JPS63122676A - Phenyl(or phenylamino)alkylamine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A phenyl(or phenylamino)alkylamine derivative shown by formula I (R<1> is H, halogen or lower, alkyl; R<2> is group shown by formula II, group shown by formula III, etc.; R<3> and R<4> are H or lower alkyl with the proviso that R<3> and R<4> may be bonded to form morpholine ring or piperidine ring; a is methine group or N; B is lower alkylene; R<5> and R<6> are H, alkyl, pyridyl, thienyl, etc.; R<7> is H, lower alkyl or phenyl) or a salt thereof. EXAMPLE:2-{[N-3-Dimethylamino)propyl-N-phenyl]amino}-5-hexyl-4-methylt hiaz ole.fumarate. USE:Useful as a preventive and remedy for gastric diseases, such as inhibitor of secretion of acid in the stomach, preventive and remedy for gastric ulcer, etc., being orally or parenterally administered. PREPARATION:For example, a compound shown by formula IV is reacted with a haloketone shown by formula V is a solvent such as methanol, etc., under heating to give a compound shown by formula I.

Description

[Detailed description of the invention] (Field of application of the invention) The present invention is useful as a preventive and therapeutic agent for gastric diseases.

The present invention relates to phenyl (or phenylamino)alkylamine derivatives represented by the following general formula (I), salts thereof, and methods for producing these.

t [The symbols in the formula have the following meanings.

R1; May be substituted with a hydrogen atom, a halogen atom, or a halogen atom (lower alkyl group.

R3 and R4; same or different, a hydrogen atom; R5 and R6; same or different, a hydrogen atom.

Alkyl group, pyridyl group, chenyl group.

an adamantyl group, or a phenyl group optionally substituted with 1 to 3 lower alkoxy groups;

R7; hydrogen atom, lower alkyl group or phenyl group.

R8 and RQ; Same or different, hydrogen atom or alkyl group. (Prior art) (imidazol-2-yl)alkylamine derivatives having a substituted or unsubstituted phenyl group bonded to the 1-position of the alkylene chain are described in JP-A-56-90063.

(Detailed Description of the Invention) The present inventors have identified n+, K+-adenosine triphosphatase (hereinafter referred to as H", K"-ATPa).
As a result of intensive searches for compounds that have inhibitory activity against (referred to as se), it was found that a compound represented by the general formula (I) shown in the following figure shows remarkable efficacy, and the present invention was completed.

(Compound) The compound (I) of the present invention is a novel compound having a different ring group from the above-mentioned known compounds, and is characterized in that it has a pharmacological action not described in the above-mentioned known literature.

In the present invention, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

Therefore, the 'lower alkyl group' includes, for example, a methyl group, an ethyl group, and a propyl group in the A form.

Isopropyl group, butyl group, isobutyl group.

5ec-butyl group, tert-butyl group, pentyl group.

Impentyl group, neopentyl group, tert-pentyl group, ■-methylbutyl group, 2-methylbutyl group,
1.2-dimethylpropyl group, hexyl group.

Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1゜1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethyl Butyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1.2-)
Dimethylpropyl group.

1.2.2-1-dimethylpropyl group, ]-ethyl-1
-methylpropyl group, 1-ethyl-2-)propyl group, and the like.

Also,? Specific examples of lower alkoxy groups include methoxy, ethoxy, and propoquine groups.

Isopropoxy group, butoxy group, imbutoxy group・5
ee-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group + tert-pentyloxy group.

Hexyloxy group A linear or branched alkoxy group having 1 to 6 ring carbon atoms can be mentioned.

Furthermore, the r-lower alkylene group specifically includes a methylene group, an ethylene group, a methylmethylene group (-CH-), a trimethylene group, and a 1-methylene group.
H.

ethylene group (-CHCH2-), 2-methylethylethyltrimethylene group, 2-metholtrimethylene group, 3
-Methyltrinotylene group, 1-ethylethylene group, 2-
A straight chain with 1 to 6 carbon atoms such as ethylethylene group, hentamethylene group, l-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, hexamethylene group, etc. Chain or branched alkylene groups may be mentioned.

As the alkyl group represented by R5, R6, R8 or R9, linear or branched ones having 1 to 10 carbon atoms are particularly suitable, and specifically, in addition to the specific examples of lower alkyl groups mentioned above, , further n-hebutyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4
-Methylhexyl group, 5-methylhexyl group, 1,1-
Dimethylpentyl group, 1,2-dimethylpentyl group, 1
, 3-dimethylpentyl group, 1.4-dimethylpentyl group 2.2-dimethylpentyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 1-nitylpentyl group, 2-ethylpentyl group, 3 -ethylpentyl group, 1-ethyl-1-methylbutyl group, 1-ethyl-2
-methylbutyl group, l-ethyl-3-methylbutyl group,
2-ethyl-1-methylbutyl group.

2-ethyl-2-methylbutyl group, 1,1.2-trimethylbutyl group, 1,2.2-trimethylbutyl group, 1.2.3-t! , I methylbutyl group.

1.1.2-trimethylbutyl group, 1.2.2-trimethylbutyl group * J 2 + 3 )”J Methylbutyl group, 1-propylbutyl group, n-octyl group, 6-methylhebutyl group, n -nonyl group, 7-methyloctyl group, n-decyl group, 8-methylnonyl group, etc.

In addition, "halogen atoms" include heptadon atoms, chlorine atoms, bromine atoms, and iodine atoms, and "lower alkyl groups substituted with halogen atoms" refer to any hydrogen atom of the above-mentioned "lower alkyl group J". Examples include groups substituted with the above-mentioned r halogen atoms, and lower alkyl groups having 1 to 3 halogen atoms are particularly preferred.

In the case of a piperazine ring formed by combining R3 and R4 with a nitrogen atom, the nitrogen atom at position 4 of the piperazine ring may be substituted with a specific group of the above-mentioned lower alkyl group.

Compound (I) of the present invention forms a salt. The present invention also includes salts of compound (I). Specifically, such salts include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid.

Acid addition salts with organic acids such as acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, sulfuric acid, fumaric acid, tartaric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, etc.
Salts with acidic amino acids such as glutamic acid and aspartic acid, methyl chloride.

Examples include quaternary ammonium salts formed by bonding with alkyl halides such as methyl bromide and methyl iodide.

The compound (I) of the present invention includes compounds in which tautomers and optical isomers exist. The present invention also includes separated stereoisomers and mixtures thereof.

(Production method) The compound (I) of the present invention can be synthesized by various methods. Typical manufacturing methods are illustrated below.

1st manufacturing method (la) 2nd manufacturing method (I'll/) 3rd manufacturing method R (Ic) 4th manufacturing method R' (■) (Vllll) R'' (Id) 5th manufacturing method (■n (Is) 6th Manufacturing method R' (If) Seventh manufacturing method [In the reaction formula, R'l R2, R3, R', A, B
, R', R6, R1, R' and R9 have the above meanings, and other symbols have the following meanings.

Xl; halogen atom or organic sulfonic acid residue.

R10; lower alkyl group.

R11; hydrogen atom, halogen atom, or lower alkyl group.

R12: a hydrogen atom, a halogen atom, a lower alkyl group, or a group that can be converted into a lower alkyl group upon reduction.

RI4 and R15; the same or different hydrogen atoms, lower alkyl groups, or groups that can be converted into lower alkyl groups by reduction.

However, R14 and R15 are a group that can be combined with a nitrogen atom to form a morpholine ring, a group that can be converted into a morpholine ring by reduction, and a piperidine ring.

A group that can be converted into a piperidine ring by reduction.

Pyrrolidine ring, reduction produces pyrrolidine A group convertible into a ring, a piperazine ring or a ring A group that can be converted into a piperazine ring depending on the origin Form it (・Teroyoshi・).

B/11 Lower alkylene group or a group that can be converted into a lower alkylene group by reduction.

R5' and R6': Same or different hydrogen atom, alkyl group, group convertible into an alkyl group by reduction, pyridyl group, chenyl group.

Adamantyl group, 1 to 3 lower adamantyl groups Phenyl group optionally substituted with alkoxy group.

R'': a hydrogen atom, a lower alkyl group, a group convertible into a lower alkyl group by reduction, or a phenyl group.

R81 and R9': Same or different hydrogen atoms, alkyl groups, or groups that can be converted into alkyl groups upon reduction.

R16 and R17; the same or different lower alkyl groups.

However, R16 and R17 are combined with the nitrogen atom to form one morpholine ring or piperidine ring.

Substituted with pyrrolidine ring or lower alkyl group It forms a converted piperazine ring. Good too.

R18; lower alkyl group.

X2; halogen atom RI9: Lower alkyl group different from R18.

D: Tetramethylene group, pentamethylene group.

A group represented by the formula -(CH2)2- N-(CH2)2- or a group represented by the formula -(CH2)20 (CH2)2-.

R2°; lower alkyl group. ] Here, as the norogen atoms represented by XI and X2,
Examples include iodine atom, bromine atom and chlorine atom, and organic sulfonic acid residues include benzenesulfonyloxy group,
Examples include toluenesulfonyloxy group, methanesulfonyloxy group, ethanesulfonyloxy group, and the like. Further, as the group that can be transformed into a lower alkyl group, an alkyl group, a piperidine ring, a pyrrolidine ring, or a lower alkylene group by reduction, a corresponding group having a double or triple carbon-carbon bond is preferably used.

First Production Method Among the compounds of the present invention, the thiazole compound represented by the general formula (Ia) is produced by mesh cyclization of the thioamide compound represented by the general formula (II) and the α-no-loketones represented by the general formula (II). It can be produced by reaction, that is, by applying Hantzsch's thiazole synthesis method.

The reaction can proceed without a solvent, but if a solvent is used,
It is advantageous to use alcohols such as methanol, ethanol, and impropatol, organic solvents such as dioxane, benzene, and chloroform, water, or mixed solvents thereof.

Although the reaction proceeds at room temperature, it is usually preferable to carry out the reaction under heating, preferably under heating and reflux. The liquid nature of the reaction solution is preferably neutral to basic.

The amounts of raw material compounds used are compound (rI) and compound (In
) is approximately equal in mole, or it is appropriate to have a slight excess molar amount of one of them.

In addition, among the raw material compounds, a compound crr in which A is a methine group
a) is described in Section 2 below. In relation to the third production method, it is advantageous to synthesize by the method shown by the reaction formula below, and it can be easily obtained.

(XV) (XVI) N (XVII) (R', R3, R', B and X2 have the above meanings) In addition, the compound (IIb) in which A is a nitrogen atom,
It can be obtained by manufacturing according to the method shown in the reaction formula below.

(In the reaction formula, R', R3, R', and B have the above meanings.

Second Production Method The compound of general formula (Ib) can be produced by heating the compound represented by general formula (IV).

The reaction is carried out in an organic solvent such as methanol, ethanol, inpropatol, etc. by heating.

Compound (IV) can be isolated from the reaction mixture in the first stage and subjected to the main reaction, but the reaction mixture can also be subjected to the main reaction without being isolated.

In addition, compound (IV) can be obtained by the method shown by the following reaction formula.

The compound of the present invention having the general formula (Ic) can be produced by condensation cyclization of an amidine derivative represented by the general formula (V) and an acylacetate derivative represented by the general formula (Vl).

This reaction is usually advantageously carried out in an organic solvent at room temperature or under heating. (Leaking solvents include alcohols such as methanol, ethanol, isopropanol, etc.)
Dimethylformamide, dimethyl sulfoxide, dioxane, methylcellosolve, ethylcellosolve, diglyme and the like can be mentioned. A base as necessary during the reaction.

may be added as such a base.

Alkali metal alcolade, sodium hydroxide.

Potassium hydroxide is preferably used.

Note that the amounts of the raw material compounds (V) and (Vl) to be used may be approximately equal moles, and at a certain degree C., one may be used in a slightly excess molar amount than the other.

The compound of general formula (Ic) can also be produced by condensing and cyclizing a corresponding imidic acid ester with a 3-aminoacrylic acid derivative.

(In the reaction formula + R'+ R3t R', A + B
, R8, R9* R'' has the same meaning as above, R22
means a lower alkyl group) This reaction can be carried out under substantially the same reaction conditions as in the method using amidine as a raw material. That is, the amidine derivative and the 3-aminoacrylic acid derivative are dissolved in approximately equal moles, or one in slightly excess mole, in an organic solvent used in the method using the above-mentioned amidine as a raw material, and if necessary, the above-mentioned amidine is used as a raw material. Compound (Ic) can be obtained by adding the base used in the method and reacting with heating under reflux.

Note that the raw material compound (V) can be easily obtained by the reaction shown below.

/C% 1(IN NF(2.HCI (V) Fourth Production Method The compound of the present invention represented by the general formula (Id) is phenyl (
Alternatively, it is produced by reacting phenylamino)alkylhala ide (or sulfoxide) (1) with amine (~'II).

A compound in which X is a halogen atom is used as the raw material compound (■1).
In an organic solvent that does not participate in the reaction, such as toluene, chisol, dimethylformamide, dichloromethane, dichloroethane, methanol, or ethanol, use an equimolar to slightly excess molar amount of compound (Vlll) to compound (■1) at room temperature. It is advantageous to carry out the reaction under heating or under heating under reflux.

During this reaction, pyridine, picoIJ7. N,N-dimethylaniline, N-methylmorpholine.

It may be advantageous to add a secondary or tertiary base such as trimethylamine, triethylamine, dimethylamine, or an inorganic base such as potassium carbonate, sodium bicarbonate, or the like to make the reaction proceed smoothly.

Furthermore, in order to suppress side reactions, it is also possible to adopt a method in which a protecting group is introduced into the amine group of the compound (■), the reaction is caused, and the protecting group is removed after one reaction.

As such a protecting group, potassium phthalic acid imide is used as the compound (■), or a toluenesulfonyl group, an acetyl group, a phenacyl snophonyl group, or a trifluoromethanesulfonyl group.

Examples include bisbenzenesulfonyl group. Elimination of the protecting group can be easily accomplished by conventional hydrolysis using an acid, a base, or hydrazine monohydrate.

In the reaction using a compound having a side chain substituted with an organic sulfonic acid residue as the starting compound (■1), the compound having a side chain substituted with an organic sulfonic acid residue (■) and the compound having a side chain substituted with an organic sulfonic acid residue (■) are used in a reaction in which the starting material compound (■1) is equimolar to that of the compound (■) having a side chain substituted with an organic sulfonic acid residue. A slight molar excess of the compound (■) and an inert organic solvent 2 for the reaction, such as ether, methanol,
It is advantageous to carry out the reaction in ethanol, toluene, tetrahydrofuran, etc. under cooling at room temperature.The reaction time is appropriately set in consideration of various reaction conditions.

Fifth Production Method The compound of general formula (Ie) is produced in accordance with 1 by reducing the compound represented by general formula (rX).

The reduction is preferably carried out by catalytic reduction under a catalyst such as palladium, or by treatment with sodium in liquid ammonia. Catalytic reduction can also be carried out in an organic solvent such as toluene. The reducing agent is reduced to form the compound of the present invention (Ie
) are used in chemical equivalents, taking into account the presence of groups that give

Note that the raw material compound (IX) can be manufactured and obtained, for example, by the method shown below.

R'5 <XW> RIB (XXVI) (In the reaction formula, R'2. R", B', R14, R
IB has the above meaning, ph is a phenyl group, R2
3 and R24 have a protective group (having the meaning of R+4 and RIB which may be .) The compound of the present invention represented by the general formula (If) of the sixth production method is a
) can be produced by reacting the phenylamine derivative represented by () with an aminoalkyl halide or an aminoalkyl sulfonate.

The reaction is produced in the same manner as the fourth production.

Seventh Production Method When R3 and R4 in the compound of the present invention are the same lower alkyl group, the primary amine represented by the general formula (Ig) is substituted with a lower alkyl halide or a lower alkyl sulfonate represented by the general formula (■). It can be produced by reacting Ne-1.

The asymmetric dialkylamine 9 (N) is obtained by limiting the above reaction to the mono-lower alkylamine of the general formula (Ih) and allowing this compound (Ih) to act as a lower alkylno-ride different from the compound (Xll). Manufactured by.

Furthermore, a compound that forms a ring by combining with R3 and R4 of general formula (Ik) and a nitrogen atom can be obtained by reacting a primary amine represented by general formula (rg) with a civalide represented by general formula (XIV). Manufactured.

These reactions are carried out in substantially the same manner as the reactions using halides in the second production.

Compound (I) of the present invention produced by these various methods
is isolated and purified as a free compound or its salt. Salts can be produced by subjecting them to conventionally known salt-forming reactions. isolated.

Purification is also a chemical operation commonly used in the art.

For example, the compound (I) and its salt provided by the present invention are
It has gastric acid secretion suppressing action and antiulcer action, and is useful as a gastric acid secretion suppressing agent, gastric ulcer preventive and therapeutic agent, and other gastric disease preventive and therapeutic agents.

The gastric acid secretion suppressing action and anti-ulcer action of the compound of the present invention are expressed by the following H+, adenosine triphosphatase (
The following was confirmed by the inhibitory activity (ic, 50% inhibitory concentration) against H+ and K+ ATPase (B.
iochimica et biophisjca A
cta).

728, 31-38 (1983)].

The compound of the present invention has an IC10 of 30 according to this pharmacological test method.
It was confirmed that it is effective at µM or more.

The compound (I) of the present invention and its salts may be used as such or in a known pharmaceutically acceptable carrier.

It is used as a pharmaceutical composition mixed with excipients. Administration is in tablets, capsules, powders, and granules.

Oral administration such as pills, injections, syrups, and ointments.

It may be a deviation from parenteral administration such as in prison.

The dosage varies depending on the subject, administration route, symptoms, etc., but it is usually 40 to 400 mg orally per day for adults.
This is administered in divided doses 2 to 4 times a day.

(Example) EXAMPLES The present invention will be described in further detail with reference to Examples below.

However, the present invention is not limited to only those described in the examples.

In addition, the main raw material compounds used in the examples (
・Production Example 1 will be explained as a reference example. However, in the descriptions of Examples and Reference Examples, mp refers to melting point.

bp means boiling point, Mass means mass spectrum, and NMR means nuclear magnetic resonance spectrum.

Reference example I CH3 C1hi(2CN + C1α2CH, CH2N<.□3
- Oily (60 w/w%) sodium hydride 8 to 300 mt of dry 1,2-dimethoxyethane under HCI nitrogen atmosphere
．． 30.3 g of (p-chlorophenyl)acetonitrile and 24.2 g of chloropropylamine were added to a solution of 150 g of dried 1,2-dimethoxyethane under reflux.
A solution dissolved in m1 is added dropwise over 30 minutes. After continuing to reflux at ℃ for 3 hours, the solvent was distilled off under reduced pressure.

Dilute hydrochloric acid was added to the residue to adjust the pH to 2, and the mixture was washed with ether. Then, the pH was adjusted to 8 with a concentrated aqueous potassium hydroxide solution, and the mixture was extracted with chloroform.

The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then distilled.

bpH6~117°c10.65mm HgMass
(CI) rv'z 237 (M”+1) Reference example
2-5 The following compounds were obtained in the same manner as in Reference Example 1.

Reference Example 6 11.84 g of 2-(p-10lophenyl)-5-dimethylaminopentanenitrile was mixed with 7.0 g of triethylamine.
Hydrogen sulfide gas was passed through the solution in 0 ml and 12 g of pyridine for 8.5 hours while cooling with water, and the mixture was stirred for 3 days while the mixture was sealed. This solution was poured into ice water, and the precipitated crystals were
The mixture was washed with water first and then with ether to obtain 10.5 g of middide.

mp 120-122°C Mass (El) m/z, 270 (M+) Reference Examples 7-10 The following compounds were obtained in the same manner as in Reference Example 6.

Reference Example 11 7903 g of Nl2 (3-dimethylamino)probylanili is dissolved in 90 ml of chloroform, 9.1 g of penzoylthioisocyanate) is added thereto, and the mixture is stirred under reflux for 6 hours.

Then, the solvent was distilled off under reduced pressure, and 50 mt of a 30% methanol solution of methylamine was added to the residue.

After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure.

Dilute hydrochloric acid was added to the residue to adjust the pH to 2, and the mixture was washed with ether and then with dichloromethane. This aqueous layer was adjusted to pH=9 with a potassium carbonate aqueous solution.

After extraction with dichloromethane and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure71),
N-(3-dimethylamine)propyl-N-phenylthiourea was obtained. This was not purified further (used in the next reaction).

Mass m/z 237 (M”) E ICl3
(CH2), CHl HOOC-CH CH-COOH 0.59 g of N-(3-dimethylaminopropyl)-N-phenylthiourea obtained in Reference Example 11 and 0.55 g of 3-promo-2-oxononane were added to 4 ml of ethanol.
and stir overnight at room temperature. After the solvent was distilled off under reduced pressure, the mixture was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography and recrystallized from ethanol-acetonitrile as the 7-malate salt.
0.36 g of -[[N-(3-dimethylamino)propyl-N-phenyl]amino]-5-hexyl-4-methylthiazole fumarate was obtained.

mp 104-106℃ Mass (EI) (m/z) 359 (M") Anal (C, IH3, N, S-C,) (as 40) e (@H (chi) N (%) S ( %) Calculated value 63.13 7.84 8,83 6.74 Actual value 63.03 7.78 8,76 6.74 Example
2 The following compound was obtained in the same manner as in Example 1.

Reference example 12゜4-(1-pyrrolidinyl)-1-(3-trif/l/
, +i myromethylphenylbutyronitrile 4.41 g
'i = Dissolve 30 m of minichloroform, add 1.1 g of anhydrous ethanol, and bring to saturation by passing hydrogen chloride gas under cooling with water. After further stirring at 5°C for 5 days, one reaction solution was poured into 100 mt of 20% potassium carbonate aqueous solution under water cooling.
Extract twice with 70rnl chloroform. After drying the extracted solution with anhydrous magnesium sulfate.

After filtration and concentration under reduced pressure, 5.06 g i! %is.

This product was used in the next reaction without purification.

NMR (δ: in CDC15) 1.24 (3H,t), 1.64-2.60 (
12H, m), 3.68 (LH, t).

4.12 (2H, q), 7.10 (IH, bs),
7.40~7.72 (4H, m) Mass (m/z)
: 329 (M++ 1) Reference Example 13゜2.1 g of ethyl 4-(1-pyrrolidinyl)-2-(m-trifluoromethylphenyl)butylimide) obtained in Reference Example 12 was dissolved in 25 m4 of methanol, and ammonium chloride was dissolved. After adding 0.34g.

Stir overnight at room temperature. The solvent was distilled off under reduced pressure, treated with activated carbon using an ethanol solution, and then filtered.

Distillation under reduced pressure, crystallization by adding ether to the resulting residue, and recrystallization from ethanol-ether yielded 4-(1-pyrrolidinyl)-2-(m-)lifluoromethylphenyl)butyramidine hydrochloride. 2.2
I got 5g.

NMR (δ: in DMS 026) 1.70-2.
20 (4H, m), 2.40~3.24 (6H,
m), 3.40-3.70 (211, m), 4.1
4 (IH, t), 7.60-8.06 (4H, m
).

9.10 (LH, d), 9.64 (LH, s), 1
1. ．． 33 (IH, bs) Mass (m/z):
300 (M+) Example 3 087 g of 2-(P-chlorophenyl)-5-dimethylaminopentanethioamide and 0.68 g of 3-bromo-2-ocyneoctane are added to 5 m of ethanol and stirred under reflux for 6 hours. Then, the solvent was distilled off.

2-[[1
-(p-chlorophenyl)-4-dimethylamino]butyl]-4-methyl-5=pentylthiazole fumaray)1. :33g was obtained.

mp 118-120℃ bias (FAB) (
m/z) 379 (M”+ 1) Anal (C
21H3,N,5CI-C,H,04--! As LH20) CHN S C1 Calculated value (%) (50,217,165,626,,43
7,11 Actual value (%) 60.21 7.03 5.
53 6.41 7.38 Examples 4 to 28 The following compounds were obtained in the same manner as in Example 3.

Reference example 14 Ethyl-4-(l-pyrrolidinyl) = 2- (3-
trifluoromethylphenyl) butylimide at 6 °C
Heat for 5 hours. From now on, 30m of ethanol! As a solution,
After adding 150,111 g of activated carbon and stirring for 30 minutes.

Filter and remove the solvent under reduced pressure. Ethanolic hydrogen chloride was added to the residue, and the resulting crystals were recrystallized from ethanol-isopropyl ether. -Phenyl-IH-1,2°4-triazole hydrochloride 0.5 g was obtained.

m2206~207°C Mass (m/z): 400 (M”) Ana l (
C22H24N4 F3 (as Cl) C (%) H
(%) N (%) CI (%) F (%) Calculated value 60,
48 5.54 12.82 8.11 13.05
□ Actual value 60°33 5.48 12.78
8.23 2.5 g of 13.04 g of methanol 20 r
Add 1.04 g of benzoylhydrazine and stir at room temperature for 26 hours. 1. Separate the precipitated crystals, wash with an ethanol-ether mixture, and dry under reduced pressure to obtain N-benzoyl-4-(l). -pyrrolidinyl)
2.2O2 of 2-(m-trifluoromethylphenyl)butylamithracine was obtained. This product was used in the next reaction without purification.

NMR (δ: CDCl,) 1.64-2.0O (4H,
m), 2.04-2.72° (8H, m), 4.12 (
t, LH), 7.18-7.92 (9H, rn) Mas
s (m/z): 418 (M”) Example 29 N-benzoyl-4-(1-pyrrolidinyl)-2-(m
Example 30 1.05 g of trifluoromethylphenyl)butylamithracine was dissolved under reduced pressure using an aspirator in 30 m/m of absolute ethanol in a nitrogen stream, and then 0.96 g of powdered sodium methylate was dissolved. Water cooling 4
-Pyrrolidinyl-2-(m-trifluoromethylphenyl)butyramidine hydrochloride 2.0g dissolved in methanol f'
1110 mt is added dropwise in 15 minutes. Then ethyl-α-
Ethanol solution 1 of 1.38 g of n-hexyl acetate
After dropping 0 ml over 15 minutes, the mixture was returned to room temperature and stirred for 14 hours. After filtering the precipitated salt, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography using chloroform-methanol-ammonia water (90:10:l) as a developing solvent, and 170 mg of fumaric acid was extracted with ethanol. Add the solution to the resulting crystals.

By recrystallizing from acetonitrile, 5-hexyl-2-43-(1-pyrrolidinyl)-1-(m-trifluoromethylphenyl)]]propyl-6-methyl-4(IH)-pyrimide/·7malate 07g of was obtained.

m p 178~179°C Mass, (m/z): 450 (M”+1) (
FAB ) Anal (as C2gH38N305F3) C (%) H (%) N (%) F (%) Calculated value 61.58 6.77 7.43 10.08 Actual value 61.42 6.71 7.40 10. 08 Example 31 The following compound was obtained in the same manner as in Example 30.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [Symbols in the formula have the following meanings. R^1; Hydrogen atom, halogen atom, or lower alkyl group optionally substituted with a halogen atom, R^2; Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Groups represented by ▼, formula ▲ Numerical formula, chemical formula, There are tables, etc. ▼ Groups, or formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ Groups R^3 and R^4; Same or different, hydrogen atom or lower alkyl group. However, R^3 and R^4 may be combined with the nitrogen atom to form a morpholine ring, a piperidine ring, a pyrrolidine ring, or a piperazine ring. A: Methine group (▲There are mathematical formulas, chemical formulas, tables, etc.▼) or nitrogen atoms (▲There are mathematical formulas, chemical formulas, tables, etc.▼) B: Lower alkylene groups R^5 and R^6: Same or different, Hydrogen atom, alkyl group, pyridyl group, thienyl group, adamantyl group, or phenyl group optionally substituted with 1 to 3 lower alkoxy groups, R^7; Hydrogen atom, lower alkyl group, or phenyl group, R^ 8 and R^9; the same or different, hydrogen atom or alkyl group. ] A phenyl (or phenylamino) alkylamine derivative or a salt thereof. 2. General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the method for producing the phenyl (or phenylamino) alkylamine derivative represented by (I), (a) General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) React the thioamide compound shown by the general formula (III) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (III) React with the haloketones shown by the general formula (III), or (b) General formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) By heating the amidrazone derivative represented by (IV) or (c) General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) A manufacturing method that involves reacting the general formula (VI) with acylacetic acid esters represented by the formula (VI). [The symbols in the above general formula have the following meanings. R^1: Hydrogen atom, halogen atom, or lower alkyl group optionally substituted with a halogen atom, R^2; Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Groups represented by ▼, ▲ Numerical formulas, chemical formulas, tables, etc. etc. Groups represented by ▼, or groups represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼, R^3 and R^4; Same or different, hydrogen atom or lower alkyl group. However, R^3 and R^4 may be combined with the nitrogen atom to form a morpholine ring, a piperidine ring, a pyrrolidine ring, or a piperazine ring. A: Methine group (▲There are mathematical formulas, chemical formulas, tables, etc.▼) or nitrogen atoms (▲There are mathematical formulas, chemical formulas, tables, etc.▼), B: Lower alkylene group, R^5 and R^6: Same or different a hydrogen atom, an alkyl group, a pyridyl group, a thienyl group, an adamantyl group, or a phenyl group optionally substituted with 1 to 3 lower alkoxy groups, R^7; a hydrogen atom, a lower alkyl group, or a phenyl group, R^8 and R^9; same or different; hydrogen atom or alkyl group; X^1; halogen atom or organic sulfonic acid residue; R^1^0; lower alkyl group. ]