JPH02178A - Novel aminoalkylbenzene derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [Y is (OH-substituted) 1- pyrrolidinyl, 1-piperidinyl or 1-perhydroazepinyl; R1 is H or lower alkyl; Z is =N-CN or =CH-NH2; R2 is lower alkyl; m is 0 or 1; n is integer of 1-4; group of formula II is bonded to meta- or para-site relative to the group of formula III] or its salt. EXAMPLE:N-cyano-N'-methyl-N'-[4-[3-(1-piperidinylmethyl) phenoxy]-cis-2- butenyl] guanidine. USE:An antiulcer agent having excellent gastric inhibitory action originated from histamine H2 receptor antagonistic action. PREPARATION:A compound of formula I (Z is =N-CN) is produced by reacting a compound of formula IV or its salt with a compound of formula V (R4 is lower alkyl) and reacting the resultant compound of formula VI or its salt with a compound of formula R2-NH2.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel aminoalkylbenzene derivatives,
More specifically, in the following formula (1), Y represents l-pyrrolidinyl, l-piperidinyl or l-perhydroazepinyl group which may be substituted with a hydroxyl group, and R
1 represents a hydrogen atom or a lower alkyl group, Z is =N-
CN or =CH-NH2, R2 represents a lower alkyl group, m represents 0 or l, n represents an integer of 1 to 4, provided that the group (OCH2)CH=CH(CHz)-nNHCNHRz
The m group is bonded in the meta- or para-position to Y-CH-, and relates to an aminoalkylbenzene derivative or a salt thereof.

The compound of formula (I) and its salts exhibit excellent gastric acid secretion suppressing action 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 H2 receptor antagonistic effect has been developed. It has been proposed [e.g.
Special Publication No. 53-24422, Special Publication No. 56-1309
No. 18557, JP 53-18557, JP 53-18557-
149936, JP-A-56-8352, etc. 1゜The compound of the above formula (I) provided by the present invention is bonded to the aminoalkyl group of the aminoalkylbenzene derivative at the meta- or para-position. Unsaturated bonds (
-CH-CH-''), is a novel compound that has not been described in conventional literature, and has an excellent gastric acid secretion suppressing effect in addition to histamine H2 receptor antagonism, and is a new type of compound. It is a compound useful as an 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.

The "lower alkyl group" represented by Ro or R2 in the formula (I) may be linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5eC-butyl, ter
Examples include t-butyl group, among which methyl or ethyl group is preferred.

In addition, "l-pyrrolidinyl, l-piperidinyl, or l-perhydroazepinyl group optionally substituted with a hydroxyl group" CH represented by Y.

C,H.

■ On the other hand, as the group -N H-C-N HR, NHC
NHCHs, -NH-C-NH-CH.

is particularly preferred.

Furthermore, the unsaturated bond (-C
The above-mentioned groups in which each carbon atom of H-CH-') is monosubstituted with a xyl group, for example, cis (-C-C-), etc., are included in the present hydrogen atom. However, base Y
-CH- as R.

stomach.

In the formula (I), m is particularly preferably 0 or 1, and n is an integer from 1 to 4, but the sum of both (m +
n) is preferably within the range of 2 to 4.

Representative examples of the compound of formula (1) provided by the present invention include the following in addition to those listed in Examples below.

N-cyano-N'-methyl-N"-[4-[3-(1-
pyrrolidinylmethyl)phenoxy] -cis-2-butenyl]guanidine, N-methyl-N'-[4-[3-[1-(1-pyrrolidinyl)ethyl]phenyl] -trans -3-butenyl]-2 -Nitro-1,1-ethenediamine, N-cyano-N'-ethyl-N'-[4-[3-(1-
piperidinylmethyl)phenyl]-cis-3-butenyl]guanidine, N-methyl-N'-[5-[3-(1-piperidinylmethyl)phenyl] -trans -4-pentenyl]
-2-nitro-1,1-ethenediamine, N-ethyl-
N'-[4-[4-(1-piperidinylmethyl)phenoxy] -trans -2-butenyl -2-nitro-1,1-ethenediamine, N-cyano-N'-methyl-N"- [4-[3-(4-hydroxy-I-piperidinylmethyl)phenoxy]-cis-2-butenyl]
Guanidine etc.

According to the invention, salts of the compounds of formula (I) above are also provided. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, p-toluenesulfonic acid, etc. Among these, pharmacologically acceptable salts are suitable.

According to the present invention, the above formula (
I), i.e., in the following formula (1-a), 7%R
3, R2, m and n have the above-mentioned meanings, (a) a compound of the following formula (II), where R3 represents a lower alkyl group and xI represents a halogen atom, especially an iodine atom; react with a compound,
Then, the resulting compound of the following formula 1), in which Y, R, m and n have the above-mentioned meanings, or a salt thereof, is converted into the following formula (III) R2-N=C-
A compound of the following formula (IV) R1 obtained by reacting with a compound of 5(I[[) in which R2 has the above-mentioned meaning, or The salt is represented by the following formula (V) R3-X+ (v) where Y
, R, , R8, R3, m and n have the above-mentioned meanings, or a salt thereof is added to cyanamide (H) in the presence of a strong base.
, N-CN); or (b) the compound of formula (n) or its salt is reacted with the following formula (
■) Ra S CS R4 In the formula, R1 represents a lower alkyl group, and the resulting compound is reacted with the following formula (■) Pl In the formula, Y, R,, R, m and n have the above-mentioned meanings. , or a salt thereof, represented by the following formula (II) R, -NH! (h) In the formula, R
2 can be produced by reacting with an alkylamine having the above meaning.

According to the above reaction (a), the compound of the above formula (If) or a salt thereof is first reacted with the lower alkyl isothiocyanate of the formula (II[).

The reaction is usually carried out in a suitable inert solvent, for example water;
The reaction is carried out in alcohols such as methanol, ethanol, and impropatol; halogenated hydrocarbons such as dichloromethane and chloroform; niacetonitrile; and mixtures thereof.

The reaction temperature and pressure are not critical and can be varied over a wide range depending on the starting materials used, the type of solvent, etc.
Generally, the above reaction is carried out at a temperature between 0°C and the reflux temperature of the reaction mixture.
Preferably, it is advantageous to carry out at a temperature in the range of about 15-40°C. Although normal pressure is sufficient for the reaction pressure, the reaction may be carried out under reduced pressure or increased pressure, if necessary. Under such reaction conditions, the reaction can be completed in about 1 to 20 hours.

The above formula (I) for the compound of the above formula (If) or a salt thereof
The proportion of the compound of formula I[ ), preferably 1 to 2 mol, preferably 1.1
It is advantageous to use within the range -1.5 mol.

In this way, the compound of the above formula (IV) or a salt thereof is obtained,
This compound is then alkylated with an alkyl norogenide of formula (V) above.

This alkylation reaction is usually carried out in an inert organic solvent, such as alcohols such as methanol, ethanol, and impropatol; halogenated hydrocarbons such as dichloromethane and chloroform; amides such as dimethylformamide: dimethylacetamide; tetrahydrofuran. , ethers such as dioxane, and mixtures thereof. The reaction temperature and pressure are not critical and can vary widely depending on the starting materials and type of solvent used, but generally the reaction is carried out at a temperature between 0°C and the reflux temperature of the reaction mixture, preferably about 15-40°C. It is advantageous to carry out the reaction at a temperature within the range of 100 to 100 ml, and normal pressure is sufficient as the reaction pressure, but the reaction may be carried out under reduced pressure or increased pressure if necessary. Under such reaction conditions, the reaction can be completed in about 1 to 24 hours.

In the above reaction, the ratio of the halogenated lower alkyl of formula (IV) to the compound of formula (IV) or its salt is also not critical and can be varied widely depending on the reaction conditions used, but in general, It is appropriate to use the lower alkyl halide of formula (V) in an amount of 1 to 5 mol, preferably 1.2 to 2 mol, per mol of the compound of formula (IV) or its salt.

Note that as the lower alkyl halide in the above formula (V), it is advantageous to use, for example, methyl iodide, ethyl iodide, and the like.

In this way, a compound of the above formula (VI) is obtained, and this compound or a salt thereof can then be converted into the desired compound of the above formula (I-a) by reacting with cyanamide in the presence of a strong base. The reaction between the compound of formula (Vl) or a salt thereof and cyanamide is usually carried out in an inert organic solvent, such as alcohols such as methanol, ethanol and t-butanol, dihalogenated hydrocarbons such as dichloromethane and chloroform: The reaction can be carried out in the presence of a strong base such as sodium hydride, potassium t-butoxy, etc. in tetrahydride, ethers such as dioxane, dimethylformamide, dimethyl sulfoxide, etc., and mixtures thereof. The reaction temperature and pressure are not critical and can be varied widely depending on the starting materials and type of solvent used, but generally the reaction is
OoC to reflux temperature of the reaction mixture, preferably 50°C
It is advantageous to carry out the reaction at the reflux temperature of the reaction mixture, and although normal pressure is sufficient, the reaction may be carried out under reduced pressure or increased pressure if necessary. Under such conditions, the reaction can be completed in about 5 to 72 hours.

In the above reaction, the amount of cyanamide used relative to the compound of formula 1) or its salt is also not critical and can be varied widely depending on the reaction conditions used, etc., but in general,
It is appropriate to use the compound in an amount of 1 to 5 mol, preferably 1.2 to 2 mol, per mol of the compound of formula (Vl).

According to the reaction (b), first, the compound of the formula (II) or a salt thereof is reacted with the compound of the formula (■).

The reaction of the compound of formula (rl) or a salt thereof with the compound of formula (■) is usually carried out in an appropriate inert solvent, for example, water;
The reaction is carried out in alcohols such as methanol, ethanol and butanol; ketones such as acetone and methyl ethyl ketone; amides such as dimethylformamide and dimethylacetamide; ethers such as tetrahydro7rane and dioxane; and mixtures thereof. The reaction temperature and pressure are not critical and can vary widely depending on the starting materials used, the type of solvent, etc., but generally the reaction is carried out between about 0°C and the reflux temperature of the reaction mixture, preferably about It is advantageous to carry out the reaction at a temperature within the range of O'C to room temperature, and normal pressure is sufficient as the reaction pressure, but the reaction may be carried out under reduced pressure or increased pressure if necessary.

Under such reaction conditions, the reaction can be completed in about 30 minutes to about 48 hours.

In the above reaction, the ratio of the compound of formula (■) to the compound of formula (I[) or its salt is also not critical and can be varied widely depending on the reaction conditions used, etc.; The amount of the compound of formula (■) is 1 to 1.5 mol, preferably 1 to 1.5 mol, per 1 mol of the compound n) or its salt.
It is appropriate to use within the range of 2 moles.

In this way, a compound of the above formula (■) is obtained, and this compound or a salt thereof can then be converted into the desired compound by reacting with an alkylamine of formula (II).

The reaction of the compound of formula (■) or a salt thereof with the alkylamine of formula (TI) is generally carried out in an inert solvent, such as water;
The reaction can be carried out in alcohols such as methanol, ethanol and butanol; ketones such as acetone and methyl ethyl ketone; amides such as dimethylformamide and dimethylacetamide; ethers such as tetrahydrofuran and dioxane; acetonitrile and mixtures thereof. The reaction temperature and pressure are not critical and can be varied over a wide range, but generally the reaction temperature is within the range of about 0°C to the reflux temperature of the reaction mixture, preferably room temperature to about 50°C, and normal pressure is sufficient. However, reduced pressure or increased pressure may be used if necessary.

Under these conditions, the reaction can be completed within about 1 hour to about 48 hours.

The amount of the alkylamine of formula ([) to be used relative to the compound of formula (■) or its salt is not critical and can be varied widely depending on the reaction conditions used, but in general,
The alkylamine of formula 1) is present in an amount of 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of the compound of formula (■) or its salt.
It is appropriate to use it within a molar range.

As a result, the desired compound of formula (I-a) can be obtained in good yield.

Note that the compound of formula (II) or its salt used as a starting material in the above reaction (a) is a novel compound that has not been described in conventional literature, and can be produced by the method described below. can. In addition, the other raw material, the formula (
The compound III) is a known compound, such as methyl inthiocyanate, ethyl inthiocyanate, and the like.

Further, the compound of formula (■) which is reacted with the compound of formula (II) or a salt thereof in reaction (b) above is a known compound, such as N-cyano-bismethylthiocarboimide, N-cyano-bismethylthiocarboimide, N-cyano- Examples include bisethylthiocarboimide.

Furthermore, according to the present invention, the compound of the formula (I), i.e. the following formula (r-b) R, when Z represents =CHNO3.

In the formula, Y, R, , R3, m and n have the above-mentioned meanings, the compound of the above formula (■), i.e., the compound of the above-mentioned formula (■), where Y%R+1m and n have the above-mentioned meanings Or its salt has the following formula (X) R5S-C-NHR.

In the formula, R6 represents a lower alkyl group, and R2 has the above meaning. It can be produced by reacting with a compound of the following.

The reaction between the compound of formula (II) or a salt thereof and the compound of formula (X) is usually carried out in an appropriate inert solvent, for example, by
water; alcohols such as methanol, ethanol, and butanol; ethers such as tetrahydrofuran and dioxane; amides such as dimethylformamide and dimethylacetamide; acetonitrile; dimethyl sulfoxide; ketones such as acetone and methyl ethyl ketone, and mixtures thereof. It is done. The reaction temperature and pressure are not critical and can vary widely depending on the starting materials and solvent used, but generally the reaction is carried out at room temperature to the reflux temperature of the reaction mixture, preferably about 50°C.
It is advantageous to work at a temperature in the range from O to the reflux temperature of the reaction mixture. Although normal pressure is sufficient for the reaction pressure, the reaction may be carried out under reduced pressure or increased pressure, if necessary. Under such reaction conditions, the reaction can be completed within about 1 to about 48 hours.

The above formula (X
The proportion of the compound represented by formula (1) is also not critical and can be changed as appropriate depending on the reaction conditions used, but in general, the proportion of the compound represented by formula (l[) or its salt per mole of
It is advantageous to use the compound of X) in a range of 1 to 2 mol, preferably 1-1.2 mol.

In this way, the compound of the above formula (r-b) is obtained in good yield.

The compound of formula (X) reacted with the compound of formula (n) or a salt thereof in the above reaction is a known compound, such as l-methylamino-1-methylthio-2-nitroethylene, l- Methylamino-1-ethylthio-2
-nitroethylene, l-ethylamino-1-methylthio-2-nitroethylene, and the like.

The compound of formula (U) or its salt used as a starting material in the two methods described above is a novel compound as described above, and is a compound of formula (II) when m is 0.
A compound of the following formula (■-a), in which Y, R, and n have the above-mentioned meanings, is, for example, a compound of the following formula (X I), where Y and R1 have the above-mentioned meanings. , is reacted with a compound of the following formula (x n), in which X2 represents a halogen atom, and n has the above-mentioned meaning, to obtain the following formula (XIII) n.

On the other hand, a compound in which the hydrogen atoms of the double bond moiety are trans-coordinated with each other in the above formula (II-a) can be synthesized, for example, by the route shown in the reaction formula below.

In the formula, YSR and n have the above-mentioned meanings, and the compound can be produced by subjecting it to hydrazine decomposition.

The reaction between the compound of formula (XI) and the compound of formula (x n) can be carried out by the Wittig reaction, which is known per se. Elimination can be carried out by hydrazinolysis methods known per se.

Thus, in the above formula (II-a), the compound in which the hydrogen atoms of the double bond portion have mutual cis-coordination is -CH R3 (trans) In the above formula, YSR,, X2 and n have the above meanings. death,
R6 represents a lower alkyl group;

represents a halogen atom, and Ml represents a hydrogen atom or an alkali metal.

In the above reaction formula, a compound of formula (XI) and a compound of formula (XIV
) The reaction of the compound of formula (Xv) is carried out according to the Wittig reaction, which is known per se.The resulting compound of formula (Xv) is then reacted with the alcohol of formula R, OH or its ester-forming reactivity according to the esterification method, which is known per se. It is converted into the ester of the above formula (XVI) by reacting with a derivative. This ester of formula (xvr) is then reduced by a method known per se using a complex metal hydride such as lithium aluminum hydride or t-butoxylithium aluminum hydride to convert the ester into an alcohol of formula (X■). The resulting alcohol of formula (X■) is treated with a halogenating agent such as thionyl halide, sulfuryl halide, phosphorus pentahalide, phosphorus trihalide, etc. to produce the compound of formula (X■).

The generated compound of formula (X■) is then reacted with 7-talimide or its alkali metal in dimethyl sulfoxide in the presence of an alkali metal hydride when 7-talimide is used to produce a compound of formula (Xff). and then subjecting it to hydrazinolysis, which is known per se, to obtain the trans form of the compound of formula (II-a).

In addition, the compound (trans form) in which R, in the former formula (I[-a) represents a hydrogen atom, can also be synthesized according to the following reaction formula. For details of the reaction conditions, please refer to Method B in Production Example 1O below.

Ten human 7 decomposition (Xff-a) Xs CHi In each of the above formulas, Y, R,, X2, Xl, M, and n represent the above-mentioned meanings, and R7 represents a lower alkyl group.

Further, a compound of formula (I[) when m is l, ie, the following formula (n - b) h.

In the formula, Y, R, and n have the above-mentioned meanings, for example, the compound of the following formula (xxvr) VI. method (for example, the above-mentioned Japanese Patent Application Laid-Open No. 53-149)
According to the method described in Publication No. 936), the following formula (XX■) X 4CH2CH-CH(CHz ) A(XX■) In the formula, It can be easily produced by reacting with a compound, which represents an acetylamine/group, etc., and where n has the meaning described above, and then removing the amino protecting group.

The reaction between the compound of formula (XXVT) and the compound of formula (XX■) can be carried out by reacting the compound of formula (XXVI) with the compound of formula (XX■) in the form of a phenolate, or by reacting the compound of formula (XXVI) with the compound of formula (XX■) in the form of a phenolate.
This can be carried out by reacting a compound of formula (XXVI) with a compound of formula (XX■) in the presence of a base.

The 7-elate of the compound of formula (XXVI) is generally represented by the following formula (XXVI-a) where Yl and R have the meanings, and M2 is an alkali metal.

Examples of the base include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium azide, sodium amide, etc., and these are generally used at least per mole of the compound of formula (XXVI). It can be used in an amount of 1 equivalent, preferably 1 to 5 equivalents, more preferably 1 to 1.5 equivalents.

A compound of formula (XXVI) or formula (XXVI-a) and a compound of formula (
The reaction with the compound XX■) can be carried out in the absence of a solvent or in an inert solvent such as water; alcohols such as methanol, ethanol, butanol; ketone necks such as acetone and methyl ethyl ketone; aromatic carbonization such as benzene and toluene. The reaction can be carried out in hydrogen; amides such as dimethylformamide and dimethylacetamide; dimethyl sulfoxide and the like. The reaction temperature is not critical and can vary widely depending on the type of starting materials used, but in general,
between about room temperature and the reflux temperature of the reaction mixture, preferably about 2
Temperatures between 0°C and the reflux temperature of the reaction mixture are suitable.

The amount of the compound of formula (XX) relative to the compound of formula (XXVI) or formula (XXVI-a) is also not critical and may vary widely, but in general, the amount of compound of formula (XXVI) or formula (XXVI-a) ) per mole of compound of formula (xx■)
at least 1 mol, preferably 1-1 o mol, of the compound of
More preferably, it is advantageous to use it in a proportion of 1 to 2 moles.

There is thus obtained a compound of the following formula (XX■) VI in which Y, R+, A and n have the meanings given above, which is then removed by methods known per se, for example hydrazitrilysis or mild hydrolysis to remove the amino protecting group. By eliminating , the target compound of the formula ([-b) can be obtained.

In addition, a compound in which R3 represents a hydrogen atom in the above formula (n-b), that is, a compound of the following formula (n-bl) (n-b-1) in which Y and n have the above meanings. is, for example, a compound in which A and n have the meanings given above,
/A halogenation by a method known per se, for example, by treatment with a halogenating agent such as decahydric acid, thionylno\ride, sulfuryl halide, gono\halogenated phosphorus, trihalogenated phosphorus, etc. (XXXI) 3-(or 4-)hydroxybenzyl alcohol of the above formula (XX■), that is, formula X, -CH, -CH-CH(CH,)-A(XX■), where XA and The following formula (X X Among tetrahydrofuran, benzene, toluene, dimethylformamide, dimethylacetamide, etc., the above formula (XXV)
, that is, a compound of the formula Y-H(XXV), in which Y has the above meaning, in the presence of a deoxidizing agent such as triethylamine, sodium hydroxide, sodium carbonate, etc., at room temperature to the reflux temperature of the reaction mixture. It can also be produced by reacting and removing the amino protecting group from the resulting compound using the method described above.

The compound of formula (1) produced by the method described above can be converted into a corresponding salt if necessary. The salt-forming reaction can be easily carried out by treating the compound of formula (I) with the above-mentioned inorganic or organic acid according to a method known per se.

Thus, said formula (I) prepared according to the method of the invention
The compound or a salt thereof can be isolated and/or purified from the reaction mixture by means known per se, such as recrystallization, distillation, column chromatography, thin layer chromatography, etc.

The aminoalkylbenzene derivatives represented by the formula (I) of the present invention and their salts described above have an effect of suppressing gastric acid secretion based on an excellent histamine H2 receptor antagonism, and are effective against diseases caused by gastric acid, such as gastric acid secretion. It is also an extremely useful compound for the treatment of duodenal ulcer.

The following animal experiments demonstrate that the compound represented by formula (I) of the present invention has excellent histamine H2 receptor antagonism.

The compounds of the present invention used in the following animal experiments are represented by the following symbols.

Compound A: N-methyl-N'-[4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenyl]-2
-nitro-1,1-ethenediamine, B: N-cyano-N'-methyl-N"-[4-[3-(
1-piperidinylmethyl)phenoxy]-trans
-2-butenyl] guanidine, CAM-methyl-N'
-[4-[3-(1-piperidinylmethyl)phenoxy] -trans -2-butenyl 1-2-nitro-1,1-ethenediamine, D: N-methyl-N'-[4-[3 -(+-piperidinylmethyl)phenyl]-cis-3-phenyl]-2-
Nitro 1.1-ethenecyamine, E:N-cyano-N'-methyl-N'-[4-[3-(
1-piperidinylmethyl)phenyl]trans-3
-butenyl]guanidine.

The head of a Hartley guinea pig (male: 400-550 g) was bruised to exsanguinate blood, and the heart was removed. The right atrium was dissected in oxygen-saturated Tyrode's solution and silk sutures were attached to both ends. A tension cuff was placed in a Magnus tube (25 mQ) containing Tyrode's solution kept at 36°C and aerated with a mixed gas (0295%: CO15%) using silk thread attached to both ends.
The atrium was suspended at 0 mg. The contraction movement of the atrium is 7 ohs.
Displacement transducer (F or
ce-displacement-transduc
er) and the heart rate was calculated.

Histamine (used in the form of diphosphate, the same hereinafter) was administered at doses equally spaced such that the logarithm of the added amount was 1, until the maximal response of increased heart rate was obtained. I
Dose-response curve (D) of histamine added cumulatively into the Magnus tube at concentrations of X I O-'M.

5e-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 inside of the Magnus tube several times, the tissue was allowed to stabilize for 50 minutes. Next, the test compound (IXIO-'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 dose-response curve of histamine and the third dose-response curve of histamine in the presence of the test compound, J,
M. Van Rossum's method (Arch.

int, Pharmacodyn, l 43.
299, l 963) for each test compound (the negative logarithm of the molar concentration of the test compound required to double the histamine concentration in the Magnus tube required to produce a given reaction).
hm) ) was calculated. The results are shown in Table 1 below.

Table 1 A2 7.69 6.64 6.95 6.37 6.54 Thus, the compound represented by formula (1) of the present invention can be used as an antiulcer agent for treatment and treatment of humans and other warm-blooded animals. for oral or parenteral administration (e.g. intramuscular injection, intravenous injection,
(subcutaneous administration, rectal administration, 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 present invention may be incorporated into non-toxic excipients, binders, lubricants, disintegrants, preservatives, etc. commonly used in such drugs.
It can be formulated using additives such as tonicity agents, stabilizers, dispersants, antioxidants, colorants, flavoring agents, and buffering agents.

Depending on the intended use, such drugs may be in solid form (e.g. tablets, hard capsules, soft capsules, granules, powders, fine granules, emulsions, lozenges, etc.), semi-solid forms (e.g. tablets, ointments, etc.) and liquid forms (injections, emulsions, suspensions, syrups, sprays, etc.). Therefore, the non-toxic additives that can be used include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, magnesium aluminate metasilicate, synthetic aluminum silicate, silicic anhydride, talc, stearic acid. Magnesium, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, petrolatum, carpowax,
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% for liquid forms. It is desirable to contain the active compound in a concentration of ~10% by weight.

The dosage of the compound of the present invention can vary widely depending on the type of warm-blooded animal including humans, the route of administration, severity of symptoms, doctor's diagnosis, etc., but in general, the dosage is 0.2 per day. ~80mg/Kg, preferably 0,5-5
0 mg/Kg. but,
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 is 1 per day.
It can be administered in one or several divided doses.

The present invention will be further explained below with reference to Examples.

Example 1 i) 300 mg of cis-4-[3-(1-piperidinylmethyl)phenoxy-1-2-butenylamine is dissolved in 3 mQ of ethanol and 185 mg of N-cyano-bismethylthiocarboimide is added. After reacting at room temperature for 3 hours, the solvent was distilled off under reduced pressure, and the residue was purified by TLC (developing solvent: chloroform:methanol (9:l)) to give N-cyano-N'-[4-[ 400 mg of 3-(1-piperidinylmethyl)phenoxy]-cis-2-butenyl]-8-methylisothiourea was obtained as an oil.

IR (liquid film, Cm-'): 3240.1965.15
50°NMR (CDC123, δ): 1.2-1.8 (6H,
multiplet), 2.2 to 2.6 (4H, multiplet), 2.48
(3I], - double line), 3.44 (2H, - double line), 3.
9-4.2 (2 days 1 multiplet), 4.3-4.8 (2H
, multiplet), 5.3-6.2 (2H, multiplet), 6.6
~7°4 (4H, multiplet).

1j) N-cyano-N'-[4-[3-
(1-piperidinylmethyl)phenoxy] -cis-
2-butenyl]-3-methylisothiourea 400mg
Dissolve in 10 mQ of 30% methylamine ethanol solution and leave at room temperature overnight. The solvent was distilled off under reduced pressure and the TL
C (developing solvent; chloroform:methanol (9:1))
to give N-cyano-N'-methyl-N"-[4
-[3-(1-piperidinylmethyl)phenoxy] -
360 mg of cis-2-butenyl]guanidine were obtained as an oil.

IR (liquid film, am-ri: 3280.2160.159
0°NMR (CDC12, δ): 1.1-1.9 (6H
, multiplet), 2.2 to 2.7 (4H, multiplet), 2.7
7 (double line on 3H, J = 5Hz), 3.8 to 4.2 (2H
.

multiplet), 4.4~4.8 (2H, multiplet), 5.3~
6.2 (2H, multiplet), 6.6-7.4 (1 multiplet in 4 days).

Example 2 In Example 1, in place of cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-/thenylamine, trans 5-4-[3-(1-piperidinyl methyl)phenoxy]-2-butenylamine 400m
The following compound was obtained as an oil by the same operation using g.

i) N-cyano-N'-[4-[3-(1-piperidinylmethyl)phenoxy] -t r a n S
-2-7'tenyl]-5-methylisothiourea 450
mg, NMR (CDCI23, δ): 1.2-1.9 (
6H', multiplet), 2.2 to 2.7 (4H, multiplet),
2.51 (3H.

double line), 3.43 (2H, - double line), 3.8 to 4.2 (
2 days 1 multiplet), 4.3-4.7 (2H, multiplet), 5
゜6~6.4 (2H, multiplet), 6.6~7.3 (4H
.

multiplet).

u) N-cyano-N'-methyl-N#-[4-[
3(l-piperidinylmethyl)phenoxy]-tran
s-2-butenyl]guanidine 370+++g, I
R (liquid film, Cm-'): 3280.2160.15
90°N MR (CD CQ 3, δ): 1.2-1
．． 9 (1 multiplet on 6 days), 2.2-2.7 (4H, multiplet), 2.81 (multiplet in 3H, J = 5Hz), 3.43 (
2H, - multiplet), 3.7-41 (2J (, multiplet), 4
．． 3-4°7 (2H, multiplet), 5,6-6.4 (2H
, multiplet), 6.6-7.3 (4H, multiplet).

Example 3 In Example 1, cis-4-[3-(1-piperidinylmethyl)phenyl was used instead of cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-7/thenylamine. A similar operation was performed using 300 mg of co-3-butenylamine to obtain the following compound as an oil.

i) N-cyano-N'-[4-[3-(1-piperidinylmethyl)phenoxy]-cis-3-phthynyl]-S methylisothiourea 410 mg, I R
(Liquid film, cm-'): 3250.2180.1560
°NMR (CDCQ3, δ) + 1.2 to 1.8 (6H
1 multiplet), 2.1 to 3.0 (6H, multiplet), 2.4
6 (3H.

multiplet), 3.3 to 3.7 (2H, multiplet), 3°47 (
2H1-multitet), 5.3-5.9(II(, multiplet),
6゜59 (double line on lH, J-12Hz), 7.0-7
°4 (4H, multiplet).

ij) N-cyano-N'-methyl-N"-[4-
[3-(1-piperidinylmethyl)phenyl] -ci
s-3-butenyl]guanidine 370 mg, IR (liquid film, cm-'): 3280.2160.1590° NMR (CDCQ3, δ): 1.2-1.8 (6H, multiplet), 2.1- 3.0 (9H, multiplet), 3.1-3
゜7 (2H1 multiplet), 3.47 (2H, - multiplet), 5
°2-6.0 (IH, multiplet), 6.54 (lH, doublet, J=12Hz), 7.0-7.4 (4H, multiplet).

Example 4 In Example 1, tr a n 5-4-[3-(1-piperidinylmethyl) ) Phenyl]-3-butenylamine 400mg
The following compound was obtained as an oil by performing the same operation using .

i>N-cyano-N'-[4-[3-(1-piperidinylmethyl)phenyl]-trans-3-butenyl 1-8-methylisothiourea 300 mg, IR (liquid film, Cm-'): 3270.2170.1560°N
MR (CDCQ, δ): 1.1-1.9 (6H, multiplet), 2.1-2.8 (6H, multiplet), 3.2-3
．． 7 (2H1 multiplet), 3.44 (3H, - multiplet),
5.6-6.7 (2H1 multiplet), 7.0-7.5C4
H1 multiplet).

ii) N-cyano-N'-methyl-N"-[4-[
3-(1-piperidinylmethyl)phenyl]-tran
260 mg of s-3-butenyl 1 guanidine. IR (liquid film, cm''): 3250.2160.1583°NMR
(CDCQs, δ): 1.1-1.9 (6H, multiplet), 2.2-3.0 (6H, multiplet), 2.83 (31
1, double line, J=5Hz), 3.1-3.6 (2H.

multiplet), 3.67 (2H, - multiplet), 5.6-6.7
(2H1 multiplet), 7.0-7.5 (4H1 multiplet).

Example 5 cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine 300 mg51-methylamino-1-methylthio-2-nitroethylene 188 mg
and water 1. Reflux the Qm12 mixture for 30 minutes.

After cooling, the mixture is extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was analyzed by TLC (
N-methyl-N'-[4-[3-(1-piperidinylmethyl)phenoxy]-cis2-butenyl]-2-nitro 320 mg of 1.1-ethenediamine was obtained as an oil.

IR (liquid film, cm-') = 3200.1610.158
0゜N M R(CD CQs, δ>: 1.1-1.9(
6H1 multiplet), 2.2 to 2.6 (4H, multiplet), 2
．． 7-3°2 (3H, multiplet), 3.49 (2H, -multiplet), 3°8-4.3 (2H, multiplet), 4.4-4.
9 (2H.

multiplet), 5.3-6.2 (2H1 multiplet), 6.60
(l H, -multiplet), 6.6-7.4C4H, multiplet)
.

Example 6 In Example 5, 250 mg of cis-4-(3-dimethylaminomethylphenoxy)-2-butenylamine was used instead of cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine. 290 mg of N-methyl-N'-[4-(3-dimethylaminomethylphenoxy)-cis-2-butenyl]-2nitro-1,1-ethenediamine was obtained as an oil.

IR (liquid film, am-〇: 3220.1610% 158
0゜NMR(CD C(ls-δ):2.26(6H1
- multiplet), 2.7 to 3.1 (3H, multiplet), 3.42
(2H.

multiplet), 3.7-4.3 (2H, multiplet), 4.4-4
°7 (2H, multiplet), 5.3-6.0 (21 (, multiplet), 6.5-7.2 (4H, multiplet), 6.55 (l
H.

heavy line).

Example 7 In Example 5, cis-4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy was used instead of cis-4-[3-(1-piperidinylmethyl)phenoxy1-2-butenylamine. ]-2-Butenylamine (220 mg) was used to prepare N-methyl-N'-[4-[3-
[1-(1-pyrrolidinyl)ethyl]phenoxy] −
150 mg of cis-2-butenyl 1-2-nitro-1,1-ethenediamine was obtained as an oil.

IRC liquid film, am-'): 3220.1610.15
80°NMR (CD(1,,δ)21.38(3H, doublet,
J=6Hz), 1.5-2.1 (4H, multiplet), 26
2-3.0 (7H, multiplet), 3.23 (I H, quartet, J-6Hz), 3.7-4.3 (2H, multiplet),
4.4-4.9 (2H, multiplet), 5.3-6.2 (2
H1 multiplet), 6.56 (IHl multiplet), 6.5-7
．． 4 (4H, multiplet).

Example 8 In Example 5, trans-4-[3-(1-piperidinylmethyl) instead of cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine
A similar operation was performed using 60 mg of N-methyl-N'-[4-[3-(1piperidinylmethyl)phenoxy]-trans-2-
butenyl]-2-nitro-1,1-ethenediamine 27
Obtained mg as an oil.

IR (liquid film, cm-re: 3240, ?610,158
O NMR (CD+1., a): 1.2-1.9 (6H, multiplet), 2.2-2.6 (4H, multiplet), 2.7-3
゜2 (3H, multiplet), 3.47 (2H, -multiplet), 3
°7~4.2 (2H1 multiplet), 4.3~4.7 (2H
.

multiplet), 5.6~6.4 (2H, multiplet), 6.6~
7.3(4)1. multiplet).

Example 9 In Example 5, cis-4-[3-(1-piperidinylmethyl)phenyl]-3 was used instead of cis-4-[3-(1-piperidinylmethyl)phenoxyno-2-butenylamine. -N-methyl-N'-[4-[3-(1-piperidinylmethyl)phenyl] -cis-3-butenyl]-2-nitro 1.1- Ethendiamine 280mg
was obtained as an oil.

IR (liquid film, cm-1: 3260.1620.1580
°NMR (CD(1, δ): 1.2 to 1.8 (6H,
multiplet), 2.1~3.0 (9H, multiplet), 3.1~
3°7 (2H, multiplet), 3.48 (2H, -multiplet),
5°2~5.6 (I H, multiplet), 6.54 (l H
double line, J=I2Hz), 6.55 (IH, - double line),
7°0-7.5 (4H, multiplet).

Example 10 In Example 5, trans-4-[3-(1-piperidinylmethyl) was substituted for cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine.
260 mg of phenyl-3-butenylamine was treated in the same manner with Ql to give N-methyl-N'-[4-[3-(
1piperidinylmethyl)phenyl] -trans-3
-phthynyl]-2-nitro 1,1-ethenediamine 1
Obtained 80 mg as an oil.

IR (liquid film, cm-'): 3240.1620.15
80°NMR (CD(1,, δ): 1.1-1.9 (6H,
multiplet), 2,2~3.0 (9H, multiplet), 3.1~
3°5 (2H, multiplet), 3.43 (2H1-multiplet),
5°6-6.7 (2H, multiplet), 6.58 (IH,
- multiplet), 7.0 to 7.5 (4H, multiplet).

Example 11 In Example 5, cis-6-[3-(1-piperidinylmethyl)phenyl] instead of cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-'thenylamine Using 170 mg of -5-hexenylamine, N-methyl-N'-[6-[3-(1-piperidinylmethyl)phenyl]-cis-5-hexenyl]-2-nitro 1.1-edenediamine 133m
g was obtained as an oil.

IR (liquid film, cm-'): 3250.1610.15
80°N MR (CD CQs, δ): 1.1-1.9 (
l OH.

multiplet), 2.1~2.7 (6H1 multiplet), 2.7~
3.0 (3H, multiplet), 3.0-3.4 (2H, multiplet), 3.46 (2H, -multiplet), 5.3-6.0 (
IH1 multiplet), 6.40 (IH, doublet, J-12
Hz), 7.0-7.9 (4H, multiplet).

Example 12 In Example 5, cis-4-[3-(1-perhydroazepinylmethyl)phenoxy was used instead of cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine. ]-2-Butenylamine (250 mg) was used to prepare N-methyl-N'-[4-[3-
(1-perhydroazepinylmethyl)phenoxy]-c
270 mg of is-2-butenyl]-2-nitro-1,1-ethenediamine was obtained as an oil.

IR (liquid film, cm-'): 3240.1610,15
80°NMRCCDCQ,, a): 1.4-1.9 (8H,
multiplet), 2.4-3.1 (5H1 multiplet), 3.63
(2H1-multiplet), 3.7-4.3 (2H, multiplet)
, 4°4-4.7 (2H, multiplet), 5.3-6.1 (
2H.

multiplet), 6.5-7.4 (4H, multiplet), 6.56
(l H, - double line).

Example 13 In Example 5, cis-4-[3-(3-hydroxy-l-
Using 320 mg of N-methyl-N-methyl-N-
'-[4-[3-(3-hydroxy-l-piperidinylmethyl)phenoxy]-cis-2-butenyl]-
220 mg of 2-nitro-1,1-ethenediamine was obtained as an oil.

IR (liquid film, Cm-'): 3 4 0 0, 3260
, 1610, 1580.

NMR (CDCI2,, δ): 1.3-2, 0 (4
H, multiplet), 2.1 to 2.7 (4H, multiplet), 2
．． 7-3.

0 (3H, multiplet), 3.47 (2H, -multiplet), 3.

6-4.2 (2H, multiplet), 4.4-4.8 (2H
.

multiplet), 5.3-6.2 (2H, multiplet), 6.54
(11(,-multiplet), 6.6-7.4(4H1 multiplet)
.

Example 14 In Example 5, cis-4-[3-(1-
cis-4-[4-(1-piperidinylmethyl)phenoxy]-2-butenylamine instead of [piperidinylmethyl)phenoxy]-2-7'thenylamine 250 m
In the same manner using g, N-methyl-N'-[4
- [4-(1piperidinylmethyl)phenoxy] -
260 mg of cis-2-butenyl]-2nitro-1,1-ethenediamine was obtained as an oil.

IR (liquid film, cm-'): 3 2 2 0, 1610
, 1580.

NMR (CDCQs, δ): 1.1~
1.9 (6H, multiplet), 2.1-2.6 (4H, multiplet), 2.6-3.

1 (3H, multiplet), 3.40 (2H, -multiplet), 3.

8-4.2 (2H, multiplet), 4.3-4.7 (2H.

multiplet), 5.3-6.2 (2H, multiplet), 6.55
(l H, -multiplet), 6.6-7.4 (4H, multiplet)
.

The raw materials for the above examples were synthesized according to the following production examples.

Production Example 1 Method A i) 1.15 g of 60% sodium hydride was suspended in 15 m4 of dry dimethyl sulfoxide, and 5.0 g of 3-(1-piperidinylmethyl)phenol was added little by little as a solid and stirred. do. After stirring at room temperature for 20 minutes,
Add 6.75 g of N-(4-chloro-cis-2-butenyl)phthalimide and stir at room temperature for 2 hours. Add ice water to the reaction solution and extract with ether. After washing with water, the mixture is extracted with 10% hydrochloric acid, the aqueous layer is collected, made alkaline with ammonia, and then extracted with chloroform. After washing with water, it was dried over anhydrous magnesium sulfate, the solvent was distilled off, and N-[4-[3-(
1-piperidinylmethyl)phenoxy] -cis-2
8.3 g of ~butenyl]phthalimide were obtained as an oil.

IR (liquid film, cm-'): I 765.1706°N
M R (CD CQs1δ): 1.1-1.9 (6
H, multiplet), 2.1 to 2.6 (4H, multiplet), 3.
45 (2H1 doublet), 4.36 (2H1 doublet, J-
7Hz), 4.6~5.0C2H, multiplet), 5.3~
6.2 (2H1 multiplet), 6.7-7.4 (4H, multiplet), 7°5-8.0 (4H, multiplet).

ii) A mixture of 8.3 g of N-[4-[3-(1-piperidinylmethyl)phenoxy] -cis-2-butenyl] phthalimide, 8.3 J of hydrazine hydrate, and 83 mα of ethanol is left at room temperature for 4 hours. . The precipitated phthalazine is thoroughly loosened and filtered off, benzene is added and the solvent is distilled off under reduced pressure, and when insoluble matter precipitates, it is filtered off.

After repeating this operation several times, the residue is distilled under reduced pressure.
4.2 g of cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine was obtained. boiling point 16
8-170℃/0.55mmHg.

IR (liquid film, Cm-'): 3240.1593°NM
R (CD(43, δ), 1.1 to 1.9 (6H, multiplet), 2.1 to 2.6 (4H, multiplet), 3.1 to 3°7
(2H, multiplet), 3.43C2H, -multiplet), 4.3
~4.7 (2H1 multiplet), 5.3-6.0 (2H1 multiplet), 6.6-7.7 (4H, multiplet).

Method B: 1.15 g of 60% sodium hydride is suspended in 15 m+2 of dry dimethyl sulfoxide, and 5.0 g of 3-(1-piperidinylmethyl)phenol is added little by little as a solid, followed by stirring. After stirring for 20 minutes at room temperature, this liquid is added dropwise into a mixture of 9.7 g of cis-1,4-dichloro-2-butene and 5 mf2 of dry dimethyl sulfoxide. After reacting at room temperature for 1 hour, the mixture was poured into ice water and extracted with ether. After washing with water, the ether layer is extracted with 10% hydrochloric acid, the aqueous layers are collected, made alkaline with potassium carbonate, and extracted again with ether. After washing with water, it was dried over anhydrous magnesium sulfate, the solvent was distilled off, and l-chloro-4-[3-(
3.3 g of 1-piperidinylmethyl was obtained as an oil. This product is used immediately in the next reaction.

3.3 g of the obtained l-chloro-4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butene was added to 0-53 g of 60% sodium hydride, 7.3 ma of dry dimethyl sulfoxide and 1 phthalimide. It was produced from .92g and dropped into the liquid.

After reacting at room temperature for 2 hours, ice water was added and extracted with ether. After washing with water, drying with hot water tUt magnesium and distilling off the solvent, 2.4 g of N-[4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenyl]phthalimide was obtained as an oily substance. obtained as. This compound is A method i
) was completely identical to the compound obtained in .

Production Example 2 1) In method A i) of Production Example 1, N −( 1 −
In the same manner, using 6.75 g of N-(4-chloro-trans-2-butenyl)phthalimide instead of chloro-cis-2-butenyl)phthalimide, N-[
4- [3(1-cubiperidinylmethyl)phenoxy]
-trans-2-butenyl 1-phthalimide 8.1g
was obtained as an oil.

IR (liquid film, Cm-'): l 7 6 2, 1706
.

N M R (C D C Qs, δ) = 1.1 to 1.
9 (6H, multiplet), 2.1 to 2.7 (4H, multiplet)
, 3.45 (2H, - double line), 3.9-4.7 (4H,
multiplet), 5.6~6.4 (2H, multiplet), 6.6~
7.3 (4H, multiplet), 7.5-8.0 (4H, multiplet).

i) In method A (■) of Production Example 1, N-[4-[3
-(1-piperidinylmethyl)phenoxy] -cis
-2-butenyl]phthalimide instead of N-[4-
[3-(1-piperidinylmethyl)phenoxy] -t
Trans-4-[3-
(1-Piperidinylmethyl)phenoxy]-2-butenylamine 4,0g was obtained as an oil.

NMR (CDC+23, δ): 1.1-1.9 (6H
, multiplet), 2.1 to 2.7 (4H, multiplet), 3.2
~3°8 (2H, multiplet), 3.46 (2H, -multiplet)
, 4.3-4.7 (2H, multiplet), 5.6-6.4
(2H, multiplet), 6.6-7.3 (4H, multiplet).

Production Example 3 1) Perform the same procedure as in Method A i) of Production Example 1, using 1.0 g of 3-[1-(1-pyrrolidinyl)ethyl]phenol instead of 3-(1piperidinylmethyl)phenol. and N-[4-[3-[1-(1pyrrolidinyl)
1.7 g of ethyl]phenoxy]-cis-2-7'thenyl]phthalimide was obtained as an oil.

IR (liquid film, am-”): l 770.1712°N
MR (CDCQ3, δ): l, 37 (3H, doublet, J=6Hz), 1.5-2.0 (4H1 multiplet), 2
゜1~2.8 (4H, multiplet), 3.16 (I H1 quartet, J=6Hz), 4.2~4.6 (2H, multiplet)
, 4.6-5.0 (2H, multiplet), 5.3-6.2 (
2H1 multiplet), 6.6-7.4 (4H, multiplet),
7°5-8.0 (4H, multiplet).

ii) In method A if) of Production Example 1, N-[4-
[3-(1-piperidinylmethyl)phenoxy]-ci
s-2-butenyl] N-[4- instead of phthalimide
[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl]phthalimide 1.7 g
cis-4-[3-[1-(
0.9 g of 1-pyrrolidinyl)ethyl]phenoxy]-2-butenylamine was obtained as an oil.

NMR (CDI: l, 1.9): 1.3B (3H, doublet, J=6Hz), 1.5-2.0 (4H, multiplet)
, 2°2~2.8 (4H, multiplet), 3.17 (l H
, quartet, J=6Hz), 3.2-3.7 (2H, multiplet), 4.3-4.8 (2H, multiplet), 5.3-6.
2 (2H2 multiplet), 6.6-7.4 (4H, multiplet)
.

Production Example 4 1) In Method A i) of Production Example 1, 3-dimethylaminomethylphenol was used instead of 3-(1piperidinylmethyl)phenol. Perform the same operation using Og to obtain N-
[4-(3-dimethylaminomethylphenoxy)-ci
s-2-butenyl] 7-talimide l.

Og was obtained as an oil.

IR (liquid film, Cm-'): 1775.1720°N
MR (CD CQs, δ): 2.23 (6H, - double line), 3.39 (2H1 - double line), 4.2-4.6 (2
H, multiplet), 4,7-4.9 (2H, multiplet), 5.
3-6°2 (2H, multiplet), 6.6-7.4 (4H,
multiplet), 7.5-8.0 (4H, multiplet).

ii) In method A U) of Production Example 1, N-[4-[
3-(1-piperidinylmethyl)phenoxy] -ci
N-[4-(
3dimethylaminomethylphenoxy)-cis-2-butenyl]phthalimide1. 0.7 g of cis-4-(3-dimethylaminomethylphenoxy)-2-butenylamine was obtained as an oil by the same procedure using 0.0 g.

NMR (CDC12s, δ): 2.22 (6H, -multiplet), 3.2-3.5 (2H, multiplet'), 3.36
(2H.

- multiplet), 4.3~4.8 (2H, multiplet), 5.3~
6.0 (2H, multiplet), 6.6-7.7 (4H, multiplet).

Production Example 5 i) Perform the same procedure as in Method A i) of Production Example 1, using 1.0 g of 3-(1 perhydroazepinylmethyl)phenol instead of 3-(1piperidinylmethyl)phenol. Then, 1.1 g of N-[4-[3-(1-perhydroazepinylmethyl)phenoxy]-cis-2butenyl 17-talimide was obtained as an oil.

IR (liquid film, cm-'): l 772.1719°N
M R (CD CQ3, δ): 1.4-1.9 (8H
, multiplet), 2.4-2.9 (4H, multiplet), 3.6
0 (2H1-multiplet), 4.2-4.6 (2H, multiplet)
, 4°7~4.9 (2H1 multiplet), 5.3~6.1 (
2H.

multiplet), 6.5~7.4 (4H, multiplet), 7.5~
8.0 (4H1 multiplet).

i) In method A i) of Production Example 1, N-[4[3-(
1-piperidinylmethyl)phenoxy] -cis2-
butenyl]phthalimide instead of N-[4-[3-(1
-perhydroazepinylmethyl)phenoxy]cis-
A similar operation using 1.1 g of 2-butenyl 1 phthalimide yielded 0.8 g of cis-4-[3-(1-perhydroazevinylmethyl)phenoxy]-2-butenylamine.
g was obtained as an oil.

NMR (CDCI2., δ): 1.3-1.9 (8H
, multiplet), 2.3 to 2.8 (4H, multiplet), 3.1
~3°6 (2H, multiplet), 3.58 (2H, -multiplet), 4°3~4.7 (2H, multiplet), 5.3~6.
0 (2H.

multiplet), 6.5-7.6 (4H1 multiplet).

Production Example 6 1) In Method A i) of Production Example 1, 4-(1-piperidinylmethyl)phenol was used instead of 3-(1-piperidinylmethyl)phenol. Similarly, N-[4-[4-(1-piperidinylmethyl)phenoxy] -cis-2-butenyl]7talimide 1.
4 g were obtained as an oil.

IR (liquid film, Cm-'): l 770.1710°N
MR (CDC et al., δ): 1.1-1.9 (6H, multiplet), 2.1-2.7 (4H, multiplet), 3.40 (2
H1-double line), 4.35 (2H, double line, J-6H7,
), 4.6-5.1 (2H1 multiplet), 5.3-6.
2 (2H1 multiplet), 6.7-7.4 (4H, multiplet)
, 7.5-8.0 (4H, multiplet).

ii) In method A it) of Production Example 1, N-[4-
[3-(1-Pidridinylmethyl)phenoxy] -c
is-2-butenyl]phthalimide instead of N-[4-
[4-(l-piperidinylmethyl)phenoxy] -c
In the same manner using 1.4 g of is-2-butenyl]phthalimide, 0.78 g of cis-4-[4-(1-piperidinylmethyl)phenoxy]-2-butenylamine was obtained.
was obtained as an oil.

NMR (CD(1,,a): 1.1-1.9(6H,
multiplet), -2,1 to 2.6 (2H, multiplet), 3.2
~3°5 (2H1 multiplet), 3.37 (2H, - multiplet)
, 4°3-4.7 (2H, multiplet), 5.3-6.
5 (2H.

multiplet), 6.7-7.4 (4H, multiplet).

Example 7 i) 24 g of 3-7 taliminopropyl triphenylphosphonium bromide in THF14OmQ and 60%
After suspending 1.8 g of sodium hydride and stirring for 15 minutes under water cooling, 7.0 g of 3-(1-piperidinylmethyl)benzaldehyde is added. After stirring at room temperature for 1.5 hours, the solvent was distilled off under reduced pressure, ice water was added, and the mixture was extracted with ether. After washing with water, the ether layer is extracted with 10% hydrochloric acid, the aqueous layer is collected, made alkaline with ammonia, and then extracted with chloroform. After washing with water, drying over anhydrous magnesium sulfate and distilling off the solvent, 9.2 g of N-[4-[3-(1-piperidinylmethyl)phenyl]-cis-3-butenyl]phthalimide was obtained as an oil. Obtained.

IR (liquid film, cm-re: 1770.1700°N M
R(CD CQ s, δ): 1.1-1.9 (6
H.

multiplet), 2.2 to 2.6 (4H, multiplet), 2゜7
0 (2H, quartet), 3.49 (2H, - doublet), 3
．． 70 (2H, triple line, J=7Hz), 5.2-5.
6 (IH, multiplet), 6.49 (IH, doublet, J =
12Hz), 7.0 to 7.4 (4H, multiplet),
7.5-8.0 (4H1 multiplet).

ii) In method A ii) of Production Example 1, N-[4
-[3-(1-piperidinylmethyl)phenoxy]ci
s-2-butenyl] N-[4- instead of phthalimide
[3-(1-piperidinylmethyl)phenyl]-cis
-3-Butenyl]7thalimide 9.2g was used in the same manner, and the oily substance obtained was distilled under reduced pressure to a temperature of 140 to 142℃.
4.0 g of cis-4-[3-(1-piperidinylmethyl)phenyl]3-butenylamine at 10.15 mmHg
I got it.

NMR (CD CQs, δ): 1.1-1.9 (6
H.

multiplet), 2.2 to 2.6 (6H, multiplet), 2゜6
~3.0 (2H, multiplet), 3.45 (2H.

multiplet), 5.2 to 6.0 (IH, multiplet), 6.5+,
(IH, doublet, J = 12Hz), 7.0-7°4 (4H, multiplet).

Production Example 8 1) In i) of Production Example 7, 5-7thaliminopentyltriphenylphosphonium bromide 4 was used instead of 3-phthaliminopropyltriphenylphosphonium bromide.
．． In the same manner using 6 g, N-[6-[3-(1
1.5 g of -piperidinylmethyl)phenyl]-cis-5-hexenyl]7talimide were obtained as an oil.

IR (liquid film, cm-'): 1765.1700°NMR (CDCI231.9): 1.1-2.0
(IOH.

multiplet), 2.1 to 2.6 (6H, multiplet), 3゜4
4 (2H, -multiplet), 3.5-3.9 (2H, multiplet), 5.2-6.0 (IH, multiplet), 6.40 (IH
1 doublet, J-12Hz), 7-0~B.

Q (8H, multiplet).

ii) According to the manufacturing method A), N-[4
-[3-(1-piperidinylmethyl)phenoxy]ci
N-[6-[ instead of s-2-butenyl]phthalimide
3-(1-piperidinylmethyl)phenyl]-cis-
cis-6-[3-(1-piperidinylmethyl)phenyl]-5-hexenylamine 1. Og was obtained as an extract.

NMRCCDCQ, 1.9): 1.1-1.9 (I
Oh.

multiplet), 2.0 to 3.0 (8H, multiplet), 3゜4
4 (2H, -11 line), 5.2 to 6.0 (I H
, multiplet), 6.40 (IH, doublet, J=12Hz)
, 7.0-7.9 (4H1 multiplet).

Production Example 9 Method A i) 2.1 g of 60% sodium hydride was mixed with 15 mQ of tetrahydro7ran and 15 mQ of dry dimethyl sulfoxide.
10.1 g of oxycarbonylethyltriphenylphosphonium chloride is added little by little while cooling with water and stirring. After stirring for 10 minutes under water cooling, 3-(1
A solution of 5.0 g of -piperidinylmethyl)benzaldehyde in 5 mQ of tetrahydrofuran is added and stirred at room temperature for 4 hours. After adding a small amount of water, tetrahydrofuran was distilled off under reduced pressure, 30+++Q of ice water was added, and the mixture was shaken with ether. Take the aqueous layer and distill off most of the water under reduced pressure. Add ether to the residue, shake it, let it stand, and remove the ether layer by decant. After repeating this operation several times, methanol 201Tla is added, and then 25 mff of 20% hydrochloric acid solution in ether is added. After filtering off the precipitated insoluble matter, the mixture is heated to distill off the ether and refluxed for 10 minutes. Methanol is distilled off under reduced pressure, ice water is added, the mixture is made alkaline with potassium carbonate, and extracted with ether. After washing with water,
It is dried with Glauber's salt and the solvent is distilled off. The residue was analyzed by TLC (7
7%: opening solvent; chloroform:methanol (9:1)
to give methyl 3-[3-(1-1:'peridinylmethyl)phenyl]-trans-2-butenoate 3
．． Obtained 0 g as an oil.

IR (liquid film, Cm-'): 1735° NMRCCDCQs, δ): 1.2-1.9 (6H.

multiplet), 2.2 to 2.6 (4H, multiplet), 3゜1
~3.4 (2N, multiplet), 3.49 (2H.

multiplet), 3.68 (3H, -multiplet), 6.0-7°0 (2H, multiplet), 7.1-7.5 (4H, multiplet).

li) Suspend 1.2 g of lithium aluminum hydride in 50 mM of dry tetrahydrofuran, and add methyl 3-[3-(1-piperidinylmethyl)phenyl]-trans-2-butenoate 3 under water cooling and stirring. .0
g of dry tetrahydro 7 run lQm12 solution is added dropwise. Ice water was added dropwise to the reaction mixture for 1 hour under water cooling, 3 g of sodium chloride was added, and insoluble matter was filtered off.

The solvent was distilled off from the filtrate under reduced pressure, and the residue was purified with TLC (developing solvent: chloroform methanol (9:1) to give 4-[3-(1-piperidinylmethyl)phenyl]-trans -3-futhynyl alcohol 2.5g
was obtained as an oil.

IR (liquid film, cm-'): 3330°N MR (CD CQs, δ): 1.2-1.9 (6
H1 multiplet), 2.1 to 2.7 (6H, multiplet), 3
゜41 (2H, - doublet), 3.68 (2H, triplet, J=6Hz), 5.7-6.7 (2H, multiplet),
7.0-7.9 (4H, multiplet).

in) 2.5 g of 4-[3-(1-piperidinylmethyl)phenyl]-trans-3-butenyl alcohol are refluxed with thionyl chloride for 91 hours. Thionyl chloride is distilled off under reduced pressure, ice water is added, the mixture is made alkaline with potassium carbonate, and then extracted with ether. After washing with water, drying with Glauber's salt and distilling off the solvent, ■-Chloro 4- [3
-(1-biperidinylmethyl)phenyl] -tran
1.75 g of s-3-butene was obtained as an oil.

NMR (CD CQs, δ): 1.1-1.9 (6
H.

multiplet), 2.1 to 2.9 (6H, multiplet), 3゜4
3 (2H1-multiplet), 3.4-3.8 (2H1-multiplet), 5.6-6.7 (2H, multiplet), 7.0-7.
5 (4H, multiplet).

1v) 1-chloro-4-[3-(1-piperidinylmethyl)phenyl]-trans-3-butene 1°7g
, 5.1 g of potassium phthalimide and 7 mQ of dimethyl sulfoxide L are heated on a steam bard for 30 minutes, then cooled, ice water is added, and extracted with ether. After washing with water, 10
% salt water, the aqueous layer was collected, made alkaline with ammonia, and then extracted with chloroform. After washing with water, it is dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue was analyzed by TLC (developing solvent: chloroform:methanol (19:
1)) to obtain 8 g of N-[4-[3-(1-piperidinylmethyl)phenyl]-trans-3-7'tenyl]phthalimide O, as an oil.

IR (liquid film, Cm-'): 1770.1710°NMRCCDCQ3, δ): 1.1-1.9 (6H1
multiplet), 2.1 to 2.9 (6H, multiplet), 3゜4
2 (2H, -multiplet), 3.5-4.0 (2H, multiplet), 5.6-6.7 (2H, multiplet), 7.0-7.
4 (4H, multiplet), 7.5-8.0 (4H.

multiplet).

V) In method A i) of Production Example 1, N-[4-[3-(
N-[4-[3-(1-piperidinylmethyl)phenoxy]cis-2-butenyl 1-phthalimide instead of
piperidinylmethyl)phenyl] -trans -3
The same procedure was carried out using 2.6 g of -butenyl 1-phthalimide to obtain 1.3 g of murans-4-[3-(1-piperidinylmethyl)phenyl]-3-butenylamine as an oil.

NMR (CD CQl, δ): 1.1-1.9 (6
H1 multiplet), 2.1 to 3.0 (8H1 multiplet), 3
°43 (2H, -multiplet), 5.6-6.7 (2H, multiplet), 7.0-7.5 (4H, multiplet).

Method B i) Suspend 60% sodium hydride in 37 mg of a mixture of dry tetrahydro 7rane and dry dimethyl sulfoxide (1:l), and add 15.8 g of oxycarbonylethyltriphenylphosphonium chloride at once while stirring in ice water. . After stirring for 20 minutes under water cooling, a solution of 7.5 g of 3-(ethoxycarbonyl)benzaldehyde in dry tetrahydrofuran (7.5 ma) is added all at once. After stirring for 2 minutes under ice cooling, the mixture is stirred at room temperature for 3 hours. 100m of ice water
+2 and 300 ml of ether were added, shaken, the aqueous layer was taken, and the mixture was made acidic with hydrochloric acid, followed by extraction with ether. After washing with water, the ether was distilled off and the resulting residue was dissolved in 80 mQ of methanol, bubbled with hydrochloric acid gas, and exposed for 30 minutes. Methanol is distilled off under reduced pressure, and ether is added for extraction. 5%
After shaking with an aqueous potassium carbonate solution, the mixture is washed with water, dried over Glauber's salt, and the solvent is distilled off under reduced pressure. The obtained crude oil was purified by column chromatography (wakogel-C-200, chloroform emitted) and then distilled under reduced pressure to obtain a boiling point of 150~
4.5 g of methyl 3-[3-(ethoxycarbonyl)phenyl]-trans-2-butenoate with 154'O/Q and 6 mmHg was obtained.

IR (liquid film, Cm-'): 1720°NMRCCDC
Q,, δ): 1.37 (3H, triple line), 3.0~
3.5 (2H, multiplet), 3.70 (3H1-multiplet)
, 3.39 (2H, -multiplet), 4.45 (2H, quartet, J=7Hz), 6.0-7.0 (2H, multiplet), 7.1-8.3 (4H, multiplet) .

multiplet).

ii) 10 g of lithium aluminum hydride is suspended in dry tetrahydro7ran 500+n12;
3-[3-(ethoxycarbonyl)phenyl]tran
A solution of 25 g of methyl s-2-butenoate in dry tetrahydrofuran (l OOm12) was cooled with water and stirred at an internal temperature of 10°C.
Drop below. After reacting for 1 hour at room temperature, 50 mQ of water was added dropwise to the mixture under ice-cooling and stirring at an internal temperature of 10°C or higher.

After stirring at room temperature for 30 minutes, 50 g of sodium chloride was added and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was distilled under reduced pressure to obtain a boiling point of 167-170°C/lmm.
Hg 4-(3-hydroxymethylphenyl)-t
14 g of rans-3-futhynyl alcohol was obtained.

IR (liquid film, Cm-'): 3320° NMR (CDC (23, δ): 2.37 (2H, quartet, J-7H2), 3.57 (2H, triplet, J
=7Hz), 4.50 (2H, - double line), 5.7~6
°7 (2H, multiplet), 6.9-7.5 (4H, multiplet).

1ii) 4-(3-hydroxymethylphenyl)-t
14 g of rans-3-butenyl alcohol are added portionwise to thionyl chloride 50+n+2 at room temperature.

After reacting for 1 hour under reflux, thionyl chloride was distilled off under reduced pressure. The residue was dissolved in ether, shaken twice with 5% potassium carbonate aqueous solution, washed with water, dried over Glauber's salt, and the solvent was distilled off. The residue was purified by column chromatography (wakogel
-c-200, chloroform effluent) and purified with l
-chloro-4-(3-chloromethylphenyl) -tr
15.5 g of ans-3-butene were obtained as an oil.

When this compound is distilled under reduced pressure, its boiling point is 123-126℃1
Although it is distilled at 0.6 mmHg, the decomposition is severe and the yield is low.

NMR(CD CQ s, δ)22.56(2H,
quartet, J=7Hz), 3.59 (2H, triplet,
J-7Hz), 4.54 (2H, - double line), 5.7
~6°7 (2H, multiplet), 7.0~7.5 (4H,
multiplet).

1v) 1-chloro-4-(3-chloromethylphenyl)
A mixture of 4,1 g of -trans-3-butene, 3.3 g of piperidine, and 41 mQ of tetrahydro7rane is heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, ether was added, and the precipitated insoluble matter was filtered off. The filtrate is extracted with 10% hydrochloric acid, the aqueous layer is collected, made alkaline with potassium carbonate, and then extracted with chloroform. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and l-chloro-
[3-(1-piperidinylmethyl)phenyl] -t
3.7 g of rans-3-7'ten was obtained as an oil. This compound was completely identical to the compound obtained in Production Example 9, Method A 1ii).

Preparation Example 10 To 0.71 g of 6% sodium hydride is suspended in 6% dry dimethyl sulfoxide, 2.0 g of 3-hydroxymethylphenol is added in solid form little by little. After stirring at room temperature for 20 minutes, N-(4-chloro-cis
4.17 g of -2-butenyl)7talimide was added and reacted at room temperature for 2 hours.

After the reaction, add ice water and extract with ether. After washing with water, it is dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was extracted several times with 50 m<+ of hot hexane, allowed to stand, and the hexane layer was removed by decantation to obtain 3.3 g of N-[4-(3-hydroxymethylphenoxy)-cis-2-butenyl]7-talimide. was obtained as an oil.

IR (liquid film, cm-1: 3420.1775.17
00°NMRCCDCQ3, δ): 4. O~4.6 (2H1
multiplet), 4.62 (2H, - multiplet), 4.6~5
°0 (2H, multiplet), 5.3 to 6-2 (2H, multiplet), 6.7 to 7.4 (4H, multiplet), 7.5 to 8
．． 0 (4H, multiplet).

ii) N-[4-(3-hydroxymethylphenoxy)-cis-2-butenyl] 7-talimide 3°3g
and 21 ml (l) of thionyl chloride are reacted under reflux for 1 hour. Thionyl chloride is distilled off under reduced pressure, the residue is dissolved in ether, shaken three times with 5% potassium carbonate aqueous solution, washed with water, and dried with Glauber's salt. and evaporate the solvent to give N-[4
-(3-chloromethylphenoxy)-cis-2-butenyl] 3.4 g of 7-talimide were obtained as an oil.

IR (liquid film, cm-'): 1770.1715°N
MR (CDCQ, δ) = 4.0 to 4.6 (2H.

multiplet), 4.52 (2H, -multiplet), 4.6~5°0 (2H, multiplet), 5.3~6.2 (2H, multiplet), 6.7~7.4 (4H, multiplet), 7.5-8.
0 (4H, multiplet).

1n) N-[4-(3-chloromethylphenoxy)-c
is-2-butenyl] 2.4 g of phthalimide and 3-
1.42 g of hydroxypiperidine is reacted in 20 mQ of tetrahydro7ran under reflux for 1 hour. After cooling, 20 mQ of ether was added and insoluble matter was filtered off. The ether layer was washed with water and then extracted with 10% hydrochloric acid.

The aqueous layer is collected, made alkaline with ammonia, and then extracted with chloroform. After washing with water, drying over anhydrous magnesium sulfate and distilling off the solvent, N-[4-[3-(3-hydroxy-1-piperidinylmethyl)phenoxy]-cis
1.2 g of -2-butenyl]phthalimide were obtained as an oil.

IR (liquid film, cm-1: 3440.1767.170
5°NMRCCDC (As, δ): 1.1-1.9 (4H.

multiplet), 2.2 to 2.8 (4H, multiplet), 3°4
9 (2H, -multiplet), 3.6-4.0 (IH, multiplet), 4.2-4.6 (2H1 multiplet), 4.6-5.
0 (2H, multiplet), 5.3-6.1 (2H.

multiplet), 6.7 to 7.4 (4H, multiplet), 7°5
~8.0 (4H, multiplet).

iv) In method A i) of Production Example 1, N-[4-[
3-(1-piperidinylmethyl)phenoxy]cis-
2-butenyl]7thalimide instead of N-[4-[3-
(3-hydroxy-1-piperidinylmethyl)phenoxyE-cis-2-7'tenyl]phthalimide 1
．． In the same manner using 2g, cis-4-[3-(
0.7 g of 3-hydroxy-1-piperidinylmethyl)phenoxy-2-butenylamine was obtained as an oil.

NMR(CDC(As, δ): 1.2-1.9(
4H.

multiplet), 2.0 to 2.6 (4H, multiplet), 3°3
~3.6 (2H, multiplet), 3.46 (2H.

multiplet), 3.5-4.0 (LH, multiplet), 4.4-4
．． 8 (2H, multiplet), 5.3-6.1 (2H.

multiplet), 6.6-7.4 (4H, multiplet).

Production example 11 N-(3-bromopropyl)phthalimide 100g1
Triphenylphosphine 100g and benzene 200m
The mixture of ff is refluxed overnight. The precipitated crystals were collected by filtration and dried to obtain 128 g of 3-phthaliminopropyltriphenylphosphonium bromide having a melting point of 216-217°C.

IR (KBr, cm-'): 3400.17
70.1700゜NMRCCDCQ31 δ): 1.8~2.5 (2
)(.

multiplet), 3.5~4.3 (4H1 multiplet), 7°5~
8.1 (19H, multiplet).

Production Example 12 5.0 g of N-(5-bromopentyl)phthalimide and 4.4 g of triphenylphosphine were heated at 140 to 145°C.
Heat for 30 minutes to react. After the reaction, acetone is added to make a solution, then ether is added and the separated oil is removed by decantation. After treating with ether and repeating decantation several times, the solvent was thoroughly distilled off using a vacuum pump to obtain amorphous and hygroscopic 5-phthaliminopentyltriethylphosphonium bromide 4.
゜6g was obtained.

IR(KBrXcm-'): 3400.176
0.1700°NMRCCDCQs, δ): 1.4-2.0 (6H.

multiplet), 3.2~4.0 (4H, multiplet), 7°4~
8.1 (19H, multiplet).

Preparation Example 13 2.8 g of 60% sodium hydride are suspended in 20 m<2 of dry dimethyl sulfoxide and log phthalimide is added in solid form little by little. After stirring at room temperature for 20 minutes, the solution was diluted with 1,4-dichloro-cis-2-
16.8 g of butene 16 ml of dry dimethyl sulfoxide
2 solution at room temperature.

After leaving it at room temperature for 2 hours, put it in ice water and add 5 ml of n-hexane.
Add 0 mQ, stir, and leave to stand. The precipitated crystals are taken out of the furnace and washed with water, then washed with n-hexane, and the wet crystals are extracted six times with 50 mff of ether. After drying the ether layer with Glauber's salt, the solvent was distilled off.

The crude crystals were recrystallized from n-hexane to a melting point of 66°9~
5.0 g of N-[4-chloro-cis-2-butenyl)phthalimide was obtained at 68.9°C.

I R (KBr, 'cnr'''): 1760.17
00°NMR (CD CQs, J): 3.9~4
．． 6 (4H.

multiplet), 5.4 to 6.1 (2N, multiplet), 7゜5
~8.0 (4H, multiplet).

Production Example I4 In Production Example 13, 1,4-diC7Cl -cis
-1,4-dichloro-trans instead of 2-butene
The crude crystals obtained in the same manner using 27.2 g of -2-butene were recrystallized from acetone-n-hexane,
N-(4-chloro-t) with a melting point of 104.5-105.7°C
13.2 g of rans-2-butenyl)phthalimide was obtained.

IR (KBr, cm-”): 1765.17
05°NMR (CD(1,, δ): 3.9-4.6 (
4H.

multiplet), 5.5 to 6.2 (2H, multiplet), 7゜5
~8.0 (4H, multiplet).

An example of manufacturing a drug containing the compound of the present invention is as follows.

Example A: Capsules - Example formulations for capsules containing 50 mg and 100 mg of active ingredient per capsule are as follows.

Formulation 1-a 50mg Capsule Active Ingredient Powder Lactose Magnesium Aluminate Metasilicate Formulation 1-bloomg Capsule mg/Capsule Active Ingredient 100 Powdered Lactose 200 Magnesium Aluminate Metasilicate 10000mg The manufacturing method is as follows.

The active ingredient is added to a mixed powder of powdered lactose and magnesium aluminate metasilicate and kneaded. Let this dry,
After grinding well, fill it 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 make the whole volume IIIQ.

The manufacturing method is as follows.

Methyl p-hydroxybenzoate is dissolved in distilled water for injection with stirring, and then the active ingredient and sodium chloride are added, and then dilute hydrochloric acid is added to adjust the pH to around 7.0. This solution is sterile-filtered using a membrane filter (0.2 microns), filled into ampoules, and sealed.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) In the formula, Y is 1- which may be substituted with a hydroxyl group.
represents a pyrrolidinyl, 1-piperidinyl or 1-perhydroazepinyl group, R_1 represents a hydrogen atom or a lower alkyl group, Z represents =N-CN or =CH-NH_2, R_2 represents a lower alkyl group, m represents 0 or 1, and n represents an integer from 1 to 4. However, the group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is the meta- for the group ▲There are mathematical formulas, chemical formulas, tables, etc.▼
or an aminoalkylbenzene derivative or a salt thereof, which is bonded to the para-position.