JPH07179337A - Antithrombotic agent containing alkyl-phenoxyalkylamine derivative as active ingredient - Google Patents

Abstract

PURPOSE:To obtain an agent for treating and preventing circulatory diseases, containing an alkyl-phenoxyalkylamine derivative having strong and selective serotonin 2 receptor antagonism as an active ingredient. CONSTITUTION:This antithrombotic agent contains a compound of the formula {R<1> is a 1-12C alkyl or A-R<3> (R<3> is a substitutable 3-7C cycloalkyl; A is a substitutable 2-6C alkylene); R<2> is B-NR<4>R<5> [R<4> and R<5> each is H, a substitutable 1-4C alkyl or they form a 3-6 membered cyclic heterocyclyl containing N, O or S together with binding N; B is a 2-5C alkylene, CH2CH(OR<6>)CH2 (R<6> is H, a 1-5C alkanoyl, a 6-10C arylacyl, etc.)], D-R<7> (R<7> is a 5-6 membered cyclic saturated heterocycle; D is a single bond or a 1-4C alkylene)} or its pharmacologically permissible salt, e.g. N,N-methyl-3-[2-(4-methylpentyl) phenoxy]propylamine as an active ingredient.

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

BACKGROUND OF THE INVENTION The present invention provides an excellent serotonin 2
The present invention relates to an antithrombotic agent containing an alkyl-phenoxyalkylamine derivative having a receptor antagonistic action or a pharmacologically acceptable salt thereof as an active ingredient.

[0003]

BACKGROUND OF THE INVENTION Serotonin is classically classified as an autacoid, is also known as a neurotransmitter, and exhibits various physiological actions in vivo through various receptors. It is known that there are various subtypes of this serotonin receptor, but in the circulatory system, receptors classified as serotonin 2 receptors are distributed in vascular endothelial cells and platelets, and It is deeply involved in contraction and aggregation of platelets (for example, SJ Peroutka et al., Federation Proceedings, 42, 213 (19)
(1983): SJ Peroutka et. Al., Fed. Proc., 42 , 213
(1983)), the antagonist is useful for preventing vasoconstriction and inhibiting platelet aggregation. Currently, ketanserin is known as a serotonin 2 receptor antagonist (for example, J.
I S Robertson, Current Opinion in Cardiology, Volume 3, 702 (1988): JI
S. Robertson, Curr. Opinion Cardiol., 3 , 702 (198
8)), this drug was developed as an adrenergic α ₁ antagonist and has the drawback of having a strong antihypertensive effect. In addition, MCI-9042 and the like have recently been reported as platelet aggregation inhibitors having serotonin 2 receptor antagonistic activity (eg, Journal of Medicinal Chemistry, Vol. 35, p. 189, (1992). ): J. Med. Che
m., 35 , 189 (1992)), but these do not show an adrenergic α ₁ antagonism, but the serotonin 2 receptor antagonism is not sufficient. Therefore, in order to obtain clinical effects, development of a drug having a strong and selective serotonin 2 receptor antagonistic action has been desired.

[0004]

[Chemical 2]

In the phenoxyalkylamine derivative, for example, the following compounds A and B are known to have an antihistamine action [Japanese Patent Publication No. 52-14, Journal of Medicinal Chemistry,
Volume 20, P. 1317 (1977): J. Med. Che
m., 20 , 1317 (1977), etc.].

[0006]

[Chemical 3]

[0007]

The present inventors have, over the years, synthesized a series of phenoxyalkylamine derivatives and investigated their pharmacological actions. As a result, MCI-
Alkyl-phenoxyalkylamine derivatives, which are structurally different from 9042, do not show adrenergic α ₁ antagonism, have strong serotonin 2 receptor antagonism, inhibit platelet aggregation, and treat cardiovascular diseases Further, they have found that they are useful as preventive agents, and have completed the present invention.

[0008]

[Constitution of the invention]

[0009]

The alkyl-phenoxyalkylamine derivative, which is the active ingredient of the present invention, has the general formula:

[0010]

[Chemical 4]

[0011]

In the above formula, R ¹ is a C ₁ -C ₁₂ alkyl group or a formula -A-R ³ (wherein R ³ is a C ₃ -C ₇ cycloalkyl group or hydroxy, C ₁ -C ₄ alkoxy). or shows a C ₃ -C ₇ cycloalkyl group substituted with halogen, a is a group having a.) showing a C ₂ -C ₆ alkylene group substituted by a C ₂ -C ₆ alkylene group or a hydroxy or halogen And R ² is of the formula −B−N
R ⁴ R ⁵ [wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a C ₁ -C ₄ alkyl group or hydroxy,
Alternatively or showing a di -C ₁ -C ₄ alkylamino or C ₁ -C ₄ alkyl group substituted with C ₆ -C ₁₀ aryl,
Represents a 3- to 6-membered cyclic heterocyclyl group containing a nitrogen, oxygen or sulfur atom together with a nitrogen atom bonded thereto, B
Is a C ₂ -C ₅ alkylene group or the formula —CH ₂ CH (O
R ⁶ ) CH ₂ — (In the formula, R ⁶ is a hydrogen atom, C ₁ -C ₅
Shows the alkanoyl group, C ₂ -C ₅ alkanoyl group or a C ₆ -C ₁₀ aryl acyl groups substituted with carboxy. ) Is shown. ] Or a group of formula -D-
R ⁷ (wherein, R ⁷ represents a 5- to 6-membered cyclic saturated heterocyclyl group containing a nitrogen, oxygen or sulfur atom, and D is
It represents a single bond or a C ₁ -C ₄ alkylene group. However, R ⁷
The heterocyclyl group of has a bond on its cyclic carbon atom. ) Is shown.

The C ₁ -C ₁₂ alkyl group of R ¹ is, for example,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 2-ethylpropyl,
Hexyl, 1-methylpentyl, 2-methylpentyl,
3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 3-ethylpentyl, octyl , 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 3-ethylhexyl, 4-ethylhexyl, 3-propynepentyl, nonyl, 3-methyloctyl, 3-ethylhexyl, 3-propyhexyl , A decyl, undecyl or dodecyl group, preferably a C ₄ -C ₁₀ alkyl group, more preferably a C ₅ -C ₈ alkyl group, even more preferably 3-methylbutyl, Hexyl, 3-methylpentyl, 4-methylpentyl, heptyl, 3-methylhexyl, 4-methylhexyl Le, 5-methylhexyl, 3-ethylpentyl, octyl, 3-ethylhexyl or 4
It is an ethylhexyl group, particularly preferably a 4-methylpentyl group.

The C ₃ -C ₇ cycloalkyl group of R ³ can be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, preferably a cyclopentyl or cyclohexyl group.

The C ₁ -C ₄ alkoxy group contained in R ³ may be, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy or t-butoxy group, preferably methoxy or An ethoxy group, particularly preferably a methoxy group.

The halogen atom contained in R ³ or A is
For example, it may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

The hydroxy, C ₁ -C ₄ alkoxy or halogen-substituted C ₃ -C ₇ cycloalkyl group of R ³ is, for example, 2-hydroxycyclopropyl, 2-
Fluorocyclopropyl, 3-hydroxycyclobutyl, 3-fluorocyclobutyl, 3-chlorocyclobutyl, 3-methoxycyclobutyl, 3-hydroxycyclopentyl, 3-fluorocyclopentyl, 3-chlorocyclopentyl, 3-methoxycyclopentyl, 3- Ethoxycyclopentyl, 3- or 4-hydroxycyclohexyl, 3- or 4-fluorocyclohexyl, 3- or 4-chlorocyclohexyl, 3- or 4-methoxycyclohexyl, 3- or 4-ethoxycyclohexyl, 3- or 4-propoxycyclohexyl , 3- or 4-butoxycyclohexyl, 3-hydroxycycloheptyl, 3-fluorocycloheptyl or 3-methoxycycloheptyl group, preferably 3-hydr Carboxymethyl cyclopentyl, 3-fluoro-cyclopentyl, 3-methoxy-cyclopentyl,
3- or 4-hydroxycyclohexyl, 3- or 4-fluorocyclohexyl, 3- or 4-chlorocyclohexyl, 3- or 4-methoxycyclohexyl or 3- or 4-ethoxycyclohexyl group, particularly preferably 3- Methoxycyclopentyl or 3- or 4-methoxycyclohexyl group.

The C ₂ -C ₆ alkylene group of A is, for example,
Ethylene, propylene, trimethylene, be a tetramethylene, pentamethylene or hexamethylene group, preferably a C ₂ -C ₄ alkylene group, particularly preferably an ethylene group.

The C ₂ -C ₆ alkylene group substituted with hydroxy or halogen of A is, for example, 2-hydroxyethylene, 2-fluoroethylene, 2-chloroethylene,
2-bromoethylene, 2-iodoethylene, 3-hydroxytrimethylene, 3-chlorotrimethylene, 4-hydroxytetramethylene, 4-chlorotetramethylene, 5
-Hydroxypentamethylene, 5-chloropentamethylene, 6-hydroxyhexamethylene or 6-chlorohexamethylene group, preferably 2-hydroxyethylene, 2-fluoroethylene, 2-chloroethylene, 2
-Bromoethylene, 2-iodoethylene, 3-hydroxytrimethylene, 3-chlorotrimethylene, 4-hydroxytetramethylene or 4-chlorotetramethylene group, more preferably 2-hydroxyethylene, 2-fluoroethylene. , 2-chloroethylene or 2-bromoethylene group, particularly preferably 2-chloroethylene group.

The C ₁ -C ₄ alkyl group of R ⁴ , R ⁵ etc. or contained in R ⁴ , R ⁵ etc. is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s.
It may be a -butyl or t-butyl group, preferably a methyl or ethyl group, particularly preferably a methyl group.

The aryl part of the C ₆ -C ₁₀ aryl acyl group C ₆ -C ₁₀ aryl group or R ⁶ contained in R ⁴ and R ⁵ may be a phenyl or naphthyl group, preferably is a phenyl group . Further, the ring may have a substituent, which may be the above-mentioned C ₁ -C ₄ alkyl group, C ₁ -C
₄ may be an alkoxy group, a halogen atom or a nitro group,
It is preferably a methyl group, a methoxy group, a fluorine atom or a chlorine atom.

R ⁴ and R ⁵ hydroxy, di C ₁ -C
Examples of the C ₁ -C ₄ alkyl group substituted with ₄ alkylamino or C ₆ -C ₁₀ aryl include 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2- (N, N-dimethylamino) ethyl, 2-
(N, N-diethylamino) ethyl, 3- (N, N-dimethylamino) propyl, benzyl, phenethyl, 3-
It may be a phenylpropyl, 4-phenylbutyl, diphenylmethyl, 1-naphthylmethyl or 2-naphthylmethyl group, preferably 2-hydroxyethyl, 3-hydroxypropyl, 2- (N, N-dimethylamino) ethylbenzyl or A phenethyl group, more preferably 2-
Hydroxyethyl, 2- (N, N-dimethylamino) ethyl or benzyl group.

A 3- to 6-membered cyclic heterocyclyl group containing a nitrogen, oxygen or sulfur atom which is formed together with the nitrogen atom to which R ⁴ and R ⁵ are bonded is, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, It may be 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-triazinyl or 1-tetrazolidinyl group, preferably 1-azetidinyl, 1-pyrrolidinyl, 1-. A piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-imidazolidinyl or 1-pyrazolidinyl group, more preferably 1
A pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl or 1-imidazolidinyl group. Further, a carbon atom on the heterocycle or a 4-position of the piperazinyl group may have a substituent, which is hydroxy (only carbon atom on the heterocycle), the above-mentioned C ₁ -C ₄
Alkyl group, hydroxy-C ₁ -C ₄ alkyl group or C
It may be a _6- C ₁₀ aryl group, preferably a hydroxy (only carbon atoms on the heterocycle), methyl, ethyl, hydroxyethyl or phenyl group. Specific examples thereof are, for example, 4-phenylpiperazino, 4-methylpiperazino, 4-phenylpiperidino, 4-methylpiperidino or 4-hydroxypiperidino groups.

The C ₂ -C ₅ alkylene group of B is, for example,
It may be an ethylene, propylene, trimethylene, tetramethylene or pentamethylene group, preferably an ethylene or trimethylene group.

The C ₁ -C ₅ alkanoyl group of R ⁶ can be, for example, a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or pivaloyl group, preferably an acetyl or propionyl group.

C ₂ -C ₅ substituted with R ⁶ carboxy
The alkanoyl group is, for example, succinyl, glutaryl,
It may be an adipoyl or pimeloyl group, preferably a succinyl or glutaryl group.

The 5- to 6-membered cyclic saturated heterocyclyl group containing a nitrogen, oxygen or sulfur atom of R ⁷ can be, for example, a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group, preferably pyrrolidinyl, piperidinyl, morpholinyl. Or a thiomorpholinyl group, more preferably a pyrrolidinyl, piperidinyl or morpholinyl group. In addition, the ring may have a substituent, which may be used as a substituent on the carbon atom, which is the above-mentioned C ₁ -C ₄ alkyl group, hydroxy group, the above-mentioned C ₁ -C ₄ alkoxy group, A C ₁ -C ₅ alkanoyloxy group (the alkanoyl part of the group is as described above), a C ₂ -C ₅ alkanoyloxy group substituted with carboxy (the alkanoyl part of the group is the same as those described above). .), Carbamoyloxy group or mono-C ₁ -C
₄ alkyl or di-C ₁ -C ₄ alkylcarbamoyl group (the alkyl portion of the group is. For what was described above) to give a, preferably, methyl, ethyl, hydroxy, methoxy, ethoxy, acetyloxy, propionyl Oxy, succinyloxy, glutaryloxy, carbamoyloxy, N-methylcarbamoyloxy, N-
An ethylcarbamoyloxy group, an N, N-dimethylcarbamoyloxy group or an N, N-diethylcarbamoyloxy group, more preferably a methyl, hydroxy, acetyloxy, succinyloxy, carbamoyloxy or N, N-dimethylcarbamoyloxy group. And also
The substituent on the nitrogen atom may be the above-mentioned C ₁ -C ₄ alkyl group, preferably a methyl or ethyl group.

Further, specific examples of the 5- to 6-membered cyclic saturated heterocyclyl group containing a nitrogen, oxygen or sulfur atom of R ⁷ are, for example, pyrrolidinyl, 1-methylpyrrolidinyl, 1-ethylpyrrolidinyl, 1 -Propylpyrrolidinyl, 1-isopropylpyrrolidinyl, 1-butylpyrrolidinyl, hydroxypyrrolidinyl, methoxypyrrolidinyl, ethoxypyrrolidinyl, propoxypyrrolidinyl,
Isopropoxypyrrolidinyl, butoxypyrrolidinyl,
Formyloxypyrrolidinyl, acetyloxypyrrolidinyl, propionyloxypyrrolidinyl, butyryloxypyrrolidinyl, pivaloyloxypyrrolidinyl, valeryloxypyrrolidinyl, (succinoyloxy) pyrrolidinyl, (gluta (Royloxy) pyrrolidinyl, (carbamoyloxy) pyrrolidinyl, (N-methylcarbamoyloxy) pyrrolidinyl, (N-ethylcarbamoyloxy) pyrrolidinyl, (N, N-dimethylcarbamoyloxy) pyrrolidinyl, (N, N-diethylcarbamoyloxy) pyrrolidinyl , (N-methyl-N-ethylcarbamoyloxy) pyrrolidinyl, 1-methyl-hydroxypyrrolidinyl, 1-methyl-methoxypyrrolidinyl, 1-methyl-ethoxypyrrolidinyl, 1-methyl-acetyloxy Loridinyl, 1-methyl-propionyloxypyrrolidinyl, 1-methyl- (succinoyloxy) pyrrolidinyl, 1-methyl- (glutaroyloxy) pyrrolidinyl, 1-methyl- (carbamoyloxy) pyrrolidinyl, 1-methyl- ( N-methylcarbamoyloxy) pyrrolidinyl, 1-methyl- (N-ethylcarbamoyloxy) pyrrolidinyl, 1-methyl-
(N, N-dimethylcarbamoyloxy) pyrrolidinyl, 1-methyl- (N, N-diethylcarbamoyloxy) pyrrolidinyl, 1-methyl- (N-methyl-N-ethylcarbamoyloxy) pyrrolidinyl, 1-ethyl-
Hydroxypyrrolidinyl, 1-ethyl-methoxypyrrolidinyl, 1-ethyl-acetoxypyrrolidinyl, 1-ethyl- (succinoyloxy) pyrrolidinyl, piperidinyl, 1-methylpiperidinyl, 1-ethylpiperidinyl , 1-propylpiperidinyl, 1-isopropylpiperidinyl, 1-butylpiperidinyl, hydroxypiperidinyl, methoxypiperidinyl, ethoxypiperidinyl, acetyloxypiperidinyl, propionyloxypiperidinyl, sucrose Cinoyloxypiperidinyl, glutaroyloxypiperidinyl, carbamoyloxypiperidinyl, (N-methylcarbamoyloxy) piperidinyl, (N-ethylcarbamoyloxy) piperidinyl, (N, N-dimethylcarbamoyloxy) piperidinyl, 1 -Methyl- ( - methyl -N- ethylcarbamoyl oxy) piperidinyl, 1-methyl - hydroxy piperidinylmethyl, 1-methyl - methoxy piperidinylmethyl, 1-
Methyl-ethoxypiperidinyl, 1-methyl-acetyloxypiperidinyl, 1-methyl-propionyloxypiperidinyl, 1-methyl- (succinoyloxy) piperidinyl, 1-methyl- (N-methylcarbamoyloxy) Piperidinyl, 1-methyl-carbamoyloxypiperidinyl, 1-methyl- (N-ethylcarbamoyloxy) piperidinyl, 1-methyl- (N, N-dimethylcarbamoyloxy) piperidinyl, 1-methyl-
(N-methyl-N-ethylcarbamoyloxy) piperidinyl, 1-ethyl-hydroxypiperidinyl, 1-ethyl-methoxypiperidinyl, 1-ethyl-ethoxypiperidinyl, 1-ethyl-acetoxypiperidinyl, 1
-Ethyl-succinoyloxypiperidinyl, piperazinyl, 1,4-dimethylpiperazinyl, morpholinyl,
4-methylmorpholinyl, 4-ethylmorpholinyl, 4
-Propylmorpholinyl, 4-isopropylmorpholinyl, 4-butylmorpholinyl, thiomorpholinyl, 4-
It may be a methylthiomorpholinyl, 4-ethylthiomorpholinyl, 4-propylthiomorpholinyl, 4-isopropylthiomorpholinyl or 4-butylthiomorpholinyl group, preferably pyrrolidinyl, 1-methyl. Pyrrolidinyl, 1-ethylpyrrolidinyl, 4-hydroxy-2-
Pyrrolidinyl, 4-methoxy-2-pyrrolidinyl, 4-
Formyloxy-2-pyrrolidinyl, 4-acetyloxy-2-pyrrolidinyl, 4-pivaloyloxy-2-pyrrolidinyl, 4-valeryloxy-2-pyrrolidinyl,
4- (succinoyloxy) -2-pyrrolidinyl, 4-
(Glutaroyloxy) -2-pyrrolidinyl, 4- (carbamoyloxy) -2-pyrrolidinyl, 4- (N-methylcarbamoyloxy) -2-pyrrolidinyl, 4-
(N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 4- (N-methyl-N-ethylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4- Methoxy-2
-Pyrrolidinyl, 1-methyl-4-acetyloxy-2
-Pyrrolidinyl, 1-methyl-4-succinoyloxy-2-pyrrolidinyl, 1-methyl-4-glutaroyloxy-2-pyrrolidinyl, 1-methyl-4- (carbamoyloxy) -2-pyrrolidinyl, 1-methyl -4-
(N-methylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-4- (N-
Methyl-N-ethylcarbamoyloxy) -2-pyrrolidinyl, 1-ethyl-4-hydroxy-2-pyrrolidinyl, 1-ethyl-4-methoxy-2-pyrrolidinyl, 1
-Ethyl-4-acetoxy-2-pyrrolidinyl, 1-ethyl-4-succinoyloxy-2-pyrrolidinyl, piperidinyl, 1-methylpiperidinyl, 1-ethylpiperidinyl, hydroxypiperidinyl, methoxypiperidinyl Nyl, acetyloxypiperidinyl, succinoyloxypiperidinyl, glutaroyloxypiperidinyl, carbamoyloxypiperidinyl, (N-methylcarbamoyloxy) piperidinyl, (N, N-dimethylcarbamoyloxy) piperidinyl, ( N-methyl-N-ethylcarbamoyloxy) piperidinyl, 1-methyl-hydroxypiperidinyl, 1-methyl-methoxypiperidinyl, 1-methyl-acetyloxypiperidinyl, 1-
Methyl- (succinoyloxy) piperidinyl, 1-methyl-carbamoyloxypiperidinyl, 1-methyl-
(N-methylcarbamoyloxy) piperidinyl, 1-
Methyl- (N, N-dimethylcarbamoyloxy) piperidinyl, 1-ethyl-hydroxypiperidinyl, 1-
Ethyl-methoxypiperidinyl, 1-ethyl-acetoxypiperidinyl, 1-ethyl-succinoyloxypiperidinyl, piperazinyl, 1,4-dimethylpiperazinyl, morpholinyl, 4-methylmorpholinyl, 4- Ethylmorpholinyl, 4-propylmorpholinyl, 4-isopropylmorpholinyl, 4-butylmorpholinyl, thiomorpholinyl, 4-methylthiomorpholinyl, 4-ethylthiomorpholinyl, 4-propylthiomorpholinyl ,
4-isopropylthiomorpholinyl or 4-butylthiomorpholinyl group, more preferably pyrrolidinyl,
1-methyl-2-pyrrolidinyl, 1-methyl-3-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-methoxy-2-pyrrolidinyl, 4-acetyloxy-2-
Pyrrolidinyl, 4- (succinoyloxy) -2-pyrrolidinyl, 4- (glutaroyloxy) -2-pyrrolidinyl, 4- (carbamoyloxy) -2-pyrrolidinyl, 4- (N-methylcarbamoyloxy) -2- Pyrrolidinyl, 4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-methoxy-2-
Pyrrolidinyl, 1-methyl-4-acetyloxy-2-
Pyrrolidinyl, 1-methyl-4-succinoyloxypyrrolidinyl, 1-methyl-4-glutaroyloxy-2
-Pyrrolidinyl, 1-methyl-4-carbamoyloxy-2-pyrrolidinyl, 1-methyl-4- (N-methylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-
4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 1-ethyl-4-hydroxy-2-pyrrolidinyl, 1-ethyl-4-acetoxy-2-pyrrolidinyl, 1-ethyl-4-succinoyloxy 2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl-2-piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, piperazinyl, 1,4-dimethylpiperazinyl 2
-Morpholinyl, 4-methyl-2-morpholinyl, 4-
An ethyl-2-morpholinyl, 2-thiomorpholinyl or 4-methyl-2-thiomorpholinyl group, and even more preferably 2-pyrrolidinyl, 3-pyrrolidinyl, 1-
Methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-methoxy-2-pyrrolidinyl, 4-acetyloxy-2-pyrrolidinyl, 4- (succinoyloxy) -2-pyrrolidinyl, 4- (carbamoyloxy) -2-Pyrrolidinyl, 4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-4
-Hydroxy-2-pyrrolidinyl, 1-methyl-4-methoxy-2-pyrrolidinyl, 1-methyl-4-acetyloxy-2-pyrrolidinyl, 1-methyl-4-succinoyloxy-2-pyrrolidinyl, 1-methyl -4-carbamoyloxy-2-pyrrolidinyl, 1-methyl-4-
(N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl-2-piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 2-morpholinyl, 4-methyl-2-morpholinyl or 2-thiomorpholinyl group, particularly preferably 2
-Pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-
Hydroxy-2-pyrrolidinyl, 4-methoxy-2-pyrrolidinyl, 4-acetyloxy-2-pyrrolidinyl,
4- (succinoyloxy) -2-pyrrolidinyl, 4-
(Carbamoyloxy) -2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-
4-succinoyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-
It is a methyl-2-piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 2-morpholinyl or 4-methyl-2-morpholinyl group.

The C ₁ -C ₄ alkylene group of D is, for example,
It may be a methylene, ethylene, propylene, trimethylene or tetramethylene group, preferably a methylene or ethylene group.

In the compound (I) which is the active ingredient of the present invention, B is of the formula --CH ₂ CH (OR ⁶ )-CH ₂
-Wherein R ⁶ has the same meaning as described above, or R ⁷ is a 5- to 6-membered cyclic saturated heterocyclyl group containing a nitrogen, oxygen or sulfur atom (provided that it is 1-methylpiperidyl). (Excluding nil) (preferably,
Pyrrolidinyl, 1-methylpyrrolidinyl, hydroxy-1-methylpyrrolidinyl, piperidinyl, morpholinyl, 4-methylmorpholinyl or thiomorpholinyl group, more preferably 2-pyrrolidinyl, 1-methyl-
2-pyrrolidinyl, 4-hydroxy-1-methyl-2-
Pyrrolidinyl, 2-morpholinyl or 4-methyl-2-
It is a morpholinyl group. ) Is new.

The compound (I) which is the active ingredient of the present invention is
The corresponding pharmacologically acceptable acid addition salt can be converted by treatment with an acid according to a conventional method. Examples of such acid addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, organic acids such as acetic acid, benzoic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid and citric acid. Acids, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and other sulfonic acid addition salts may be mentioned.
Furthermore, when an asymmetric carbon atom is present in the molecule of compound (I), it includes a racemate and an optically active form.

In the compound having the general formula (I), (1) R ¹ is preferably a C ₄ -C ₁₀ alkyl group, and (2) R ¹ is a C ₅ -C ₈ alkyl group. A compound, (3) R ¹ has the formula —A—R ³ (wherein R ³ is C
_3- C ₇ cycloalkyl group or hydroxy, methoxy,
C ₅ − substituted with ethoxy, fluoro or chloro
Indicates C ₆ cycloalkyl group, A is illustrated C ₂ -C ₄ alkylene group or a hydroxy, fluoro, chloro or C ₂ -C ₄ alkylene group substituted with bromo. A compound having a group of (4) R ¹ has the formula —A—R ³
(In the formula, R ³ represents a C ₅ -C ₆ cycloalkyl group or a methoxy-substituted C ₅ -C ₆ cycloalkyl group,
A represents C ₂ -C ₄ alkylene group, 2-hydroxyethylene group, 2-fluoroethylene group, a 2-chloro-ethylene or 2-bromo ethylene. A compound having the formula (5) R ¹ has the formula —A—R ³ (wherein R ³
Shows the C ₅ -C ₆ cycloalkyl group substituted with a C ₅ -C ₆ cycloalkyl group or methoxy, A is shows the ethylene or 2-chloroethylene group. A compound having the group (6) R ¹ has the formula —A—R ³ (wherein R ^1
3 represents a C ₅ -C ₆ cycloalkyl group or a C ₆ cycloalkyl group substituted at the 3-position with methoxy, and A represents an ethylene group or a 2-chloroethylene group. A compound having a group of (7) R ¹ has the formula —A—R ³ (wherein
R ³ represents a C ₆ cycloalkyl group third in C ₆ cycloalkyl group or methoxy substituted, A is shows the ethylene or 2-chloroethylene group. (8) R ² is a compound represented by the formula: —B—NR ⁴ R ⁵ [wherein R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, C
₁ -C ₄ alkyl group, benzyl group, phenethyl group, 2-
Hydroxyethyl group, 3-hydroxypropyl group, 2-
(N, N-dimethylamino) ethyl group or 3- (N, N)
1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-, together with the nitrogen atom which is or is attached to -dimethylamino) propyl. Ethyl-
1-piperazinyl, 4-phenyl-1-piperazinyl,
1-imidazolyl, shows a 1-pyrazolyl or 1-triazolyl group, B is, C ₂ -C ₅ alkylene radical or formula -CH
₂ CH (OR ⁶ ) CH ₂ — (In the formula, R ⁶ represents a hydrogen atom, a C ₁ -C ₅ alkanoyl group, a C ₂ -C ₅ alkanoyl group substituted with carboxy, or a C ₆ -C ₁₀ arylacyl group. Show.)
Represents a group having ] A compound which is a group having
R ² is of the formula —B—NR ⁴ R ⁵ [wherein R ⁴ and R ⁵
Are the same or different and each represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydroxyethyl group, or
1-pyrrolidinyl, 1-with a nitrogen atom attached
Piperidinyl, 4-hydroxy-1-piperidinyl, 4
-Morpholinyl, 4-methyl-1-piperazinyl, 4-
Phenyl-1 shows a piperazinyl or 1-imidazolyl group, B is, C ₂ -C ₅ alkylene group, or a group represented by formula -CH ₂ CH (OR
⁶ ) CH ₂ — (In the formula, R ⁶ represents a hydrogen atom, a C ₁ -C ₅ alkanoyl group, a C ₂ -C ₅ alkanoyl group substituted with carboxy, or a C ₆ -C ₁₀ arylacyl group). The group having is shown. ] A compound which is a group having
There, C ₂ -C ₄ alkylene group, or a group represented by formula ^{_{-CH 2 CH (OR 6) CH}} 2 -
(Wherein R ⁶ represents a hydrogen atom, an acetyl group, a propionyl group, a succinyl group or a glutaroyl group), and (11) B is an ethylene group, a trimethylene group or a formula —CH ₂ CH _2. A compound having a group of (OR ⁶ ) CH ₂ — (in the formula, R ⁶ represents a hydrogen atom, an acetyl group or a succinyl group), (12) R ² has the formula —D—R ⁷ (wherein , R ⁷ represents a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group, the substituent on the carbon atom of which is a C ₁ -C ₄ alkyl group, a hydroxy group, C ₁ -C ₄
Alkoxy group, acetoxy group, propionyl group, succinyloxy group, glutaryloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group or N, N-diethyl group. It is a carbamoyloxy group, the substituent on the nitrogen atom is a C ₁ -C ₄ alkyl group, and D represents a single bond or a C ₁ -C ₄ alkylene group. A compound having the formula (13) R ² has the formula
During -D-R ⁷ (wherein, R ⁷ is pyrrolidinyl, piperidinyl, shows a morpholinyl or thiomorpholinyl group, the substituent is a methyl group on its carbon atom, an ethyl group, a hydroxy group, a methoxy group, an ethoxy group, an acetoxy group, A propionyl group, succinyloxy group, glutaryloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group or N, N-diethylcarbamoyloxy group, (14) R, wherein the substituent on the nitrogen atom is a methyl group or an ethyl group, and D is a group having a single bond or a C ₁ -C ₄ alkylene group.
^2, the formula -D-R ⁷ (wherein, R ⁷ is pyrrolidinyl,
1-methylpyrrolidinyl, hydroxy-1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, morpholinyl, 4-methylmorpholinyl or thiomorpholinyl group, D is a single bond or C ₁ -C ₄ alkylene. Indicates a group. A compound having a group), (15) R ²
Has the formula -D-R ⁷ (wherein R ⁷ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-1-methyl-2-pyrrolidinyl, 2-piperidinyl, 1
-Methyl-2-piperidinyl, 2-morpholinyl, 4-
A methyl-2-morpholinyl or 2-thiomorpholinyl group is shown, and D is a single bond or a C ₁ -C ₄ alkylene group. And a compound in which (16) D is a single bond, an ethylene group or a trimethylene group. Also, (1)-(7) and (8)-
It is also preferable to use an arbitrary combination of those selected from the group consisting of (16). Specific examples of suitable compounds in the general formula (I) include the compounds shown in Table 1 below.

[0033]

[Chemical 5]

[0034]

[Table 1] ─────────────────────────────────── Example compound R ¹ R ² number (No.) ─────────────────────────────────── 1 (CH ₂ ) ₃ Me CH ₂ CH ₂ NMe ₂ 2 ( CH ₂ ) ₃ Me CH ₂ CH ₂ NEt ₂ 3 (CH ₂ ) ₃ Me CH ₂ CH ₂ CH ₂ NMe ₂ 4 (CH ₂ ) ₃ Me CH ₂ CH (OH) CH ₂ NMe ₂ 5 (CH ₂ ) ₃ Me CH ₂ CH (OH) CH ₂ (1-Pip) 6 (CH ₂ ) ₃ Me CH ₂ CH ₂ (2-Pyr) 7 (CH ₂ ) ₃ Me CH ₂ CH ₂ (1-Me-2-Pyr) 8 (CH ₂ ) ₃ Me CH ₂ CH ₂ (2-Pip) 9 (CH ₂ ) ₃ Me CH ₂ CH ₂ (1-Me-2-Pip) 10 (CH ₂ ) ₃ Me CH ₂ (3-Pip) 11 (CH ₂ ) ₃ Me CH ₂ (1-Me-3-Pip) 12 (CH ₂ ) ₃ Me CH ₂ (1-Et-3-Pip) 13 (CH ₂ ) ₃ Me CH ₂ (2-Mor) 14 (CH ₂ ) ₃ Me CH ₂ (4-Me-2-Mor) 15 (CH ₂ ) ₃ Me 4-Pip 16 (CH ₂ ) ₃ Me 1-Me-4-Pip 17 CH ₂ CH (Me) ₂ CH ₂ CH ₂ NMe ₂ 18 CH ₂ CH (Me) ₂ CH ₂ CH ₂ CH ₂ NMe ₂ 19 CH ₂ CH (Me) ₂ CH ₂ CH ₂ CH ₂ NEt ₂ 20 CH ₂ CH (Me) ₂ CH ₂ CH ₂ CH ₂ NPr ₂ 21 CH ₂ CH (Me) ₂ CH ₂ CH (OH) CH ₂ NMe ₂ 22 CH ₂ CH (Me) ₂ CH ₂ CH ( OH) CH ₂ (4-OH-1-Pip) 23 CH ₂ CH (Me) ₂ CH ₂ CH (OH) CH ₂ (4-Me-1-Pir) 24 CH ₂ CH (Me) ₂ CH ₂ CH ₂ (2-Pyr) 25 CH ₂ CH (Me) ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 26 CH ₂ CH (Me) ₂ CH ₂ CH ₂ (1-Et-2-Pyr) 27 CH ₂ CH (Me) ₂ CH ₂ CH ₂ (1-Me-2-Pip) 28 CH ₂ CH (Me) ₂ CH ₂ CH ₂ (1-Et-2-Pip) 29 CH ₂ CH (Me) ₂ CH ₂ ( 3-Pip) 30 CH ₂ CH (Me) ₂ CH ₂ (1-Me-3-Pip) 31 CH ₂ CH (Me) ₂ CH ₂ CH ₂ (1-Me-4-OH-2-Pyr) 32 CH ₂ CH (Me) ₂ CH ₂ (2-Mor) 33 CH ₂ CH (Me) ₂ CH ₂ (4-Me-2-Mor) 34 CH ₂ CH (Me) ₂ CH ₂ (1-Me-4-Pip ) 35 CH ₂ CH (Me) ₂ CH ₂ (1-Et-4-Pip) 36 CH (Me) Et CH ₂ CH ₂ NMe ₂ 37 CH (Me) Et CH ₂ CH ₂ N (Me) Et 38 CH ( Me) Et CH ₂ CH ₂ CH ₂ NMe ₂ 39 CH (Me) Et CH ₂ CH (OH) CH ₂ NMe ₂ 40 CH (Me) Et CH ₂ CH (OH) CH ₂ N (CH ₂ CH ₂ OH) ₂ 41 CH (Me) Et CH ₂ CH (OH) CH ₂ (4-Ph-1-Pir) 42 CH (Me) Et CH ₂ CH (OH) CH ₂ (1-Pir) 43 CH (Me) Et CH ₂ CH ₂ (2-Pyr) 44 CH (Me) Et CH ₂ CH ₂ (1-Me-2-Pyr) 45 CH (Me) Et CH ₂ CH ₂ (2-Pip) 46 CH (Me) Et CH ₂ CH ₂ (1-Me-2-Pip) 47 CH (Me) Et CH ₂ (3-Pip) 48 CH (Me) Et CH ₂ (1-Me-3-Pip) 49 CH (Me) Et CH ₂ (1 -Et-3-Pip) 50 CH (Me) Et 4-Pip 51 CH (Me) Et 1-Pr-4-Pip 52 CH (Me) Et CH ₂ (2-Mor) 53 CH (Me) Et CH ₂ (4-Me-2-Mor) 54 (CH ₂ ) ₄ Me CH ₂ CH ₂ NMe ₂ 55 (CH ₂ ) ₄ Me CH ₂ CH ₂ NPr ₂ 56 (CH ₂ ) ₄ Me CH ₂ CH ₂ CH ₂ NMe ₂ 57 (CH ₂ ) ₄ Me CH ₂ CH ₂ CH ₂ N (Me) Et 58 (CH ₂ ) ₄ Me CH ₂ CH (OH) CH ₂ NMe ₂ 59 (CH ₂ ) ₄ Me CH ₂ CH (OH) CH ₂ NEt ₂ 60 (CH ₂ ) ₄ Me CH ₂ CH (OH) CH ₂ (1-Pyr) 61 (CH ₂ ) ₄ Me CH ₂ CH (OH) CH ₂ (4-Mor) 62 (CH ₂ ) ₄ Me CH ₂ CH ₂ (2-Pyr) 63 (CH ₂ ) ₄ Me CH ₂ CH ₂ (1- Me-2-Pyr) 64 (CH ₂ ) ₄ Me CH ₂ CH ₂ (2-Pip) 65 (CH ₂ ) ₄ Me CH ₂ CH ₂ (1-Me-2-Pip) 66 (CH ₂ ) ₄ Me CH ₂ (3-Pip) 67 (CH ₂ ) ₄ Me (1-Me-3-Pip) 68 (CH ₂ ) ₄ Me 4-Pip 69 (CH ₂ ) ₄ Me CH ₂ CH ₂ (1-Me-4- Pip) 70 (CH ₂ ) ₄ Me 1-Me-4-Pip 71 (CH ₂ ) ₄ Me CH ₂ (2-Mor) 72 (CH ₂ ) ₄ Me CH ₂ (4-Me-2-Mor) 73 ( CH ₂ ) ₂ CHMe ₂ CH ₂ CH ₂ NMe ₂ 74 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH ₂ CH ₂ NMe ₂ 75 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH (OH) CH ₂ NMe ₂ 76 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH (OH) CH ₂ (1-Pyr) 77 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH (OH) CH ₂ (1-Pip) 78 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH ( OH) CH ₂ (4-OH-1-Pip) 79 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH (OH) CH ₂ (4-Et-1-Pir) 80 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH (OH) CH ₂ (4-CH ₂ CH ₂ OH-1-Pir) 81 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH ₂ CH ₂ N (Me) CH ₂ CH ₂ OH 82 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH ₂ (2-Pyr) 83 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH ₂ (1-Me- 2-Pyr) 84 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH ₂ (2-Pip) 85 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 86 (CH ₂ ) ₂ CHMe ₂ CH ₂ CH ₂ (1-Me-2-Pip) 87 (CH ₂ ) ₂ CHMe ₂ CH ₂ (3-Pip) 88 (CH ₂ ) ₂ CHMe ₂ CH ₂ (1-Me-3-Pip) 89 (CH ₂ ) ₂ CHMe ₂ 1-Me-4-Pip 90 (CH ₂ ) ₂ CHMe ₂ CH ₂ (2-Mor) 91 (CH ₂ ) ₂ CHMe ₂ CH ₂ (4-Me-2-Mor) 92 ( CH ₂ ) ₅ Me CH ₂ CH ₂ NMe ₂ 93 (CH ₂ ) ₅ Me CH ₂ CH ₂ CH ₂ NMe ₂ 94 (CH ₂ ) ₅ Me CH ₂ CH (OH) CH ₂ NMe ₂ 95 (CH ₂ ) ₅ Me CH ₂ CH (OH) CH ₂ (1-Pip) 96 (CH ₂ ) ₅ Me CH ₂ CH ₂ (1-Me-2-Pyr) 97 (CH ₂ ) ₅ Me CH ₂ CH ₂ (1-Me-4 -OH-2-Pyr) 98 (CH ₂ ) ₅ Me CH ₂ CH ₂ (1-Me-2-Pip) 99 (CH ₂ ) ₅ Me CH ₂ CH ₂ CH ₂ (1-Me-2-Pip) 100 (CH ₂ ) ₅ Me CH ₂ (1-Me-3-Pip) 101 (CH ₂ ) ₅ Me CH ₂ (1-Me-4-Pip) 102 (CH ₂ ) ₅ Me 1-Me-4-Pip 103 (CH ₂ ) ₅ Me CH ₂ (4-Me-2-Mor) 104 (CH ₂ ) ₃ CH (Me) ₂ CH ₂ CH ₂ NMe ₂ 105 (CH ₂ ) ₃ CH (Me) ₂ CH ₂ CH ₂ CH ₂ NMe ₂ 106 (CH ₂ ) ₃ CH (Me) ₂ CH ₂ CH (OH) CH ₂ NMe ₂ 107 (CH ₂ ) ₃ CH (Me ) ₂ CH ₂ CH (OH) CH ₂ (1-Pip) 108 (CH ₂ ) ₃ CH (Me) ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 109 (CH ₂ ) ₃ CH (Me) ₂ CH ₂ CH ₂ (1-Me-2-Pip) 110 (CH ₂ ) ₃ CH (Me) ₂ CH ₂ (1-Me-3-Pip) 111 (CH ₂ ) ₃ CH (Me) ₂ 1-Me- 4-Pip 112 (CH ₂ ) ₃ CH (Me) ₂ CH ₂ (4-Me-2-Mor) 113 (CH ₂ ) ₃ CH (Me) ₂ CH ₂ CH ₂ (1-Me-4-OH-2 -Pyr) 114 (CH ₂ ) ₂ CH (Me) Et CH ₂ CH ₂ NMe ₂ 115 (CH ₂ ) ₂ CH (Me) Et CH ₂ CH ₂ CH ₂ NMe ₂ 116 (CH ₂ ) ₂ CH (Me) Et CH ₂ CH (OH) CH ₂ NMe ₂ 117 (CH ₂ ) ₂ CH (Me) Et CH ₂ CH ₂ (1-Me-2-Pyr) 118 (CH ₂ ) ₂ CH (Me) Et CH ₂ CH ₂ ( 1-Me-2-Pip) 119 (CH ₂ ) ₂ CH (Me) Et CH ₂ (1-Me-3-Pip) 120 (CH ₂ ) ₂ CH (Me) Et 1-Me-4-Pip 121 ( CH ₂ ) ₂ CH (Me) Et CH ₂ (4-Me-2-Mor) 122 (CH ₂ ) ₆ Me CH ₂ CH ₂ NMe ₂ 123 (CH ₂ ) ₆ Me CH ₂ CH ₂ CH ₂ NMe ₂ 124 ( CH ₂ ) ₆ Me CH ₂ CH (OH) CH ₂ NMe ₂ 125 (CH ₂ ) ₆ Me CH ₂ CH ₂ (1-Me-2-Pyr) 126 (CH ₂ ) ₆ Me CH ₂ CH ₂ (1-Me -2-Pip) 127 (CH ₂ ) ₆ Me CH ₂ (1-Me-3-Pip) 128 (CH ₂ ) ₆ Me 1-Me-4-Pip 129 (CH ₂ ) ₆ Me CH ₂ (4-Me-2-Mor) 130 (CH ₂ ) ₄ CHMe ₂ CH ₂ CH ₂ NMe ₂ 131 (CH ₂ ) ₄ CHMe ₂ CH ₂ CH ₂ CH ₂ NMe ₂ 132 (CH ₂ ) ₄ CHMe ₂ CH ₂ CH (OH) CH ₂ NMe ₂ 133 (CH ₂ ) ₄ CHMe ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 134 (CH ₂ ) ₄ CHMe ₂ CH ₂ CH ₂ (1-Me-2- Pip) 135 (CH ₂ ) ₄ CHMe ₂ CH ₂ (1-Me-3-Pip) 136 (CH ₂ ) ₄ CHMe ₂ 1-Me-4-Pip 137 (CH ₂ ) ₄ CHMe ₂ CH ₂ (4-Me -2-Mor) 138 (CH ₂ ) ₃ CH (Me) Et CH ₂ CH ₂ NMe ₂ 139 (CH ₂ ) ₃ CH (Me) Et CH ₂ CH ₂ CH ₂ NMe ₂ 140 (CH ₂ ) ₃ CH (Me ) Et CH ₂ CH (OH) CH ₂ NMe ₂ 141 (CH ₂ ) ₃ CH (Me) Et CH ₂ CH ₂ (1-Me-2-Pyr) 142 (CH ₂ ) ₃ CH (Me) Et CH ₂ CH ₂ (1-Me-2-Pip) 143 (CH ₂ ) ₃ CH (Me) Et CH ₂ (1-Me-3-Pip) 144 (CH ₂ ) ₃ CH (Me) Et 1-Me-4-Pip 145 (CH ₂ ) ₃ CH (Me) Et CH ₂ (4-Me-2-Mor) 146 (CH ₂ ) ₂ CHEt ₂ CH ₂ CH ₂ NMe ₂ 147 (CH ₂ ) ₂ CHEt ₂ CH ₂ CH ₂ CH ₂ NMe ₂ 148 (CH ₂ ) ₂ CHEt ₂ CH ₂ CH (OH) CH ₂ NMe ₂ 149 (CH ₂ ) ₂ CHEt ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 150 (CH ₂ ) ₂ CHEt ₂ CH ₂ CH ₂ (1-Me-2-Pip) 151 (CH ₂ ) ₂ CHEt ₂ 1-Me-4-Pip 152 (CH ₂ ) ₂ CHEt ₂ CH ₂ (4-Me-2-Mor) 153 (CH ₂ ) ₂ CH (Me) Pr CH ₂ CH ₂ NMe ₂ 154 (CH ₂ ) ₂ CH (Me) Pr CH ₂ CH ₂ CH ₂ NMe ₂ 155 (CH ₂ ) ₂ CH (Me) Pr CH ₂ CH ₂ (1-Me-2-Pyr) 156 (CH ₂ ) ₂ CH ( Me) Pr CH ₂ CH ₂ (1-Me-2-Pip) 157 (CH ₂ ) ₂ CH (Me) Pr CH ₂ (4-Me-2-Mor) 158 (CH ₂ ) ₇ Me CH ₂ CH ₂ NMe 159 (CH ₂ ) ₇ Me CH ₂ CH ₂ CH ₂ NMe ₂ 160 (CH ₂ ) ₇ Me CH ₂ CH ₂ (1-Me-2-Pyr) 161 (CH ₂ ) ₇ Me CH ₂ CH ₂ (1-Me -2-Pip) 162 (CH ₂ ) ₇ Me CH ₂ (4-Me-2-Mor) 163 (CH ₂ ) ₅ CHMe ₂ CH ₂ CH ₂ NMe ₂ 164 (CH ₂ ) ₅ CHMe ₂ CH ₂ CH ₂ CH ₂ NMe ₂ 165 (CH ₂ ) ₅ CHMe ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 166 (CH ₂ ) ₅ CHMe ₂ CH ₂ CH ₂ (1-Me-2-Pip) 167 (CH ₂ ) ₅ CHMe ₂ CH ₂ (4-Me-2-Mor) 168 (CH ₂ ) ₄ CH (Me) Et CH ₂ CH ₂ CH ₂ NMe ₂ 169 (CH ₂ ) ₄ CH (Me) Et CH ₂ CH (OH) CH ₂ NMe ₂ 170 (CH ₂ ) ₄ CH (Me) Et CH ₂ CH ₂ (1-Me-2-Pyr) 171 (CH ₂ ) ₄ CH (Me) Et CH ₂ CH ₂ (1-Me-2- Pip) 172 (CH ₂ ) ₄ CH (Me) Et CH ₂ (4-Me-2-Mor) 173 (CH ₂ ) ₃ CHEt ₂ CH ₂ CH ₂ CH ₂ NMe ₂ 174 (CH ₂ ) ₃ CHEt ₂ CH ₂ CH (OH) CH ₂ NEt ₂ 175 (CH ₂ ) ₃ CHEt ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 176 (CH ₂ ) ₃ CHEt ₂ CH ₂ CH ₂ (1-Me-2-Pip) 177 (CH ₂ ) ₃ CHEt ₂ CH ₂ (4-Me-2-Mor) 17 8 (CH ₂ ) ₃ CH (Me) Pr CH ₂ CH ₂ CH ₂ NMe ₂ 179 (CH ₂ ) ₃ CH (Me) Pr CH ₂ CH ₂ (1-Me-2-Pyr) 180 (CH ₂ ) ₃ CH (Me) Pr CH ₂ CH ₂ (1-Me-2-Pip) 181 (CH ₂ ) ₃ CH (Me) Pr CH ₂ (1-Me-3-Pip) 182 (CH ₂ ) ₂ CH (Et) Pr CH ₂ CH ₂ CH ₂ NMe ₂ 183 (CH ₂ ) ₂ CH (Et) Pr CH ₂ CH ₂ (1-Me-2-Pyr) 184 (CH ₂ ) ₂ CH (Et) Pr CH ₂ CH ₂ (1- Me-2-Pip) 185 (CH ₂ ) ₂ CH (Et) Pr CH ₂ (4-Me-2-Mor) 186 (CH ₂ ) ₂ -c-Pn CH ₂ CH ₂ NMe ₂ 187 (CH ₂ ) ₂ -c-Pn CH ₂ CH ₂ NEt ₂ 188 (CH ₂ ) ₂ -c-Pn CH ₂ CH ₂ CH ₂ NMe ₂ 189 (CH ₂ ) ₂ -c-Pn CH ₂ CH (OH) CH ₂ NMe ₂ 190 ( CH ₂ ) ₂ -c-Pn CH ₂ CH (OH) CH ₂ NEt ₂ 191 (CH ₂ ) ₂ -c-Pn CH ₂ CH (OH) CH ₂ (1-Pyr) 192 (CH ₂ ) ₂ -c- Pn CH ₂ CH (OH) CH ₂ (1-Pip) 193 (CH ₂ ) ₂ -c-Pn CH ₂ CH ₂ (2-Pyr) 194 (CH ₂ ) ₂ -c-Pn CH ₂ CH ₂ (1- Me-2-Pyr) 195 (CH ₂ ) ₂ -c-Pn CH ₂ CH ₂ (2-Pip) 196 (CH ₂ ) ₂ -c-Pn CH ₂ CH ₂ (1-Me-2-Pip) 197 ( CH ₂ ) ₂ -c-Pn CH ₂ (3-Pip) 198 (CH ₂ ) ₂ -c-Pn CH ₂ (1-Me-3-Pip) 199 (CH ₂ ) ₂ -c-Pn CH ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 200 (CH ₂ ) ₂ -c-Pn CH ₂ (2-Mor) 201 (CH ₂ ) ₂ -c-Pn CH ₂ (4-Me-2-Mor) 202 (CH ₂ ) ₂ -c-Pn 1-Me-4-Pip 203 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ NMe ₂ 204 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ NEt ₂ 205 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ CH ₂ NMe ₂ 206 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ CH ₂ NEt ₂ 207 (CH ₂ ) ₂ -c-Hx CH ₂ CH (OH) CH ₂ NMe ₂ 208 (CH ₂ ) ₂ -c-Hx CH ₂ CH (OH) CH ₂ NEt ₂ 209 (CH ₂ ) ₂ -c-Hx CH ₂ CH (OH) CH ₂ (1-Pyr) 210 (CH ₂ ) _2- c-Hx CH ₂ CH (OH) CH ₂ (1-Pip) 211 (CH ₂ ) ₂ -c-Hx CH ₂ CH (OH) CH ₂ (4-OH-1-Pip) 212 (CH ₂ ) _2- c-Hx CH ₂ CH (OH) CH ₂ (4-Ph-1-Pir) 213 (CH ₂ ) ₂ -c-Hx CH ₂ CH (OH) CH ₂ (4-Et-1-Pir) 214 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ (2-Pyr) 215 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ (1-Me-2-Pyr) 216 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ (1-Me-4-OH-2-Pyr) 217 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 218 (CH ₂ ) ₂ -c- Hx CH ₂ CH ₂ (2-Pip) 219 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ (1-Me-2-Pip) 220 (CH ₂ ) ₂ -c-Hx CH ₂ CH ₂ (1- Et-2-Pip) 221 (CH ₂ ) ₂ -c-Hx CH ₂ (3-Pip) 222 (CH ₂ ) ₂ -c-Hx CH ₂ (1-Me-3-Pip) 223 (CH ₂ ) ₂ -c-Hx 4-Pip 224 (CH ₂ ) ₂ -c-Hx 1-Me-4-Pip 225 (CH ₂ ) ₂ -c-Hx CH ₂ (2-Mor) 226 (CH ₂ ) ₂ -c- Hx CH ₂ (4-Me-2-Mor) 227 (CH ₂ ) ₂ -c-Hx CH ₂ (4-Et-2-Mor) 228 (CH ₂ ) ₈ Me CH ₂ CH ₂ CH ₂ NMe ₂ 229 (CH ₂ ) ₈ Me CH ₂ CH ₂ (1-Me-2 -Pyr) 230 (CH ₂ ) ₈ Me CH ₂ CH ₂ (1-Me-2-Pip) 231 (CH ₂ ) ₈ Me CH ₂ (4-Me-2-Mor) 232 (CH ₂ ) ₉ Me CH ₂ CH ₂ CH ₂ NMe ₂ 233 (CH ₂ ) ₉ Me CH ₂ CH (OH) CH ₂ NMe ₂ 234 (CH ₂ ) ₉ Me CH ₂ CH ₂ (1-Me-2-Pyr) 235 (CH ₂ ) ₉ Me CH ₂ (4-Me-2-Mor) 236 (CH ₂ ) ₁₀ Me CH ₂ CH ₂ CH ₂ NMe ₂ 237 (CH ₂ ) ₁₀ Me CH ₂ CH ₂ (1-Me-2-Pyr) 238 (CH ₂ ) ₁₀ Me CH ₂ CH ₂ (1-Me-2-Pip) 239 (CH ₂ ) ₁₀ Me CH ₂ (4-Me-2-Mor) 240 (CH ₂ ) ₁₁ Me CH ₂ CH ₂ CH ₂ NMe ₂ 241 (CH ₂ ) ₁₁ Me CH ₂ CH ₂ (1-Me-2-Pyr) 242 (CH ₂ ) ₁₁ Me CH ₂ CH ₂ (1-Me-2-Pip) 243 (CH ₂ ) ₁₁ Me CH ₂ (1 -Me-3-Pip) 244 (CH ₂ ) ₁₁ Me CH ₂ (4-Me-2-Mor) 245 (CH ₂ ) _2- (3-OMe-c-Hx) CH ₂ CH ₂ CH ₂ NMe ₂ 246 (CH ₂ ) _2- (3-OMe-c-Hx) CH ₂ CH (OH) CH ₂ NMe ₂ 247 (CH ₂ ) _2- (3-OMe-c-Hx) CH ₂ CH ₂ (1-Me- 2-Pyr) 248 (CH ₂ ) _2- (3-OMe-c-Hx) CH ₂ CH ₂ (1-Me-4-OH-2-Pyr) 249 (CH ₂ ) _2- (3-OMe-c -Hx) CH ₂ CH ₂ CH ₂ (1-Me-2-Pyr) 250 (CH ₂ ) _2- (3-OMe-c-Hx) CH ₂ CH ₂ (1-Me-2-Pip) 2 51 (CH ₂ ) _2- (3-OMe-c-Hx) CH ₂ (1-Me-3-Pip) 252 (CH ₂ ) _2- (3-OMe-c-Hx) 1-Me-4-Pip 253 (CH ₂ ) _2- (3-OMe-c-Hx) CH ₂ (2-Mor) 254 (CH ₂ ) _2- (3-OMe-c-Hx) CH ₂ (4-Me-2-Mor) 255 CH ₂ CH (Cl) -c-Hx CH ₂ CH ₂ NEt ₂ 256 CH ₂ CH (Cl) -c-Hx CH ₂ CH ₂ CH ₂ NMe ₂ 257 CH ₂ CH (Cl) -c-Hx CH ₂ CH (OH) CH ₂ NMe ₂ 258 CH ₂ CH (Cl) -c-Hx CH ₂ CH ₂ (1-Me-2-Pyr) 259 CH ₂ CH (Cl) -c-Hx CH ₂ CH ₂ (1-Me -2-Pip) 260 CH ₂ CH (Cl) -c-Hx CH ₂ (1-Me-3-Pip) 261 CH ₂ CH (Cl) -c-Hx 1-Me-4-Pip 262 CH ₂ CH ( Cl) -c-Hx CH ₂ (4-Me-2-Mor) ────────────────────────────────── In Table 1, the abbreviations represent the following groups.

Et: ethyl group c-Hx: cyclohexyl group Me: methyl group Mor: morpholinyl group Ph: phenyl group c-Pn: cyclopentyl group Pip: piperidinyl group Pir: piperazinyl group Pr: propyl group Pyr: pyrrolidinyl group.

Further, in the above Table 1, it is preferable that the compound No. 7, 11, 63, 67, 74, 75, 76, 8 is preferably used.
3, 86, 88, 89, 91, 96, 97, 100, 1
02, 105, 106, 108, 110, 111, 11
7, 119, 120, 123, 125, 127, 12
8, 147, 148, 149, 150, 151, 15
2, 186, 187, 188, 189, 194, 19
6, 198, 201, 202, 203, 204, 20
5, 206, 207, 209, 215, 216, 21
9, 222, 224, 225, 226, 245, 24
6, 247, 248, 250, 251, 252, 25
4, 256, 257, 258, 259, 260, 261
Or the compound of No. 262, more preferably Compound No. 74, 75, 83, 88, 89, 9
1, 96, 97, 100, 102, 105, 108, 1
10, 111, 119, 120, 123, 149, 15
1, 152, 186, 188, 189, 194, 19
6, 198, 201, 202, 203, 205, 20
7,209,215,216,222,224,22
5, 226, 245, 246, 247, 248, 25
1, 252, 254, 256, 257, 258, 26
Compounds Nos. 83, 88, 96, 9 are more preferred.
7, 100, 105, 108, 110, 123, 14
9, 151, 194, 198, 201, 202, 20
7,209,215,216,222,224,22
5, 226, 247, 248, 251, 252, 25
4, 257, 258, 260, 261 or 262 can be mentioned, and particularly preferably, the compound number No.
105: N, N-dimethyl-3- [2- (4-methylpentyl) phenoxy] propylamine, Compound No.
194: 2- [2- [2- (2- (2-Cyclopentylethyl) phenoxy] ethyl] -1-methylpyrrolidine, Compound No. 198: 3- [2- (2-Cyclopentylethyl) phenoxymethyl] -1-methyl. Piperidine,
Compound No. 207: 3- [2- (2-cyclohexylethyl) phenoxy] -1- (N, N-dimethylamino) -2-propanol, Compound No. 215: 2-
[2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine, compound number No.
222: 3- [2- (2-cyclohexylethyl) phenoxymethyl] -1-methylpiperidine, compound number N
o. 226: 2- [2- (2-cyclohexylethyl)
Phenoxymethyl] -4-methylmorpholine, compound number No. 247: 2- [2- [2- [2- (3-methoxycyclohexyl) ethyl] phenoxy] ethyl] -1-
Methylpyrrolidine, Compound No. 257: 3- [2-
(2-chloro-2-cyclohexylethyl) phenoxy] -1- (N, N-dimethylamino) -2-propanol, compound number No. 258: 2- [2- [2- (2-
Chloro-2-cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine or Compound No. 260: 3- [2- (2-chloro-2-
A compound of cyclohexylethyl) phenoxymethyl] -1-methylpiperidine may be mentioned.

Further, as a therapeutic agent for psychosis, particularly preferably, Compound No. 105: N, N-dimethyl-3-
[2- (4-Methylpentyl) phenoxy] propylamine, Compound No. 123: N, N-dimethyl-3-
(2-heptylphenoxy) propylamine, compound number No. 215: 2- [2- [2- (2-cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine or compound number No. 225: 2- [2- A compound of (2-cyclohexylethyl) phenoxymethyl] morpholine may be mentioned.

The compound having the general formula (I), which is the active ingredient of the present invention, can be easily produced according to the following method.

[0039]

[Chemical 6]

[0040]

[Chemical 7]

[0041]

[Chemical 8]

In the above formula, R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷
And D have the same meanings as described above, R ¹ a is hydroxy which may be protected, and R ¹ a is R ^1.
R ⁴ a and R ⁵ a are the same as R ⁴ and R ⁵ , respectively, and R ⁴ a and R ⁵ a are the same as R ⁴ and R ^5, and R ⁷ a is the carbon of the heterocyclyl ring. The substituents on the atoms are C ₁ -C ₄ alkyl groups, C ₁ -C ₄
It is an alkoxy group or a protected hydroxy group, the nitrogen atom of the heterocyclyl ring is protected, and has the same meaning as R ⁷ , B ′ represents a C ₂ -C ₅ alkylene group,
Z is a hydroxy group, a halogen atom (preferably chlorine,
Bromine or iodine atom), a C ₁ -C ₄ alkanesulfonyloxy group or a C ₆ -C ₁₀ arylsulfonyloxy group.

The protecting group for the hydroxy group of R ⁴ a, R ⁵ a and R ⁷ a is, for example, a cyclic ether group such as tetrahydrofuranyl or tetrahydropyranyl group, a methoxymethyl group,
Methoxymethoxymethyl group, C ₆ - C ₁₀ aryl - methyl, C ₆ - C ₁₀ aryl - be a methyloxy carbonyl group, preferably, tetrahydropyranyl, methoxymethyl, benzyl, p- methoxybenzyl, p- Brombenzyl, p-nitrobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-bromobenzyloxycarbonyl or p-nitrobenzyloxycarbonyl group.

The protecting group for the nitrogen atom of the heterocyclyl ring of R ⁷ a is, for example, C ₁ -C ₄ alkoxycarbonyl group, C
₆ - C ₁₀ aryl - methyl, C ₆ - C ₁₀ aryl - be a methoxycarbonyl group, preferably, t-butoxycarbonyl, benzyl, p- methoxybenzyl, p- bromobenzyl, p- nitrobenzyl, benzyl Oxycarbonyl, p-methoxybenzyloxycarbonyl, p
-Brombenzyloxycarbonyl or p-nitrobenzyloxycarbonyl group.

Method A is the compound (I) wherein R ² is of the formula
A method for producing the compound (Ia) having —B′—NR ⁴ R ⁵ (wherein B ′, R ⁴ and R ⁵ have the same meanings as described above). Step A1 is a step of producing a compound having the general formula (Ia ′) and is achieved by reacting a compound having the general formula (II) with a compound having the general formula (III).

When Z represents a halogen atom, a C ₁ -C ₄ alkanesulfonyloxy group or a C ₆ -C ₁₀ arylsulfonyloxy group, this reaction is carried out in an inert solvent in the presence of a base.

The base used is preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, sodium fluoride or potassium fluoride. Alkali metal fluorides such as, sodium hydride, potassium hydride, alkali metal hydrides such as lithium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, alkali metal alkoxides such as lithium methoxide or It may be an organic amine such as pyridine, picoline, triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, more preferably an alkali metal carbonate, alkali metal fluoride, alkali metal hydride or alkali metal alkoxide. is there.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, for example, hydrocarbons such as hexane, benzene and toluene, halogens such as dichloromethane, chloroform and 1,2-dichloroethane. Hydrocarbons, ethers, ethers such as tetrahydrofuran and dioxane, acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, N, N-dimethylacetamide, N, N-dimethylformamide, N-methyl- It may be 2-pyrrolidinone, amides such as hexamethylphosphoramide or sulfoxides such as dimethylsulfoxide or a mixed solvent thereof, preferably ethers, ketones, amides or sulfoxides. The reaction temperature is the starting compound
(II) and (III), depending on the type of solvent and base, it is usually 0 ° C to 100 ° C (preferably 10 ° C to 80 ° C).
The reaction time varies depending on the reaction temperature, etc.,
It is 30 minutes to 48 hours (preferably 1 to 24 hours).

When Z represents a hydroxy group, the reaction is
It is carried out in the presence of triphenylphosphine and an azodicarboxylic acid ester such as methyl azodicarboxylate and ethyl azodicarboxylate in an inert solvent. In this case, R
^The hydroxy contained in ¹ a, R ⁴ a and R ⁵ a is preferably protected.

As the inert solvent to be used, those similar to the above can be mentioned, but preferably aromatic hydrocarbons, halogenated hydrocarbons or ethers. The reaction temperature is usually −20 ° C. to 100 ° C. (preferably 10 ° C. to 80 ° C.), though it varies depending on the starting compounds (II) and (III), the solvent and the type of base, and the reaction time is the reaction temperature. It is 30 minutes to 48 hours (preferably 1 to 24 hours), though it depends on the above.

After completion of the reaction, the target compound (Ia ') of this reaction
Is collected from the reaction mixture according to conventional methods. For example, if an insoluble substance is present, it is filtered off appropriately and the solvent is distilled off under reduced pressure or after the solvent is distilled off under reduced pressure, water is added to the residue, and a water-immiscible organic substance such as ethyl acetate is added. It can be obtained by extraction with a solvent, drying over anhydrous magnesium sulfate and the like, and then distilling off the solvent. If necessary, it can be further purified by a conventional method such as recrystallization or column chromatography.

The step A2 is an optional step, and includes a reaction (a): a reaction for removing the hydroxy protecting group contained in R ¹ a, R ⁴ a and / or R ⁵ a.

Reaction (a): R ¹ a, R in reaction (a)
^The reaction for removing the hydroxy protecting group contained in ⁴ a and / or R ⁵ a differs depending on the kind of the protecting group and is performed by a method well known in synthetic organic chemistry. In addition, the protecting group contained in R ¹ a, R ⁴ a and / or R ⁵ a can be selectively removed by selecting the type of protecting group and the conditions for removal. When the hydroxy-protecting group is an aryl-methyl group or an aryl-methoxycarbonyl group,
Inert solvent (preferably alcohols such as methanol, ethanol, isopropanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, toluene, benzene, xylene, etc. Aromatic hydrocarbons, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and butyl acetate,
In a fatty acid such as acetic acid or a mixed solvent of these organic solvents and water), a catalytic reduction catalyst (preferably palladium-carbon, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-) is used. In the presence of rhodium chloride, palladium-barium sulfate, etc., the corresponding compound is hydrogenated (usually 1 to 10 atm, preferably 1 to 3 atm).
(Atmospheric pressure). The reaction temperature and the reaction time are generally 0 ° C to 100 ° C (preferably 20 ° C).
To 80 ° C) and 30 minutes to 48 hours (preferably 1
To 24 hours).

When the hydroxy-protecting group is a methoxymethyl group, a methoxymethoxymethyl group or a cyclic ether group, for example, an inert solvent (hydrocarbons such as hexane and benzene, methylene chloride, chloroform and the like) can be used. Halogenated hydrocarbons, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers such as ether, tetrahydrofuran and dioxane.
Tellurium or a mixed solvent of these organic solvents and water,
Preferred are esters, ethers and halogenated hydrocarbons. ) In an acid (for example, an inorganic acid such as hydrogen chloride, nitric acid, hydrochloric acid, sulfuric acid, an acetic acid, an organic acid such as trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, or boron trifluoride). Lewis acids, strong acid cation exchange resins such as Dowex 50W, and the like, preferably inorganic acids and organic acids, and more preferably hydrochloric acid, sulfuric acid, trifluoroacetic acid. ) Is performed. The reaction temperature and the reaction time are generally -10 ° C to 100 ° C (preferably -5 ° C to 50 ° C).
C.) and 5 minutes to 48 hours (preferably 30 minutes to 10 hours).

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, by appropriately neutralizing the reaction mixture, or removing insolubles by filtration, an organic solvent immiscible with water such as ethyl acetate is added, and after washing with water, the solvent is distilled off. can get. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Method B is the compound (I) wherein R ² is of the formula
^{_{-CH 2 CH (OR 6) CH}} 2 -NR 4 R 5 ( wherein, R ^4, R ⁵ and R ^6. Showing the same meanings as defined above) is a compound (Ib) a method of producing with . Step B1 is the general formula (V)
This is achieved by reacting the compound having the general formula (II) with the compound having the general formula (IV) in the step of producing the compound having the formula: This reaction is carried out in the same manner as in the method A, step A1.

The step B2 is a step for producing a compound having the general formula (Ib ′) by reacting a compound having the general formula (V) with a compound having the general formula (VI) in an inert solvent. To be achieved.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as hexane, benzene and toluene, halogens such as dichloromethane, chloroform and 1,2-dichloroethane. Hydrocarbons, ethers, ethers such as tetrahydrofuran, dioxane, esters such as ethyl acetate, acetone, ketones such as methyl ethyl ketone,
Nitriles such as acetonitrile, N, N-dimethylacetamide, N, N-dimethylformamide, N-methyl-2-pyrrolidinone, amides such as hexamethylphosphoramide, sulfoxides such as dimethylsulfoxide, water or It may be a mixed solvent thereof, preferably ethers, esters, ketones, amides, sulfoxides, water or a mixed solvent thereof. The reaction temperature will differ depending on the kinds of raw materials (V) and (VI), the solvent and the base, but is usually 0 ° C. to 100 ° C. (preferably,
The reaction time is 30 minutes to 48 hours (preferably 1 to 24 hours), although it varies depending on the reaction temperature and the like.

After completion of the reaction, the target compound (Ib ') of this reaction
Is collected from the reaction mixture according to conventional methods. For example, by distilling off the solvent under reduced pressure or after distilling off the solvent under reduced pressure, water is added to the residue, the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate, and dried over anhydrous magnesium sulfate, etc. Can be obtained by distillation, and if necessary, can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

Step B3 is an optional step. Reaction (a): reaction for acylating the hydroxy group produced in Step B2 and reaction (b): R ¹ a, R ⁴ a and / or R ^The reaction includes removing the hydroxy protecting group contained in 5a, and the reaction may be performed in any appropriate order.

Reaction (a): The hydroxy group acylation reaction in reaction (a) is carried out by a method well known in synthetic organic chemistry. In this case, the hydroxy contained in R ¹ a, R ⁴ a and R ⁵ a is preferably protected. For example, inert solvents (preferably aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, esters such as ethyl acetate, ethers such as tetrahydrofuran and dioxane, Acetone, ketones such as methyl ethyl ketone, or amides such as N, N-dimethylacetamide)
In the presence or absence of a base (a base is preferably triethylamine, pyridine, diethylisopropylamine,
4- organic tertiary amines such as dimethylaminopyridine) in the presence, acetyl chloride, propionyl chloride, butyryl bromide, valeryl chloride, C ₂ -C ₅ alkanoyl halides such as pivaloyl chloride, formic acid and acetic acid C such as mixed acid anhydride, acetic anhydride, propionic anhydride, valeric anhydride, pivalic anhydride
It is carried out by reacting a cyclic acid anhydride such as _2- C ₆ carboxylic acid anhydride, succinic anhydride, glutaric anhydride, and adipic anhydride. The reaction temperature is 0 ° C to 120 ° C
(Preferably 0 ° C. to 80 ° C.), and the reaction time is 1
To 24 hours (preferably 1 to 16 hours).

After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method.
The same operation as in the method of collecting a compound in step A1 of the method is performed.

Reaction (b) The reaction for removing the hydroxy protecting group contained in R ¹ a, R ⁴ a and / or R ⁵ a in the reaction (b) is carried out by the reaction (a) in the A2 step of the above-mentioned Method A. ). C method is
In the compound (I), R ² has the formula —D—R ⁷ (wherein R ^2
7 and D have the same meanings as described above. ) Are included in the compound (Ic).

The step C1 is a step for producing a compound having the general formula (Ic ') and is accomplished by reacting a compound having the general formula (II) with a compound having the general formula (VII). Is performed in the same manner as in the method A, step A1.

Step C2 is an optional step. Reaction (a): reaction for removing the hydroxy protecting group contained in R ¹ a and / or R ⁷ a Reaction (b): reaction (a) the resulting alkylated hydroxy group contained in R ^7, acylation or carbamoylation reacted reaction (c): reaction of removing the protective group of the nitrogen atoms contained in R ⁷ a (d): included in R ⁷ a The reaction of converting an alkoxycarbonyl group to a methyl group or an alkanoyl group to an alkyl group and the reaction (e): a reaction of alkylating an = NH group contained in R ⁷ a are performed in an appropriate order.

Reaction (a): The reaction for removing the hydroxy protecting group contained in R ¹ a and / or R ⁷ a in the reaction (a) is carried out in the same manner as the reaction (a) in the step A2.

Reaction (b): The reaction of alkylating, acylating or carbamoylating the hydroxy group in the reaction (b) is carried out by reacting an alkylating, acylating or carbamoylating agent in the presence of a base to give the above-mentioned It is performed in the same manner as in the reaction (a) in the step B3.

The alkylating, acylating or carbamoylating agents used include methyl iodide, ethyl iodide,
C ₁ -C ₄ alkyl halides such as propyl iodide and butyl iodide, acetyl chloride, propionyl chloride, butyryl bromide, valeryl chloride, C ₂ -C ₅ alkanoyl halides such as pivaloyl chloride, formic acid and acetic acid. Mixed acid anhydrides such as C ₂ -C ₆ carboxylic acid anhydrides such as acetic anhydride, propionic anhydride, valeric anhydride, pivalic anhydride, cyclic acid anhydrides such as succinic anhydride, glutaric anhydride and adipic anhydride Compounds, isocyanic acid, C ₁ -C ₄ alkyl isocyanates such as methyl isocyanate, ethyl isocyanate, propyl isocyanate, butyl isocyanate, N, N-dimethylcarbamoyl chloride, N, N-diethylcarbamoyl chloride, N, N-dipropylcarbamoyl Chloride, N, N-dibutyrate It can be exemplified alkylcarbamoyl halide - di like carbamoyl chloride.

The bases used include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal fluorides such as sodium fluoride and potassium fluoride; alkali metal hydrides such as sodium hydride. Alternatively, organic tertiary amines such as triethylamine, pyridine, diethylisopropylamine and 4-dimethylaminopyridine may be mentioned.

Reaction (c): The reaction for removing the protecting group of the nitrogen atom contained in R ⁷ a in reaction (c) depends on the kind of the protecting group and is carried out by a method well known in synthetic organic chemistry. .

When the nitrogen atom-protecting group is an aryl-methyl group or an aryl-methoxycarbonyl group, the removal reaction when the hydroxy-protecting group in the reaction (a) in the step A2 is an aryl-methyl group. The same is done as.

When the protecting group for the nitrogen atom is a t-butoxycarbonyl group, it is carried out in the same manner as the removal reaction when the hydroxy protecting group in the reaction (a) in the step A2 is a methoxymethyl group or the like. .

Further, when the nitrogen atom-protecting group is an alkoxycarbonyl residue, an inert solvent (preferably
Alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, water or a mixed solvent of water and the above organic solvent) in a base (preferably lithium hydroxide, sodium hydroxide, potassium hydroxide). Corresponding protecting groups are removed by reaction with an alkali metal hydroxide or an alkali metal carbonate such as sodium carbonate, potassium carbonate) and hydrolysis.

The reaction temperature and reaction time will differ depending on the solvent and the like, but are usually 0 ° C. to 100 ° C. (preferably room temperature to 6 ° C.).
0 ° C.) and 1 hour to 24 hours (preferably 1 hour to 16 hours). After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method, for example, the same operation as the method for collecting the compound of Step A1 of Method A described above.

Reaction (d): The reaction for converting the alkoxycarbonyl group contained in R ⁷ a into a methyl group or the alkanoyl group into an alkyl group in the reaction (d) is carried out in an inert solvent (preferably ether, tetrahydrofuran, In a reducing agent (preferably lithium aluminum hydride, an aluminum hydride compound such as diisobutylaluminum hydride, an alkali metal borohydride such as sodium borohydride or a borane) in ethers such as dioxane). Borohydride compound).

The reaction temperature and reaction time will differ depending on the solvent and the like, but are usually 0 ° C. to 100 ° C. (preferably room temperature to 8 ° C.).
0 ° C.) and 30 minutes to 24 hours (preferably 1 hour to 16 hours).

After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method.
The same operation as in the method of collecting a compound in step A1 of the method is performed.

Reaction (e): The reaction for alkylating the = NH group contained in R ⁷ a in the reaction (e) is carried out by using methyl iodide, ethyl iodide, propyl iodide or butyl iodide as an alkylating agent. Such a C ₁ -C ₄ alkyl halide is allowed to act in the presence of a base (for example, an alkali metal carbonate such as potassium carbonate or sodium carbonate; an alkali metal hydride such as sodium hydride), and the above B 3
It is carried out in the same manner as in the reaction (a) of the step.

Compound (I) can be converted into a pharmaceutically acceptable salt by treating with an acid according to a conventional method. For example, in an inert solvent (preferably ethers such as ether, tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride and chloroform) and a corresponding acid at room temperature. It can be obtained by reacting for 5 minutes to 1 hour and then distilling off the solvent under reduced pressure. Further, the hydrochloride can be obtained by adsorbing compound (I) or an acid addition salt thereof on an acidic resin column (for example, CM-Sephadex C-25 etc.) and eluting dilute hydrochloric acid. The starting compound (II) of Method AC is publicly known or is produced by publicly known methods (for example, JP-A-55-20740, JP-A-304022, etc.).

[0080]

INDUSTRIAL APPLICABILITY The compounds of formula (I) of the present invention are excellent and selective serotonin 2 receptor antagonists. Therefore, it blocks the serotonin 2 receptor distributed in vascular endothelial cells and platelets, suppresses the aggregation of blood platelets, suppresses vasoconstriction, inhibits the formation of thrombus, and causes cardiovascular disease,
For example, treatment and recurrence of arrhythmia, angina, ischemic heart disease such as myocardial infarction, cerebral infarction, cerebrovascular disorder such as vasospasm after subarachnoid hemorrhage, Raynaud's disease, peripheral circulatory disturbance such as Burger's disease, etc. Useful for prevention.

Further, the compounds of Production Examples 2, 3, 8 and 13 and the like strongly bind to the dopamine 2 receptor and also have serotonin 2 receptor antagonism, so that the psychosis (schizophrenia) with weak side effects is ) Is useful as a therapeutic drug.

When the compound (I) of the present invention and a pharmacologically acceptable salt thereof are used as an antithrombotic agent or a therapeutic agent for schizophrenia, itself or an appropriate pharmacologically acceptable carrier, excipient It can be orally or parenterally administered as a pharmaceutical composition such as powder, granules, tablets, capsules, injections, etc. by mixing with a form, a diluent and the like. The dose varies depending on the condition of the target disease, the condition of the patient, the age, the administration method, etc.
In the case of intravenous administration, it is desirable to administer 1000 mg (preferably 10 to 500 mg) 0.1 to 500 mg (preferably 1 to 300 mg) once to 1 to 3 times per day depending on the symptoms. The present invention will be described in more detail below by showing Test Examples, Production Examples, Reference Examples and Formulation Examples, but the scope of the present invention is not limited to these.

[0083]

【Example】

Test Example 1 Vasoconstriction Experiment The smooth muscle contraction reaction was measured by Van Neuten et al. (J. Pharmacol. Exp.
Ther., 218, 217-230, 1981).
An SD male rat with a body weight of about 500 g was exsanguinated to death, and the tail artery was extracted. After removing the incidental tissue from the artery, (2 x
20 mm) spiral specimens were prepared. This sample is Tyor
It was suspended in a Magnus tube containing 10 ml of the ode solution and kept at 37 ° C., and a mixed gas (95% O ₂ , 5% CO ₂ ) was passed through the tube for 1 hour and then used in the experiment. 0 as the initial tension.
5 g was loaded and the tension was recorded isometrically using a transducer. As a vasoconstrictor, serotonin 3x10 ^-6 M was added to the serotonin 2 receptor, and phenylephrine 1x10 ^-6 M was added to the adrenal α ₁ receptor into the Magnus tube. After the contraction reaction was stabilized, each test solution was added. Cumulative additions were made and finally papaverine 10 ^-4 M was added. The tension was set to 100% before the addition of the test drug and the tension was set to 0% 5 minutes after the addition of papaverine. The concentration of the test drug required to reduce the tension to 50% was defined as an IC ₅₀ value, and the concentration was calculated by a least-squares regression line. The results for the preferred compounds are shown in Table 2.

[0084]

[Table 2] ─────────────────────────────── Compound IC ₅₀ nM Serotonin 2 Adrenaline α ₁ ─────── ───────────────────────── Preparation Example 5 Compound 10 ＞ 5,000 Production Example 6 Compound 23 ＞ 5,000 Production Example 7 Compound 11 4,900 Production Example Compound 9 of 24> 5,000 ────────────────────────────────.

Test Example 2 Receptor Binding Experiment This was carried out according to the method of Leysen et al. (Mol. Pharmacol., 21, 301-314, 1982). Male Wistar rats (weight 280-
320 g) was used. After decapitation, the removed cerebral cortex and striatum were frozen on dry ice and stored at -80 ° C until measurement. The cerebral cortex was used for serotonin receptors, and the striatum was used for dopamine receptors. For preparation of the membrane preparation, the frozen brain tissue was homogenized with 50 mM Tris-HCl buffer (pH 7.7) (Polytron PT-20) and then centrifuged at 49,000 g for 10 minutes. The precipitate was suspended in Tris buffer, centrifuged again, and then suspended in Tris buffer. The obtained membrane preparation is
After protein quantification, 0.57mg / protein / ml with Tris buffer
And stored at −80 ° C. In the receptor binding experiment, 440 μl of the membrane preparation was added to a test tube containing 50 μl of ³ H-ligand and 10 μl of a test compound (dissolved in DMSO) to start the reaction. After incubation for 1 hour at 30 ° C., the reaction was stopped by vacuum filtration on a Whatman GF / B glass filter. After washing the filter with ice-cold Tris buffer (4 ml x 2 times), ACS-II
Was added and the radioactivity of the filter was measured with a liquid scintillation counter. Non-specific binding was determined with 20 μM atropine. The binding inhibition rate (%) was determined from the binding rate in the presence of the test drug, and the concentration required to inhibit the binding by 50% was taken as the IC ₅₀ value, which was determined from the least-squares regression line. The results for the preferred compounds are shown in Table 3.

[0086]

[Table 3] ─────────────────────────────── Compound IC ₅₀ , nM / ml Serotonin 2 Dopamine 2 ──── ──────────────────────────── Production Example 2 Compound 22 147 Production Example 3 Compound 35 95 Production Example 8 Compound 38 153 Production Example Compound of 13 29 119 ────────────────────────────────

Production Example 1 1- (N, N-dimethylamino) -3- [2- (3-methylbutyl) phenoxy] -2-propanol hydrochloride (1a) 2- [2- (3-methylbutyl) phenoxymethyl ] 493 mg of oxirane 2- (3-methylbutyl) phenol was added to N, N
-Dissolved in 20 ml of dimethylacetamide, 336 mg of potassium t-butoxide was added with stirring under ice cooling to obtain a dark colored solution. After adding 616 mg of epichlorohydrin under stirring at the same temperature, the cooling bath was removed and the mixture was stirred for 24 hours. 50 ml of ethyl acetate was added to the reaction mixture, and the mixture was shaken to separate the organic layer,
Concentration under reduced pressure gave an oil. Column chromatography treatment using silica gel (elution solvent: hexane /
Ethyl acetate = 9/1) to give 250 mg of the title compound as an oil. (1b) 1- (N, N-dimethylamino) -3- [2-
(3-Methylbutyl) phenoxy] -2-propanol hydrochloride 250 mg of 2- [2- (3-methylbutyl) phenoxymethyl] oxirane obtained in (1a) was dissolved in 20 ml of tetrahydrofuran, and 10 ml of 50% dimethylamine aqueous solution was added. It was left at room temperature for 4 hours. After removing the solvent under reduced pressure, the obtained oily substance was subjected to column chromatography using silica gel (elution solvent: methylene chloride / methanol = 5/1) to give 1- (N, N-dimethylamino)-.
210 mg of 3- [2- (3-methylbutyl) phenoxy] -2-propanol was obtained as an oil. This was dissolved in ethyl acetate and 4N hydrogen chloride-dioxane solution 0.2 ml
Was added and the mixture was allowed to stand at room temperature. The generated crystals were collected by filtration and dried to give 210.9 mg of the title compound as colorless crystals. Melting point: 113-114 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.94 (6H, d, J = 6.
6Hz), 1.35-1.7 (3H, m), 2.5-2.65 (2H, m), 2.99 (6H, s),
3.25-3.5 (2H, m), 3.9-4.05 (1H, m), 4.15-4.25 (1H, m),
4.55-4.7 (1H, m), 6.8-7.0 (2H, m), 7.1-7.2 (2H, m).

Production Example 2 N, N-Dimethyl-3- [2- (4-methylpentyl)
Phenoxy] propylamine hydrochloride 890 mg of 2- (4-methylpentyl) phenol, 3.93 g of triphenylphosphine and 1.55 g of dimethylaminopropanol were dissolved in 100 ml of methylene chloride, and 2.61 g of diethyl azodicarboxylate was dissolved in methylene chloride while stirring with ice cooling. A 10 ml solution was added dropwise. After removing the ice bath and stirring at room temperature for 3 hours, water and ethyl acetate were added to the residue obtained by concentration under reduced pressure, and the mixture was shaken to separate the organic layer. The organic layer was dehydrated and then concentrated under reduced pressure. A mixture of ethyl acetate and hexane (1: 2) was added, the insoluble material was filtered off, and the solvent was removed to give an oily residue. This was subjected to column chromatography using silica gel (elution solvent: methylene chloride / methanol = 20/1) to give N, N-dimethyl- [2-
(4-Methylpentyl) phenoxy] propylamine 6
54 mg was obtained as an oil. This was dissolved in 10 ml of ethyl acetate, and 1 ml of 4N hydrogen chloride-dioxane solution was added. After removing the solvent under reduced pressure, it was dissolved in 10 ml of carbon tetrachloride and allowed to stand to precipitate crystals. This was collected by filtration and dried to obtain 450 mg of the title compound as a colorless hygroscopic solid. Melting point: 115-116 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.88 (6H, d, J = 6.
6Hz), 1.15-1.3 (2H, m), 1.5-1.65 (3H, m), 2.35-2.5 (2H,
m), 2.55 (2H, t, J = 7.9Hz), 2.87 (6H, s), 3.2-3.3 (2H, m),
4.10 (2H, t, J = 5.6Hz), 6.81 (1H, d, J = 7.9Hz), 6.91 (1H,
t, J = 7.9Hz), 7.1-7.2 (2H, m).

Production Example 3 N, N-Dimethyl-3- (2-heptylphenoxy) propylamine hydrochloride 0.96 g of 2-heptylphenol, 3.92 g of triphenylphosphine and 1.55 g of dimethylaminopropanol in 100 ml of methylene chloride, azodicarboxylic acid. Diethyl acid 2.61g
Was reacted in the same manner as in Production Example 2, extracted, and post-treated to obtain an oily crude substance. This was subjected to column chromatography treatment using silica gel (elution solvent: methylene chloride / methanol = 20/1), and N, N-dimethyl-3- (2
889 mg of -heptylphenoxy) propylamine were obtained as an oil. This was dissolved in a small amount of ethyl acetate, 4 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated under reduced pressure. The obtained solid was dissolved in carbon tetrachloride, pentane was added, and the precipitated solid was collected by filtration. Further, this was dried to obtain 932 mg of the title compound as a colorless powder. Melting point: 81-82 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.88 (3H, t, J = 6.
9Hz), 1.2-1.4 (8H, m), 1.5-1.65 (2H, m), 2.35-2.5 (2H,
m), 2.58 (2H, t, J = 7.6Hz), 2.83 (6H, s), 3.2-3.3 (2H, m),
4.10 (2H, t, J = 5.6Hz), 6.81 (1H, d, J = 7.9Hz), 6.90 (1H,
t, J = 7.6Hz), 7.1-7.2 (2H, m).

Production Example 4 2- [2- [2- (2-Cyclopentylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride 2- (2-cyclopentyl) ethylphenol 475.8 mg
Was dissolved in 20 ml of N, N-dimethylacetamide, and 561 mg of potassium t-butoxide was added and dissolved under stirring with ice cooling. To this, under stirring at the same temperature, 2- (2-chloroethyl)-
460 mg of 1-methylpyrrolidine hydrochloride was added. The reaction solution was stirred at room temperature for 1 hour and then at 55 ° C. for 5 hours, ethyl acetate and water were added, and the mixture was shaken to separate the organic layer. The organic layer was washed with brine, dehydrated and concentrated under reduced pressure to give an oil. This was subjected to column chromatography using silica gel (elution solvent: methylene chloride / methanol = 20/1), and 430 mg of 2- [2- [2- (2-cyclopentylethyl) phenoxy] ethyl] -1-methylpyrrolidine was colorless. Obtained as an oil. This was dissolved in 10 ml of ethyl acetate, and 4N hydrogen chloride-dioxane solution was added.
0.5 ml was added and the mixture was stood still, and the precipitated crystals were collected by filtration and dried to give 290 mg of the title compound as colorless crystals. Melting point: 131-132 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.0-1.25 (2H,
m), 1.4-1.9 (11H, m), 2.0-2.7 (7H, m), 2.85 (3H, s), 3.3-
3.6 (1H, m), 3.9-4.1 (2H, m), 4.2-4.35 (1H, m), 6.82 (1H,
d, J = 7.9Hz), 6.91 (1H, t, J = 6.9Hz), 7.1-7.25 (2H, m).

Production Example 5 3- [2- (2-cyclohexylethyl) phenoxy]
-1- (N, N-dimethylamino) -2-propanol hydrochloride (5a) 2- [2- (2-cyclohexylethyl) phenoxymethyl] oxirane 2- (2-cyclohexylethyl) phenol 284m
g, 1.09 g of triphenylphosphine and 313 mg of glycidol were dissolved in 9 ml of methylene chloride, to which 730 mg of diethyl azodicarboxylate was added, and the mixture was stirred at room temperature for 1.5 hours, and then saline and ethyl acetate were added for extraction. The oily substance obtained by dehydrating the extract layer and concentrating under reduced pressure was subjected to column chromatography using silica gel (eluting solvent: hexane / ethyl acetate = 10/1) to obtain 172 mg of the title compound as a colorless oily substance. (5b) 3- [2- (2-Cyclohexylethyl) phenoxy] -1- (N, N-dimethylamino) -2-propanol hydrochloride 2- [2- (2-cyclohexylethyl) obtained in (5a). Phenoxymethyl] oxirane (168 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a 50% dimethylamine aqueous solution.
0.7 ml was added and the mixture was left standing at room temperature for 20 hours. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (column: silica gel; eluting solvent: methylene chloride / methanol = 10 /
Purification in 1) yielded 160 mg of a colorless oil. This was dissolved in dioxane, and 4N hydrogen chloride-dioxane solution was added.
After adding 2 ml, the mixture was concentrated under reduced pressure to obtain 177 mg of the title compound as a colorless solid. Melting point: 122-124 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.8-1.8 (13H,
m), 2.57 (2H, t, J = 7.9Hz), 2.97 (6H, s), 3.2-3.4 (2H, m),
3.94 (1H, t, J = 9.2Hz), 4.18 (1H, dd, J = 4.6 and 9.2H
z), 4.55-4.7 (1H, m), 6.28 (1H, d, J = 7.3Hz), 6.91 (1H, t,
J = 7.3Hz), 7.1-7.2 (2H, m).

Production Example 6 3- [2- (2-chloro-2-cyclohexylethyl)
Phenoxy] -1- (N, N-dimethylamino) -2-
Propanol hydrochloride (6a) 2- [2- (2-chloro-2-cyclohexylethyl) phenoxymethyl] oxirane 230 mg 2- (2-chloro-2-cyclohexylethyl) phenol, 379 mg triphenylphosphine, 112 mg glycidol and azodicarboxylic. Diethyl acid 25
4 mg was used and reacted in 6 ml of methylene chloride in the same manner as in Production Example (5a), and column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 10/1).
The title compound (88 mg) was obtained as a colorless oil. (6b) 3- [2- (2-Chloro-2-cyclohexylethyl) phenoxy] -1- (N, N-dimethylamino) -2-propanol hydrochloride 2- [2- (2 -Chloro-2-cyclohexylethyl) phenoxymethyl] oxirane (80 mg) in tetrahydrofuran (3 ml) was added with 50% dimethylamine aqueous solution (0.6 ml) and reacted in the same manner as in Production Example (5b), followed by column chromatography (column: silica gel; elution solvent). : Methylene chloride / methanol = 10/1) to give a colorless oily substance (99 mg). This was treated with 4N hydrogen chloride-dioxane solution 0.11 ml in 3 ml of dioxane in the same manner as in Production Example (5b) to obtain 108 mg of the title compound as a colorless solid. Melting point: 92-93 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.0-2.0 (11H,
m), 2.98 (6H, s), 3.05 (2H, d, J = 7.3Hz), 3.2-3.5 (2H, m),
3.96 (1H, q, J = 8.6Hz), 4.05-4.15 (1H, m), 4.20 (1H, dd, J
= 4.6 and 9.2Hz), 4.55-4.7 (1H, m), 6.86 (1H, d, J = 7.6H
z), 6.94 (1H, t, J = 7.6Hz), 7.14 (1H, d, J = 7.6Hz), 7.23 (1
H, t, J = 7.6 Hz).

Production Example 7 2- [2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride 2- (2-cyclohexylethyl) phenol 500 m
g, 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride 530 mg and potassium t-butoxide 604 mg
Was reacted in the same manner as in Production Example 4 in 10 ml of N, N-dimethylacetamide, extracted, purified by column chromatography (column: silica gel; elution solvent: methylene chloride / methanol = 10/1), and colorless. 350 mg oil
Got This was dissolved in 4 ml of dioxane, 0.83 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated under reduced pressure. The obtained oily substance was dissolved in ethyl acetate and left standing at room temperature to precipitate crystals, which were collected by filtration and dried to give 243 mg of the title compound as colorless crystals. Melting point: 101-102 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.85-1.05 (2H,
m), 1.05-1.4 (4H, m), 1.4-1.5 (2H, m), 1.6-1.9 (5H, m),
1.95-2.2 (2H, m), 2.2-2.7 (6H, m), 2.8-3.0 (1H, m), 2.86
(3H, s), 3.3-3.55 (1H, m), 3.85-4.1 (2H, m), 4.2-4.3 (1
H, m), 6.83 (1H, d, J = 8Hz), 6.92 (1H, t, J = 7.4Hz), 7.1-7.
25 (2H, m).

Production Example 8 2- [2- (2-cyclohexylethyl) phenoxymethyl] morpholine hydrochloride (8a) 4-t-butoxycarbonyl-2- [2- (2
-Cyclohexylethyl) phenoxymethyl] morpholine 2- (2-cyclohexylethyl) phenol 1.01 g,
2.37 g of 4-t-butoxycarbonyl-2-p-toluenesulfonyloxymethylmorpholine and potassium t-
The reaction was performed in the same manner as in Production Example 4 using 824 mg of butoxide in 30 ml of N, N-dimethylacetamide, extracted, and purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 5/1). Thus, 1.99 g of the title compound was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.85-1.05 (2H,
m), 1.1-1.9 (11H, m), 1.48 (9H, s), 2.65-2.75 (2H, m), 2.
8-3.1 (2H, m), 3.5-3.7 (1H, m), 3.75-4.2 (6H, m), 6.81 (1
H, d, J = 8.6Hz), 6.89 (1H, t, J = 7.9Hz), 7.1-7.2 (2H, m). (8b) 2- [2- (2-Cyclohexylethyl) phenoxymethyl] morpholine hydrochloride 4-t-butoxycarbonyl-2- [2 obtained in (8a).
1 g of-(2-cyclohexylethyl) phenoxymethyl] morpholine was dissolved in 5 ml of dioxane, 5 ml of a 4N hydrogen chloride-dioxane solution was added at room temperature, and the mixture was left standing for 2 hours and 30 minutes. The solvent was distilled off, and the obtained oily matter was washed with ethyl acetate 2
When dissolved in 0 ml and allowed to stand, crystals were precipitated. This was collected by filtration and dried to obtain 519 mg of the title compound as colorless crystals. Melting point: 130-131 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.85-1.05 (2H,
m), 1.1-1.4 (4H, m), 1.4-1.5 (2H, m), 1.6-1.85 (5H, m),
2.59 (2H, dd, J = 7.9 and 8.6Hz), 3.0-3.25 (2H, m), 3.3
9 (1H, d, J = 12.5Hz), 3.50 (1H, d, J = 11.2Hz), 4.0-4.2 (4H,
m), 4.3-4.4 (1H, m), 6.78 (1H, d, J = 7.9Hz), 6.91 (1H, t, J
= 7.6Hz), 7.1-7.2 (2H, m).

Production Example 9 2- [2- (2-Cyclohexylethyl) phenoxymethyl] -4-methylmorpholine hydrochloride 4-t-butoxycarbonyl-2 obtained in Production Example (8a)
910 mg of-[2- (2-cyclohexylethyl) phenoxymethyl] morpholine was dissolved in 15 ml of tetrahydrofuran and added dropwise to a suspension of 257 mg of lithium aluminum hydride in 25 ml of tetrahydrofuran with cooling. This was heated under reflux for 3 hours and then cooled with ice, and sodium sulfate 1
O-hydrate was added to decompose excess hydride. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (column: silica gel; elution solvent: methylene chloride / methanol = 10/1) to obtain 670 mg of a colorless oil. This was dissolved in 5 ml of dioxane, 1.5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated under reduced pressure. The obtained oily substance was dissolved in 20 ml of ethyl acetate, and upon standing at room temperature, crystals were precipitated, which were collected by filtration and dried to obtain 402 mg of the title compound as colorless crystals. Melting point: 121-123 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.85-1.05 (2H,
m), 1.1-1.9 (11H, m), 2.60 (2H, t, J = 7.6Hz), 2.8-3.0 (1H,
m), 2.85 (3H, s), 3.03 (1H, t, J = 11.2Hz), 3.3-3.6 (2H,
m), 4.0-4.2 (3H, m), 4.40 (1H, t, J = 11.9Hz), 4.5-4.7 (1
H, m), 6.80 (1H, d, J = 7.9Hz), 6.92 (1H, d, J = 7.9Hz), 7.1-
7.2 (2H, m).

Production Example 10 trans-2- [2- [2- [2- (2- (3-methoxycyclohexyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine hydrochloride trans-2- [2- (3-methoxycyclohexyl) )
334.5 mg of ethyl] phenol, 450 mg of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 540 mg of potassium t-butoxide were reacted in 8 ml of N, N-dimethylacetamide in the same manner as in Production Example 4 and extracted. , Column chromatography (column: silica gel;
Purification with an eluting solvent: methylene chloride / methanol = 10/1) gave 271 mg of a colorless oil. This was dissolved in 5 ml of dioxane, 0.56 ml of 4N hydrogen chloride-dioxane solution.
After addition of the above, the mixture was concentrated under reduced pressure to obtain a colorless solid. This was triturated in ether, filtered, washed and 208 mg of the title compound
Got Melting point: 87-89 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.9-1.95 (11H,
m), 1.95-2.6 (8H, m), 2.5-2.9 (1H, m), 2.68 (3H, s), 3.29
(3H, s), 3.3-3.5 (2H, m), 3.85-4.0 (2H, m), 4.2-4.3 (1H,
m), 6.8 (1H, d, J = 8.6Hz), 6.9 (1H, t, J = 7.3Hz), 7.1-7.2
(2H, m).

Production Example 11 cis-2- [2- [2- [2- (3-methoxycyclohexyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine hydrochloride cis-2- [2- (3-methoxycyclohexyl) ) Ethyl] phenol 400 mg, 2- (2-chloroethyl)-
1-methylpyrrolidine hydrochloride 471 mg and potassium t
-Butoxide (575 mg) was reacted in 20 ml of N, N-dimethylacetamide in the same manner as in Preparation Example 4, extracted, and purified by column chromatography (column: silica gel; elution solvent: methylene chloride / methanol = 10/1). . Separation into two fractions by column chromatography gave isomers A (324 mg) and B (158 mg) as colorless oils due to the asymmetric carbon at the 2-position of the pyrrolidine ring. 320 mg of isomer A 3 ml of dioxane
, 4N hydrogen chloride-dioxane solution (0.69 ml) was added, the mixture was concentrated under reduced pressure and recrystallized from ether to give cis-
206 mg of the isomer A hydrochloride of 2- [2- [2- [2- (2- (3-methoxycyclohexyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was obtained. Melting point: 89-92 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.8-1.9 (9H, m),
2.0-2.25 (4H, m), 2.25-2.45 (2H, m), 2.45-2.7 (4H, m),
2.8-3.0 (1H, m), 2.87 (3H, s), 3.05-3.2 (1H, m), 3.3-3.5
(1H, m), 3.35 (3H, s), 3.85-4.1 (2H, m), 4.2-4.3 (1H, m),
6.80 (1H, d, J = 7.9Hz), 6.90 (1H, t, J = 6.9Hz), 7.1-7.2 (2
H, m). Isomer B (152 mg) was dissolved in dioxane (3 ml), 4N hydrogen chloride-dioxane solution (0.33 ml) was added, and the mixture was concentrated under reduced pressure, and recrystallized from ether to give cis-2- [2- [2- [2
107 mg of the more polar isomer B hydrochloride of-(3-methoxycyclohexyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine were obtained as a colorless powder. Melting point: 85-88 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.8-1.9 (9H, m),
2.0-2.25 (4H, m), 2.25-2.45 (2H, m), 2.45-2.7 (4H, m),
2.8-3.0 (1H, m), 2.87 (3H, s), 3.05-3.2 (1H, m), 3.3-3.5
(1H, m), 3.35 (3H, s), 3.85-4.1 (2H, m), 4.2-4.3 (1H, m),
6.80 (1H, d, J = 7.9Hz), 6.90 (1H, t, J = 6.9Hz), 7.1-7.2 (2
H, m).

Production Example 12 cis-2- [2- [2- (3-methoxycyclohexyl) ethyl] phenoxymethyl] -4-methylmorpholine hydrochloride (12a) cis-4-t-butoxycarbonyl-2-
[2- (3-Methoxycyclohexyl) ethyl] phenoxymethyl] morpholine cis-2- [2- (3-methoxycyclohexyl) ethyl] phenol 441.7 mg, 4-t-butoxycarbonyl-2-p-toluenesulfonyloxymethylmorpholine
Using 1050 mg and potassium t-butoxide 317 mg,
The reaction was carried out in the same manner as in Production Example 4 in 20 ml of N, N-dimethylacetamide, followed by extraction and column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 4).
/ 1) to obtain 800 mg of the title compound as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.75-0.95 (2H,
m), 0.95-1.6 (5H, m), 1.48 (9H, s), 1.7-1.85 (2H, m), 2.0
-2.2 (2H, m), 2.5-2.75 (2H, m), 2.8-3.2 (3H, m), 3.35 (3H,
s), 3.5-3.7 (1H, m), 3.75-4.0 (4H, m), 4.0-4.2 (2H, m),
6.81 (1H, d, J = 8.6Hz), 6.89 (1H, t, J = 7.9Hz), 7.1-7.2 (2
H, m). (12b) cis-2- [2- [2- (3-methoxycyclohexyl) ethyl] phenoxymethyl] -4-methylmorpholine hydrochloride cis-4-t-butoxycarbonyl-obtained in (12a).
2- [2- (3-Cyclohexyl) ethyl] phenoxymethyl] morpholine 462 mg, 121 mg of lithium aluminum hydride and 25 ml of tetrahydrofuran were reacted in the same manner as in Production Example 9, treated, and subjected to column chromatography (column: silica gel; elution). Solvent: methylene chloride / methanol = 6/1) and purified, colorless oil 320
to obtain mg. This was dissolved in 3 ml of dioxane, 0.67 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated. The obtained oily substance was dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried to obtain 130 mg of the title compound as colorless crystals. Melting point: 150-153 ° C. NMR spectrum _{(270MHz, CDCl 3) δppm:} 0.8-1.1 (3H, m),
1.1-1.9 (6H, m), 2.1-2.3 (2H, m), 2.45-2.8 (2H, m), 2.8
7 (3H, s), 2.9-3.25 (3H, m), 3.35 (3H, s), 3.3-3.6 (2H,
m), 4.0-4.2 (3H, m), 4.39 (1H, t, J = 12.5Hz), 4.5-4.65 (1
H, m), 6.80 (1H, d, J = 7.9Hz), 6.93 (1H, t, J = 7.6Hz), 7.1-
7.2 (2H, m).

Production Example 13 (S) -2- [2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (13a) (S) -2- [2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-ethoxycarbonylpyrrolidine 2- (2-cyclohexylethyl) phenol 133 m
g, (S) -1-ethoxycarbonyl-2- (2-p-
Toluenesulfonyloxyethyl) pyrrolidine 244mg
And potassium t-butoxide 80 mg, N, N-
The reaction was performed in 10 ml of dimethylacetamide in the same manner as in Preparation Example 4, extracted, and purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 5/1) to give 181 mg of the title compound as a colorless oil. Obtained. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.8-1.05 (2H,
m), 1.1-1.4 (7H, m), 1.4-1.55 (2H, m), 1.55-2.1 (10H,
m), 2.1-2.4 (1H, m), 2.55-2.7 (2H, m), 3.3-3.6 (2H, m),
3.9-4.2 (3H, m), 4.12 (2H, q, J = 7.3Hz), 6.75-6.95 (2H,
m), 7.1-7.2 (2H, m). (13b) (S) -2- [2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (13a) (S) -2- [2- [2- 181 mg of (2-cyclohexylethyl) phenoxy] ethyl] -1-ethoxycarbonylpyrrolidine was dissolved in 5 ml of tetrahydrofuran, added dropwise to a suspension of 55.3 mg of lithium aluminum hydride in 5 ml of tetrahydrofuran at room temperature, and heated under reflux for 1 hour. After cooling and post-treatment as in Production Example 9,
Purify by column chromatography (column: silica gel; elution solvent: methylene chloride / methanol = 6/1),
137 mg of oil was obtained. This was dissolved in 4 ml of dioxane, 0.33 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated under reduced pressure. The obtained oily substance was dissolved in a small amount of ethyl acetate, hexane was added, and the mixture was stopped just before turbidity and left standing to precipitate crystals. This was collected by filtration and dried to obtain 106 mg of the title compound as colorless crystals. Melting point: 103-105 ° C. [Α] _D = -18.4 ° (C = 1.29, methanol). NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.8-1.05 (2H,
m), 1.05-1.4 (4H, m), 1.4-1.5 (2H, m), 1.5-1.9 (5H, m),
1.95-2.2 (2H, m), 2.2-2.45 (2H, m), 2.45-2.7 (4H, m), 2.
75-2.95 (1H, m), 2.85 (3H, s), 3.3-3.55 (1H, m), 3.85-4.
1 (2H, m), 4.2-4.3 (1H, m), 6.82 (1H, d, J = 8Hz), 6.91 (1H,
t, J = 7.3Hz), 7.1-7.2 (2H, m).

Production Example 14 (R) -2- [2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (14a) (R) -2- [2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-ethoxycarbonylpyrrolidine 2- (2-cyclohexylethyl) phenol 340 m
g, (R) -1-ethoxycarbonyl-2- (2-p-
Toluenesulfonyloxyethyl) pyrrolidine 625 mg
And 205 mg of potassium t-butoxide were used, N, N
-React in 15 ml of dimethylacetamide in the same manner as in Preparation Example 4, extract, and perform column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 5/1).
The title compound (591 mg) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.8-1.05 (2H,
m), 1.05-1.4 (7H, m), 1.4-1.55 (2H, m), 1.55-2.1 (10H,
m), 2.1-2.4 (1H, m), 2.55-2.7 (2H, m), 3.3-3.6 (2H, m),
3.9-4.2 (3H, m), 4.12 (2H, q, J = 7.3Hz), 6.75-6.95 (2H,
m), 7.1-7.2 (2H, m). (14b) (R) -2- [2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (14a) obtained in (R) -2- [2- [2- [2- (2-Cyclohexylethyl) phenoxy] ethyl] -1-ethoxycarbonylpyrrolidine (570 mg), aluminum hydride (174 mg) and tetrahydrofuran (20 ml) were used and reacted in the same manner as in Production Example (13b), treated, and subjected to column chromatography (column: silica gel; Elution solvent: methylene chloride / methanol = 6/1) and purified to give an oil 476
to obtain mg. In the same manner as in Production Example (13b), 4N hydrogen chloride-dioxane solution (0.87 ml) was used as a hydrochloride in dioxane and concentrated under reduced pressure, and the obtained oil was dissolved in ethyl acetate. Crystals were precipitated when left to stand at room temperature. These crystals were collected by filtration and dried to give the title compound as colorless crystals.
mg was obtained. Melting point: 133-136 [deg.] C. [Α] _D = + 18.8 ° (C = 1.08, methanol). NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.8-1.05 (2H,
m), 1.05-1.4 (4H, m), 1.4-1.5 (2H, m), 1.5-1.9 (5H, m),
1.95-2.2 (2H, m), 2.2-2.45 (2H, m), 2.45-2.7 (4H, m), 2.
75-2.95 (1H, m), 2.85 (3H, s), 3.3-3.55 (1H, m), 3.85-4.
1 (2H, m), 4.2-4.3 (1H, m), 6.82 (1H, d, J = 8Hz), 6.91 (1H,
t, J = 7.3Hz), 7.1-7.2 (2H, m).

Reference Example 1 2-Benzyloxybenzyl triphenylphosphonium chloride 152 g of salicyl alcohol was dissolved in 600 ml of N, N-dimethylformamide, and potassium t-butoxide 15 was added.
1 g was added under ice-cooled stirring. After stirring at room temperature for 30 minutes,
160 ml of benzyl bromide was added dropwise to the reaction mixture, and 3
The mixture was stirred at 0-40 ° C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the extract was washed twice with brine, dehydrated and concentrated under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography with hexane-ethyl acetate (5: 1) to give 2-benzyloxybenzyl alcohol 228.5.
g (yield 87%) was obtained as a colorless oil. This was dissolved in tetrahydrofuran (500 ml), thionyl chloride (85 ml) was added dropwise under ice-cooling, the mixture was allowed to stand overnight at room temperature, and concentrated under reduced pressure to give a dark oil. This was dissolved in toluene, filtered on silica gel for column chromatography, decolorized, and the filtrate was concentrated under reduced pressure to give 2-benzyloxybenzyl chloride as a yellowish oil. This was dissolved in 500 ml of toluene without further purification, 420 g of triphenylphosphine was added, and the mixture was heated under reflux for 3 hours to gradually produce a white insoluble matter. After cooling the reaction solution, the resulting precipitate was collected by filtration, washed and dried to give 539.9 g of the title compound.
(Yield 96%) was obtained as a colorless solid. NMR spectrum (60 MHz, CDCl ₃ ) δppm: 4.46 (2H, s), 5.28
(2H, d, J = 14Hz), 6.5-8.0 (24H, m).

Reference Example 2 2- (3-Methylbutyl) phenol Isobutyraldehyde 0.75 g and 2-benzyloxybenzyltriphenylphosphonium chloride 3.43 g were added to 100 ml of acetonitrile, and 1,8-diazabicyclo [5.4. 0] Undesa-7-en (DB
U) 1.52 g was added dropwise. This was further stirred at the same temperature for 8 hours, the solvent was removed under reduced pressure, ethyl acetate and water were added to the residue, and the mixture was shaken to separate the organic layer. The organic layer was dehydrated and then concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1.
9/1) to obtain 1.43 g of an oily substance. This is ethanol 1
In 00 ml, hydrogenation was carried out at room temperature and normal pressure (hydrogen pressure) for 6 hours in the presence of 5% palladium-carbon catalyst. After removing the catalyst by filtration, the filtrate was concentrated, and the residue was subjected to column chromatography using silica gel (eluting solvent: hexane / ethyl acetate = 9.
/ 1) to obtain 0.85 g of the title compound as a colorless oily substance. NMR spectrum (60MHz, CDCl ₃ ) δppm: 0.94 (6H, d, J = 6H
z), 1.0-1.8 (3H, m), 2.4-2.8 (2H, m), 4.71 (1H, s, phenolic hydroxyl group), 6.6-7.3 (4H, m).

Reference Example 3 2- (4-Methylpentyl) phenol 1.72 g of isovaleraldehyde and 9.9 g of 2-benzyloxybenzyltriphenylphosphonium chloride in 50 ml of acetonitrile were added to 1,8-diazabicyclo [5.4.
0] Undesa-7-ene (3.04 g) was reacted in the same manner as in Reference Example 2, post-treated, and subjected to column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 1).
Purification by 9/1) gave 4.92 g of an oil. This was hydrogenated in 100 ml of ethanol in the same manner as in Reference Example 2 and then purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 5/1) to give 2.79 g of the title compound as a colorless oil. I got it as a thing. NMR spectrum (60 MHz, CDCl ₃ ) δppm: 0.86 (6H, d, J = 6H
z), 1.0-2.0 (5H, m), 2.60 (2H, t, J = 7.5Hz), 4.68 (1H, s, phenolic hydroxyl group), 6.65-7.3 (4H, m).

Reference Example 4 2-heptylphenol hexanal 3 g, 2-benzyloxybenzyltriphenylphosphonium chloride 15 g and acetonitrile 1
In 00 ml, 4.58 g of 1,8-diazabicyclo [5.4.0] undes-7-ene was reacted in the same manner as in Reference Example 2, treated, and subjected to column chromatography (column: silica gel; elution solvent: hexane). / Ethyl acetate = 19/1)
The oily matter was purified by 7.5 g. This is ethanol 10
It was hydrogenated in 0 ml in the same manner as in Reference Example 2 and purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 5/1) to obtain 3.75 g of the title compound as a colorless oil. NMR spectrum (60 MHz, CDCl ₃ ) δppm: 0.89 (3H, t, J = 7H
z), 1-2.0 (10H, m), 2.61 (2H, t, J = 7.5Hz), 4.73 (1H, s, phenolic hydroxyl group), 6.65-7.3 (4H, m).

Reference Example 5 2- (2-Cyclopentylethyl) phenol (5a) 2- (2-benzyloxyphenyl) -1-cyclopentylethyl chloride 1.62 g of magnesium thin piece was added to 50 ml of tetrahydrofuran, and bromocyclo was added under heating and stirring. 9.95 g of pentane was added dropwise, and the mixture was heated under reflux for 30 minutes to obtain a dark solution. After cooling, this solution was added dropwise to a solution of 7.54 g of 2-benzyloxyphenylacetaldehyde in 70 ml of tetrahydrofuran under ice cooling, and then stirred at room temperature for 30 minutes. Ice cold again,
A saturated aqueous ammonium chloride solution was added dropwise, and the separated organic solvent layer was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (elution solvent: hexane / ethyl acetate = 5/1) to obtain 4.0 g of 2- (2-benzyloxyphenyl) -1-cyclopentylethanol as a colorless liquid. Of this, 2.69 g of tetrahydrofuran 30
Dissolve in 1.3 ml, add thionyl chloride 1.3 g under ice-cooling stirring,
Then, 1.1 g of triethylamine was added dropwise. The reaction solution was brought to room temperature, left standing overnight, and then concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was shaken, the organic layer was separated, dried, and concentrated under reduced pressure. The residue was purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 40/1) to obtain 2.13 g of the title compound as a colorless oil. (5b) 2- (2-Cyclopentylethyl) phenol 2- (2-benzyloxyphenyl) -obtained in (5a)
1-Cyclopentylethyl chloride 2.13 g was added to benzene 2
Dissolve in 0 ml and add 2 g of tributyltin hydride and 2,
Add a small amount of 2'-azobisisobutyronitrile, 60 ℃
The mixture was heated and stirred for 3 hours. After the reaction solution was concentrated, it was purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 20/1) to give an oily substance 1.2.
g was obtained. This was dissolved in 20 ml of ethanol, 100 mg of 5% palladium-carbon catalyst was used, and atmospheric pressure (hydrogen pressure), 6
Reduced at 0 ° C. for 8 hours. The catalyst was filtered off, the solvent was distilled off,
Drying afforded 476 mg of the title compound as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.3 (2H, m),
1.4-2.0 (9H, m), 2.61 (2H, t, J = 7.9Hz), 4.69 (1H, s, phenolic hydroxyl group), 6.76 (1H, d, J = 7.9Hz), 6.86 (1H, t, J =
7.6Hz), 7.05-7.2 (2H, m).

Reference Example 6 2- (2-Cyclohexylethyl) phenol (6a) 2- (2-Benzyloxyphenyl) -1-cyclohexylethyl chloride 4.33 g of magnesium flakes was dissolved in tetrahydrofuran 350
2-benzyloxybenzyl chloride
41.5 g was added and the mixture was heated under reflux for 2 hours. Cool it down,
A solution of 10 g of cyclohexanecarboxaldehyde in 50 ml of tetrahydrofuran was added dropwise under ice cooling, and the mixture was further stirred under ice cooling for 3 hours. This was treated in the same manner as in Reference Example (5a), and the residue was purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 5/1) to give 2- (2-benzyloxyphenyl)-. 17.9 g of 1-cyclohexylethanol was obtained as a colorless oil. 8.1 g of this was dissolved in 200 ml of tetrahydrofuran, and 3.89 g of thionyl chloride and 3.17 of triethylamine were dissolved.
was treated with g in the same manner as in Reference Example (5b), treated, and purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 40/1) to give 5.93 g of the title compound as a colorless oil. I got it as a thing. (6b) 2- (2-Cyclohexylethyl) phenol 2- (2-benzyloxyphenyl) -obtained in (6a)
1-Cyclohexylethyl chloride 5.6 g toluene 6
The mixture was dissolved in 0 ml, tributyltin hydride (5.95 g) and 2,2'-azobisisobutyronitrile (140 mg) were added, and the mixture was heated under reflux for 1 hr. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 40/1) to obtain 4.51 g of a colorless oily substance. In 50 ml of ethanol,
Using 450 mg of 5% palladium-carbon as a catalyst, 1
The mixture was stirred at 60 ° C. for 4 hours under atmospheric hydrogen pressure. The catalyst was filtered off, the filtrate was concentrated, and the residue was subjected to column chromatography using silica gel (eluting solvent: hexane / ethyl acetate = 10/1) to obtain 2.92 g of the title compound as a colorless solid. NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.85-1.9 (13H,
m), 2.61 (2H, t, J = 7.9Hz), 4.74 (1H, s, phenolic hydroxyl group), 6.75 (1H, d, J = 7.9Hz), 6.86 (1H, t, J = 7.9Hz), 7.0
-7.2 (2H, m).

Reference Example 7 2- (2-Chloro-2-cyclohexylethyl) phenol 1.33 g of 2- (2-benzyloxy) -1-cyclohexylethyl chloride obtained in the same manner as in Reference Example (6a) was dissolved in 30 ml of ethanol. When 5% palladium-carbon (100 mg) was used and stirred at 60 ° C. for 5 hours under a hydrogen pressure of 1 atm, 2-
A mixture of (2-chloro-2-cyclohexylethyl) phenol and 2- (2-cyclohexylethyl) phenol was obtained. This is subjected to column chromatography using silica gel (elution solvent: hexane / ethyl acetate =
20/1) to obtain 245 mg of 2- (2-chloro-2-cyclohexylethyl) phenol and 447 mg of 2- (2-cyclohexylethyl) phenol as colorless solids. NMR spectrum of 2- (2-chloro-2-cyclohexylethyl) phenol (270 MHz, CDCl ₃ ) δppm: 1.0
−2.0 (11H, m), 2.95 (1H, dd, J = 9.2 and 13.9Hz),
3.16 (1H, dd, J = 4.0 and 13.9Hz), 4.1-4.2 (1H, m),
5.01 (1H, s, phenolic hydroxyl group), 6.78 (1H, d, J = 8.6H
z), 6.90 (1H, d, J = 7.3Hz), 7.1 −7.2 (2H, m). The NMR spectrum of 2- (2-cyclohexylethyl) phenol (270 MHz, CDCl ₃ ) was consistent with that of Reference Example (6b).

Reference Example 8 trans-2- [2- (3-methoxycyclohexyl)
Ethyl] phenol (8a) trans-2-benzyloxyphenyl-1-
(3-Methoxycyclohexyl) ethyl chloride 2-benzyloxybenzyl chloride 3.81 g, magnesium 398 mg, trans-3-methoxycyclohexanecarboxaldehyde 2 g and tetrahydrofuran 1
Reaction and treatment were carried out in the same manner as in Reference Example (5a) using 00 ml,
Purification by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 4/1) gave 2.31 g of an oil. This was chlorinated in the same manner as in Reference Example (5a) with 60 ml of tetrahydrofuran using 1.09 g of thionyl chloride and 0.94 g of triethylamine, extracted, and subjected to column chromatography (column: silica gel;
Purification with an elution solvent: hexane / ethyl acetate = 10/1) gave 1.50 g of the title compound as an oil. (8b) trans-2- [2- (3-methoxycyclohexyl) ethyl) phenol Reference Example Using trans-2-benzyloxyphenyl-1- (3-methoxycyclohexyl) ethyl chloride 1.14 g obtained in Reference Example (8a) as a reference example. In the same manner as in (5b), 1.6 g of tributyltin hydride and 70 mg of 2,2'-azobisisobutyronitrile were used and heated in 20 ml of toluene, and the product was subjected to column chromatography (column: silica gel; elution solvent: Purification with hexane / ethyl acetate = 8/1) gave 1 g of a colorless oil. Of this, 510 mg was stirred in 20 ml of ethanol using 5% palladium-carbon as a catalyst under a hydrogen pressure of 1 atm at 60 ° C. for 3 hours. The catalyst was filtered off, the filtrate was concentrated, and purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 4/1) to obtain 351 mg of the title compound as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.9-2.0 (11H,
m), 2.55-2.7 (2H, m), 3.31 (3H, s), 3.45-3.6 (1H, m), 4.8
8 (1H, s, phenolic hydroxyl group), 6.75 (1H, d, J = 7.9Hz), 6.
86 (1H, t, J = 7.3Hz), 7.0-7.2 (2H, m).

Reference Example 9 cis-2- [2- (3-methoxycyclohexyl) ethyl] phenol (9a) cis-2-benzyloxyphenyl-1- (3
-Methoxycyclohexyl) ethyl chloride 2-benzyloxybenzyl chloride 16.5 g, cis-3
-Methoxycyclohexanecarboxaldehyde 5.19
g, magnesium 1.73 g and tetrahydrofuran 25
The reaction was carried out in the same manner as in Reference Example (5a) using 0 ml, treated, and purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 10/1) to obtain 7.19 g of an oil. Of these, 7.03 g was reacted in the same manner as in Reference Example (5a) with 6.18 g of thionyl chloride and 3.19 g of triethylamine in 50 ml of tetrahydrofuran, treated, and subjected to column chromatography (column: silica gel;
Purification with an elution solvent: hexane / ethyl acetate = 10/1) gave 2.41 g of the title compound. (9b) cis-2- [2- (3-methoxycyclohexyl) ethyl) phenol cis-2 obtained in Reference Example (9a)
-Benzyloxyphenyl-1- (3-methoxycyclohexyl) ethyl chloride 2.41 g in toluene 30 ml with tributyltin hydride 2.35 g and 2,2'-azobisisobutyronitrile 110 mg as reference example (5b).
Was treated in the same manner as above, treated, and purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 8/1) to obtain 1.3 g of a colorless oily substance. This was stirred in 25 ml of ethanol using 5% palladium-carbon as a catalyst under a hydrogen pressure of 1 atm at 55 ° C. for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (column: silica gel; elution solvent: hexane / ethyl acetate = 4/1) to give the title compound (0.1).
91 g was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.8-1.0 (2H, m),
1.0-1.45 (4H, m), 1.5-1.65 (1H, m), 1.7-1.8 (2H, m), 2.
0-2.2 (2H, m), 2.6-2.7 (2H, m), 3.05-3.2 (1H, m), 3.37 (1
H, s), 4.98 (1H, s, phenolic hydroxyl group), 6.75 (1H, d, J =
7.9Hz), 6.86 (1H, t, J = 7.3Hz), 7.0-7.2 (2H, m).

Formulation Example 1 Capsule Compound of Production Example 5 20.0 mg Lactose 158.7 Corn starch 70.0 Magnesium stearate 1.3 250 mg The powders of the above formulation were mixed and passed through a 60 mesh sieve, and this powder, 250 mg of No. 3, Put in a gelatin capsule to make a capsule.

Formulation Example 2 Tablets Compound of Production Example 5 20.0 mg Lactose 154.0 Corn starch 25.0 Magnesium stearate 1.0 200 mg The powders of the above formulation are mixed and compressed into tablets with a tableting machine to give tablets of 200 mg each.

The tablets may be sugar-coated if necessary.

Formulation Example 3 Capsule Compound of Production Example 3 20.0 mg Lactose 158.7 Corn starch 70.0 Magnesium stearate 1.3 250 mg The powders of the above formulation were mixed and passed through a 60 mesh sieve, and this powder, 250 mg of No. 3 Put in a gelatin capsule to make a capsule.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location // C07D 207/08 207/12 211/22 211/46 265/30 295/08 AZ (72 ) Inventor Fukumi 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Hiroyuki Koike 1-2-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company

Claims (47)

[Claims] 1. A general formula: [In the formula, R ¹ represents a C ₁ -C ₁₂ alkyl group or a formula -A-
R ³ (wherein R ³ represents a C ₃ -C ₇ cycloalkyl group or a C ₃ -C ₇ cycloalkyl group substituted with hydroxy, C ₁ -C ₄ alkoxy or halogen, and A is
Shows the C ₂ -C ₆ alkylene group or a hydroxy or C ₂ -C ₆ alkylene group substituted with a halogen. R ² is a group having the formula —B—NR ⁴ R ⁵ [wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a C ₁ -C ₄ alkyl group or hydroxy, di- C ₁ -C ₄ alkylamino or C ₆
A C ₁ -C ₄ alkyl group substituted with —C ₁₀ aryl, or a 3 to 6-membered cyclic heterocyclyl group containing a nitrogen atom, an oxygen atom or a sulfur atom together with a bonded nitrogen atom, and B is C ₂ -C ₅ alkylene radical or formula -CH
_{^{2 CH (OR 6) CH 2}} - ( wherein, R ⁶ is a hydrogen atom,
C ₁ -C ₅ alkanoyl groups, C substituted with carboxy
Shows the ₂ -C ₅ alkanoyl group or a C ₆ -C ₁₀ aryl acyl group. ) Is shown. ] Or a group having the formula
-D-R ⁷ (In the formula, R ⁷ represents a 5- to 6-membered cyclic saturated heterocyclyl group containing a nitrogen, oxygen or sulfur atom,
D represents a single bond or a C ₁ -C ₄ alkylene group. However, the heterocyclyl group of R ⁷ has a bond on its cyclic carbon atom. ) Is shown. ] An antithrombotic agent comprising an alkyl-phenoxyalkylamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The antithrombotic agent according to claim 1, wherein the active ingredient is an alkyl-phenoxyalkylamine derivative in which R ¹ is a C ₄ -C ₁₀ alkyl group, or a pharmaceutically acceptable salt thereof. 3. The antithrombotic agent according to claim 1, wherein the active ingredient is an alkyl-phenoxyalkylamine derivative in which R ¹ is a C ₅ -C ₈ alkyl group, or a pharmaceutically acceptable salt thereof. 4. An active ingredient, wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₃ -C ₇ cycloalkyl group or hydroxy, methoxy, ethoxy,
Indicates fluoro or C ₅ -C ₆ cycloalkyl group substituted with chloro, A is illustrated C ₂ -C ₄ alkylene group or a hydroxy, fluoro, chloro or C ₂ -C ₄ alkylene group substituted with bromo. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 5. An active ingredient wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a C ₅ -C ₆ cycloalkyl group substituted with methoxy). And A is a group having a C ₂ -C ₄ alkylene group, a 2-hydroxyethylene group, a 2-fluoroethylene group, a 2-chloroethylene group or a 2-bromoethylene group.) Alkyl-phenoxyalkylamine The antithrombotic agent according to claim 1, which is a derivative or a pharmacologically acceptable salt thereof. 6. An active ingredient wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a methoxy-substituted C ₅ -C ₆ cycloalkyl group). The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having an ethylene group or a 2-chloroethylene group) or a pharmaceutically acceptable salt thereof. 7. An active ingredient, wherein R ¹ is a group represented by the formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a C ₆ cycloalkyl group substituted at the 3-position with methoxy). The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having an ethylene group or a 2-chloroethylene group) or a pharmaceutically acceptable salt thereof. 8. An active ingredient wherein R ¹ is a group represented by the formula: —A—R ³ (wherein R ³ is a C ₆ cycloalkyl group or a C ₆ cycloalkyl group substituted at the 3-position with methoxy; Is an alkyl-phenoxyalkylamine derivative which is a group having an ethylene group or a 2-chloroethylene group) or a pharmacologically acceptable salt thereof, The antithrombotic agent according to claim 1. 9. An active ingredient, wherein R ² is a compound represented by the formula: —B—NR ⁴ R ⁵ [wherein R ⁴ and R ^{5 are}
Are the same or different and are a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a phenethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2- (N, N-dimethylamino) ethyl group or 3 1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-morpholinyl, 4-methyl-1-, together with a nitrogen atom which is or is attached to a-(N, N-dimethylamino) propyl group. A piperazinyl, 4-ethyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1-imidazolyl, 1-pyrazolyl or 1-triazolyl group, B
Is a C ₂ -C ₅ alkylene group or the formula —CH ₂ CH (O
R ⁶ ) CH ₂ — (In the formula, R ⁶ is a hydrogen atom, C ₁ -C ₅
Shows the alkanoyl group, C ₂ -C ₅ alkanoyl group or a C ₆ -C ₁₀ aryl acyl groups substituted with carboxy. ) Is shown. ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 10. An active ingredient, wherein R ² is of the formula: —B—NR ⁴ R ⁵ [wherein R ⁴ and R ^{5 are}
Are the same or different and each represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydroxyethyl group, or
1-pyrrolidinyl, 1-with a nitrogen atom attached
Piperidinyl, 4-hydroxy-1-piperidinyl, 4
-Morpholinyl, 4-methyl-1-piperazinyl, 4-
Phenyl-1 shows a piperazinyl or 1-imidazolyl group, B is, C ₂ -C ₅ alkylene group, or a group represented by formula -CH ₂
CH (OR ⁶ ) CH ₂ — (In the formula, R ⁶ is a hydrogen atom, C ₁
-C ₅ alkanoyl group, C ₂ substituted with carboxy
-C shows a ₅ alkanoyl group or a C ₆ -C ₁₀ aryl acyl group. ) Is shown. ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 11. An active ingredient, wherein R ² is of the formula —B—NR ⁴ R ⁵ [wherein R ⁴ and R ^{5 are}
Are the same or different and are a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a phenethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2- (N, N-dimethylamino) ethyl group or 3 1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-morpholinyl, 4-methyl-1 with a nitrogen atom attached to or attached to a-(N, N-dimethylamino) propyl group. -Piperazinyl, 4-ethyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1-imidazolyl, 1-pyrazolyl or 1-triazolyl group, B
Is, C ₂ -C ₄ alkylene group, or a group represented by formula ^{_{-CH 2 CH (OR 6) CH}} 2 -
(In the formula, R ⁶ represents a hydrogen atom, an acetyl group, a propionyl group, a succinyl group or a glutaroyl group.). ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 12. An active ingredient, wherein R ² is of the formula: —B—NR ⁴ R ⁵ [wherein R ⁴ and R ^{5 are}
Are the same or different and each represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydroxyethyl group, or
1-pyrrolidinyl, 1-with a nitrogen atom attached
Piperidinyl, 4-hydroxy-1-piperidinyl, 4
-Morpholinyl, 4-methyl-1-piperazinyl, 4-
Phenyl-1-piperazinyl or 1-imidazolyl group is shown, B is ethylene group, trimethylene group or formula --CH ₂ C
H (OR ⁶ ) CH ₂ — (in the formula, R ⁶ represents a hydrogen atom, an acetyl group or a succinyl group). ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 13. An active ingredient, wherein R ² is of the formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group, the substituent on the carbon atom of which is C ₁ -C ₄ alkyl group, hydroxy group, C ₁ -C ₄ alkoxy group, acetoxy group, propionyl group, succinyloxy group, glutaryloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
N, N-dimethylcarbamoyloxy group or N, N-diethylcarbamoyloxy group, the substituent on the nitrogen atom is a C ₁ -C ₄ alkyl group, D is a single bond or C
Shows the ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 14. An active ingredient, wherein R ² is a group of the formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group, and the substituent on the carbon atom is methyl group, ethyl group or ethyl group). Group, hydroxy group, methoxy group, ethoxy group, acetoxy group, propionyl group, succinyloxy group, glutaryloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
N, N-dimethylcarbamoyloxy group or N, N-diethylcarbamoyloxy group, the substituent on the nitrogen atom is a methyl group or an ethyl group, D is a single bond or C
Shows the ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 15. An active ingredient, wherein R ² is a compound represented by the formula: —D—R ⁷ (wherein R ⁷ is pyrrolidinyl, 1-methylpyrrolidinyl, hydroxy-1-methylpyrrolidinyl, piperidinyl, 1-methylpyrrole). An alkyl-phenoxyalkylamine derivative which is a group having a peridinyl, morpholinyl, 4-methylmorpholinyl or thiomorpholinyl group, and D is a single bond or a C ₁ -C ₄ alkylene group, or a pharmacologically acceptable salt thereof. The antithrombotic agent according to claim 1, which is a salt to be treated. 16. An active ingredient, wherein R ² is of the formula —D—R ⁷ (wherein R ⁷ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-1-methyl-2-pyrrolidinyl, 2-piperidinyl,
1-methyl-2-piperidinyl, 2-morpholinyl, 4
- a methyl-2-morpholinyl or 2-thiomorpholinyl group, D is a single bond or a C ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 17. An active ingredient, wherein R ² is a group of the formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group, and the substituent on the carbon atom is C ₁ -C. ₄ alkyl group, hydroxy group, C ₁ -C ₄ alkoxy group, acetoxy group, propionyl group, succinyloxy group, glutaryloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
N, an N- dimethylcarbamoyl group or N, N- diethylcarbamoyl group, the substituent on the nitrogen atom is a C ₁ -C ₄ alkyl group, D is a single bond, an ethylene group or trimethylene group . The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 18. An active ingredient, wherein R ² is a group of formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group, and the substituent on the carbon atom is a methyl group, an ethyl group or an ethyl group). Group, hydroxy group, methoxy group, ethoxy group, acetoxy group, propionyl group, succinyloxy group, glutaryloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
It is an N, N-dimethylcarbamoyloxy group or an N, N-diethylcarbamoyloxy group, the substituent on the nitrogen atom is a methyl group or an ethyl group, and D represents a single bond, an ethylene group or a trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 19. An active ingredient, wherein R ² is a compound represented by the formula: —D—R ⁷ (wherein R ⁷ is pyrrolidinyl, 1-methylpyrrolidinyl, hydroxy-1-methylpyrrolidinyl, piperidinyl, 1-methylpyrrole). An alkyl-phenoxyalkylamine derivative which is a group having a peridinyl, morpholinyl, 4-methylmorpholinyl or thiomorpholinyl group and D is a single bond, an ethylene group or a trimethylene group, or a pharmaceutically acceptable derivative thereof. The antithrombotic agent according to claim 1, which is a salt. 20. An active ingredient, wherein R ² is of the formula —D—R ⁷ (wherein R ⁷ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-1-methyl-2-pyrrolidinyl, 2-piperidinyl,
1-methyl-2-piperidinyl, 2-morpholinyl, 4
-Methyl-2-morpholinyl or 2-thiomorpholinyl group is shown, and D is a single bond, ethylene group or trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 21. An active ingredient, wherein R ¹ is a C ₄ -C ₁₀ alkyl group, R ² is a group represented by the formula: —B—NR ⁴ R ⁵ [wherein R ⁴ and R ^{5 are the same.}
Are the same or different and are a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a phenethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2- (N, N-dimethylamino) ethyl group or 3 1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-morpholinyl, 4-methyl-1 with a nitrogen atom attached to or attached to a-(N, N-dimethylamino) propyl group. -Piperazinyl, 4-ethyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1-imidazolyl, 1-pyrazolyl or 1-triazolyl group, B
Is a C ₂ -C ₅ alkylene group or the formula —CH ₂ CH (O
R ⁶ ) CH ₂ — (In the formula, R ⁶ is a hydrogen atom, C ₁ -C ₅
Shows the alkanoyl group, C ₂ -C ₅ alkanoyl group or a C ₆ -C ₁₀ aryl acyl groups substituted with carboxy. ) Is shown. ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 22. The active ingredient, wherein R ¹ is a C ₄ -C ₁₀ alkyl group, and R ² is a group represented by the formula: —B—NR ⁴ R ⁵ [wherein R ⁴ and R ^{5 are the same.}
Are the same or different and each represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydroxyethyl group, or
1-pyrrolidinyl, 1-with a nitrogen atom attached
Piperidinyl, 4-hydroxy-1-piperidinyl, 4
-Morpholinyl, 4-methyl-1-piperazinyl, 4-
Phenyl-1 shows a piperazinyl or 1-imidazolyl group, B is, C ₂ -C ₅ alkylene group, or a group represented by formula -CH ₂
CH (OR ⁶ ) CH ₂ — (In the formula, R ⁶ is a hydrogen atom, C ₁
-C ₅ alkanoyl group, C ₂ substituted with carboxy
-C shows a ₅ alkanoyl group or a C ₆ -C ₁₀ aryl acyl group. ) Is shown. ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 23. An active ingredient, wherein R ¹ is a C ₅ -C ₈ alkyl group, R ² is a group represented by the formula: —B—NR ⁴ R ⁵ [wherein R ⁴ and R ^{5 are the same.}
Are the same or different and are a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a phenethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2- (N, N-dimethylamino) ethyl group or 3 1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-morpholinyl, 4-methyl-1 with a nitrogen atom attached to or attached to a-(N, N-dimethylamino) propyl group. -Piperazinyl, 4-ethyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1-imidazolyl, 1-pyrazolyl or 1-triazolyl group, B
Is, C ₂ -C ₄ alkylene group, or a group represented by formula ^{_{-CH 2 CH (OR 6) CH}} 2 -
(In the formula, R ⁶ represents a hydrogen atom, an acetyl group, a propionyl group, a succinyl group or a glutaroyl group.). ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 24. An active ingredient, wherein R ¹ is a C ₅ -C ₈ alkyl group, and R ² is a group represented by the formula: —B—NR ⁴ R ⁵ [wherein R ⁴ and R ^{5 are the same.}
Are the same or different and each represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydroxyethyl group, or
1-pyrrolidinyl, 1-with a nitrogen atom attached
Piperidinyl, 4-hydroxy-1-piperidinyl, 4
-Morpholinyl, 4-methyl-1-piperazinyl, 4-
Phenyl-1-piperazinyl or 1-imidazolyl group is shown, B is ethylene group, trimethylene group or formula --CH ₂ C
H (OR ⁶ ) CH ₂ — (in the formula, R ⁶ represents a hydrogen atom, an acetyl group or a succinyl group). ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 25. An active ingredient, wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₃ -C ₇ cycloalkyl group or hydroxy, methoxy, ethoxy,
Indicates fluoro or C ₅ -C ₆ cycloalkyl group substituted with chloro, A is illustrated C ₂ -C ₄ alkylene group or a hydroxy, fluoro, chloro or C ₂ -C ₄ alkylene group substituted with bromo. And R ² is of the formula —B—NR ⁴ R ⁵ [wherein R ⁴ and R ⁵
Are the same or different and are a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a phenethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2- (N, N-dimethylamino) ethyl group or 3 1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-morpholinyl, 4-methyl-1 with a nitrogen atom attached to or attached to a-(N, N-dimethylamino) propyl group. -Piperazinyl, 4-ethyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1-imidazolyl, 1-pyrazolyl or 1-triazolyl group, B
Is a C ₂ -C ₅ alkylene group or the formula —CH ₂ CH (O
R ⁶ ) CH ₂ — (In the formula, R ⁶ is a hydrogen atom, C ₁ -C ₅
Shows the alkanoyl group, C ₂ -C ₅ alkanoyl group or a C ₆ -C ₁₀ aryl acyl groups substituted with carboxy. ) Is shown. ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 26. The active ingredient, wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a C ₅ -C ₆ cycloalkyl group substituted with methoxy). shown, a is, C ₂ -C ₄ alkylene group, 2-hydroxyethylene group, a 2-fluoro ethylene group, 2-chloro-ethylene group or a 2-bromo ethylene group shows a.) group having, R ² is, wherein -B-NR ⁴ R ⁵ [wherein, R ⁴ and R ⁵
Are the same or different and each represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydroxyethyl group, or
1-pyrrolidinyl, 1-with a nitrogen atom attached
Piperidinyl, 4-hydroxy-1-piperidinyl, 4
-Morpholinyl, 4-methyl-1-piperazinyl, 4-
Phenyl-1 shows a piperazinyl or 1-imidazolyl group, B is, C ₂ -C ₅ alkylene group, or a group represented by formula -CH ₂
CH (OR ⁶ ) CH ₂ — (In the formula, R ⁶ is a hydrogen atom, C ₁
-C ₅ alkanoyl group, C ₂ substituted with carboxy
-C shows a ₅ alkanoyl group or a _C 6 -C ₁₀ aryl acyl group. ) Is shown. ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 27. An active ingredient, wherein R ¹ is a group of formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a C ₅ -C ₆ cycloalkyl group substituted with methoxy). And A is a group having an ethylene group or a 2-chloroethylene group), and R ² is a group of the formula —B—NR ⁴ R ⁵ [in the formula, R ⁴ and R ⁵
Are the same or different and are a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a phenethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2- (N, N-dimethylamino) ethyl group or 3 1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-morpholinyl, 4-methyl-1 with a nitrogen atom attached to or attached to a-(N, N-dimethylamino) propyl group. -Piperazinyl, 4-ethyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1-imidazolyl, 1-pyrazolyl or 1-triazolyl group, B
Is, C ₂ -C ₄ alkylene group, or a group represented by formula ^{_{-CH 2 CH (OR 6) CH}} 2 -
(In the formula, R ⁶ represents a hydrogen atom, an acetyl group, a propionyl group, a succinyl group or a glutaroyl group.). ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 28. The active ingredient, wherein R ¹ is a group of formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a C ₆ cycloalkyl group substituted at the 3-position with methoxy). And A is a group having an ethylene group or a 2-chloroethylene group), and R ² is a group of the formula —B—NR ⁴ R ⁵ [in the formula, R ⁴ and R ⁵
Are the same or different and each represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydroxyethyl group, or
1-pyrrolidinyl, 1-with a nitrogen atom attached
Piperidinyl, 4-hydroxy-1-piperidinyl, 4
-Morpholinyl, 4-methyl-1-piperazinyl, 4-
Phenyl-1-piperazinyl or 1-imidazolyl group is shown, B is ethylene group, trimethylene group or formula --CH ₂ C
H (OR ⁶ ) CH ₂ — (in the formula, R ⁶ represents a hydrogen atom, an acetyl group or a succinyl group). ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 29. The active ingredient, wherein R ¹ is a group represented by the formula: —A—R ³ (wherein R ³ is a C ₆ cycloalkyl group or a C ₆ cycloalkyl group substituted at the 3-position with methoxy, A Represents an ethylene group or a 2-chloroethylene group), and R ² is a group represented by the formula: —B—NR ⁴ R ⁵ [in the formula, R ⁴ and R ⁵
Are the same or different and each represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydroxyethyl group, or
1-pyrrolidinyl, 1-with a nitrogen atom attached
Piperidinyl, 4-hydroxy-1-piperidinyl, 4
-Morpholinyl, 4-methyl-1-piperazinyl, 4-
Phenyl-1-piperazinyl or 1-imidazolyl group is shown, B is ethylene group, trimethylene group or formula --CH ₂ C
H (OR ⁶ ) CH ₂ — (in the formula, R ⁶ represents a hydrogen atom, an acetyl group or a succinyl group). ] The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof which is a group having 30. An active ingredient, wherein R ¹ is a C ₄ -C ₁₀ alkyl group, and R ² is a group of formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group. The substituents on the carbon atoms are C ₁ -C ₄ alkyl groups, hydroxy groups, C ₁ -C ₄ alkoxy groups, acetoxy groups, propionyl groups, succinyloxy groups, glutaryloxy groups, carbamoyloxy groups, N- Methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
N, N-dimethylcarbamoyloxy group or N, N-diethylcarbamoyloxy group, the substituent on the nitrogen atom is a C ₁ -C ₄ alkyl group, D is a single bond or C
Shows the ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 31. An active ingredient, wherein R ¹ is a C ₄ -C ₁₀ alkyl group, and R ² is a group of formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group. The substituent on the carbon atom is a methyl group, an ethyl group, a hydroxy group, a methoxy group, an ethoxy group, an acetoxy group, a propionyl group, a succinyloxy group, a glutaryloxy group, a carbamoyloxy group, an N-methylcarbamoyloxy group. An N-ethylcarbamoyloxy group,
N, N-dimethylcarbamoyloxy group or N, N-diethylcarbamoyloxy group, the substituent on the nitrogen atom is a methyl group or an ethyl group, D is a single bond or C
Shows the ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 32. An active ingredient, wherein R ¹ is a C ₄ -C ₁₀ alkyl group, R ² is of the formula —D—R ⁷ (wherein R ⁷ is pyrrolidinyl, 1-methylpyrrolidinyl, A hydroxy-1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, morpholinyl, 4-methylmorpholinyl or thiomorpholinyl group, and D represents a single bond or a C ₁ -C ₄ alkylene group). The antithrombotic agent according to claim 1, which is a basic alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof. 33. An active ingredient, wherein R ¹ is a C ₄ -C ₁₀ alkyl group, R ² is a group of formula —D—R ⁷ (wherein R ⁷ is 2-pyrrolidinyl, 1-methyl-2. -Pyrrolidinyl, 4-hydroxy-1-methyl-2-pyrrolidinyl, 2-piperidinyl,
1-methyl-2-piperidinyl, 2-morpholinyl, 4
- a methyl-2-morpholinyl or 2-thiomorpholinyl group, D is a single bond or a C ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 34. An active ingredient, wherein R ¹ is a C ₅ -C ₈ alkyl group, R ² is a group of formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group. The substituents on the carbon atoms are C ₁ -C ₄ alkyl groups, hydroxy groups, C ₁ -C ₄ alkoxy groups, acetoxy groups, propionyl groups, succinyloxy groups, glutaryloxy groups, carbamoyloxy groups, N- Methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
N, N- dimethylcarbamoyl group or N, a N- diethylcarbamoyl group, the substituent on the nitrogen atom is a C ₁ -C ₄ alkyl group, and D is a single bond, an ethylene group or trimethylene group . The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 35. An active ingredient, wherein R ¹ is a C ₅ -C ₈ alkyl group, R ² is a group of formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group. The substituent on the carbon atom is a methyl group, an ethyl group, a hydroxy group, a methoxy group, an ethoxy group, an acetoxy group, a propionyl group, a succinyloxy group, a glutaryloxy group, a carbamoyloxy group, an N-methylcarbamoyloxy group. An N-ethylcarbamoyloxy group,
It is an N, N-dimethylcarbamoyloxy group or an N, N-diethylcarbamoyloxy group, the substituent on the nitrogen atom is a methyl group or an ethyl group, and D represents a single bond, an ethylene group or a trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 36. An active ingredient, wherein R ¹ is a C ₅ -C ₈ alkyl group, R ² is of the formula —D—R ⁷ (wherein R ⁷ is pyrrolidinyl, 1-methylpyrrolidinyl, A hydroxy-1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, morpholinyl, 4-methylmorpholinyl or thiomorpholinyl group, and D is a single bond, an ethylene group or a trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof. 37. An active ingredient, wherein R ¹ is a C ₅ -C ₈ alkyl group, R ² is of the formula —D—R ⁷ (wherein R ⁷ is 2-pyrrolidinyl, 1-methyl-2. -Pyrrolidinyl, 4-hydroxy-1-methyl-2-pyrrolidinyl, 2-piperidinyl,
1-methyl-2-piperidinyl, 2-morpholinyl, 4
-Methyl-2-morpholinyl or 2-thiomorpholinyl group is shown, and D is a single bond, ethylene group or trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 38. An active ingredient wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₃ -C ₇ cycloalkyl group or hydroxy, methoxy, ethoxy,
Indicates fluoro or C ₅ -C ₆ cycloalkyl group substituted with chloro, A is illustrated C ₂ -C ₄ alkylene group or a hydroxy, fluoro, chloro or C ₂ -C ₄ alkylene group substituted with bromo. And R ² represents a formula —D—R ⁷ (wherein R ⁷ represents a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group, and the substituent on the carbon atom thereof is C ₁ -C ₄ alkyl. Group, hydroxy group, C ₁ -C ₄ alkoxy group, acetoxy group, propionyl group, succinyloxy group, glutaryloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
N, N-dimethylcarbamoyloxy group or N, N-diethylcarbamoyloxy group, the substituent on the nitrogen atom is a C ₁ -C ₄ alkyl group, D is a single bond or C
Shows the ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 39. An active ingredient, wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₃ -C ₇ cycloalkyl group or hydroxy, methoxy, ethoxy,
Indicates fluoro or C ₅ -C ₆ cycloalkyl group substituted with chloro, A is illustrated C ₂ -C ₄ alkylene group or a hydroxy, fluoro, chloro or C ₂ -C ₄ alkylene group substituted with bromo. R ² is a group having the formula —D—R ⁷ (wherein R ⁷ represents a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group, and the substituent on the carbon atom thereof is a methyl group, an ethyl group, Hydroxy group, methoxy group, ethoxy group, acetoxy group, propionyl group, succinyloxy group, glutaryloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
N, N-dimethylcarbamoyloxy group or N, N-diethylcarbamoyloxy group, the substituent on the nitrogen atom is a methyl group or an ethyl group, D is a single bond or C
Shows the ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 40. An active ingredient, wherein R ¹ is a group of formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a methoxy-substituted C ₅ -C ₆ cycloalkyl group). shown, a is, C ₂ -C ₄ alkylene group, 2-hydroxyethylene group, a 2-fluoro ethylene group, 2-chloro-ethylene group or a 2-bromo ethylene group shows a.) group having, R ² is, Formula -D-R ⁷ (In the formula, R ⁷ is pyrrolidinyl, 1-methylpyrrolidinyl, hydroxy-1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, morpholinyl, 4-methylmorpholinyl or thiomorpholinyl. Group, and D is a single bond or a C ₁ -C ₄ alkylene group), which is a group having an alkyl-phenoxyalkylamine derivative or a pharmaceutically acceptable salt thereof. 41. An active ingredient, wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a methoxy-substituted C ₅ -C ₆ cycloalkyl group). shown, a is, C ₂ -C ₄ alkylene group, 2-hydroxyethylene group, a 2-fluoro ethylene group, 2-chloro-ethylene group or a 2-bromo ethylene group shows a.) group having, R ² is, Formula -D-R ⁷ (In the formula, R ⁷ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-1-methyl-2-pyrrolidinyl, 2-piperidinyl,
1-methyl-2-piperidinyl, 2-morpholinyl, 4
- a methyl-2-morpholinyl or 2-thiomorpholinyl group, D is a single bond or a C ₁ -C ₄ alkylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 42. An active ingredient, wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a methoxy-substituted C ₅ -C ₆ cycloalkyl group). , A is a group having an ethylene group or a 2-chloroethylene group, and R ² is a group of formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group. The substituents on the carbon atoms are C ₁ -C ₄ alkyl groups, hydroxy groups, C ₁ -C ₄ alkoxy groups, acetoxy groups, propionyl groups, succinyloxy groups, glutaryloxy groups, carbamoyloxy groups, N- Methylcarbamoyloxy group, N-ethylcarbamoyloxy group,
N, an N- dimethylcarbamoyl group or N, N- diethylcarbamoyl group, the substituent on the nitrogen atom is a C ₁ -C ₄ alkyl group, D is a single bond, an ethylene group or trimethylene group . The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 43. An active ingredient, wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a C ₅ -C ₆ cycloalkyl group substituted with methoxy). , A is a group having an ethylene group or a 2-chloroethylene group, and R ² is a group of formula —D—R ⁷ (wherein R ⁷ is a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group. The substituent on the carbon atom is a methyl group, an ethyl group, a hydroxy group, a methoxy group, an ethoxy group, an acetoxy group, a propionyl group, a succinyloxy group, a glutaryloxy group, a carbamoyloxy group, an N-methylcarbamoyloxy group. An N-ethylcarbamoyloxy group,
An N, N-dimethylcarbamoyloxy group or an N, N-diethylcarbamoyloxy group is shown, the substituent on the nitrogen atom is a methyl group or an ethyl group, and D is a single bond, an ethylene group or a trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 44. An active ingredient, wherein R ¹ is a formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a C ₆ cycloalkyl group substituted at the 3-position with methoxy). , A is a group having an ethylene group or a 2-chloroethylene group, and R ² is of the formula —D—R ⁷ (wherein R ⁷ is pyrrolidinyl, 1-methylpyrrolidinyl, Hydroxy-1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, morpholinyl, 4-methylmorpholinyl or thiomorpholinyl, and D is a group having a single bond, an ethylene group or a trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative or a pharmacologically acceptable salt thereof. 45. An active ingredient, wherein R ¹ is of the formula —A—R ³ (wherein R ³ is a C ₅ -C ₆ cycloalkyl group or a C ₆ cycloalkyl group substituted at the 3-position with methoxy). , A is a group having an ethylene group or a 2-chloroethylene group, and R ² is of the formula —D—R ⁷ (wherein R ⁷ is 2-pyrrolidinyl or 1-methyl-2). -Pyrrolidinyl, 4-hydroxy-1-methyl-2-pyrrolidinyl, 2-piberedinyl,
1-methyl-2-piperidinyl, 2-morpholinyl, 4
-Methyl-2-morpholinyl or 2-thiomorpholinyl group is shown, and D is a single bond, ethylene group or trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 46. An active ingredient, wherein R ¹ is a formula —A—R ³ (wherein R ³ represents a C ₆ cycloalkyl group or a C ₆ cycloalkyl group substituted at the 3-position with methoxy, and A Is a group having an ethylene group or a 2-chloroethylene group), and R ² is of the formula —D—R ⁷ (wherein R ⁷ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-1-methyl-2-pyrrolidinyl, 2-piperidinyl,
1-methyl-2-piperidinyl, 2-morpholinyl, 4
-Methyl-2-morpholinyl or 2-thiomorpholinyl group is shown, and D is a single bond, ethylene group or trimethylene group. The antithrombotic agent according to claim 1, which is an alkyl-phenoxyalkylamine derivative which is a group having a) or a pharmacologically acceptable salt thereof. 47. The active ingredient is N, N-dimethyl-3- [2- (4-methylpentyl).
Phenoxy] propylamine or a pharmacologically acceptable salt thereof, 2- [2- [2- (2-Cyclopentylethyl) phenoxy] ethyl] -1-methylpyrrolidine or a pharmacologically acceptable salt thereof, 3- [2- (2-Cyclopentylethyl) phenoxymethyl] -1-methylpiperidine or a pharmacologically acceptable salt thereof, 3- [2- (2-cyclohexylethyl) phenoxy]
-1- (N, N-dimethylamino) -2-propanol or a pharmacologically acceptable salt thereof, 2- [2- [2- (2-cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine or its pharmacology Upper acceptable salt, 3- [2- (2-Cyclohexylethyl) phenoxymethyl] -1-methylpiperidine or a pharmacologically acceptable salt thereof, 2- [2- (2-Cyclohexylethyl) phenoxymethyl] -4 -Methylmorpholine or a pharmaceutically acceptable salt thereof, 2- [2- [2- [2- (3-methoxycyclohexyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine or a pharmaceutically acceptable salt thereof, 3. -[2- (2-chloro-2-cyclohexylethyl)
Phenoxy] -1- (N, N-dimethylamino) -2-
Propanol or a pharmaceutically acceptable salt thereof, 2- [2- [2- (2-chloro-2-cyclohexylethyl) phenoxy] ethyl] -1-methylpyrrolidine or a pharmaceutically acceptable salt thereof or 3- [ 2- (2-chloro-2-cyclohexylethyl)
The antithrombotic agent according to claim 1, which is phenoxymethyl] -1-methylpiperidine or a pharmacologically acceptable salt thereof.