JPH0380791B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel substituted benzylamine derivative, and more specifically, the present invention relates to a novel substituted benzylamine derivative, more specifically, it has the following 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 further represent hydroxy, lower alkanoyloxy, lower alkoxy, or 4 which may be substituted with a lower alkyl group
~ forms an 8-membered heterocycle; R ₃ represents a hydrogen atom or a lower alkyl group; Y is the formula

【formula】

【Formula】Also teeth

Represents a group of [Formula], where R ₄ represents a hydrogen atom, lower alkyl, hydroxy lower alkyl or lower alkanoyloxy lower alkyl group, R ₅ represents a group of the formula

Group of [Formula] [where R ₈ represents a hydrogen atom, R ₉ represents a hydrogen atom or a group of the formula -COR ₁₀
(R ₁₀ is a lower alkyl or hydroxy lower alkyl group), R ₆ is a hydrogen atom, A is a lower alkylene group, R ₇ is a pyridyl group, and B is a hydroxy group. or expression

A group of [Formula], where R ₁₄ and R ₁₅ each independently represent a hydrogen atom, lower alkyl, pyridyl lower alkyl, or hydroxy lower alkyl group, p represents 1 or 2; m is 0 or 1 and n represents an integer of 1 to 4, and relates to a compound which is a substituted benzylamine derivative or a salt thereof. The compound of the above formula () or a salt thereof exhibits an excellent gastric acid secretion suppressing effect and is useful as an active ingredient of an anti-ulcer agent. 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, and several proposals have been made [for example, Japanese Patent Publication No. 53-24422, Japanese Patent Publication No. 1309-1983, 53-18557, JP 55-85573, JP 56-40675
(See Japanese Special Publication No. 55-500898, etc.) The compound of the above formula () proposed by the present invention is characterized in that it has an unsaturated bond (-CH=CH-) in the fatty chain bonded to the meta-position to the aminoalkyl group of the benzylamine derivative. It is a new compound that has not been described in conventional literature, and it is a histamine compound.
It has an excellent suppressive effect on gastric acid secretion based on H ₂ receptor antagonism, and 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. Therefore, the "lower alkyl group" may be either linear or branched, such as methyl,
Examples include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl groups, etc., and a "lower alkanoyloxy group" is a lower alkylcarbonyloxy group in which the lower alkyl moiety has the above meaning, such as acetyloxy ,
A "lower alkoxy group" includes a propionyloxy group, and a "lower alkoxy group" is a lower alkyloxy group in which the lower alkyl moiety has the above meaning, and examples include methoxy, ethoxy, and propoxy groups. Furthermore, "lower alkylene group" means a divalent group of the above-mentioned "lower alkyl", such as methylene and ethylene groups. The expression "listing two names of substituents" used herein, for example the expression "hydroxy lower alkyl group", is used to mean a lower alkyl group substituted with preferably one hydroxy group, such as hydroxymethyl, hydroxy Ethyl, hydroxypropyl groups, etc. are included. Similarly, the expressions "lower alkanoyloxy lower alkyl group" and "pyridyl lower alkyl group" mean a lower alkyl group substituted with one substituent written in the first half of each group. In the above formula (), the "4- to 8-membered heterocycle" that can be formed when R ₁ and R ₂ are combined with the nitrogen atom to which they are bonded does not contain any heteroatoms other than the nitrogen atom. is desirable and the ring is preferably saturated. Specific examples of such heterocyclic groups include 1-azetidinyl group (

[Formula]), 1-pyrrolidinyl group (pyrrolidinyl group) Same as the group

[Formula]), 1-piperidinyl group (same as piperidino group,

[Formula]), 1-perhydroazepinyl group (

[Formula]) and 1-perhydroazo Cynyl group (

[Formula]) can be mentioned. These nitrogen-containing heterocyclic groups may further have a substituent, and examples of such substituents include a hydroxyl group, a lower alkanoyloxy group such as an acetyloxy group, a lower alkoxy group such as a methoxy or ethoxy group, a lower Mention may be made of alkyl radicals, especially methyl radicals, and the heterocycle can be monosubstituted by these radicals. Therefore, specific examples of substituted nitrogen-containing heterocyclic groups include:

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

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

Suitable as [formula] In the group,

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

[Formula] etc. are included Among them, especially

【formula】

【formula】

【formula】

[Formula] is preferred. 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] teeth,

【formula】

【formula】

【formula】

[Formula] is mentioned. Note that in the above formula (), m is 0 or 1 and n is an integer of 1 to 4, but it is desirable that the sum of both (m+n) is within the range of 2 to 4. In addition, in formula (), the hydrogen atoms present on each carbon atom of the double bond are mutually cis

[Formula] or transformer

[Formula] may have any configuration. Representative examples of the compound of formula () provided by the present invention include the following in addition to those listed in the Examples below. 1-Methyl- ^N5- [4-[3-(1-pyrrolidinylmethyl)phenoxy]-cis-2-butenyl]-
1H-1,2,4-triazole-3,5-diamine, 1-(2-hydroxyethyl) ^-N5- [4-[3
-[1-pyrrolidinylmethyl)phenoxy]-
trans-2 ^- butenyl]-1H-1,2,4-triazole-3,5-diamine, N5-[4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl ]−1H−
1,2,4-triazole-3,5-diamine, 1-methyl- ^N5- [4-[3-[1-(1-piperidinyl)ethyl]phenoxy]-cis-2-butenyl]-1H-1 ,2,4-triazole-3,5
-diamine, 1-methyl- ^N5- [4-[3-(3-hydroxy-1-pepyridinylmethyl)phenoxy]-cis-
2-butenyl]-1H-1,2,4-triazole-3,5-diamine, 1-methyl- ^N5- [5-[3-(1-piperidinylmethyl)phenoxy]-cis-3-pentenyl ]
-1H-1,2,4-triazole-3,5-diamine, 1-methyl-N ⁵ -[4-[3-[1-(1-pyrrolidinyl)ethyl]phenyl]-cis-3-butenyl]- 1H-1,2,4-triazole-3,5-
Diamine, N-[1-methyl-5-[4-[3-(1-perhydroazepinylmethyl)phenoxy]-trans-2
-butenylamino]-1H-1,2,4-triazol-3-yl]acetamide, 2-[4-[3-(1-piperidinylmethyl)phenyl]-cis-3-butenylamino]-5-(3 −
pyridylmethyl)-4-pyrimidone, 1,1-dioxidized 3-methylamino-4-[4-
[3-(1-pyrrolidinylmethyl)phenoxy]-
trans-2-butenylamino]-1,2,5-thiadiazole, 1,1-dioxidized 3-ethylamino-4-[4-
[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenylamino]-1,2,5
-thiadiazole, 1-oxidized-3-(2-hydroxyethylamino)
-4-[4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenylamino]-1,2,
5-thiadiazole, 1,1-dioxidized 3-methylamino-4-[4-
[3-(1-piperidinylmethyl)phenyl]-cis
-3-butenylamino]-1,2,5-thiadiazole, etc. According to the invention, salts of the compounds of formula () above are also provided. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid, propionic acid, lactic acid, citric acid,
Examples include acid addition salts with organic acids such as tartaric acid and p-toluenesulfonic acid, among which pharmacologically acceptable salts are suitable. According to the present invention, the novel compound represented by the formula () or a salt thereof can be produced by any of the methods described below depending on the type of substituent Y. In addition, in a certain reaction described below, if the starting material contains a reactive substituent (e.g., hydroxy, amino group, etc.), the substituent may be
Reactions can be carried out in a protected state. The protecting group varies depending on the type of reaction and the type of reactive substituent, but can be appropriately selected from, for example, phthaloyl, formyl, acetyl, benzoyl, benzyl, benzyloxycarbonyl, tetrahydropyranyl, acetal group, etc. can.
These protective groups can be removed by conventional methods such as hydrazinolysis or aminolysis (for phthaloyl groups, etc.), hydrolysis (for formyl, acetyl, benzoyl, tetrahydropyranyl, acetal groups, etc.), hydrogenolysis (for benzyl, In the case of a benzyloxycarbonyl group, etc.), etc. [A] Y is the formula

When representing a group of [formula]: [a-1] When R ₄ represents a group other than a lower alkanoyloxy lower alkyl group, the compound of the above formula () is (i) the following formula: In the formula, R ₁ , R ₂ , R ₃ , m and n have the above-mentioned meanings, and a compound of the formula or a salt thereof; In the formula, L ₁ represents a leaving group such as a lower alkylthio group, and V ₁ is =NCOR ₅ ' or =
Representing NCN (where R ₅ ' has the same meaning as R ₅ or is a group that can be converted to R ₅ under the present reaction conditions), the following formula obtained by reacting with a compound of In the formula, R ₁ , R ₂ , R ₃ , V ₁ , L ₁ , m and n
has the meaning as defined above, or a salt thereof is reacted with a compound of the formula R ₄ -NH-NH ₂ ...(V) where R ₄ has the meaning defined above; or (ii) The following formula In the formula, R ₁ , R ₂ , R ₃ , R ₄ , V ₁ , m and n
has the meaning given above, V ₂ is benzylidene,
It can be produced by treating a compound or a salt thereof representing a protecting group such as isopropylidene in the presence of an acid. In the above reaction (i), the reaction between the compound of formula () or a salt thereof and the compound of formula () is usually carried out in a suitable inert solvent, for example, water; alcohols such as methanol, ethanol, butanol; dimethyl The reaction is carried out in amides such as formamide and dimethylacetamide; ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform, 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 about 0°C.
to the reflux temperature of the reaction mixture, preferably about 0
It is advantageous to carry out the reaction at a temperature within the range of .degree. C. to room temperature, and normal pressure is sufficient as the reaction pressure, but the reaction may be carried out under reduced or increased pressure if necessary. Under such reaction conditions, the reaction can be completed in about 30 minutes to about 48 hours. The ratio of the compound of formula () to the compound of formula () or its salt in this reaction is also not critical and can be varied widely depending on the reaction conditions used, but in general, the compound of formula () or Formula () per mole of its salt
of the compound is 1 to 1.5 mol, preferably 1 to 1.2 mol
It is appropriate to use it within a molar range. Thus, a compound of formula () is obtained, which compound or a salt thereof is then converted to formula ()
can be converted into the initial compound by reacting with a compound or a salt thereof. The reaction of a compound of formula () or a salt thereof with a compound of formula () or a salt thereof is usually carried out using a suitable inert solvent, for example, an alcohol such as methanol, ethanol, or isopropanol;
The reaction can be carried out in aromatic hydrocarbons such as toluene and xylene; nitriles such as acetonitrile; tetrahydrofuran; ethers such as dioxane; and the like. The reaction temperature and pressure are not critical and can be varied over a wide range;
Generally, the reaction temperature is within the range of room temperature to the reflux temperature of the reaction mixture, preferably 40°C to the reflux temperature of the reaction mixture, and normal pressure is sufficient, but reduced pressure or increased pressure may be used if necessary. . The ratio of the compound of formula () or its salt to the compound of formula () or its salt is also not critical and can be varied widely depending on the reaction conditions used, etc.; It is advantageous to use the compound of formula () or its salt in an amount of 1 to 5 mol, preferably 1 to 2 mol, per mol of the compound of formula () or its salt. As a result, the following formula (-a-
1) In the formula, R ₁ , R ₂ , R ₃ , m and n have the above-mentioned meanings, R ₄₁ has the same meaning as R ₄ except for the lower alkanoyloxy lower alkyl group, and R ₅₁ has the same meaning as R 4 A compound or a salt thereof having the same meaning as ₅ is obtained in good yield. In addition, in the above reaction, the following formula is temporarily used as an intermediate. In the formula, R ₁ , R ₂ , R ₃ , R ₄ , V ₁ , m and n have the above-mentioned meanings. A compound of formula (-a-1 ) can be converted into compounds. In the reaction (ii), the treatment of the compound of the formula () or a salt thereof in the presence of an acid is usually carried out using water; ketones such as acetone and methyl ethyl ketone; alcohols such as methanol and ethanol; and nitriles such as acetonitrile. and mixtures thereof. Although the reaction temperature and pressure are not critical and can be varied over a wide range, generally the reaction temperature is within the range of 0°C to the reflux temperature of the reaction mixture, preferably 15° to 50°C, and the reaction pressure is sufficient at normal pressure. However, reduced pressure or increased pressure may be used if necessary. Under these conditions, the reaction can be completed in about 30 minutes to 10 hours. Suitable acids used in this reaction include, for example, hydrochloric acid, sulfuric acid, perchloric acid, etc.
It is advantageous to use these acids in an amount of about 1 to 5 moles per mole of the compound of formula (). Thus, the desired formula (-a-
The compound 1) or its salt is obtained. In addition, in this reaction, the protecting group V ₂
A compound of formula (') is produced from which is eliminated, but it is not necessary to isolate this compound as well. Furthermore, the compound of the formula () used as a starting material in the above reaction is a novel compound that has not been described in any conventional literature, and can be produced by the method described below. On the other hand, the compound of the formula () or a salt thereof, which is the starting material in the reaction (ii), is a compound of the formula () or a salt thereof of the following formula: In the formula, R ₄ , L ₁ , V ₁ and V ₂ have the above-mentioned meanings, or the compound of the formula () or a salt thereof is reacted with the compound of the following formula R ₄ -NH -N=V ₂ ...(V') In the formula, R ₄ and V ₂ have the above-mentioned meanings. It can be produced by reacting with a compound or a salt thereof. The reaction of the compound of formula () or its salt with the compound of formula () or its salt may be carried out in the absence of a solvent or in a suitable inert solvent, such as water; alcohols such as methanol, ethanol, and isopropanol; toluene, xylene. The reaction can be carried out in aromatic hydrocarbons such as; halogenated hydrocarbons such as chloroform; ethers such as tetrahydrofuran and dioxane; nitrites such as acetonitrile. 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 room temperature to the reflux temperature of the reaction mixture, preferably 50° to the reflux temperature of the reaction mixture, and the reaction pressure is sufficient at normal pressure. However, reduced pressure or increased pressure may be used if necessary. Under these conditions the reaction can be completed in about 30 minutes to 48 hours. The ratio of the compound of formula () or its salt 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 compound of formula () or its salt is used. or formula () per mole of its salt
or a salt thereof in a proportion of 1 to 2 mol, preferably 1 to 1.5 mol. Compound of formula () or its salt and formula (′)
The reaction with the compound of formula () or its salt can be carried out in the same manner as described above for the reaction of the compound of formula () or its salt with the compound of formula () or its salt in reaction (i). . In this way, the compound of the formula () or a salt thereof is produced. Furthermore, other raw materials of the formula (),
The compounds (), (') and () are described, for example, in the above-mentioned JP-A-55-85573, or can be produced according to the methods described therein. [a-2] The compound of the above formula () when R ₄ represents a lower alkanoyloxy lower alkyl group,
It can be produced by reacting a compound of the above formula () in which R ₄ represents a hydroxy lower alkyl group with a lower alkanoic acid or a reactive derivative thereof. This reaction is a so-called esterification reaction, and follows a normal esterification reaction, for example,
This can be carried out by treatment with lower alkanoic anhydride under heating. [a-4] R ₅ is the formula

The above formula () represents a group of [Formula] and R ₉ represents a group of formula -COR ₁₀
The compounds can also be prepared by reacting a compound of the above formula () in which R ₅ represents a group of the formula -NHR ₈ with a carboxylic acid of the formula R ₁₀ COOH or a reactive derivative thereof. This reaction is a so-called amidation reaction, and can be carried out according to a normal amidation reaction. Reactive derivatives of carboxylic acids to be used include acid halides, acid anhydrides, etc., and the reaction is carried out, for example, in the absence of a solvent or in a suitable inert solvent such as pyridine, triethylamine, tetrahydrofuran, etc. at 0°C or the reaction mixture. It can be carried out within the range of reflux temperature. Thus, by any of the methods [a-1] to [a-4] above, the desired formula (-
a) In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m and n have the above-mentioned meanings, or a salt thereof can be obtained in good yield. In addition, the compound of the above formula (-a) or a salt thereof of the present invention can also be synthesized by a method known per se other than the method described above. Regarding their synthesis methods, for example, the above-mentioned Japanese Patent Application Laid-Open No. 55
Examples include a method similar to the method described in Publication No. -85573 and the like. [B] Y is the formula

The compound of the above formula () when representing a group of [Formula] is the compound of the above formula (), that is, the formula In the formula, R ₁ , R ₂ , R ₃ , m and n have the above-mentioned meanings, and a compound of the formula or a salt thereof; In the formula, L ₂ is a halogen atom, nitroamino,
It can be prepared by reacting the compounds of the following, which represent a leaving group such as a lower alkylthio or benzylthio group, and R ₆ , R ₇ and A have the meanings given above. The reaction of the compound of formula () or a salt thereof with the compound of formula () may be carried out in the absence of a solvent or in an inert solvent such as alcohols such as ethanol and isopropanol; aromatic amines such as pyridine; dimethylformamide, dimethyl Amides such as acetamide; tetrahydrofuran,
It can be carried out in ethers such as dioxane; halogenated hydrocarbons such as chloroform, etc. Although the reaction temperature and pressure are not critical and can be varied over a wide range, the reaction temperature is generally room temperature to the reflux temperature of the reaction mixture, preferably the reflux temperature of the reaction mixture, and the pressure is preferably normal pressure, but may be adjusted as necessary. Reduced or increased pressure may be used. Under such reaction conditions, the reaction can be completed in about 2 to 48 hours. In the above reaction, the ratio of the compound of formula () to the compound of formula () or its salt is also not critical and can be varied widely depending on the reaction conditions used, but in general
It is advantageous to use the compound of formula () in an amount of 1 to 5 mol, preferably 1 to 2.5 mol, per mol of the compound or salt thereof. Thus, the desired formula (-b) In the formula, R ₁ , R ₂ , R ₃ , R ₆ , R ₇ , A, m and n
has the above-mentioned meaning, or a salt thereof is obtained in good yield. In addition, the compound of formula (), which is one of the raw materials in the above reaction, is
It is described in Japanese Patent No. 500898 or can be produced according to the method described therein. [C] Y is the formula

A place that represents a group of [formula] If: (C-1) B is the formula

The compound of the above formula () when representing a group of [Formula] is: (i) The compound of the above formula (), that is, the formula In the formula, R ₁ , R ₂ , R ₃ , m and n have the above-mentioned meanings, and a compound of the formula or a salt thereof; In the formula, L ₃ represents a leaving group such as a halogen atom, lower alkoxy, phenoxy, lower alkylthio or phenylthio group, and p
has the above meaning, and the following formula obtained by reacting with the compound of In the formula, R ₁ , R ₂ , R ₃ , L ₃ , m, n and p
has the above meaning, a compound or a salt thereof of the formula wherein R ₁₄ and R ₁₅ have the above meanings, or (ii) a compound of the formula () or a salt thereof and a compound of the formula In the formula, L ₃ , R ₁₄ , R ₁₅ and p have the above-mentioned meanings. It can be produced by reacting the following compounds. The reaction of the compound of formula () or its salt with the compound of formula () in reaction (i) above is usually carried out by
The reaction can be carried out in a suitable inert organic solvent, such as alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and dioxane. Reaction temperature and pressure are not critical;
Although the reaction can be varied widely depending on the starting materials used, the type of solvent, etc., it is generally advantageous to carry out the above reaction at a temperature of -20°C to room temperature, preferably 0° to 10°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 10 minutes to 2 hours. The ratio of the compound of formula () to the compound of formula () or its salt is also not critical, but generally the compound of formula () is used from 1 to 1 mole of the compound of formula () or salt thereof. It is suitable to use it in a proportion of 1.5 mol, preferably 1 to 1.1 mol. The reaction of the resulting compound of formula () or a salt thereof with the compound of formula (XI) is usually carried out using a suitable inert solvent, such as alcohols such as methanol and ethanol; ethers such as ethyl ether and tetrahydrofuran; acetonitrile. Nitriles such as; amides such as dimethylformamide and dimethylacetamide; and the like. 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 temperature is 0°C to the reflux temperature of the reaction mixture, preferably room temperature to the reflux temperature of the reaction mixture. The reaction temperature is within the reflux temperature range, and normal pressure is sufficient for the reaction pressure, but reduced pressure or increased pressure may be used as necessary. Under such reaction conditions, the reaction proceeds from about 1 to
It can be finished in 24 hours. The amount of the compound of formula (XI) to be used relative to the compound of formula (X) or its salt is not critical and can be varied widely depending on the reaction conditions used, but in general, the amount of the compound of formula (X) or its salt is 1 to 3 compounds of formula (XI) per mole
It is advantageous to use moles, preferably in the range from 1 to 1.5 moles. In the reaction (ii), the reaction between the compound of () or a salt thereof and the compound of formula (XII) is
The reaction of the compound of formula () or a salt thereof with the compound of formula () in reaction (i) above can be carried out in the same manner as described above. Thus, the desired formula (-c-
1) In the formula, R ₁ , R ₂ , R ₃ , R ₁₄ , R ₁₅ , m, n and p have the above-mentioned meanings. A compound of the following is obtained in a good yield. Further, the compounds of formulas () and (XII) which are raw materials in the above reaction are those described in, for example, the above-mentioned Japanese Patent Application Laid-Open No. 56-40675,
Alternatively, it can be manufactured according to the method described therein. (C-2) The compound of the formula () where B represents a hydroxy group can be produced by reacting the compound of the formula () or a salt thereof with sodium hydroxide or potassium hydroxide. This reaction can be easily achieved, for example, by treating the compound of formula (XI) or a salt thereof with sodium hydroxide or potassium hydroxide at a temperature of about 0°C to room temperature in a solvent such as methanol or ethanol. . Thus, the desired formula (-C-
2) In the formula, R ₁ , R ₂ , R ₃ , m, n and p have the above-mentioned meanings. A compound of the following is obtained in a good yield. The compound of formula () or its salt used as a starting material in the methods [A] to [C] described above is a novel compound as described above, and the compound of formula () when m is 0 A compound of the following formula (-a) In the formula, R ₁ , R ₂ , R ₃ and n have the above-mentioned meanings. For example, the compound of the following formula In the formula, R ₁ , R ₂ and R ₃ have the above meanings, and a compound of the following formula In the formula, X ₁ represents a halogen atom, and n has the above meaning. In the formula, R ₁ , R ₂ , R ₃ and n have the above-mentioned meanings, and the compound can be produced by hydrazinolysis. The reaction between the compound of formula () and the compound of formula () is per se known in Wittig.
The removal of the phthaloyl group from the compound of the above formula () thus obtained can be carried out by hydrazinolysis, which is known per se. In this way, a compound in the above formula (-a) in which the hydrogen atoms of the double bond portion have mutual cis-coordination is obtained. On the other hand, a compound in which the hydrogen atoms of the double bond portions in the above formula (-a) are trans-coordinated with each other can be synthesized, for example, by the route shown in the reaction formula below. In the above formula, R ₁ , R ₂ , R ₃ , X ₁ and n have the above meanings, R ₁₆ represents a lower alkyl group, X ₂ represents a halogen atom, and M ₁ represents a hydrogen atom or an alkali metal atom. represents. In the above reaction formula, the reaction between the compound of formula () and the compound of formula () can be carried out according to the Witschutsch reaction, which is known per se. It is converted into an ester of formula () above by reaction with an alcohol of formula R ₁₆ OH or an ester-forming reactive derivative thereof. The ester of the formula () is then reduced by a method known per se using a complex metal hydride such as lithium aluminum hydride or t-butoxylithium aluminum hydride, and the ester is converted into the ester of the formula (
), and the resulting alcohol of formula () is treated with a halogenating agent such as thionyl halide, sulfuryl halide, phosphorus pentahalide, phosphorus trihalide, etc. to produce the compound of formula () above. The resulting compound of formula () is then reacted with phthalimide or its alkali metal in dimethyl sulfoxide in the presence of an alkali metal hydride when phthalimide is used to produce the compound of formula (XI), which is then reacted with By hydrazinolysis, a trans compound of formula (-a) is obtained. In addition, the compound (trans form) in which R ₃ represents a hydrogen atom in the above formula (-a) can also be synthesized according to the following reaction formula. For details of the reaction conditions, please refer to Method B in Production Example 10 below. In each of the above formulas, R ₁ , R ₂ , R ₁₆ , X ₁ , X ₂ , M ₁ and n have the above-mentioned meanings, and R ₁₇ represents a lower alkyl group. Also, a compound of formula () when m is 1,
That is, the following formula (-b) In the formula, R ₁ , R ₂ , R ₃ and n have the above-mentioned meanings. For example, the compound of the following formula In the formula, M ₂ represents a hydrogen atom or an alkali metal, _and R ₁ , R _{2 and} R ₃ have the above-mentioned meanings _. Q
...() In the formula, X ₃ represents a halogen atom, Q represents a protected amino group, such as a phthalimino group, an acetylamino group, etc., and n has the above meaning. The following formula In the formula, R ₁ , R ₂ , R ₃ , Q and n have the above-mentioned meanings. It can be produced by removing the amino protecting group of the compound. The reaction between the compound of the above formula () and the compound of the formula () can be carried out according to a method known per se (for example, the method described in JP-A-56-7760), or the reaction of the compound of the formula () The amino protecting group can be removed from the compound of formula (-b) by a method known per se, such as hydrazinolysis or mild hydrolysis, to give the target compound of formula (-b). can. In addition, a compound in which R ₃ represents a hydrogen atom in the above formula (-b) can also be synthesized according to the following reaction formula. In each of the above formulas, R ₁ , R ₂ , Q, M ₂ , X ₃ and n have the above-mentioned meanings, and X ₄ represents a halogen atom. In the above reaction formula, the reaction between the compound of formula (XI) and the compound of formula () is carried out in accordance with a method known per se.
) can be carried out in the same manner as described above, and the resulting formula (
Halogenation of the compound XII) can be achieved, for example, by treatment with a halogenating agent such as thionyl halide or hydrohalic acid. The resulting compound of formula () is then reacted with an amine of formula () in the presence of a deoxidizing agent such as triethylamine, sodium hydroxide, etc., and the thus obtained compound of formula (-a) is converted into an amino acid by the method described above. The desired compound of formula (-b-1) can also be obtained by removing the protecting group. The formula () produced by the method described above
The compounds can be converted into corresponding salts if necessary. The salt-forming reaction can be easily carried out by treating the compound of formula () with an inorganic or organic acid as described above, 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 substituted benzylamine derivatives represented by the formula () and salts thereof of the present invention described above have an effect of suppressing gastric acid secretion based on an excellent histamine H ₂ receptor antagonism, and are effective against diseases caused by gastric acid, such as gastric or It is an extremely useful compound in the treatment of duodenal ulcers. The following animal experiments demonstrate that the compound represented by formula () of the present invention has excellent histamine H ₂ receptor antagonism. The compounds of the present invention used in the following animal experiments are represented by the following symbols. Compound A: 1-methyl- ^N5- [4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenyl]-1H-1,2,4-triazole-3,5
-diamine, B:1-methyl- ^N5- [4-[3-(1-piperidinylmethyl)phenyl]-cis-3-butenyl)
-1H-1,2-4,-triazole-3,5-
Diamine, C:1-methyl- ^N5- [4-[3-(1-perhydroazepinylmethyl)phenoxy]-cis-2-
butenyl]-1H-1,2,4-triazole-
3,5-diamine, D:2-[4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenylamino]-5-(3-pyridylmethyl)-4-pyrimidone, E :1,1-dioxidized 3-(4-pyridylmethylamino)-4-[4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenylamino]-1,2,5 -thiadiazole, F: 1,1-dioxidized 3-methylamino-4-[4
-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenylamino]-1,2,5
-thiadiazole, G: 1,1-dioxidized 3-amino-4-[4-[3-
(1-piperidinylmethyl)phenoxy]-
trans-2-butenylamino]-1,2,5-thiadiazole, H:1,1-dioxidized 3-methylamino-4-[4
-[3-(3-hydroxy-1-pepyridinylmethyl)phenoxy]-trans-2-butenylamino]-1,2,5-thiadiazole. (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 each end. 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. The contraction movement of the atrium is controlled by a force-displacement transducer (Force-displacement-).
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.
A dose response curve of histamine was obtained by adding cumulatively into the Magnus tube at concentrations of ×10 ⁻⁸ M to 1×10 ⁻⁴ M. 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 test compound (1×10 ⁻⁵ M)
was added into a Magnus tube, and 20 minutes later, 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 produce a given reaction) The negative logarithm) was calculated. The results are shown in Table 1 below. Table 1 Compound PA ₂ A 6.23 B 6.28 C 6.26 D 6.57 E 6.79 F 6.89 G 6.63 H 6.88 Thus, the compound represented by the formula () of the present invention can be used as an anti-ulcer agent for the treatment of humans and other warm-blooded animals. For treatment, oral or parenteral administration (for example intramuscular, intravenous, subcutaneous, rectal, transdermal, etc.), preferably oral administration is possible. 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 in 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 cis-4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-2-butenylamine (150 mg)
and N-cyano-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioic acid methyl ester (140 mg) in chloroform (3 ml).
The mixture was heated under reflux for 5 hours. The reaction mixture was subjected to TLC [developing solvent: chloroform:methanol (19:1)]
to separate and purify N′-cyano-N-[4-[3-
[1-(1-pyrrolidinyl)ethyl]phenoxy]
-cis-2-butenyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidamide (210 mg) was obtained. NMR (CDCl ₃ , δ): 1.36 (3H, doublet, J = 6.5
Hz), 1.5 to 2.1 (4H, multiplet), 2.1 to 2.7 (4H, multiplet), 3.18 (1H, quartet, J = 6.5Hz), 3.46
(3H, singlet), 4.3~4.8 (4H, multiplet), 5.85
(2H, multiplet), 6.6-7.8 (10H, multiplet). N'-cyano-N-[4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidamide (150 mg ) in acetone (5 ml) with 6N hydrochloric acid (3 ml).
Stir for hours. Water was added to the reaction mixture, washed with ether, made basic with aqueous ammonia, and extracted with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was separated and purified using TLC [developing solvent: chloroform:methanol (9:1)] to obtain 1-methyl- ^N5- [4-[ 3-[1-
(1-pyrrolidinyl)ethyl]phenoxy]-cis
-2-butenyl]-1H-1,2,4-triazole-3,5-diamine (115 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.36 (3H, doublet, J
= 6.5Hz), 1.5 to 2.1 (4H, multiplet), 2.1 to 2.7
(4H, multiplet), 3.15 (1H, quartet, J=6.5
Hz), 3.33 (3H, singlet), 4.00 (2H, multiplet),
4.62 (2H, multiplet), 5.80 (2H, multiplet), 6.6~
7.4 (4H, multiplet). Example 2 trans-4-[3-(1-piperidinylmethyl)
Phenoxy]-2-butenylamine (130 mg) and 2-nitroamino-5-(3-pyridylmethyl)
A mixture of -4-pyrimidine (120 mg) was heated under reflux in ethanol (1 ml) for 16 hours. The reaction mixture was separated and purified by TLC [developing solvent: chloroform:methanol (9:1)] to obtain 2-[4-[3-(1
-piperidinylmethyl)phenoxy]-trans-2
-butenylamino]-5-(3-pyridylmethyl)
-4-pyrimidone (50 mg) was obtained. Melting point 161.5-163.7℃ NMR (CDCl ₃ −D ₂ O, δ): 1.2-1.8 (6H, multiplet), 2.2-2.6 (4H, multiplet), 3.42 (2H, singlet), 3.60 (2H, singlet) line), 3.95 (2H, multiplet line),
4.44 (2H, multiplet), 5.84 (2H, multiplet), 6.6~
7.7 (7H, multiplet), 8.2-8.5 (2H, multiplet). Mass (m/z); 445 (M ⁺ ), 362, 255, 202, 190. Example 3 trans-4-[3-(1-piperidinylmethyl)
A methanol (2 ml) solution of phenoxy]-2-butenylamine (75 mg) was added to a methanol (10 ml) suspension of 1,1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (55 mg) under ice cooling. It was added dropwise into the solution while stirring well. After stirring for 45 minutes under ice cooling,
15N aqueous ammonia (1 ml) was added to the reaction mixture, and the mixture was further stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and subjected to TLC [developing solvent: methanol]
1,1-dioxidized 3-amino-4
-[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]-1,2,
5-thiadiazole (70 mg) was obtained. Melting point 151.8-153.7℃ NMR (CD ₃ OD, δ): 1.3-1.8 (6H, multiplet),
2.3~2.7 (4H, multiplet), 3.53 (2H, singlet),
4.08 (2H, multiplet), 4.57 (2H, multiplet), 5.99
(2H, multiplet), 6.6-7.4 (4H, multiplet). Example 4 In Example 1, cis-4-[3-[1-(1-
cis-4-(3-dimethylaminomethylphenoxy)-2-butenylamine (85
1-methyl-N ⁵
-[4-(3-dimethylaminomethylphenoxy)
-cis-2-butenyl]-1H-1,2,4-triazole-3,5-diamine (90 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 2.24 (6H, singlet),
3.35 (3H, singlet), 3.40 (2H, singlet), 4.02
(2H, multiplet), 4.62 (2H, multiplet), 5.81 (2H,
multiplet), 6.6 to 7.4 (4H, multiplet). Example 5 In Example 1, cis-4-[3-[1-(1-
1-Methyl- N ⁵ -[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenyl]-1H-
1,2,4-triazole-3,5-diamine (105 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3−1.8 (6H, multiplet), 2.2-2.5 (4H, multiplet), 3.33 (3H, singlet), 3.41 (2H, singlet), 3.93 ( 2H, multiplet),
4.46 (2H, multiplet), 5.88 (2H, multiplet), 6.6~
7.4 (4H, multiplet). Mass (m/z): 356 (M ⁺ ), 273, 190, 166. Example 6 In Example 1, cis-4-[3-[1-(1-
1-Methyl- N ⁵ -[4-[3-(1-piperidinylmethyl)
Phenoxy]cis-2-butenyl]-1H-1,2,
4-triazole-3,5-diamine (200mg)
I got it. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.2-2.5 (4H, multiplet), 3.33 (3H, singlet), 3.41 (2H, singlet), 4.00 ( 2H, multiplet),
4.60 (2H, multiplet), 5.83 (2H, multiplet), 6.6~
7.4 (4H, multiplet). Mass (m/z): 356 (M ⁺ ), 273, 190, 166. Example 7 In Example 1, cis-4-[3-[1-(1-
1-Methyl-
N ⁵ -[4-[3-(1-piperidinylmethyl)phenyl]-cis-3-butenyl]-1H-1,2,4-
Triazole-3,5-diamine (270 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.2-2.8 (6H, multiplet), 3.22 (3H, singlet), 3.34 (3H, singlet), 3.40 ( 2H, single line),
5.3-5.9 (1H, multiplet), 6.47 (1H, doublet, J
= 12Hz), 7.0 to 7.4 (4H, multiplet). Example 8 In Example 1, cis-4-[3-[1-(1-
1-Methyl- N ⁵ -[4-[3-(1-piperidinylmethyl)
phenyl]-trans-3-butenyl]-1H-1,
2,4-triazole-3,5-diamine (105
mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.2-2.8 (6H, multiplet), 3.32 (3H, singlet), 3.41 (2H, singlet), 3.41 ( 2H, multiplet),
5.6 to 6.7 (2H, multiplet), 7.0 to 7.4 (4H, multiplet). Mass (m/z): 340 (M ⁺ ), 257, 215, 103, 84. Example 9 In Example 1, cis-4-[3-[1-(1-
cis-4-[3-(3-methyl-1-piperidinylmethyl)phenoxy]-2- instead of pyrrolidinyl)ethyl]phenoxy]-2-butenylamine
Using butenylamine (50 mg), 1-methyl-N ⁵ -[4-[3-(3-methyl-
1-piperidinylmethyl)phenoxy]-cis-2
-butenyl]-1H-1,2,4-triazole-
3,5-diamine (45 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 0.83 (3H, doublet, J
= 5.5Hz), 1.3 to 3.0 (9H, multiplet), 3.34 (3H,
singlet), 3.42 (2H, singlet), 4.00 (2H, multiplet), 4.62 (2H, multiplet), 5.85 (2H, multiplet),
6.6-7.4 (4H, multiplet). Example 10 In Example 1, cis-4-[3-[1-(1-
trans-4-[3-(3-methyl-1-piperidinylmethyl)phenoxy]-2 instead of pyrrolidinyl)ethyl]phenoxy]-2-butenylamine
-butenylamine (60 mg) and 1-methyl-N ⁵ -[4-[3-(3-methyl-
1-piperidinylmethyl)phenoxy]-trans-
2-Butenyl]-1H-1,2,4-triazole-3,5-diamine (64 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 0.83 (3H, doublet, J
= 5.5Hz), 1.3 to 3.0 (9H, multiplet), 3.37 (3H,
singlet), 3.42 (2H, singlet), 3.98 (2H, multiplet), 4.50 (2H, multiplet), 5.92 (2H, multiplet),
6.6-7.4 (4H, multiplet). Example 11 In Example 1, cis-4-[3-[1-(1-
A similar procedure was carried out using cis-4-[3-(1-perhydroazepinylmethyl)phenoxy]-2-butenylamine (55 mg) in place of pyrrolidinyl)ethyl]phenoxy]-2-butenylamine.
-Methyl- ^N5- [4-[3-(1-perhydroazepinylmethyl)phenoxy]-cis-2-butenyl]-1H-1,2,4-triazole-3,5-
Diamine (50mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.4-1.9 (8H, multiplet), 2.4-2.8 (4H, multiplet), 3.33 (3H, singlet), 3.60 (2H, singlet), 4.02 ( 2H, multiplet),
4.60 (2H, multiplet), 5.81 (2H, multiplet), 6.6~
7.4 (4H, multiplet). Example 12 trans-4-[3- in chloroform (5 ml)
A mixture of (1-piperidinylmethyl)phenoxy]-2-butenylamine (1.5 g) and cyanocarbonimidothioic acid dimethyl ester (600 mg) was stirred at room temperature for 12 hours, and the resulting reaction mixture was stirred at room temperature for 12 hours.
Separate and purify with TLC [developing solvent: chloroform:methanol (19:1)] to obtain N′-cyano-N-
[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenyl]carbamiimidothioic acid methyl ester (1.7 g) was obtained. NMR ( _CDCl3 , δ): 1.3-1.8 (6H, multiplet), 2.2
~2.5 (4H, multiplet), 2.52 (3H, singlet), 3.43
(2H, singlet), 4.00 (2H, multiplet), 4.49 (2H,
multiplet), 5.86 (2H, multiplet), 6.6~7.4 (4H,
multiplet). Ethanol (1 ml) and acetonitrile (4
N'-cyano-N-[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenyl]carbamimidothioic acid methyl ester (700 mg) and hydrazine hydrate (0.5 ml) in ml) was stirred at 50°C for 18 hours. After the reaction, the solvent was distilled off, and the resulting residue was separated and purified by TLC [developing solvent: methanol] to obtain N ⁵ -[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2- Butenyl]-1H-1,2,4-triazole-3,5
-diamine (540 mg) was obtained. NMR (CD ₃ OD, δ): 1.3-1.8 (6H, multiplet),
2.2~2.5 (4H, multiplet), 3.40 (2H, singlet),
3.81 (2H, multiplet), 4.47 (2H, multiplet), 5.89
(2H, multiplet), 6.6-7.4 (4H, multiplet). Mass (m/z): 342 (M ⁺ ), 190, 152, 84. Example 13 In Example 12, trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine was replaced with cis-4-[3-(1-piperidinylmethyl)phenoxy]- A similar operation was performed using 2-butenylamine (600 mg) to obtain ^N5- [4-
[3-(1-piperidinylmethyl)phenoxy]-
cis-2-butenyl)-1H-1,2,4-triazole-3,5-diamine (570 mg) was obtained. NMR (CD ₃ OD, δ): 1.3-1.8 (6H, multiplet),
2.2~2.5 (4H, multiplet), 3.40 (2H, singlet),
3.90 (2H, multiplet), 4.62 (2H, multiplet), 5.73
(2H, multiplet), 6.6-7.4 (4H, multiplet). Example 14 In Example 12, instead of hydrazine hydrate, 2
-Hydroxyethylhydrazine (0.8ml) was used in the same manner to produce 1-(2-hydroxyethyl).
-N ⁵ -[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenyl]-1H-1,
2,4-triazole-3,5-diamine (590
mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.2-2.5 (4H, multiplet), 3.37 (2H, singlet),
3.6~4.0 (6H, multiplet), 4.42 (2H, multiplet), 5.88
(2H, multiplet), 6.6-7.4 (4H, multiplet). Example 15 In Example 12, trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine was replaced with cis-4-[3-(1-piperidinylmethyl)phenoxy]- 1-(2-Hydroxyethyl)-
N ⁵ -[4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenyl]-1H-1,2,4
-Triazole-3,5-diamine (390 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3 to 1.8 (6H, multiplet), 2.2 to 2.5 (4H, multiplet), 3.37 (2H, singlet), 3.6 to 4.0 (6H, multiplet), 4.57 (2H, multiplet), 5.70 (2H, multiplet), 6.6-7.4 (4H, multiplet). Example 16 1-Methyl- ^N5- in chloroform (2 ml)
[4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl]-1H-1,2,
4-triazole-3,5-diamine (60mg),
Acetic anhydride (0.1ml) and triethylamine (0.1ml)
ml) was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and after 1 hour, aqueous ammonia was further added, and the product was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the extract was separated and purified using TLC [developing solvent: methanol] to obtain N-[1-methyl-5-[4-[3-[1-(1
-pyrrolidinyl)ethyl]phenoxy]-cis-2
-Butenylamino]-1H-1,2,4-triazol-3-yl]acetamide (55 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.36 (3H, doublet, J
= 6.5Hz), 1.5 to 2.1 (4H, multiplet), 2.18 (3H,
wide singlet), 2.1 to 2.7 (4H, multiplet), 3.14
(1H, quartet, J=6.5Hz), 3.43 (3H, singlet), 3.99 (2H, multiplet), 4.58 (2H, multiplet),
5.75 (2H, multiplet), 6.6-7.4 (4H, multiplet). Example 17 In Example 16, 1-methyl- ^N5- [4-
[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl)-1H-1,2,4-
1-methyl- ^N5- [4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenyl]-1H- instead of triazole-3,5-diamine
A similar operation using 1,2,4-triazole-3,5-diamine (250 mg) yielded N-[1-methyl-5-[4-[3-(1-piperidinylmethyl)].
Phenoxy]-trans-2-butenylamino]-1H
-1,2,4-triazol-3-yl]acetamide (230 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.18 (3H, wide singlet), 2.2-2.5 (4H,
multiplet), 3.42 (2H, multiplet), 3.47 (3H, singlet), 3.95 (2H, multiplet), 4.46 (2H, multiplet),
5.89 (2H, multiplet), 6.6-7.4 (4H, multiplet). Mass (m/z): 398 (M ⁺ ), 315, 208, 190, 155,
84. Example 18 In Example 16, 1-methyl- ^N5- [4-
[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl]-1H-1,2,4-
1- instead of triazole-3,5,-diamine
Methyl- ^N5- [4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenyl]-1H-
A similar operation using 1,2,4-triazole-3,5-diamine (140 mg) yielded N-[1-methyl-5-[4-[3-(1-piperidinylmethyl)].
Phenoxy]-cis-2-butenylamino]-1H-
1,2,4-triazol-3-yl]acetamide (125 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.18 (broad singlet), 2.2-2.5 (4H, multiplet), 3.43 (2H, singlet), 3.47 (3H , single line),
4.00 (2H, multiplet), 4.58 (2H, multiplet), 5.75
(2H, multiplet), 6.6-7.4 (4H, multiplet). Example 19 In Example 16, 1-methyl- ^N5- [4-
[3-[-1(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl]-1H-1,2,4-
1- instead of triazole-3,5-diamine
(2-hydroxyethyl) ^-N5- [4-[3-(1-
piperidinylmethyl)phenoxy]-trans-2-
butenyl]-1H-1,2,4-triazole-
In the same manner using 3,5-diamine (175 mg), N-[1-(2-acetoxyethyl)-5-
[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]-1H-1,
2,4-triazol-3-yl]acetamide (150 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3 to 1.8 (6H, multiplet), 2.00 (3H, singlet), 3.14 (3H, wide singlet), 2.2 to 2.5 (4H, multiplet), 3.40 (2H, singlet), 3.7-4.7 (8H, multiplet), 5.90 (2H, multiplet), 6.6-7.4 (4H, multiplet). Example 20 In Example 16, 1-methyl- ^N5- [4-
[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl]-1H-1,2,4-
1- instead of triazole-3,5-diamine
(2-hydroxyethyl) ^-N5- [4-[3-(1-
piperidinylmethyl)phenoxy]-cis-2-butenyl]-1H-1,2,4-triazole-3,
Similarly, using 5-diamine (130 mg),
N-[1-(2-acetoxyethyl)-5-[4-
[3-(1-piperidinylmethyl)phenoxy]-
cis-2-butenylamino]-1H-1,2,4-
Triazol-3-yl]acetamide (125mg)
I got it. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.00 (3H, singlet), 3.14 (3H, wide singlet), 2.2-2.5 (4H, multiplet), 3.40 (2H, singlet), 3.7-4.7 (8H, multiplet), 5.80 (2H, multiplet), 6.6-7.4 (4H, multiplet). Example 21 In Example 16, 1-methyl- ^N5- [4-
[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenyl]-1H-1,2,4-
1-methyl- ^N5- [4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenyl]-1H- instead of triazole-3,5-diamine
N-[1-methyl-5-[ 4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]-1H-1,2,4-triazole-
3-yl]acetoxyacetamide (304 mg) was obtained. This compound (300 mg) was mixed with methanol (5 ml).
A 10% methanol solution of potassium hydroxide (2 ml) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the product was extracted with chloroform and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was separated and purified by TLC [developing solvent: chloroform:methanol (9:1)] to obtain N-[1-
Methyl-5-[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]
-1H-1,2,4-triazol-3-yl]
Hydroxyacetamide (272mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.2-2.5 (4H, multiplet), 3.42 (2H, singlet), 3.44 (3H, singlet), 3.92 ( 2H, multiplet),
4.12 (2H, wide singlet), 4.43 (2H, multiplet),
5.85 (2H, multiplet), 6.6-7.4 (4H, multiplet). Mass (m/z): 414 (M ⁺ ), 331, 224, 166, 84. Example 22 In Example 21, 1-methyl- ^N5- [4-
[3-(1-piperidinylmethyl)phenoxy]-
1-methyl-N5-[ ^4- [3-(1-piperidinylmethyl)phenoxy]-cis instead of trans-2-butenyl]-1H-1,2,4-triazole-3,5-diamine -2-butenyl]-1H-1,2,
4-triazole-3,5-diamine (220mg)
N-[1-methyl-5
-[4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenylamino]-1H-1,
2,4-triazol-3-yl]hydroxyacetamide (205 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.2-2.5 (4H, multiplet), 3.42 (2H, singlet), 3.44 (3H, singlet), 3.98 ( 2H, multiplet),
4.12 (2H, wide singlet), 4.58 (2H, multiplet),
5.73 (2H, multiplet), 6.6-7.4 (4H, multiplet). Example 23 In Example 21, 1-methyl- ^N5- [4-
[3-(1-piperidinylmethyl)phenoxy]-
1-methyl-N5-[ ^4- [3-(1-piperidinylmethyl)phenyl]-cis instead of trans-2-butenyl]-1H-1,2,4-triazole-3,5-diamine -3-butenyl]-1H-1,2,4
-Triazole-3,5-diamine (95 mg) was used in the same manner as N-[1-methyl-5-[4
-[3-(1-piperidinylmethyl)phenyl]-
cis-3-butenylamino]-1H-1,2,4-
Triazol-3-yl]hydroxyacetamide (80 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3 to 1.8 (6H, multiplet), 2.2 to 2.9 (6H, multiplet), 3.2 to 3.6 (7H, multiplet), 4.10 (2H, wide singlet) ,5.3~5.9(1H,
multiplet), 6.48 (1H, doublet, J=12Hz), 7.0~
7.4 (4H, multiplet). Mass (m/z): 398 (M ⁺ ), 378, 315, 215, 171. Example 24 In Example 2, cis-4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy was used instead of trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine. ]-2-Butenylamine (100 mg) was used in the same manner to obtain 2-[4
-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenylamino]-5-(3-
pyridylmethyl)-4-pyrimidone (45 mg) was obtained. NMR (CDCl ₃ , δ): 1.36 (3H, doublet, J = 6.5
Hz), 1.5 to 2.0 (4H, multiplet), 2.1 to 2.8 (4H, multiplet), 3.22 (1H, quartet, J = 6.5Hz), 3.60
(2H, wide singlet), 4.01 (2H, multiplet), 4.62
(2H, multiplet), 5.73 (2H, multiplet), 6.6~7.7
(7H, multiplet), 8.3-8.5 (2H, multiplet). Mass (m/z): 445 (M ⁺ ), 430, 376, 255, 202,
190, 176, 98. Example 25 In Example 2, trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine was replaced with cis-4-[3-(1-piperidinylmethyl)phenoxy]- In the same manner using 2-butenylamine (120 mg), 2-[4-[3
-(1-piperidinylmethyl)phenoxy]-cis
-2-butenylamino]-5-(3-pyridylmethyl)-4-pyrimidone (60 mg) was obtained. NMR ( _CDCl3 , δ): 1.3-1.8 (6H, multiplet), 2.2
~2.6 (4H, multiplet), 3.45 (2H, singlet), 3.61
(2H, wide singlet), 4.01 (2H, multiplet), 4.57
(2H, multiplet), 5.74 (2H, multiplet), 6.6~7.7
(7H, multiplet), 8.3-8.5 (2H, multiplet). Mass (m/z): 445 (M ⁺ ), 362, 255, 190, 84. Example 26 In Example 2, trans-4-[3-(3-methyl-
Similarly, using 1-piperidinylmethyl)phenoxy]-2-butenylamine (95 mg),
2-[4-[3-(3-methyl-1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]-5-(3-pyridylmethyl)-4-pyrimidone (35 mg) was obtained. NMR (CDCl ₃ , δ): 1.81 (3H, doublet, J = 5.5
Hz), 1.3 to 3.1 (9H, multiplet), 3.47 (2H, singlet), 3.61 (2H, wide singlet), 3.95 (2H, multiplet), 4.42 (2H, multiplet), 5.83 (2H, multiplet),
6.6-7.7 (7H, multiplet), 8.3-8.5 (2H, multiplet). Example 27 In Example 2, cis-4-[3-(3-methyl-1
-piperidinylmethyl)phenoxy]-2-butenylamine (80 mg) and
-[4-[3-(3-methyl-1-piperidinylmethyl)phenoxy]-cis-2-butenylamino]
-5-(3-pyridylmethyl)-4-pyrimidone (32 mg) was obtained. NMR (CDCl ₃ , δ): 1.81 (3H, doublet, J = 5.5
Hz), 1.3 to 3.1 (9H, multiplet), 3.47 (2H, singlet), 3.61 (2H, wide singlet), 4.02 (2H, multiplet), 4.58 (2H, multiplet), 5.73 (2H, multiplet),
6.6-7.7 (7H, multiplet), 8.3-8.5 (2H, multiplet). Example 28 In Example 2, trans-4-[3-(3-hydroxy-1-piperidinylmethyl) was used instead of trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine. ) Phenoxy]-2
2-[4-[3-(3-hydroxy-1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]-5-(3-pyridyl methyl)-4-
Pyrimidone (21 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-2.0 (4H, multiplet), 2.0-2.7 (4H, multiplet), 3.45 (2H, singlet), 3.60 (2H, wide singlet), 3.79 (1H, multiplet), 3.96 (2H, multiplet), 4.48 (2H, multiplet),
5.80 (2H, multiplet), 6.6~7.7 (7H, multiplet),
8.3-8.5 (2H, multiplet). Example 29 In Example 3, cis-4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy was substituted for trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine. ]-2-Butenylamine (46 mg) was used in the same manner to obtain 1,1-
Dioxidized 3-amino-4-[4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-cis-2-butenylamino]-1,2,5-thiadiazole (50 mg) was obtained. NMR (CD ₃ OD, δ): 1.43 (3H, doublet, J = 6.5
Hz), 1.4 to 2.1 (4H, multiplet), 2.1 to 3.0 (4H, multiplet), 3.43 (1H, quartet, J = 6.5Hz), 4.14
(2H, multiplet), 4.69 (2H, multiplet), 5.82 (2H,
multiplet), 6.6 to 7.4 (4H, multiplet). Example 30 In Example 3, cis-4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy was substituted for trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine. ] -2-Butenylamine (60mg) was used, and 4-2-butenylamine was used instead of ammonia water.
In the same manner using pyridylmethylamine (60 mg), 1,1-dioxidized 3-(4-pyridylmethylamino)-4-[4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxylate] ]-cis-2-butenylamino]-1,2,5-thiadiazole (85mg)
I got it. NMR (CD ₃ OD, δ): 1.47 (3H, doublet, J = 6.5
Hz), 1.6 to 2.3 (4H, multiplet), 2.3 to 3.2 (4H, multiplet), 3.60 (1H, quartet), J = 6.5Hz), 4.14
(2H, multiplet), 4.58 (2H, singlet), 4.70 (2H,
multiplet), 5.82 (2H, multiplet), 6.6~7.5 (6H,
multiplet), 8.3-8.6 (2H, multiplet). Example 31 In Example 3, a methanol (5%) solution of potassium hydroxide (0.5 ml) was used instead of ammonia water.
1,1-dioxidized 3-hydroxy-4-[4-[3-(1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]-1,2,5 - Thiadiazole (54 mg) was obtained. Melting point 271.5-272.6℃ (decomposition). NMR ((CD ₃ ) ₂ SO−D ₂ O, δ): 1.3-1.8 (6H, multiplet), 2.1-2.5 (4H, multiplet), 3.37 (2H, singlet), 3.86 (2H, multiplet) ), 4.50 (2H, multiplet), 5.83 (2H, multiplet), 6.6-7.4 (4H, multiplet). Example 32 In Example 3, trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine was replaced with cis-4-[3-(1-piperidinylmethyl)phenoxy]- A similar operation was performed using 2-butenylamine (70 mg) to give 1,1-dioxidized 3-amino-4-[4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenylamino]. -1,2,5-thiadiazole (76 mg) was obtained. NMR (CD ₃ OD, δ): 1.3-2.0 (6H, multiplet),
2.3~2.8 (4H, multiplet), 3.59 (2H, singlet),
4.16 (2H, multiplet), 4.75 (2H, multiplet), 5.88
(2H, multiplet), 6.6-7.4 (4H, multiplet). Example 33 In Example 3, cis-4-[3-(1-piperidinylmethyl)phenoxy]-2 was used instead of trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine. -butenylamine (43
1,1-dioxidized 3-methylamino-
4-[4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenylamino]-1,2,
5-thiadiazole (50 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.9 (6H, multiplet), 2.3-2.8 (4H, multiplet), 3.05 (3H, singlet), 3.60 (2H, singlet), 4.14 ( 2H, multiplet),
4.69 (2H, multiplet), 5.85 (2H, multiplet), 6.6~
7.4 (4H, multiplet). Example 34 In Example 3, 1,1-dioxidized 3-methylamino-4-[4- [3-(1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]
-1,2,5-thiadiazole (82 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-1.9 (6H, multiplet), 2.3-2.8 (4H, multiplet), 3.05 (3H, singlet), 3.53 (2H, singlet), 4.09 ( 2H, multiplet),
4.54 (2H, multiplet), 5.97 (2H, multiplet), 6.6~
7.4 (4H, multiplet). Example 35 In Example 3, trans-4-[3-(3-methyl-
Similarly, using 1-piperidinylmethyl)phenoxy]-2-butenylamine (70 mg),
1,1-dioxidized 3-amino-4-[4-[3-(3
-Methyl-1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]-1,2,5
- Thiadiazole (90 mg) was obtained. NMR (CD ₃ OD, δ): 0.86 (3H, doublet, J=5.5
Hz), 1.2 to 3.2 (9H, multiplet), 3.56 (2H, singlet), 4.02 (2H, multiplet), 4.55 (2H, multiplet),
5.98 (2H, multiplet), 6.6-7.4 (4H, multiplet). Example 36 In Example 3, cis-4-[3-(3-methyl-1
-Piperidinylmethyl)phenoxy]-2-butenylamine (70 mg) was used in the same manner.
1,1-dioxidized 3-amino-4-[4-[3-(3
-Methyl-1-piperidinylmethyl)phenoxy]-cis-2-butenylamino]-1,2,5-
Thiadiazole (87 mg) was obtained. NMR (CD ₃ OD, δ): 0.86 (3H, doublet, J=5.5
Hz), 1.2 to 3.2 (9H, multiplet), 3.58 (2H, singlet), 4.14 (2H, multiplet), 4.70 (2H, multiplet),
5.83 (2H, multiplet), 6.6-7.4 (4H, multiplet). Example 37 In Example 3, trans-4-[3-(3-methyl-
1-piperidinylmethyl)phenoxy]-2-butenylamine (70 mg) and 2-hydroxyethylamine (100 mg) instead of aqueous ammonia were used to obtain 1,1-dioxidized 3-(2 −
hydroxyethylamino)-4-[4-[3-(3-
Methyl-1-piperidinylmethyl)phenoxy]
-trans-2-butenylamino]-1,2,5-thiadiazole (70 mg) was obtained. NMR (CD ₃ OD, δ): 1.84 (3H, doublet, J = 5.5
Hz), 1.3 to 3.1 (9H, multiplet), 3.4 to 3.9 (4H, multiplet), 3.52 (2H, singlet), 4.02 (2H, multiplet), 4.55 (2H, multiplet), 5.98 (2H , multiplet),
6.6-7.4 (4H, multiplet). Example 38 In Example 3, cis-4-[3-(3-methyl-1
-piperidinylmethyl)phenoxy]-2-butenylamine (70 mg) and 2-hydroxyethylamine (100 mg) in place of ammonia water. hydroxyethylamino)-4-[4-[3-(3-methyl-1-piperidinylmethyl)phenoxy]-
cis-2-butenylamino]-1,2,5-thiadiazole (73 mg) was obtained. NMR (CD ₃ OD, δ): 1.84 (3H, doublet, J = 5.5
Hz), 1.3 to 3.1 (9H, multiplet), 3.4 to 3.9 (4H, multiplet), 3.53 (2H, singlet), 4.14 (2H, multiplet), 4.68 (2H, multiplet), 5.83 ( 2H, multiplet),
6.6-7.4 (4H, multiplet). Example 39 In Example 3, trans-4-[3-(3-hydroxy-1-piperidinylmethyl) was substituted for trans-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine. ) Phenoxy]-2
1,1-
Dioxidized 3-methylamino-4-[4-[3-(3-
Hydroxy-1-piperidinylmethyl)phenoxy]-trans-2-butenylamino]-1,2,5
- Thiadiazole (30 mg) was obtained. NMR (CDCl ₃ −D ₂ O, δ): 1.3-2.0 (4H, multiplet), 2.0-2.7 (4H, multiplet), 2.99 (3H, singlet), 3.48 (2H, singlet), 3.80 ( 1H, multiplet),
3.98 (2H, multiplet), 4.55 (2H, multiplet), 5.85
(2H, 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 Synthesis A of cis-4-[3-(1-piperidinylmethyl)phenoxy]-2-butenylamine Method (i) 1.15 g of 60% sodium hydride was suspended in 15 ml of dry dimethyl sulfoxide, and 3 Add 5.0 g of -(1-piperidinylmethyl)phenol in a solid state little by little and stir. After stirring at room temperature for 20 minutes, 6.75 g of N-(4-chloro-cis-2-butenyl)phthalimide was added, and the mixture was stirred at room temperature for 2 hours. Add ice water to the reaction solution and extract with ether. After washing with water and extracting with 10% hydrochloric acid, the aqueous layer was collected and made alkaline with ammonia.
Extract with chloroform. After washing with water, drying with anhydrous magnesium sulfate, distilling off the solvent, and
[4-(3-(1-piperidinylmethyl)phenoxy]-cis-2-butenyl]phthalimide 8.3
g was obtained as an oil. IR (liquid film, cm ^-1 ): 1765, 1706. NMR ( _CDCl3 , δ): 1.1-1.9 (6H, multiplet),
2.1~2.6 (4H, multiplet), 3.45 (2H, singlet),
4.36 (2H, double line, J=7Hz), 4.6~5.0
(2H, multiplet), 5.3 to 6.2 (2H, multiplet), 6.7
~7.4 (4H, multiplet), 7.5~8.0 (4H, multiplet). (ii) N-[4-[3-(1-piperidinylmethylphenoxy]-cis-2-butenyl]phthalimide
8.3g, hydrazine hydrate 8.3ml and ethanol 83
ml of the mixture is left at room temperature for 4 hours. The precipitated phthalazine is thoroughly loosened and removed, benzene is added and the solvent is distilled off under reduced pressure, and when insoluble matter is precipitated, it is removed. After repeating this operation several times, the residue was distilled under reduced pressure to obtain cis-4-[3-
(1-piperidinylmethyl)phenoxy]-2-
4.2 g of butenylamine was obtained. Boiling point 168-170
°C/0.55mmHg. IR (liquid film, cm ^-1 ): 3240, 1593. NMR ( _CDCl3 , δ): 1.1-1.9 (6H, multiplet),
2.1~2.6 (4H, multiplet), 3.1~3.7 (2H, multiplet), 3.43 (2H, singlet), 4.3~4.7 (2H, multiplet), 5.3~6.0 (2H, multiplet), 6.6~ 7.7
(4H, multiplet). Method B: Suspend 1.15 g of 60% sodium hydride in 15 ml of dry dimethyl sulfoxide, add 5.0 g of 3-(1-piperidinylmethyl)phenol in solid form little by little, and stir. 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 ml 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 1-chloro-4-[3-(1
-piperidinylmethyl)phenoxy]-cis-2-
3.3 g of butene were obtained as an oil. This product is used immediately in the next reaction. Obtained 1-chloro-4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butene 3.3
g is added dropwise into a solution prepared from 0.53 g of 60% sodium hydride, 7.3 ml of dry dimethyl sulfoxide and 1.92 g of phthalimide. After reacting at room temperature for 2 hours, ice water was added and extracted with ether. After washing with water, it was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 2.4 g of N-[4-[3-(1-piperidinylmethyl)phenoxy]-cis-2-butenyl]phthalimide as an oil. Ta. This compound was completely identical to the compound obtained by method A (i). Production Example 2 In Method A of Production Example 1, N-(4-chloro-
N- instead of cis-2-butenyl) phthalimide
In the same manner using 6.75 g of (4-chloro-trans-2-butenyl)phthalimide, trans-4-
[3-(1-piperidinylmethyl)phenoxy]-
4.0 g of 2-butenylamine was obtained as an oil. NMR ( _CDCl3 , δ): 1.1-1.9 (6H, multiplet), 2.1
~2.7 (4H, multiplet), 3.2~3.8 (2H, multiplet),
3.46 (2H, singlet), 4.3~4.7 (2H, multiplet),
5.6 to 6.4 (2H, multiplet), 6.6 to 7.3 (4H, multiplet). Production Example 3 In Method A of Production Example 1, 3-[1-(1-
The same procedure was carried out using 1.0 g of pyrrolidinyl)ethyl]phenol to obtain 0.9 g of cis-4-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]-2-butenylamine as an oil. NMR (CDCl ₃ , δ): 1.38 (3H, doublet, J=6
Hz), 1.5 to 2.0 (4H, multiplet), 2.2 to 2.8 (4H, multiplet), 3.17 (1H, quartet, J = 6Hz), 3.2 to
3.7 (2H, multiplet), 4.3 to 4.8 (2H, multiplet), 5.3
~6.2 (2H, multiplet), 6.6~7.4 (4H, multiplet). Production Example 4 In Method A of Production Example 1, cis-4-(3-dimethyl 0.7 g of aminomethylphenoxy)-2-butenylamine was obtained as an oil. NMR ( _CDCl3 , δ): 2.22 (6H, singlet), 3.2~
3.5 (2H, multiplet), 3.36 (2H, singlet), 4.3~
4.8 (2H, multiplet), 5.3~6.0 (2H, multiplet), 6.6
~7.7 (4H, multiplet). Production Example 5 In Method A of Production Example 1, 1.0 g of 3-(1-perhydroazepinylmethyl)phenol was used instead of 3-(1-piperidinylmethyl)phenol, and cis 0.8 g of -4-[3-(1-perhydroazepinylmethyl)phenoxy]-2-butenylamine was obtained as an oil. NMR ( _CDCl3 , δ): 1.3-1.9 (8H, multiplet), 2.3
~2.8 (4H, multiplet), 3.1~3.6 (2H, multiplet),
3.58 (2H, singlet), 4.3~4.7 (2H, multiplet),
5.3 to 6.0 (2H, multiplet), 6.5 to 7.6 (4H, multiplet). Production Example 6 In the same manner as in Method A of Production Example 1, using 3-(3-methyl-1-piperidinylmethyl)phenol instead of 3-(1-piperidinylmethyl)phenol, cis -4-[3-(3-methyl-1-piperidinylmethyl)phenoxy]-2-
Butenylamine was obtained. NMR (CDCl ₃ −D ₂ O, δ): 0.83 (3H, doublet, J
= 5.5Hz), 1.3 to 2.2 (7H, multiplet), 2.6 to 3.0
(2H, multiplet), 3.36 (2H, multiplet), 3.44 (2H,
singlet), 4.57 (2H, multiplet), 5.74 (2H, multiplet), 6.6-7.4 (4H, multiplet). Production Example 7 In Method A of Production Example 1, 3-(3-methyl-1-piperidinylmethyl)phenol was used instead of 3-(1-piperidinylmethyl)phenol, and N-(4-chloro- N-(4-chloro-trans-2-
A similar operation using (butenyl)phthalimide gave trans-4-[3-(3-methyl-1-piperidinylmethyl)phenoxy]-2-butenylamine. NMR (CDCl ₃ −D ₂ O, δ): 0.83 (3H, doublet, J
= 5.5Hz), 1.3 to 2.2 (7H, multiplet), 2.6 to 3.0
(2H, multiplet), 3.34 (2H, multiplet), 3.44 (2H,
3-(1-piperidinylmethyl) in Method A of Production Example 1. 3-(3-hydroxy-1-piperidinylmethyl)phenol was used instead of phenol, and N-(4-chloro-trans-2) was used instead of N-(4-chloro-cis-2-butenyl)phthalimide.
-butenyl)phthalimide to give trans-4-[3-(3-hydroxy-1-piperidinylmethyl)phenoxy]-2-butenylamine. NMR (CDCl ₃ −D ₂ O, δ): 1.3 to 3.0 (8H, multiplet), 3.33 (2H, multiplet), 3.46 (2H, singlet),
3.70 (1H, multiplet), 4.00 (2H, multiplet), 5.84
(2H, multiplet), 6.6-7.4 (4H, multiplet). Production Example 9 (i) 24g of 3-phthaliminopropyltriphenylphosphonium bromide in 140ml of THF and 60%
Suspend 1.8g of sodium hydride and cool on ice.
After stirring for 15 minutes, 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
Extract the ether layer with 10% hydrochloric acid, collect the aqueous layer, make alkaline with ammonia, and extract with chloroform. After washing with water, it was dried over anhydrous magnesium sulfate, the solvent was distilled off, and N-[4-[3
-(1-piperidinylmethyl)phenyl]-cis
9.2 g of -3-butenyl]phthalimide were obtained as an oil. IR (liquid film, cm ^-1 ): 1770, 1700. NMR ( _CDCl3 , δ): 1.1-1.9 (6H, multiplet),
2.2-2.6 (4H, multiplet), 2.70 (2H, quartet),
3.49 (2H, single line), 3.70 (2H, triple line, J=
7Hz), 5.2 to 5.6 (1H, multiplet), 6.49 (1H,
Double line, J=12Hz), 7.0~7.4 (4H, multiple line),
7.5-8.0 (4H, multiplet). (ii) In method A (ii) of Production Example 1, N-[4-[3-
(1-piperidinylmethyl)phenoxy]-cis
-2-butenyl]N- instead of phthalimide
[4-[3-(1-piperidinylmethyl)phenyl]-cis-3-butenyl]phthalimide 9.2 g
The oily substance obtained by the same procedure was distilled under reduced pressure to obtain cis-4-[3-
4.0 g of (1-piperidinylmethyl)phenyl]-3-butenylamine was obtained. NMR ( _CDCl3 , δ): 1.1-1.9 (6H, multiplet),
2.2 to 2.6 (6H, multiplet), 2.6 to 3.0 (2H, multiplet), 3.45 (2H, singlet), 5.2 to 6.0 (1H, multiplet), 6.51 (1H, doublet), J = 12Hz ), 7.0
~7.4 (4H, multiplet). Production example 10 trans-4-[3-(1-piperidinylmethyl)
Synthesis of phenyl]-3-butenylamine A Method (i) Add 2.1 g of 60% sodium hydride to 15 ml of tetrahydrofuran and 15 ml of dry dimethyl sulfoxide.
10.1 g of oxycarbonylethyltriphenylphosphonium chloride was suspended in ice-cooled stirrer.
Add it little by little while it is solid. After stirring for 10 minutes under ice cooling, 5.0 g of 3-(1-piperidinylmethyl)benzaldehyde and tetrahydrofuran 5
ml solution and stir at room temperature for 4 hours. After adding a small amount of water, tetrahydrofuran is distilled off under reduced pressure, 30 ml of ice water is added, and the mixture is 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, 20 ml of methanol is added, followed by 25 ml of a 20% hydrochloric acid solution in ether. After removing the precipitated insoluble matter, heat to distill off the ether, and reflux for 10 minutes. Methanol 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,
It is dried with Glauber's salt and the solvent is distilled off. residue
Purification by TLC (developing solvent: chloroform:methanol (9:1)) gave 3.0 g of methyl 3-[3-(1-piperidinylmethyl)phenyl]-trans-2-butenoate as an oil. Ta. IR (liquid film, cm ^-1 ): 1735. NMR ( _CDCl3 , δ): 1.2-1.9 (6H, multiplet),
2.2-2.6 (4H, multiplet), 3.1-3.4 (2H, multiplet), 3.49 (2H, singlet), 3.68 (3H, singlet), 6.0-7.0 (2H, multiplet), 7.1-7.5 ( 4H,
multiplet). (ii) Suspend 1.2 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran,
Methyl 3-[3-(1-piperidinylmethyl)phenyl]-trans-2-butenoate under ice-cooling and stirring.
A solution of 3.0 g in 10 ml of dry tetrahydrofuran is added dropwise. After reacting for 1 hour under ice-cooling, ice water was added dropwise, and 3 g of sodium chloride was added to remove insoluble materials. The solvent was distilled off from the solution under reduced pressure, and the residue was purified by TLC (developing solvent: chloroform:methanol (9:1)) to give 4-[3-(1-piperidinylmethyl)phenyl]- 2.5 g of trans-3-butenyl alcohol was obtained as an oil. IR (liquid film, cm ^-1 ): 3330. NMR ( _CDCl3 , δ): 1.2-1.9 (6H, multiplet),
2.1~2.7 (6H, multiplet), 3.41 (2H, singlet),
3.68 (2H, triple line, J=6Hz), 5.7~6.7
(2H, multiplet), 7.0-7.9 (4H, multiplet). (iii) 2.5 g of 4-[3-(1-piperidinylmethyl)phenyl]-trans-3-butenyl alcohol are refluxed in thionyl chloride for 1 hour. 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, 1.75 g of 1-chloro-4-[3-(1-piperidinylmethyl)phenyl]-trans-3-butene
was obtained as an oil. NMR ( _CDCl3 , δ): 1.1-1.9 (6H, multiplet),
2.1~2.9 (6H, multiplet), 3.43 (2H, singlet),
3.4-3.8 (2H, multiplet), 5.6-6.7 (2H, multiplet), 7.0-7.5 (4H, multiplet). (iv) 1.7 g of 1-chloro-4-[3-(1-piperidinylmethyl)phenyl]-trans-3-butene,
After heating 5.1 g of potassium phthalimide and 17 ml of dimethyl sulfoxide on a steam bard for 30 minutes, it is cooled, ice water is added, and extracted with ether. After washing with water, extract with 10% hydrochloric acid, collect the aqueous layer, make alkaline with ammonia, and extract with chloroform. After washing with water, it is dried over anhydrous magnesium sulfate and the solvent is distilled off. residue
It was purified by TLC (developing solvent: chloroform:methanol (19:1)) and N-[4-[3-(1
-piperidinylmethyl)phenyl]-trans-3
0.8 g of -butenyl]phthalimide was obtained as an oil. IR (liquid film, cm ^- ): 1770, 1710. NMR ( _CDCl3 , δ): 1.1-1.9 (6H, multiplet),
2.1~2.9 (6H, multiplet) 3.42 (2H, singlet),
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 (ii) of Production Example 1, N-[4-[3-
(1-piperidinylmethyl)phenoxy]-cis
-2-butenyl]N- instead of phthalimide
[4-[3-(1-piperidinylmethyl)phenyl]-trans-3-butenyl]phthalimide 2.6
Trans-4-[3-
1.3 g of (1-piperidinylmethyl)phenyl]-3-butenylamine was obtained as an oil. NMR ( _CDCl3 , δ): 1.1-1.9 (6H, multiplet),
2.1~3.0 (8H, multiplet), 3.43 (2H, singlet),
5.6 to 6.7 (2H, multiplet), 7.0 to 7.5 (4H, multiplet). B Method (i) 60% sodium hydride is suspended in 37 ml of a dry tetrahydrofuran-dry dimethyl sulfoxide (1:1) mixture, and 15.8 g of oxycarbonylethyl triphenylphosphonium chloride is added at once while stirring in ice water. After stirring for 20 minutes under ice cooling, a solution of 7.5 g of 3-(ethoxycarbonyl)benzaldehyde in dry tetrahydrofuran (7.5 ml) is added all at once. After stirring for 2 minutes under ice cooling, the mixture is stirred at room temperature for 3 hours. Add 100 ml of ice water and 300 ml of ether, shake, take the aqueous layer, acidify with hydrochloric acid, and extract with ether. After washing with water, the ether was distilled off and the resulting residue was mixed with methanol 80%
ml, blow in hydrochloric acid gas, and reduce for 30 minutes. Methanol is distilled off under reduced pressure, and ether is added for extraction. After shaking with a 5% aqueous potassium carbonate solution, the mixture was washed with water, dried over sodium sulfate, and the solvent was 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~
Methyl 3-[3-(ethoxycarbonyl)phenyl]-trans-2-butenoate at 154℃/0.6mmHg
4.5g was obtained. IR (liquid film, cm ^-1 ): 1720. NMR ( _CDCl3 , δ): 1.37 (3H, triplet), 3.0~
3.5 (2H, multiplet), 3.70 (3H, singlet), 3.39
(2H, singlet), 4.45 (2H, quartet, J=7
Hz), 6.0 to 7.0 (2H, multiplet), 7.1 to 8.3 (4H,
multiplet). (ii) Suspend 10 g of lithium aluminum hydride in 500 ml of dry tetrahydrofuran,
-[3-(ethoxycarbonyl)phenyl]--
A solution of 25 g of methyl trans-2-butenoate in dry tetrahydrofuran (100 ml) is added dropwise under ice-cooling and stirring at an internal temperature of 10°C or lower. After reacting at room temperature for 1 hour, 50 ml of water was added dropwise under ice-cooling and stirring at an internal temperature of 10°C or less. After stirring for 30 minutes at room temperature, sodium chloride
Add 50g and remove insoluble matter. After removing the solvent under reduced pressure, the residue was distilled under reduced pressure to obtain a boiling point of 167
4-(3-hydroxymethylphenyl)-trans-3-butenyl alcohol at ~170℃/1mmHg
Obtained 14g. IR (liquid film, cm ^-1 ): 3320. NMR (CDCl ₃ , δ): 2.37 (2H, quartet, J=
7Hz), 3.57 (2H, triple line, J=7Hz), 4.50
(2H, singlet), 5.7-6.7 (2H, multiplet), 6.9
~7.5 (4H, multiplet). (iii) 4-(3-hydroxymethylphenyl)-
14 g of trans-3-butenyl alcohol is added portionwise to 50 ml of thionyl chloride 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% aqueous potassium carbonate 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 elution) to obtain 1-chloro-
4-(3-chloromethylphenyl)-trans-3
-15.5 g of butene were obtained as an oil. When this compound is distilled under reduced pressure, its boiling point is 123-126℃/0.6mm.
Although it is distilled with Hg, the decomposition is severe and the yield is low. NMR (CDCl ₃ , δ): 2.56 (2H, quartet, J=
7Hz), 3.59 (2H, triple line, J=7Hz), 4.54
(2H, singlet), 5.7-6.7 (2H, multiplet), 7.0
~7.5 (4H, multiplet). (iv) 4.1 g of 1-chloro-4-(3-chloromethylphenyl)-trans-3-butene, 3.3 g of piberidine
A mixture of g and 41 ml of tetrahydrofuran is heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and ether was added to remove the precipitated insoluble matter. The liquid 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, it was dried over anhydrous sodium sulfate, the solvent was distilled off, and 1-chloro-[3-(1-
piperidinylmethyl)phenyl]-trans-3-
3.7 g of butene were obtained as an oil. This compound was completely identical to the compound obtained by Method A (iii) of Production Example 10. Production example 11 N-(3-bromopropyl)phthalimide 100
g, triphenylphosphine 100g and benzene
Reflux 200 ml of the mixture overnight. The precipitated crystals were collected and dried to obtain 3-phthaliminopropyltriphenylphosphonium bromide with a melting point of 216-217°C.
Obtained 128g. IR (KBr, cm ^-1 ): 3400, 1770, 1700. NMR ( _CDCl3 , δ): 1.8-2.5 (2H, multiplet), 3.5
~4.3 (4H, multiplet), 7.5~8.1 (19H, multiplet). Production Example 12 2.8 g of 60% sodium hydride is suspended in 20 ml of dry dimethyl sulfoxide, and 10 g of phthalimide is added little by little as a solid. at room temperature
After stirring for 20 minutes, the solution was diluted with 1,4-dichloro-
A solution of 16.8 g of cis-2-butene in 16 ml of dry dimethyl sulfoxide is added dropwise at room temperature. 2 at room temperature
After standing for a while, pour into ice water, add 50ml of n-hexane, stir, and leave to stand. The precipitated crystals are collected and washed with water, then with n-hexane, and the wet crystals are extracted six times with 50 ml of ether. After drying the ether layer with Glauber's salt, the solvent was distilled off. Crude crystals are n-
Recrystallized from hexane with a melting point of 66.9-68.6℃
5.0 g of -[4-chloro-cis-2-butenyl)phthalimide was obtained. IR (KBr, cm ^-1 ): 1760, 1700. NMR ( _CDCl3 , δ): 3.9-4.6 (4H, multiplet), 5.4
~6.1 (2H, multiplet), 7.5~8.0 (4H, multiplet). Production Example 13 In Production Example 12, 1,4-dichloro-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 to give N-(4-chloro-
13.2 g of trans-2-butenyl)phthalimide was obtained. IR (KBr, cm ^-1 ): 1765, 1705. NMR ( _CDCl3 , δ): 3.9-4.6 (4H, multiplet), 5.5
~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. Manufacturing Example A Capsules Examples of formulations for capsules containing 50 mg and 100 mg of active ingredient per capsule are as follows. Prescription 1-a50mg capsule

[Table] Mu

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 further represent hydroxy, lower alkanoyloxy, lower alkoxy, or 4 which may be substituted with a lower alkyl group
~8-membered heterocycle; R ₃ represents a hydrogen atom or a lower alkyl group; Y represents a group of the formula [Formula] [Formula] or [Formula], where R ₄ is a hydrogen atom, a lower alkyl group; represents an alkyl, hydroxy lower alkyl or lower alkanoyloxy lower alkyl group, R ₅ is a group of the formula [Formula] [Here, R ₈ represents a hydrogen atom, R ₉ represents a hydrogen atom or a group of the formula -COR ₁₀
(R ₁₀ is a lower alkyl or hydroxy lower alkyl group), R ₆ is a hydrogen atom, A is a lower alkylene group, R ₇ is a pyridyl group, and B is a hydroxy group. or a group of the formula [Formula], where R ₁₄ and R ₁₅ each independently represent a hydrogen atom, lower alkyl, pyridyl lower alkyl, or hydroxy lower alkyl group, p represents 1 or 2; m is 0 or 1; and n represents an integer of 1 to 4. A compound which is a substituted benzylamine derivative or a salt thereof. 2. The compound according to claim 1, wherein the formula [Formula] represents a 1-pyrrolidinyl or 1-piperidinyl group optionally substituted with a hydroxy or methyl group. 3. Claim 1 in which n represents 1 or 2
A compound according to item 1 or item 2.