
ethyl]phenoxy]propyl]-2-furoyloxyacetamide, N-[3-[3-(1-perhydroazepinylmethyl)phenoxy]propyl]-2-furoyloxyacetamide, N-[3-[ 3-(3-methyl-1-piperidinylmethyl)phenoxy]propyl]-2-furoyloxyacetamide, N-[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]-4-(2-furoyloxy)butanamide, N-[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]-2-thenoyloxyacetamide, N-[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]-3-thenoyloxyacetamide, N-[4-(3-dimethylaminomethylphenoxy)butyl]sulfoxyacetamide, N-[3-[3-[1-(1-pyrrolidinyl)
ethyl]phenoxy]propyl]-2-tetrahydropyranyloxyacetamide, etc. According to the invention, salts of the compounds as defined above are also provided. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfuric acid, phosphoric acid, and organic acids such as acetic acid, propionic acid, oxalic acid, lactic acid, citric acid, tartaric acid, p-toluenesulfonic acid, etc. Among these, pharmacologically acceptable salts are suitable. The compound of formula () above can be produced by any of the methods described below. (A) Z is the formula -COY ₁ , -SO ₃ Y ₂ , -PO(OY ₃ ) ₂ ,

[Formula] or

Production of a compound of formula () [referred to as a compound of formula (-A)] when [formula] is represented: The compound of formula (-A) is prepared by the following formula: In the formula, R ₁ , R ₂ , R ₃ , m and n have the above-mentioned meanings; M represents a hydrogen atom or an alkali metal (e.g., sodium, potassium). A compound of the following formula Z ₁ -X ₁ () where Z ₁ is the formula -COY ₁ , -SO ₃ Y ₂ , -PO
(OY ₃ ) ₂ ,

[Formula] and

Represents a monovalent group selected from the group consisting _of [Formula];
is a halogen atom, especially a chlorine atom; Y ₁ ,
Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ and Y ₈ have the above meanings, provided that these groups (Y ₁ to _{Y 8} )
When contains an active group that can react with -OM in the above formula (), those active groups shall be temporarily protected with an easily removable common protecting group. When M in the above formula () is a hydrogen atom, it can be produced by reacting in the presence of an alkali as necessary. The reaction between the compound of formula () and the compound of formula () can be carried out in the absence of a solvent or in a suitable inert solvent, such as alcohols such as methanol and ethanol; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran and dioxane. The reaction is carried out in ethers such as; amides such as dimethylformamide and dimethylacetamide; dimethyl sulfoxide; pyridine and the like. Z ₁ is the formula

For the compounds of formula () when M represents a group of [formula] and the compounds of formula (), in general, the compound of formula () when M represents an alkali metal is used as a raw material, or else the presence of an alkali is used. It is important to carry out the reaction below, but in other cases there are no particular restrictions, and it is also possible to directly react the compound of formula () with the compound of formula () when M is a hydrogen atom. . Examples of the alkali that can be used here include alkali metal hydrides such as sodium hydride; alkali metal alkoxides such as sodium methoxide; and sodium amide. equivalent, preferably from 1 to
Advantageously, a proportion of 1.5 equivalents is used. The temperature of the above reaction is not critical and can be varied widely depending on the type of starting materials used, etc., but is generally between -15°C and the reflux temperature of the reaction mixture, preferably between 0°C and the reflux temperature of the reaction mixture. is suitable. The amount of the compound of formula () to be used is also not critical, but generally at least 1 mol, preferably 1 to 5 mol, per 1 mol of the compound of formula ().
More preferably, it is advantageous to use the amount within the range of 1 to 1.5 mol. The compound of the above formula () used as a starting material is a known compound per se (Japanese Unexamined Patent Application Publication No. 1986-
7760), or can be synthesized by a method similar to that of the known compound. In addition, Z is the formula

When it represents a group of [Formula] and Y ₇ and Y ₈ together represent a tetramethylene group, that is, Z is a tetrahydropyranyl group.

[Formula] In the case where the compound of the formula (-A) is the compound of the formula (-A), as described in detail in Example 41 below, the compound of the formula () is dihydropyran.

It can also be produced by reacting with [Formula]. (B) Production of a compound of formula () [referred to as a compound of formula (-B)] when Z represents a group of formula -COY ₁ and Y ₁ represents an amino group or a di-lower alkylamino group: Formula ( -B) The compound has the following formula: In the formula, R ₆ represents a lower alkyl group, R ₁ ,
R ₂ , R ₃ , m and n have the above meanings, and the compound can be produced by reacting with ammonia or di-lower alkylamine. Amidation of the compound of formula () with ammonia or the amine can be carried out according to methods known per se. For example, the amidation can be carried out without a solvent, but generally in an inert solvent, such as water; alcohols such as methanol and ethanol; benzene, toluene,
Aromatic hydrocarbons such as xylene; ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diglyme; amides such as dimethylformamide and dimethylacetamide; halogenated hydrocarbons such as dichloromethane and chloroform; It is preferable to carry out the reaction in a boiling point alcohol such as dimethyl sulfoxide. The reaction temperature and pressure are not particularly limited and can be varied widely depending on the raw materials used, but the reaction temperature is usually about -20°C to the reflux temperature of the reaction mixture, preferably 0°C to 180°C. and the pressure is advantageously normal pressure. In the above amidation reaction, the amount of ammonia or amine used with respect to the compound of formula () is not critical and can vary widely depending on the type of ammonia or amine used, but in general, it is per mole of the compound of formula (). It is advantageous to use at least 1 mol of ammonia or amine, preferably in the range of 1 to 10 mol, more preferably in the range of 1 to 2 mol. The compound of formula () used as a starting material in the above amidation reaction can be synthesized by the method described in the previous section (A). (C) Z is Compounds of formula () [formula (--
Production of the compound of formula (-C)]: The compound of formula (-C) is produced by the following formula: In _the formula, R ₁ , R ₂ , R ₃ and m have the above-mentioned meanings _.
—(CH ₂ —) _o COOH () where n has the above meaning, dicarboxylic acids or reactive derivatives thereof (e.g. acid chlorides, esters, mixed acid anhydrides, activated amides, acid azides, etc.) and It can be produced by reaction. The reaction between the amine of formula () or its reactive derivative and the dicarboxylic acid of formula () or its reactive derivative can be carried out according to a known amidation reaction. For example, the amidation reaction may be carried out in the absence of a solvent or with a suitable inert solvent, such as an aromatic hydrocarbon such as benzene or toluene;
Ethers such as tetrahydrofuran and dioxane; amides such as dimethylformamide;
Among halogenated hydrocarbons such as chloroform; dimethyl sulfoxide, etc., generally -
20°C to the reflux temperature of the reaction mixture, preferably 0
It can be carried out at temperatures between 200°C and 200°C. The amount of the amine of formula () or its reactive derivative used is not critical and can vary widely depending on the type of starting material used, but generally the dicarboxylic acid of formula () or its reactive derivative 1
at least 2 moles per mole, preferably 2 to 4
It is advantageous to use moles, more preferably in the range from 2 to 2.5 moles. In addition, the above amidation reaction is carried out as usual,
The reaction may be carried out in the presence of a condensing agent such as dicyclohexylbodiimide, carbonyldiimidazole, or Lewis acid. The amine of formula () used as a starting material in the above amidation reaction is a compound known per se (see JP-A-56-7760), or
Alternatively, it can be synthesized in the same manner as the known compound. (D) Furthermore, as a special case, when Z represents a 3-carboxypropionyl group or an O-carboxyaroyl group, the compound of the formula () may be a compound of the formula () as shown in Examples 17 and 18 below. Compound succinic anhydride or

It can also be produced by reacting with [Formula] (where Ar represents an O-arylene group). The compound of formula () produced by the various methods described above can be converted into the corresponding salt. The salt-forming reaction can be easily carried out by treating the compound of formula () with the above-mentioned inorganic or organic acid according to a method known per se. Thus, the compound of the formula () or a salt thereof produced according to the method of the present invention can be prepared from a reaction mixture by a method known per se, such as recrystallization, distillation, column chromatography, thin layer chromatography, etc. can be isolated and/or purified from The phenoxyalkylamine derivative and its salt represented by the formula () of the present invention explained above are:
It has a long-lasting suppressive effect on gastric acid secretion based on its excellent histamine H ₂ receptor antagonism, and is an extremely useful compound in the treatment of diseases caused by gastric acid, such as gastric or duodenal ulcers. The following animal experiments demonstrate that the compound represented by the formula () of the present invention has an excellent histamine _H2 receptor activity. The compounds of the present invention used in the following animal experiments are represented by the following symbols. Compound A: N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-3-carboxypropionyloxyacetamide, B: N-[3-[3-(1-piperidinylmethyl)phenoxy] [Propyl]-4-nitrophenylacetoxyacetamide, C:N-[3-[3-(1-perhydroazepinylmethyl)phenoxy]propyl]-2-(3
-Benzoylphenyl)propionyloxyacetamide, D:N-[3-[3-(3-methyl-1-piperidinylmethyl)phenoxy]propyl]-3-
Acetylpropionyloxyacetamide, E:N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]cinnamoyloxyacetamide, F:N-[3-[3-(1-piperidinylmethyl)] Phenoxy]propyl]cyclohexanecarbonyloxyacetamide, G: N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1-naphthoyloxyacetamide H: N-[3-[3-(1 -hyperidinylmethyl)phenoxy]propyl]-4-methylbenzoyloxyacetamide, I:N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-methoxybenzoyloxyacetamide, J: N-[3-[3-(1-perhydroazepinylmethyl)phenoxy]propyl]-4-dimethylaminobenzoyloxyacetamide, K:N-[3-[3-(1-piperidinylmethyl)phenoxy] [Propyl]acetylsalicyloyloxyacetamide, L:N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]ethoxycarbonyloxyacetamide, M:N-[3-[3-(1- perhydroazepinylmethyl)phenoxy]propyl]methoxycarbonyloxyacetamide, N:N-[3-[3-(1-perhydroazepinylmethyl)phenoxy]propyl]isopropyloxycarbonyloxyacetamide, C:N- [3-[3-(1-piperidinylmethyl)phenoxy]propyl]-3-methoxycarbonyloxypropionamide, P:N-[3-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] Nicotice Noyloxyacetamide, Q: N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-furoyloxyacetamide, R: N-[4-[3-(1-piperidinyl) methyl)phenoxy]butyl]-4-thenoyloxybutanamide, S:N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-tetrahydropyranyloxyacetamide, T:N- [3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-methoxyethoxymethoxyacetamide, U: Oxydi-[N[3-[3-(1-piperidinylmethyl)phenoxy]propyl] (1) Histamine _H2 from Guinea pig right atrium specimen
Measurement of receptor antagonism A Hartley guinea pig (male: 400-550 g) was beaten on the head to exsanguinate, and the heart was removed. The right atrium was dissected in oxygen-saturated Tyrode's solution and silk sutures were attached to both ends. Suspend the atrium with a tension of 700 mg using silk threads attached to both ends in a Magnus tube (25 ml) containing Tyrode's solution kept at 36°C and ventilating a mixed gas (95% O _{2 :} 5% CO 2 ). did. A force-displacement transducer (Force-displacement-) controls the contraction movement of the atrium.
transducer), and the heart rate was calculated. Histamine (used in the form of diphosphate, the same applies hereinafter) was administered at equal intervals of 1/2 the logarithm of the amount added until the maximum response of increasing heart rate was obtained.
The histamine dose ^- response ^curve (Dose-
response curve) was obtained. After washing the inside of the Magnus tube several times and stabilizing the atrium for 1 hour, the above procedure was repeated again to obtain a histamine dose-response curve. After washing the Magnus tube several times, the tissue was allowed to stabilize for 50 minutes. Then, the test compound (1×10 ⁻⁵ M) was added into the Magnus tube, and after 20 minutes, a dose-response curve of histamine in the presence of the test compound was obtained. From the second histamine dose-response curve and the third histamine dose-response curve in the presence of the test compound, JMVan Rossum's method (Arch.int.
Pharmacodyn., 143 , 299, 1963), the _PA2 value of each test compound (the logarithm of the molar concentration of the test compound required to double the histamine concentration in the Magnus tube to cause a given reaction) The negative logarithm) was calculated. The results are shown in Table 1 below. Table-1 Compound PA ₂ A 6.16 B 6.54 C 6.55 D 6.02 E 6.58 F 6.82 G 6.31 H 6.69 I 6.53 J 6.25 K 6.60 L 6.61 M 6.67 N 6.48 O 6.04 P 6.38 Q 6 .89 R 6.86 S 6.34 T 6.18 U 6.72 Thus, The compound represented by the formula () of the present invention can be administered orally or parenterally (e.g., intramuscularly, intravenously, subcutaneously, rectally, (transdermal administration, etc.), but oral administration is particularly preferred. When used as a medicament, the compounds of the invention can be formulated into a variety of forms suitable for oral or parenteral administration. For example, the compounds of the invention may be added to non-toxic excipients, binders, lubricants, disintegrants, preservatives, tonicity agents, stabilizers, dispersants, antioxidants, etc. commonly used in such drugs. It can be formulated using additives such as agents, colorants, flavoring agents, and buffering agents. Depending on the use, such drugs may be in solid form (e.g., tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, pastilles, etc.);
It can be prepared in either semi-solid form (eg suppositories, ointments, etc.) and liquid forms (injections, emulsions, suspensions, syrups, sprays, etc.). Therefore, examples of the above-mentioned non-toxic additives that can be used include starch, gelatin, glucose,
Lactose, fructose, maltose, magnesium carbonate, magnesium aluminate metasilicate, synthetic aluminum silicate, silicic anhydride, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol, alkyl p-hydroxybenzoate Ester, syrup, ethanol, propylene glycol, petrolatum, carbo wax,
Examples include glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid, and the like. The medicament may also contain other therapeutically useful agents. The content of the compound of the invention in the medicament varies depending on its dosage form, but generally at a concentration of 5 to 100% by weight for solid and semisolid forms and 0.1 to 10% for liquid forms. It is desirable to contain the active compound in a concentration of % by weight. The dosage of the compound of the present invention can vary widely depending on the type of warm-blooded animal including humans, route of administration, severity of symptoms, doctor's diagnosis, etc., but in general, it is 0.2 to 80 mg per day. /Kg, preferably 0.5 to 50 mg/Kg. However, as mentioned above, depending on the severity of the patient's symptoms and the doctor's diagnosis, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range. The above dosage can be administered once a day or in divided doses. The present invention will be further explained below with reference to Examples. Example 1 N-[3-[3-(1-piperidinylmethyl)
Phenoxy]propyl]hydroxyacetamide (215 mg) was dissolved in chloroform (1 ml). Cyclohexanecarbonyl chloride (150 mg) was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours. Cold water and an aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the extract layer over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting crude product was separated and purified by TLC using silica gel [developing solvent: chloroform:methanol (9:1)] to obtain N- [3-[3-(1-piperidinylmethyl)phenoxy]propyl]cyclohexanecarbonyloxyacetamide (210 mg) was obtained. IR (liquid film, cm ^-1 ); 1740, 1665. NMR ( _CDCl3 , δ); 1.3-2.6 (23H, multiplet),
3.42 (2H, singlet), 3.49 (2H, quartet, J=6
Hz), 4.01 (2H, triple line, J=6Hz), 4.51 (2H,
singlet), 6.6 to 7.4 (4H, multiplet). Example 2 In Example 1, cinnamoyl chloride (140 mg) was used instead of cyclohexanecarbonyl chloride.
Using the same procedure as in Example 1, N-[3-
[3-(1-piperidinylmethyl)phenoxy]
Propyl]cinnamoyloxyacetamide (170 mg) was obtained. IR (liquid film, cm ^-1 ); 1720, 1665. NMR ( _CDCl3 , δ); 1.3-2.6 (12H, multiplet),
3.41 (2H, singlet), 3.55 (2H, quartet, J=6
Hz), 4.06 (2H, triple line, J=6Hz), 4.68 (2H,
single line), 6.44 (1H, double line, J=17Hz), 6.6~
7.4 (10H, multiple line), 7.73 (1H, double line, J=17
Hz). Example 3 In Example 1, myristoyl chloride (220mg) was used instead of cyclohexanecarbonyl chloride.
Using the same procedure as in Example 1, N-[3-
[3-(1-piperidinylmethyl)phenoxy]
Propyl] myristoyloxyacetamide (230 mg) was obtained. IR (liquid film, cm ^-1 ); 1745, 1665. NMR ( _CDCl3 , δ); 0.7-2.6 (39H, multiplet),
3.46 (2H, singlet), 3.54 (2H, quartet, J=6
Hz), 4.05 (2H, triple line, J=6Hz), 4.53 (2H,
singlet), 6.55 (1H, wide singlet), 6.6~7.4 (4H,
multiplet). Example 4 In Example 1, phenylacetyl chloride (116 mg) was used instead of cyclohexane carbonyl chloride, and the same procedure as in Example 1 was performed to obtain N.
-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]phenylacetoxyacetamide (170 mg) was obtained. IR (liquid film, cm ^-1 ); 1745, 1670. NMR ( _CDCl3 , δ); 1.3-1.7 (6H, multiplet),
1.86 (2H, quintet, J = 6Hz), 2.2-2.6 (4H, multiplet), 3.36 (2H, quartet, J = 6Hz), 3.42 (2H,
singlet), 3.66 (2H, singlet), 3.92 (2H, triplet,
J = 6Hz), 4.52 (2H, singlet), 6.30 (1H, wide singlet), 6.6-7.4 (4H, multiplet), 7.23 (5H, singlet). Example 5 In Example 1, 4-nitrophenyl acetyl chloride (160 mg) was used instead of cyclohexanecarbonyl chloride, and the same procedure as in Example 1 was repeated to prepare N- Nylmethyl)phenoxy]propyl]-4-nitrophenylacetoxyacetamide (220 mg) was obtained. IR (liquid film, cm ^-1 ); 1745, 1660, 1515, 1345. NMR ( _CDCl3 , δ); 1.3-1.7 (6H, multiplet),
1.97 (2H, quintet, J = 6Hz), 2.2-2.6 (4H, multiplet), 3.44 (2H, quartet, J = 6Hz), 3.45 (2H,
singlet), 3.81 (2H, singlet), 4.01 (2H, triplet), 4.58 (2H, singlet), 6.6 to 7.4 (5H, multiplet), 7.38 (2H, doublet, J=9Hz) , 8.09 (2H,
double line, J=9Hz). Example 6 In Example 1, 4-chlorobutyryl chloride (150 mg) was used instead of cyclohexane carbonyl chloride, and the same procedure as in Example 1 was carried out to prepare N.
-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-4-chlorobutyryloxyacetamide (210 mg) was obtained. IR (liquid film, cm ^-1 ); 1745, 1665. NMR ( _CDCl3 , δ); 1.3-2.8 (16H, multiplet),
3.45 (2H, singlet), 3.46 (2H, quartet, J=6
Hz), 3.55 (2H, triple line, J=6Hz), 4.02 (2H,
Triple line, J=6Hz), 4.53 (2H, single line), 6.6~
7.4 (5H, multiplet). Example 7 In Example 1, 4-methylbenzoyl chloride (160 mg) was used instead of cyclohexane carbonyl chloride, and the same procedure as in Example 1 was performed to obtain N.
-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-4-methylbenzoyloxyacetamide (270 mg) was obtained. Melting point: 79.2-80.7°C. IR (KBr-disk, cm ^-1 ); 1725, 1655. NMR ( _CDCl3 , δ); 1.3-2.6 (12H, multiplet),
2.40 (3H, single line), 3.40 (2H, single line), 3.55
(2H, quartet, J=6Hz), 4.04 (2H, triplet,
J=6Hz), 4.77 (2H, singlet), 6.6-7.4 (5H,
multiplet), 7.18 (2H, doublet, J=9Hz), 7.90
(2H, double line, J=9Hz). Example 8 In Example 1, 1-naphthoyl chloride (180
mg) and operated in the same manner as in Example 1 to obtain N-
[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1-naphthoyloxyacetamide (175 mg) was obtained. IR (liquid film, cm ^-1 ); 1725, 1665. NMR (CDCl ₃ , δ); 1.3-1.7 (6H, multiplet)
1.96 (2H, quintet, J=6Hz), 2.1-2.5 (4H, multiplet), 3.32 (2H, singlet), 3.47 (2H, quartet,
J=6Hz), 3.97 (2H, triple line, J=6Hz), 4.80
(2H, singlet), 6.4-9.0 (12H, multiplet). Example 9 In Example 1, 2-methoxybenzoyl chloride (170 mg) was used instead of cyclohexanecarbonyl chloride, and the same procedure as in Example 1 was carried out,
N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-methoxybenzoyloxyacetamide (255 mg) was obtained. IR (liquid film, cm ^-1 ); 1725, 1675. NMR ( _CDCl3 , δ); 1.3-1.7 (6H, multiplet),
2.01 (2H, quintet, J=6Hz), 2.1-2.6 (4H, multiplet), 3.37 (2H, singlet), 3.53 (2H, quartet,
J=6Hz), 3.78 (3H, singlet), 4.01 (2H, triplet, J=6Hz), 4.74 (2H, singlet), 6.5-8.0
(9H, multiplet). Example 10 In Example 1, N-[3-[3-
(1-perhydroazepinylmethyl)phenoxy]
4-dimethylaminopenzoyl chloride (140 mg) was used in place of cyclohexanecarbonyl chloride.
mg) in the same manner as in Example 1 to obtain N-
[3-[3-(1-perhydroazepinylmethyl)]
Phenoxy]propyl]-4-dimethylaminobenzoyloxyacetamide (90 mg) was obtained. IR (liquid film, cm ^-1 ): 1710, 1670. NMR ( _CDCl3 , δ); 1.3-1.7 (8H, multiplet),
2.00 (2H, quintet, J=6Hz), 2.4-2.9 (4H, multiplet), 3.00 (6H, singlet), 3.52 (2H, quartet,
J=6Hz), 6.58 (2H, singlet), 4.02 (2H, triplet, J=6Hz), 4.71 (2H, singlet), 6.53 (2H,
Double line, J=9Hz), 6.6 to 7.4 (5H, multiple line),
7.85 (2H, double line, J=9Hz). Example 11 In Example 1, N-[3-[3-
[1-(1-pyrrolidinyl)propyl]phenoxy]propyl]hydroxyacetamide (20mg)
N-[3-
[3-[1-(1-pyrrolidinyl)propyl]phenoxy]propyl]-4-cyanobenzoyloxyacetamide (17.7 mg) was obtained. IR (liquid film, cm ^-1 ); 2215, 1735, 1675. NMR (CDCl ₃ , δ); 0.67 (3H, triplet, J=
7Hz), 1.4-2.9 (12H, multiplet), 3.02 (1H, double doublet, J = 10Hz, J = 5Hz), 3.56 (2H, quartet, J = 6Hz), 4.08 (2H, triplet) line, J=6Hz),
4.84 (2H, singlet), 6.6 to 7.4 (5H, multiplet), 7.66
(2H, double line, J=9Hz), 8.14 (2H, double line,
J=9Hz). N-[3-[3-[1] used as starting material
-(1-piperidinyl)propyl phenoxy
Propyl]hydroxyacetamide was synthesized by the following procedure. Step (A) 3-hydroxypropiophenone (1.0
g), pyrrolidine (1.1ml), ethanol (ml)
and sodium cyanoborohydride (0.34
The mixture of g) was stirred at room temperature for 15 hours. After the reaction mixture was acidified with hydrochloric acid and washed with ethyl acetate, the aqueous layer was separated and made basic by adding aqueous ammonia, and the precipitated oil was extracted with ethyl acetate. After washing the ethyl acetate layer with water, it was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the 3-
[1-[1-pyrrolidinyl)propyl]phenol (650 mg was obtained. NMR (CDCl ₃ , δ); 0.63 (3H, triplet, J=
7Hz), 1.4-2.1 (6H, multiplet), 2.1-2.9 (4H, multiplet), 2.94 (1H, doublet, J=10Hz, J=
5Hz), 6.6-7.4 (4H, multiplet), 7.32 (1H, singlet). Step (B) A solution of 3-[1-(1-pyrrolidinyl)propyl]phenol (500 mg) in dry dimethyl sulfoxide (3 mg) was added to a suspension of 50% sodium hydride (200 mg) in dry dimethyl sulfoxide (3 ml). It was gradually added dropwise to the cloudy liquid while stirring while cooling with water. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and then N-(3-chloropropyl)acetamide (500 mg) was added. After reacting at 100°C for 1 hour, ice water was added, and the mixture was extracted with ethyl acetate. After washing the ethyl acetate layer with water, it was dried over anhydrous magnesium sulfate, the solvent was distilled off, and silica gel was used.
Separate and purify with TLC [developing solvent: chloroform:methanol (9:1)] to obtain N-[3-[3-
[1-(1-pyrrolidinyl)propyl]phenoxy]propyl]acetamide (660 mg) was obtained. IR (liquid film, cm ^-1 ); 1650. NMR (CDCl ₃ , δ); 0.67 (3H, triplet, J=
7Hz), 1.4-2.9 (12H, multiplet), 1.98 (3H, singlet), 2.95 (1H, doublet, J=10Hz, J=5
Hz), 3.43 (2H, quartet, J=6Hz), 4.02 (2H,
Triple line, J=6Hz), 6.05 (1H, wide single line), 6.6
~7.4 (4H, multiplet). Step (C) N-[3-[3-[1-(1-pyrrolidinyl)propyl]phenoxy]propyl]acetamide (500 mg) and 40% aqueous sulfuric acid solution (1.5
ml) was heated under reflux for 17 hours. After cooling,
Make it basic by adding aqueous sodium hydroxide solution,
Extracted with ether. The ether layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and N-
[3-[3-[1-(1-piperidinyl)propyl]phenoxy]propylamino (395mg)
I got it. NMR (CDCl ₃ , δ); 0.67 (3H, triplet, J=
7Hz), 1.3-3.1 (13H, multiplet), 2.90 (2H, triplet, J=6Hz), 4.02 (2H, triplet, J=6Hz),
6.6-7.4 (4H, multiplet). Step (D) A mixture of N-[3-[3-[1-(1-pyrrolidinyl)propyl]phenoxy]propylamine (200 mg) and glycolic acid (64 mg) was heated at 200°C for 2 hours while blowing nitrogen gas. . After cooling, the product was dissolved in chloroform and washed with aqueous ammonia. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the N-[3-[3-[1] -(1-pyrrolidinyl)propyl]phenoxy]propyl]hydroxyacetamide (138 mg) was obtained. IR (liquid film, cm ^-1 ); 1655. NMR (CDCl ₃ , δ); 0.67 (3H, triplet, J=
7Hz), 1.4 to 2.9 (12H, multiplet), 2.95 (1H, double doublet, J = 10Hz, J = 5Hz), 3.52 (2H, quartet, J = 6Hz), 4.04 (2H, singlet) line), 4.08 (2H,
Triplet, J=6Hz), 6.6-7.4 (5H, multiplet). Example 12 In Example 1, nicotinoyl chloride (140 mg) was used instead of cyclohexane carbonyl chloride.
Using the same procedure as in Example 1, N-[3-
[3-(1-piperidinylmethyl)phenoxy]
Propyl]nicotinoyloxyacetamide (150mg) was obtained. IR (liquid film, cm ^-1 ): 1735, 1660. NMR ( _CDCl3 , δ); 1.3-2.6 (12H, multiplet),
3.40 (2H, singlet), 3.54 (2H, quartet, J=6
Hz), 4.03 (2H, triple line, J=6Hz), 4.80 (2H,
singlet), 6.6 to 9.3 (9H, multiplet). Example 13 In Example 1, 2-furoyl chloride (130 mg) was used instead of cyclohexanecarbonyl chloride.
Using the same procedure as in Example 1, N-[3-
[3-(1-piperidinylmethyl)phenoxy]
Propyl]-2-furoyloxyacetamide (250 mg) was obtained. IR (liquid film, cm ^-1 ): 1730, 1670. NMR ( _CDCl3 , δ); 1.3-1.9 (6H, multiplet),
2.02 (2H, quintet, J=6Hz), 2.1-2.7 (4H, multiplet), 3.42 (2H, singlet), 3.54 (2H, quartet,
J=6Hz), 4.05 (2H, triple line, J=6Hz), 4.74
(2H, singlet), 6.4-7.6 (8H, multiplet). Example 14 In Example 1, 6-quinoline carbonyl chloride (200 mg) was used instead of cyclohexane carbonyl chloride, and the procedure was repeated in the same manner as in Example 1.
N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-6-quinolinecarbonyloxyacetamide (190 mg) was obtained. Melting point: 86.2-88.2°C. IR (KBr-disk, cm ^-1 ); 1725, 1655. NMR ( _CDCl3 , δ); 1.3-2.7 (12H, multiplet),
3.30 (2H, singlet), 3.57 (2H, quartet, J=6
Hz), 4.06 (2H, triple line, J=6Hz), 4.88 (2H,
singlet), 6.5-9.1 (11H, multiplet). Example 15 In Example 1, 1-(4-methylphenyl)- was used instead of cyclohexanecarbonyl chloride.
N-[3-
[3-(1-piperidinylmethyl)phenoxy]
propyl]-1-(4-methylphenyl)-5-
Isoquinolyl acetoxyacetamide (190mg)
I got it. IR (liquid film, cm ^-1 ); 1755, 1657. NMR ( _CDCl3 , δ); 1.3-2.7 (12H, multiplet),
2.47 (3H, singlet), 3.35 (2H, quartet, J=6
Hz), 3.53 (2H, singlet) 3.93 (2H, triplet, J =
6Hz), 4.69 (2H, singlet), 6.12 (1H, wide singlet), 6.6-8.8 (13H, multiplet). Example 16 In Example 1, N-[4-[3-] instead of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide
(1-Piperidinylmethyl)phenoxybutyl
Using -4-hydroxybutanamide (50mg),
N-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]-4-thenoyl Oxybutanamide (45 mg) was obtained. IR (liquid film, cm ^-1 ); 1705, 1640. NMR ( _CDCl3 , δ); 1.2-2.6 (18H, multiplet),
3.29 (2H, quartet, J=6Hz), 3.45 (2H, singlet), 3.94 (2H, triplet, J=6Hz), 4.30 (2H,
Triple line, J=6Hz), 6.04 (1H, wide single line), 6.6
~7.9 (7H, multiplet). N-[4-[3-(1
-piperidinylmethyl)phenoxy]butyl]-
4-Hydroxybutanamide was synthesized by the following procedure. 4-[3-(1-piperidinylmethyl)phenoxybutylamine (100
After heating under reflux for 7 hours, N-[4-[3-( 1-piperidinylmethyl)phenoxy]butyl]-4-hydroxybutanamide (90 mg) was obtained. IR (liquid film, cm ^-1 ); 1640. NMR ( _CDCl3 , δ); 1.2-2.6 (18H, multiplet),
3.28 (2H, quartet, J=6Hz), 3.44 (2H, singlet), 3.63 (2H, triplet, J=6Hz), 3.96 (2H,
Triple line, J=6Hz), 4.04 (1H, single line), 6.5~
7.4 (5H, multiplet). Example 17 N-[3-[3-(1-piperidinylmethyl)
A mixture of phenoxy[propyl]hydroxyacetamide (180mg), phthalic anhydride (87mg), chloroform (1ml) and triethylamine (0.2ml) was heated at 100°C for 1 hour. After cooling, add water,
The product was extracted with chloroform. The chloroform layer was dried over magnesium anhydride, the solvent was distilled off, and the layer was separated and purified using TLC using silica gel [developing solvent: chloroform:methanol (4:1)].
N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-carboxybenzoyloxyacetamide (150 mg) was obtained. IR (liquid film, cm ^-1 ): 1725, 1655. NMR (CD ₃ OD, δ); 1.3-2.1 (6H, multiplet),
2.02 (1H, quintet, J = 6Hz), 2.8-3.2 (4H, multiplet), 3.44 (2H, triplet, J = 6Hz), 4.06 (2H,
triple line, J=6Hz), 4.09 (2H, single line), 4.68
(2H, singlet), 6.6-7.9 (8H, multiplet). Example 18 In Example 17, succinic anhydride (72 mg) was used instead of phthalic anhydride, and the procedure was repeated in the same manner as in Example 17 to prepare N-[3-[3-(1-piperidinylmethyl)phenoxy] [Propyl]-3-carboxypropionyloxyacetamide (125 mg) was obtained. IR (liquid film, cm ^-1 ); 1735, 1665. NMR (CD ₃ OD, δ); 1.3-2.1 (6H, multiplet),
1.89 (2H, quintet, J=6Hz), 2.57 (4H, singlet), 2.8-3.2 (4H, multiplet), 3.41 (2H, triplet,
J=6Hz), 3.98 (2H, triple line, J=6Hz), 4.09
(2H, singlet), 4.51 (2H, singlet), 6.6-7.4
(4H, multiplet). Example 19 In Example 1, acetylsalicyloyl chloride (240 mg) was used in place of cyclohexane carbonyl chloride, the procedure was repeated in the same manner as in Example 1, and N
-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetylsalicyloyloxyacetamide (220 mg) was obtained. Mass (m/z); 468 (M ⁺ ). IR (liquid film, cm ^-1 ); 1760, 1735, 1670. NMR ( _CDCl3 , δ); 1.2-1.9 (6H, multiplet),
2.00 (2H, quintet, J = 6Hz), 2.30 (3H, singlet), 2.1-2.6 (4H, multiplet), 3.42 (2H, singlet), 3.51 (2H, quartet, J = 6Hz) ), 4.00 (2H,
Triple line, J=6Hz), 4.73 (2H, single line), 6.5~
8.1 (9H, multiplet). Example 20 In Example 1, ethyladipoyl chloride (150 mg) was used instead of cyclohexane carbonyl chloride, the procedure was repeated in the same manner as in Example 1, and N
-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]ethyladipoyloxyacetamide (190 mg) was obtained. IR (liquid film, cm ^-1 ): 1735, 1660. NMR (CDCl ₃ , δ); 1.23 (3H, triplet, J=
7Hz), 1.3-2.7 (20H, multiplet), 3.47 (2H, singlet), 3.52 (2H, quartet, J = 6Hz), 4.04 (2H,
triplet, J=6Hz), 4.11 (2H, quartet, J=7
Hz), 4.55 (2H, singlet), 6.6-7.4 (5H, multiplet). Example 21 In Example 1, N-[3-[3-
[1-(1-pyrrolidinyl)ethyl]phenoxy]
N-[3-[3-
[1-(1-piperidinyl)ethyl]phenoxy]
Propyl] acetylsalicyloyloxyacetamide (35 mg) was obtained. IR (liquid film, cm ^-1 ); 1760, 1735, 1675. NMR (CDCl ₃ , δ); 1.44 (3H, doublet, J=
6.5Hz), 1.5 to 3.0 (10H, multiplet), 2.30 (3H, singlet), 3.0 to 3.8 (2H, multiplet), 4.03 (2H, triplet,
J=6Hz), 4.74 (2H, singlet), 6.5-8.1 (9H,
multiplet). Example 22 In Example 1, N-[3-[3 -(1
-piperidinylmethyl)phenoxy]propyl]
-2-(3-benzoylphenyl)propionyloxyacetamide (290 mg) was obtained. Mass (m/z); 542 (M ⁺ ). IR (liquid film, cm ^-1 ); 1745, 1655. NMR ( _CDCl3 , δ); 1.3-2.3 (8H, multiplet),
1.56 (3H, doublet, J=7Hz), 2.5-3.0 (4H, multiplet), 3.39 (2H, quartet, J=6Hz), 3.72 (2H,
singlet), 3.6-4.1 (1H, multiplet), 3.99 (2H, triplet, J=6Hz), 4.58 (2H, singlet), 6.2-7.9
(14H, multiplet). Example 23 In Example 1, N-[3-[3-
(1-perhydroazepinylmethyl)phenoxy]
Propyl]hydroxyacetamide (200 mg) and 2-(3-benzoylphenyl)propionyl chloride (220 mg) in place of cyclohexanecarbonyl chloride were operated in the same manner as in Example 1 to obtain N-[3-[ 3-(1-perhydroazepinylmethyl)phenoxypropyl]-2-
(3-Benzoylphenyl)propionyloxyacetamide (230 mg) was obtained. IR (liquid film, cm ^-1 ); 1745, 1655. NMR ( _CDCl3 , δ); 1.3-2.2 (10H, multiplet),
1.56 (3H, doublet, J = 7Hz), 2.5-3.0 (4H, multiplet) 3.40 (2H, quartet, J = 6Hz), 3.72 (2H,
singlet), 3.6-4.1 (1H, multiplet), 3.98 (2H, triplet, J=6Hz), 4.57 (2H, singlet), 5.95 (1H,
wide singlet), 6.3-7.9 (13H, multiplet). Example 24 In Example 1, N-[3-[3-
(3-Methyl-1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide (100
mg) and 3-acetylpropionyl chloride (110 mg) instead of cyclohexane carbonyl chloride, the same procedure as in Example 1 was carried out,
N-[3-[3-(3-methyl-1-piperidinylmethyl)phenoxy]propyl]-3-acetylpropionyloxyacetamide (65 mg) was obtained. Mass (m/Z); 418 (M ⁺ ). IR (liquid film, cm ^-1 ); 1745, 1720, 1665. NMR (CDCl ₃ , δ); 0.82 (3H, doublet, J=
5Hz), 1.3-3.0 (15H, multiplet), 2.13 (3H, singlet), 3.43 (2H, singlet), 3.52 (2H, quartet, J
= 6Hz), 4.02 (2H, triple line, J = 6Hz), 4.58
(2H, singlet), 6.6-7.4 (5H, multiplet). N-[3-[3-(3
-Methyl-1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide was synthesized by the following procedure. Step (A) 3-hydroxybenzaldehyde (6
g) Sodium borohydride (1.5 g) was gradually added to a mixture of 3-methylpiperidine (12 ml) and methanol (10 ml) at room temperature with stirring. After reacting for one hour at room temperature, an aqueous ammonium chloride solution was added. The precipitated crystals were collected, washed with water, dried, and 3-(3-methyl-1
-piperidinylmethyl)phenol (6.2g)
I got it. Melting point: 159.9-160.9℃. NMR (DMSO-d ₆ , δ); 0.79 (3H, doublet,
J=5Hz), 1.0~2.1 (7H, multiplet), 2.4~3.0
(2H, multiplet), 3.30 (2H, singlet), 6.4~7.2
(4H, multiplet). Step (B) In Step (B) of synthesis of the starting material of Example 11, 3-(3-methyl-1
-piperidinylmethyl)phenol (500mg)
, and perform the other operations in the same way to obtain N-[3-
[3-(3-methyl-1-piperidinylmethyl)
Phenoxy]propyl]acetamide (670mg)
I got it. IR (liquid film, cm ^-1 ); 1650. NMR (CDCl ₃ , δ); 0.83 (3H, doublet, J=
5Hz), 1.3-2.2 (9H, multiplet), 1.97 (3H, singlet), 2.6-3.0 (2H, multiplet), 3.47 (2H, singlet), 3.52 (2H, quartet, J = 6Hz) ), 4.03 (2H,
Triple line, J=6Hz), 6.35 (1H, wide single line), 6.6
~7.4 (4H, multiplet). Step (C) In Step (C) of synthesis of the starting material of Example 11, N-[3-[3-[1-(1-piperidinyl)propyl]phenoxy]propyl]acetamide was replaced with N-[3-[3] 3-[3-(3-methyl-
1-piperidinylmethyl)phenoxy]propylamine (405 mg) was obtained. NMR (CDCl ₃ - D ₂ O, δ); 0.82 (3H, doublet,
J=5Hz), 1.2~2.2 (9H, multiplet), 2.5~3.0
(2H, multiplet), 2.86 (2H, triplet, J=7Hz),
3.41 (2H, single line), 4.01 (2H, triple line, J6Hz),
6.6-7.4 (4H, multiplet). Step (D) In Step (D) of synthesis of the starting material of Example 11, 3-[3-(3-methyl- 1-Piperidinylmethyl)phenoxy]propylamine (1.4g)
, and perform the other operations in the same way to obtain N-[3-
[3-(3-methyl-1-piperidinylmethyl)
Phenoxy]propyl]hydroxyacetamide (1.35g) was obtained. IR (liquid film, cm ^-1 ); 1655. NMR (CDCl ₃ , δ); 0.83 (3H, doublet, J=
5Hz), 1.3 to 2.3 (9H, multiplet), 2.6 to 3.1 (2H, multiplet), 3.42 (2H, singlet), 3.49 (2H, quartet,
J=6Hz), 3.97 (2H, singlet), 4.06 (2H, triplet, J=6Hz), 4.87 (1H, wide singlet), 6.6~
7.4 (5H, multiplet). Example 25 N-[3-[3-(1-piperidinylmethyl)
Ethyl chloroformate (120 mg) was added dropwise to a solution of phenoxy[propyl]hydroxyacetamide (205 mg) in pyridine (1 ml) in ice-cold water with stirring. After stirring at 0°C for 10 minutes, ice water was added and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and separated and purified by TLC using silica gel [developing solvent: chloroform:methanol (19:1)] to obtain N-[3-[ 3-(1-piperidinylmethyl)phenoxy]propyl]ethoxycarbonyloxyacetamide (200 mg) was obtained. IR (liquid film, cm ^-1 ); 1755, 1675. NMR (CDCl ₃ , δ); 1.30 (3H, triplet, J=
7Hz), 1.3 to 1.9 (6H, multiplet), 2.02 (2H, quintet), J = 6Hz), 2.2 to 2.6 (4H, multiplet), 3.48
(2H, singlet), 3.51 (2H, quartet, J=6Hz),
4.04 (2H, triplet, J=6Hz), 4.22 (2H, quartet, J=7Hz), 4.58 (2H, singlet), 6.6-7.4
(4H, multiplet). Example 26 In Example 25, N-[3-[3-
(1-perhydroazepinylmethyl)phenoxy]
Propyl]hydroxyacetamide (140mg) and methyl chloroformate (70mg) in place of ethyl chloroformate Pinylmethyl)phenoxy]propyl]methoxycarbonyloxyacetamide (90 mg) was obtained. IR (liquid film, cm ^-1 ); 1755, 1670. NMR ( _CDCl3 , δ); 1.4-1.9 (8H, multiplet),
2.02 (2H, quintet, J = 6Hz), 2.6-3.0 (4H, multiplet), 3.54 (2H, quartet, J = 6Hz), 3.71 (2H,
singlet), 3.82 (3H, singlet), 4.08 (2H, triplet,
J=6Hz), 4.61 (2H, singlet), 6.6-7.4 (5H,
multiplet). Example 27 In Example 25, N-[3-[3-
(1-perhydroazepinylmethyl)phenoxy]
Propyl]hydroxyacetamide (140 mg) and isopropyl chloroformate (70 mg) in place of ethyl chloroformate were used in the same manner as in Example 25 to produce N-[3-[3-(1-perhydroaze). pinylmethyl)phenoxy]propyl]isopropyloxycarbonyloxyacetamide (80
mg) was obtained. IR (liquid film, cm ^-1 ): 1750, 1665. NMR (CDCl ₃ , δ); 1.31 (6H, doublet, J=
7Hz), 1.4-1.9 (8H, multiplet), 2.01 (2H, quintet, J = 6Hz), 2.5-2.9 (4H, multiplet), 3.54
(2H, quartet, J=6Hz), 3.68 (2H, singlet),
4.08 (2H, triplet, J=6Hz), 4.58 (2H, singlet), 4.89 (1H, septet, J=7Hz), 6.6-7.4
(5H, multiplet). Example 28 In Example 25, N-[3-[3-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide was replaced with
(1-piperidinylmethyl)phenoxypropyl]-3-hydroxypropionamide (70mg)
N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]- 3-methoxycarbonyloxypropionamide (67 mg) was obtained. NMR ( _CDCl3 , δ); 1.3-1.9 (6H, multiplet),
1.98 (2H, quintet, J = 6Hz), 2.2-2.6 (4H, multiplet), 2.52 (2H, triplet, J = 6Hz), 3.43 (2H,
singlet), 3.45 (2H, quartet, J=6Hz), 3.73
(3H, single line), 4.02 (2H, triple line, J=6Hz),
4.40 (2H, triplet, J=6Hz), 6.30 (1H, wide singlet), 6.6-7.4 (4H, multiplet). N-[3-[3-(1
-piperidinylmethyl)phenoxy]propyl]
-3-Hydroxypropionamide was synthesized by the following procedure. 3-[3-(1-piperidinylmethyl)phenoxy]propylamine (550
mg) and 3-hydroxypropionic acid (50% aqueous solution, 500 mg) was heated at 200° C. for 2 hours. N-[3-
[3-(1-piperidinylmethyl)phenoxy]
Propyl]-3-hydroxypropionamide (230 mg) was obtained. Mass (m/Z); 320 (M ⁺ ). IR (liquid film, cm ^-1 ); 1640. NMR ( _CDCl3 , δ); 1.3-1.9 (6H, multiplet),
1.97 (2H, quintet, J = 6Hz), 2.2-2.6 (4H, multiplet), 2.41 (2H, triplet, J = 6Hz), 3.43 (2H,
singlet), 3.43 (2H, quartet, J=6Hz), 3.68
(1H, wide single line), 3.83 (2H, double line, J=6
Hz), 4.04 (2H, triple line, J=6Hz), 6.5-7.4
(5H, multiplet). Example 29 In Example 25, N-[4-[3-] instead of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide
N-[4-
[3-[1-(1-pyrrolidinyl)propyl]phenoxy]butyl]ethoxycarbonyloxyacetamide (27 mg) was obtained. IR (liquid film, cm ^-1 ): 1745, 1660. NMR (CDCl ₃ , δ); 0.69 (3H, triplet, J=
6.5Hz), 1.32 (3H, triple line, J=7Hz), 1.4-2.9
(14H, multiplet), 3.03 (1H, double doublet, J=10
Hz, J=5Hz), 3.39 (2H, quartet, J=6Hz),
4.00 (2H, triplet, J=6Hz), 4.24 (2H, quartet, J=7Hz), 4.59 (2H, singlet), 6.40 (1H,
wide singlet), 6.6 to 7.4 (4H, multiplet). N-[4-[3-[1] used as starting material
-pyrrolidinyl)propyl]phenoxy]butyl]hydroxyacetamide was synthesized by the following procedure. Step (A) In Step (B) of synthesis of the starting material of Example 11, N-bromobutylphthalimide (825
Synthesis step (B) of the starting material of Example 11 using
Operate in the same way as N-[4-[3-[1-
(1-pyrrolidinyl)propyl phenoxy
Butyl]phthalimide (610 mg) was obtained. Step (B) A mixture of N-[4-[3-[1-(1-pyrrolidinyl)propyl]phenoxy]butyl]phthalimide (940 mg), hydrazine hydrate (1 ml) and ethanol (2 ml) was left at room temperature for 12 hours. did. Distillation was performed under reduced pressure, the product was dissolved in chloroform, and the precipitate was removed. The liquid was distilled off under reduced pressure to obtain 4-[3-[1-(1-piperidinyl)propyl]phenoxy]butylamine (520 mg). NMR (CD ₃ OD, δ); 0.63 (3H, triplet, J=
7Hz), 1.4 to 2.9 (16H, multiplet), 2.95 (1H, double doublet, J = 10Hz, J = 5Hz), 3.97 (2H, triplet, J = 6Hz), 6.6 to 7.5 (4H, multiplet). Step (C) 4-[3-[1-(1-pyrrolidinyl)
Propyl]phenoxy]butylamine (250mg)
and glycolic acid (98 mg) at 200°C.
It was heated for 1 hour. TLC using silica gel
[Developing solvent; chloroform: methanol (4:
1)] to separate and purify N-[4-[3-[1
-(1-piperidinyl)propyl]funoxy]
Butyl]hydroxyacetamide (158 mg) was obtained. IR (liquid film, cm ^-1 ); 1650. Example 30 In Example 25, N-[3-[3-dimethylaminomethyl)phenoxy]propyl]hydroxy instead of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide N-[3-
(3-dimethylaminomethylphenoxy]propyl]methoxycarbonyloxyacetamide (65
mg) was obtained. IR (liquid film, cm ^-1 ): 1760, 1670. NMR (CDCl ₃ , δ); 2.01 (2H, quintet, J=
6Hz), 2.24 (6H, singlet), 3.38 (2H, singlet),
3.53 (2H, quartet, J = 6Hz), 3.81 (3H, singlet), 4.04 (2H, triplet, J = 6Hz), 4.59 (2H,
singlet), 6.6 to 7.4 (5H, multiplet). N-[3-(3-dimethylaminomethylphenoxy]propyl]hydroxyacetamide used as a starting material was synthesized by the following procedure. N-[3-(3-dimethylaminomethylphenoxy)] [propyl]benzyloxyacetamide (120 mg); A mixture of 3% hydrogen chloride-ethanol (5 ml) and 5% palladium on carbon (50 mg) was catalytically hydrogenated at room temperature and normal pressure for 8 hours. Palladium on carbon was removed, and the solution was diluted with aqueous ammonia. The product was extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and N-[3-(3-dimethylaminomethylphenoxy]propyl) was obtained. Hydroxyacetamide (60
mg) was obtained. IR (CDCl ₃ , δ); 1.98 (2H, quintet, J = 6
Hz), 2.23 (6H, singlet), 3.38 (2H, singlet),
3.47 (2H, quartet, J=6Hz), 3.95 (1H, wide singlet), 3.98 (2H, singlet), 4.08 (2H, triplet,
J=6Hz), 6.6-7.4 (5H, multiplet). Example 31 In Example 25, N-[3-[3-(4
-Methyl-1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide (100mg)
N-[3-[3-(4-
Methyl-1-piperidinylmethyl)phenoxy]
Propyl]benzyloxycarbonyloxyacetamide (95 mg) was obtained. IR (liquid film, cm ^-1 ); 1755, 1670. NMR (CDCl ₃ , δ); 0.92 (3H, wide doublet,
J=3Hz), 1.0~2.3 (9H, multiplet), 2.6~3.1
(2H, multiplet), 3.44 (2H, singlet), 3.51 (2H,
Quadruple line, J=6Hz), 4.03 (2H, triple line, J=6
Hz), 4.59 (2H, singlet), 5.17 (2H, singlet),
6.6 to 7.4 (5H, multiplet), 7.35 (5H, singlet). N-[3-[3-(4
-Methyl-1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide was synthesized by the following procedure. In the synthesis of the starting material for Example 30, N-[3-[3-(4-methyl-1-piperidi N-[3-[3
-(4-Methyl-1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide (80
mg) was obtained. NMR (CDCl ₃ , δ); 0.91 (3H, wide doublet,
J=3Hz), 1.0~2.8 (9H, multiplet), 2.6~3.1
(2H, multiplet), 3.42 (2H, singlet), 3.48 (2H,
Quadruple, J=6Hz), 3.98 (2H, singlet), 4.05
(2H, triplet, J=6Hz), 4.66 (1H, wide singlet), 6.6-7.4 (5H, multiplet). Example 32 N-[3-[3-(1-piperidinylmethyl)
A mixture of phenoxy]propyl]ethoxycarbonyloxyacetamide (100 mg), ethanol (1 ml) and concentrated aqueous ammonia (1 ml) was dissolved at room temperature for 10 minutes.
Stir for a minute. Extract the product with chloroform,
The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and silica gel was used.
Separate and purify with TLC [developing solvent: chloroform: methanol (9:1)] to obtain N-[3-[3-
(1-piperidinylmethyl)phenoxy]propyl]carbamoyloxyacetamide (65 mg) was obtained. Mass (m/Z); 349 (M ⁺ ). IR (liquid film, cm ^-1 ); 1715, 1670. NMR ( _CDCl3 , δ); 1.2-1.9 (6H, multiplet),
1.96 (2H, quintet, J = 6Hz), 2.1-2.7 (4H, multiplet), 3.35 (2H, quartet, J = 6Hz), 3.48 (2H,
singlet), 4.00 (2H, triplet, J=6Hz), 4.48
(2H, single line), 6.02 (1H, wide single line), 6.6
(2H, wide singlet), 6.6-7.4 (4H, multiplet). Example 33 In Example 32, a dimethylamine aqueous solution (1 ml) was used instead of concentrated ammonia water and the procedure was repeated in the same manner as in Example 32 to prepare N-[3-[3-(1-piperidinylmethyl)phenoxy] ]Propyl]―N′,
N'-dimethylcarbamoyloxyacetamide (40 mg) was obtained. IR (liquid film, cm ^-1 ); 1725, 1665. NMR ( _CDCl3 , δ); 1.2-1.9 (6H, multiplet),
1.99 (2H, quintet, J=6Hz), 2.2-2.6 (4H, multiplet), 2.93 (6H, singlet), 3.39 (4H, quartet,
J=6Hz), 3.44 (2H, singlet), 4.01 (2H, triplet, J=6Hz), 4.65 (2H, singlet), 5.60 (1H,
wide singlet), 6.6 to 7.4 (4H, multiplet). Example 34 N-[3-[3-(1-piperidinylmethyl)
Phenoxy]propyl]hydroxyacetamide (130mg), diethyl chlorophosphate (130mg)
and pyridine (1 ml) was stirred at room temperature for 12 hours. Water and an aqueous potassium hydroxide solution were added to the reaction mixture, and the organisms were extracted with chloroform.
The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and separated and purified by TLC using silica gel [developing solvent: chloroform:methanol (9:1)] to obtain N-[3- [3-
(1-piperidinylmethyl)phenoxy]propyl]diethoxyphosphoryloxyacetamide (95 mg) was obtained. Mass (m/Z); 442 (M ⁺ ). IR (liquid film, cm ^-1 ); 1680. NMR (CDCl ₃ , δ); 1.32 (6H, triplet, J=
7Hz), 1.3-1.9 (6H, multiplet), 2.01 (2H, quintet, J=6Hz), 2.2-2.6 (4H, multiplet), 3.45
(2H, singlet), 3.52 (2H, quartet, J=6Hz),
3.8 to 4.5 (8H, multiplet), 6.6 to 7.4 (5H, multiplet). Example 35 N-[3-[3-(1-piperidinylmethyl)
Chlorosulfonic acid (0.2 ml) was added dropwise to a solution of phenoxy[propyl]hydroxyacetamide (150 mg) and triethylamine (0.2 ml) in chloroform (1 ml) under stirring under ice cooling. After stirring at 0°C for 10 minutes, water was added and the product was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and silica gel was used.
Separate and purify with TLC [developing solvent, chloroform:methanol (9:1)] to obtain N-[3-[3-
(1-piperidinylmethyl)phenoxy]propyl]sulfoxyacetamide (95 mg) was obtained. IR (liquid film, cm ^-1 ); 1660. NMR ( _CDCl3 , δ); 1.3-2.4 (8H, multiplet),
2.9-3.2 (6H, multiplet), 4.14 (2H, triplet, J=
6Hz), 4.15 (2H, singlet), 4.52 (2H, singlet),
4.88 (1H, wide singlet), 6.7-7.8 (4H, multiplet). Example 36 N-[3-[3-(1-piperidinylmethyl)
A solution of phenoxy[propyl]hydroxyacetamide (255 mg) in dry tetrahydrofuran (1 ml) was gradually added dropwise to a suspension of 60% sodium hydride (40 mg) in dry tetrahydrofuran (1 ml) under ice-cooling and stirring. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, then 2-methoxyethoxymethyl chloride (120 mg) was added, and the mixture was stirred for 30 minutes under ice-cooling.
Water was added to the reaction mixture, the product was extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and TLC using silica gel was performed.
[Developing solvent; chloroform:methanol (9:
1)] to obtain N-[3-[3-(1-
Piperidinylmethyl)phenoxy]propyl]-
2-methoxyethoxymethoxyacetamide (270 mg) was obtained. IR (liquid film, cm ^-1 ); 1670. NMR ( _CDCl3 , δ); 1.2-1.9 (6H, multiplet),
2.01 (2H, quintet, J=6Hz), 2.2-2.6 (4H, multiplet), 3.37 (3H, singlet, 3.3-3.8 (6H, multiplet), 3.46 (2H, singlet), 4.05 ( 2H, Mie Line, J
= 6Hz), 4.06 (2H, singlet), 4.75 (2H, singlet), 6.6-7.4 (5H, multiplet). Example 37 N-[3-[3-(1-piperidinylmethyl)
Phenoxy]propyl]hydroxyacetamide (130 mg), dihydropyran (200 mg), para-toluenesulfonic acid (70 mg) and methylene chloride (1
ml) was stirred at room temperature for 90 minutes. Aqueous potassium hydroxide solution was added to make it basic, and the product was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and separated and purified by TLC using silica gel [developing solvent: chloroform:methanol (9:1)] to obtain N-[3-[3-(1)]. -piperidinylmethyl)
Phenoxy]propyl]-2-tetrahydropyranyloxyacetamide (80 mg) was obtained. Mass (m/Z); 390 (M ⁺ ). IR (liquid film, cm ^-1 ); 1665. NMR ( _CDCl3 , δ); 1.2-2.2 (12H, multiplet),
2.02 (2H, quintet, J=6Hz), 2.2-2.6 (4H, multiplet), 3.2-4.3 (6H, multiplet), 3.46 (2H, singlet), 4.04 (2H, triplet, J= 6Hz), 4.56(1H,
multiplet), 6.6 to 7.4 (5H, multiplet). Example 38 N-[3-[3-(1-piperidinylmethyl)
A mixture of phenoxy]propyl]hydroxyacetamide (140 mg), t-butyldimethylsilyl chloride (100 mg) and pyridine (1 ml) was stirred at room temperature for 12 hours. Water and an aqueous potassium hydroxide solution were added to the reaction mixture, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and separated and purified by TLC using silica gel [developing solvent: chloroform:methanol (19:1)] to obtain N-[3-[ 3
-(1-piperidinylmethyl)phenoxy]propyl]-t-butyldimethylsilyloxyacetamide (140 mg) was obtained. IR (liquid film, cm ^-1 ); 1680. NMR (CDCl ₃ , δ); 0.11 (6H, singlet), 0.90
(9H, singlet), 1.3~1.9 (6H, multiplet), 2.01
(2H, quintet, J=6Hz), 2.2-2.6 (4H, multiplet), 3.49 (2H, singlet), 3.52 (2H, quartet, J
= 6Hz), 4.02 (2H, triple line, J = 6Hz), 4.08
(2H, singlet), 6.6-7.4 (5H, multiplet). Example 39 A mixture of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine (270 mg) and diglycolic acid (75 mg) was heated at 200°C for 2.5 hours. The reaction mixture was dissolved in chloroform and diluted with water. The chloroform layer was washed with an aqueous potassium oxide solution, dried over anhydrous magnesium sulfate, the solvent was distilled off, and TLC using silica gel [developing solvent; chloroform:
methanol (4:1)] to obtain oxydi-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide] (260
mg) was obtained. Mass (m/Z); 594 (M ⁺ ). IR (liquid film, cm ^-1 ); 1660. NMR ( _CDCl3 , δ); 1.2-1.9 (12H, multiplet),
1.97 (4H, quintet, J = 6Hz), 2.2-2.7 (8H, multiplet), 3.45 (4H, quartet, J = 6Hz), 3.46 (4H,
singlet), 4.00 (4H, triplet, J=6Hz), 4.03
(4H, singlet), 6.6-7.4 (10H, multiplet). Example 40 In Example 39, N-[3-[3-(3-methyl-1-piperidinylmethyl)phenoxy]propyl instead of 3-[3-(1-piperidinylmethyl)phenoxy]propylamino Amine (290mg)
Using oxydi-
[N-[3-[3-(3-methyl-1-piperidinylmethyl)phenoxy]propyl]acetamide] (270 mg) was obtained. Mass (m/Z); 622 (M ⁺ ). IR (liquid film, cm ^-1 ); 1660. NMR (CDCl ₃ , δ); 0.83 (6H, doublet, J=
5Hz), 1.0~2.3 (18H, multiplet line), 2.3~3.1 (4H,
multiplet), 3.45 (4H, quartet, J=6Hz), 3.46
(4H, single line), 4.00 (4H, triple line, J=6Hz),
4.02 (4H, singlet), 6.6-7.4 (10H, multiplet). An example of manufacturing a drug containing the compound of the present invention is as follows. Example A: Capsules Examples of capsule formulations containing 50 mg and 100 mg of active ingredient per capsule are as follows. Formulation 1-a 50mg capsule mg/capsule Active ingredient 50 Powdered lactose 100 Magnesium aluminate metasilicate 50 200mg Formulation 1-b 100mg capsule mg/Capsule Active ingredient 100 Powdered lactose 200 Magnesium aluminate metasilicate 100 400mg The manufacturing method is as follows. It is. The active ingredient is added to a mixed powder of powdered lactose and magnesium aluminate metasilicate and kneaded. This is dried, ground well, and then filled into capsules. Example B: Injection Active ingredients 20 mg Methyl p-hydroxybenzoate 1.2 mg Sodium chloride 6.0 mg Distilled water for injection was added to bring the total volume to 1 ml. The manufacturing method is as follows. Dissolve methyl p-hydroxybenzoate in distilled water for injection with stirring, then add the active ingredient and sodium chloride, and then add dilute hydrochloric acid to adjust the pH to around 7.0.
Filter this solution through a membrane filter (0.2 micron)
The mixture is sterilized, filled into ampoules, and sealed.

Claims (1)

[Claims] 1. General formula In the formula, R ₁ and R ₂ each independently represent a lower alkyl group, or R ₁ and R ₂ together with the nitrogen atom to which they are bonded may be further substituted with a lower alkyl group. Forms a good 5- to 7-membered nitrogen-containing heterocycle; R ₃ represents a hydrogen atom or a lower alkyl group; m is 3 or 4; n is an integer of 1 to 3; Z is the following formula -COY ₁ , ―SO ₃ Y ₂ , ―PO(OY ₃ ) ₂ , [Formula] and represents a monovalent group selected from the group consisting of, where Y ₁ is a tridecyl group, a substituted lower alkyl group [here, the substituent is a halogen atom, a phenyl group, a nitrophenyl group, a benzoyl phenyl group,
carboxy group, lower alkoxycarbonyl group, lower alkanoyl group, or 1-(4-methylphenyl)isoquinolin-5-yl group], styryl group, cyclohexyl group, naphthyl group, substituted phenyl group [wherein, substituent is a lower alkyl group, a lower alkoxy group, a cyano group, a carboxy group, a lower alkanoyloxy group or a dimethylamino group], a lower alkoxy group, a benzyloxy group, an amino group, a di-lower alkylamino group, a pyridyl group, a furanyl group, represents a quinolyl group or a thienyl group; Y ₂ and Y ₃ each represent a hydrogen atom or a lower alkyl group; Y ₄ , Y ₅ and Y ₆ each independently represent a lower alkyl group; Y ₇ represents a hydrogen atom; Y ₈ represents a lower alkyl group substituted with lower alkoxy, or Y ₇
Y ₈ together represent a trimethylene group or a tetramethylene group; R ₁ , R ₂ , R ₃ , m and n have the above meanings; and a salt thereof.