JPH08283219A - Aralkylaminoalkylamide derivative - Google Patents

Abstract

PURPOSE: To obtain the subject new compound excellent in safety useful as a medicine for preventing, treating and improving diseases effective when using a dopamine D3 receptor-antagonizing action therefor, especially as a treating and improving medicine of schizophrenia, high in usability in clinical field. CONSTITUTION: A compound of formula I [R1 , R2 are each H, OH, a halogen, a lower alkoxy, amino, a lower alkyl; R3 is H, a lower alkyl; R4 is a group of formula II (R5 , R6 are each H, a halogen, a lower alkyl; (r) is 0, 1), a group of formula III, a group of formula IV, etc.; (m) is 2-4; (n) is 1-3], its salt. For example, N-[(4- N'-methyl-N'-[2-(3,5-dimethoxy)phenetyl]amino}butyl)]-(4fluoro) cinnamide. The exampled compound is obtained by reacting p-fluorocinnamic acid with N-methyl-N-(3,5-dimethoxyphenetyl)-1,4-diaminobutane.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preventive / therapeutic / ameliorating agent for diseases for which a dopamine D ₃ receptor antagonistic action is effective, and preferably to a highly clinically useful preventive / therapeutic / ameliorating agent for schizophrenia.

[0002]

BACKGROUND OF THE INVENTION Schizophrenia is considered to be caused by excessive excitation of dopaminergic nerves, and anti-schizophrenia drugs currently in clinical use are drugs having anti-dopaminergic activity. Among them, most are dopamine D ₂ receptor antagonists.

However, these drugs have a problem that extrapyramidal symptoms, particularly Parkinson's disease-like symptoms are likely to occur as a side effect. However, recently, the conventional dopamine D ₂ receptor has been newly divided into three subtypes, D ₂ , D ₃ , and D ₄ (N
ature, 347: 146-151, 1990.). And dopamine D ₂
Receptors are densely distributed in the striatum and pituitary gland, which are thought to be involved in the development of side effects, whereas dopamine
It was also revealed that the D ₃ receptor was not distributed (Brain R
es., 564: 203-219,1991.).

[0004]

2. Description of the Related Art To improve these problems, for example,
WO-93 / 23035 discloses that Ropinirole, IN
A dopamine D ₃ receptor agonist or agonist containing N registered name) as an active ingredient is disclosed.

Further, WO-94 / 03426 discloses a dopamine D ₃ receptor antagonist containing a 5- (2-oxaphenyl) pyrrole derivative as an active ingredient.

Further, WO-94 / 22495 discloses a ligand for a dopamine D ₃ receptor and a serotonin receptor, which contains a bicyclo derivative as an active ingredient.

[0007]

[Problems to be Solved by the Invention] Ropinirole disclosed in WO-93 / 23035 has an affinity ratio to a dopamine subtype receptor (as described in the result column of the publication). D ₂ / D ₃ = 1380 / 69.1 = 20), and actually had no specific affinity for the dopamine D ₃ receptor.

Next, 5 disclosed in WO-94 / 03426
With respect to the-(2-oxaphenyl) pyrrole derivative, the affinity for dopamine D ₂ receptor was not described at all in the same publication, and the specific affinity for dopamine D ₃ receptor was not clear.

Further, in the bicyclo derivative disclosed in WO-94 / 22495, as described in Table 2 on page 28 or Table 4 on page 31 of the publication, the bicyclo derivative has a receptor for a dopamine subtype receptor. The affinity ratio (D ₂ / D ₃ ) is 3.1 to 191, and although it has high selectivity for the dopamine D ₃ receptor, it pharmacologically acts as an agonist (see below, effects of the invention, pharmacological test example 2). reference). Therefore, the effect as an anti-schizophrenia drug could not be expected.

As described above, a preventive / therapeutic / ameliorating agent for a disease for which a dopamine D ₃ receptor antagonism is effective, particularly a therapeutic / ameliorating agent with high clinical usefulness and safety for schizophrenia, is It was the current situation.

[0011]

In order to overcome such a situation, the present inventors have long sought for a drug having a specific affinity for the dopamine D ₃ receptor, and have eagerly pursued it.
As a result, the novel aralkylaminoalkylamide derivative (I), the aralkylaminoalkylamide derivative (II) or a pharmacologically acceptable salt thereof was treated with dopamine D ₃
The present inventors have completed the present invention by finding that they have a specific affinity for a receptor and are excellent in safety and can solve the above problems.

Therefore, an object of the present invention is to improve the drawbacks of conventional drugs having an antidopaminergic activity, especially dopamine D ₂ receptor antagonists, and dopamine D ₃ receptor antagonists having high clinical safety and utility. It is an object of the present invention to provide a preventive / therapeutic / ameliorating agent for a disease having an effective action, particularly an anti-schizophrenic agent which does not cause side effects such as extrapyramidal symptoms and Parkinson's disease-like symptoms.

The aralkylaminoalkylamide derivative (I) according to the present invention is represented by the following general formula.

[0014]

[Chemical 7]

In the formula, R ¹ and R ² represent the same or different groups selected from a lower alkoxy group, a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a lower alkyl group, and R ¹ and R ² May form a ring. R ³ represents a hydrogen atom or a lower alkyl group. R ⁴ means a group represented by the following general formula.

[0016]

Embedded image

[Wherein R ⁵ and R ⁶ are a hydrogen atom, a halogen atom, a lower alkyl group, a heteroaryl group, a group represented by the following chemical formula,

[0018]

[Chemical 9]

[Wherein R ⁷ is an oxygen atom or a formula (= N
-CN) means a group represented by. ] R means 0 or 1. ] N means the integer of 1-3. m means an integer of 2 to 4. The bond represented by the following chemical formula is

[0020]

[Chemical 10]

By single bond (CC) or double bond (C = C) is meant. Means

More specifically, the halogen atom in the above definition can be a chlorine atom, a fluorine atom, a bromine atom or an iodine atom. Next, as a lower alkyl group, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group, etc. The alkyl group of 6 is a lower alkoxy group, for example, a group in which an oxygen atom is bonded to the lower alkyl group such as a methoxy group, an ethoxy group and a propoxy group is a heteroaryl group.
For example, pyridyl group, pyridazinyl group, pyrimidinyl group,
Specific examples thereof include a pyrazinyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, an oxadiazolyl group, a thiazolyl group, a thiadiazolyl group, a pyrrolidyl group, a furanyl group and a thiopheninyl group. Specific examples of the ring formed by R ¹ and R ² include a methylenedioxy group, a dimethylmethylenedioxy group and a benzylidene group.

Specific examples of the aralkylaminoalkylamide derivative (I) according to the present invention include the following compounds, but the aralkylaminoalkylamide derivative (I) according to the present invention is not limited thereto. . (1) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-(4-fluoro) cinnamide (2) N-[[4 -{N'-Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-(3,4-methylenedioxy) cinnamide (3) N-[[4- {N' -Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-[4- (1H-imidazol-1-yl)]
Cinnamide (4) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]] cinnamide (5) N-[[4- {N'- Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-[(6-Fluoro) indan-2-yl]
Carboxamide (6) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-(indan-2-yl) carboxamide (7) N-[[4- {N'-Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-benzamide (8) N-[[4- {N'-methyl-N '-[2- (3,5-Dimethoxy) phenethyl] amino} butyl]]-[4- (methylamino) cyanoiminoamino] cinnamide (9) N-[[4- {N'-methyl-N'- [2- (3,5-Dimethoxy) phenethyl] amino} butyl]]-[4- (N-methylureidyl)] cinnamide (10) N-[[4- {N'-methyl-N '-[2 -(3,5-Dimethoxy) phenethyl] amino} butyl]]-{3- [4- (N-methylureidyl)] phenyl} propionamide (11) N-[[4- {N'-methyl-N '-[2- (3,5-Dimethoxy) phenethyl] amino} butyl]]-{[6- (N-methylureidyl)] indan-2-yl} carboxamide (12) N-[[4- { N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-[4- (N-methyl Ureijiru)] benzamide (13) N-methyl-N-(3,5-dimethoxy-phenethyl)-N-{N'
[4- (N-Methylureidyl)] phenethylureidyl} butylamine (14) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl] ]-{3- [4- (N-Ethylureidyl)] phenyl} propionamide (15) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} Butyl]]-[4- (N-Ethylureidyl)] styrylacetamide (16) N-[[4- {N'-Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl] ]-{3- [N-methylcarbamoyl- (1,
2,3,4-Tetrahydroquinolin-6-yl)]} propionamide (17) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl ]]-[4- (1H-Imidazol-1-yl)]
Styryl acetic acid amide

Next, the aralkylaminoalkylamide derivative (II) according to the present invention is represented by the following general formula.

[0025]

[Chemical 11]

In the formula, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , n, m and r
Has the same meaning as described above. The bond represented by the following chemical formula is

[0027]

[Chemical 12]

By single bond (CC) or double bond (C = C) is meant.

Specific examples of the aralkylaminoalkylamide derivative (II) according to the present invention include the following compounds, but the aralkylaminoalkylamide derivative (II) according to the present invention is not limited thereto. . (1) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-(4-fluoro) cinnamide (2) N-[[4 -{N'-Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-(3,4-methylenedioxy) cinnamide (3) N-[[4- {N' -Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-[4- (1H-imidazol-1-yl)]
Cinnamide (4) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]] cinnamide (5) N-[[4- {N'- Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-benzamide (6) N-[[4- {N'-methyl-N'-[2- (3,5- Dimethoxy) phenethyl] amino} butyl]]-[4- (methylamino) cyanoiminoamino] cinnamide (7) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) Phenethyl] amino} butyl]]-[4- (N-methylureizyl)] cinnamide (8) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl]] Amino} butyl]]-{3- [4- (N-methylureidyl)] phenyl} propionamide (9) N-[[4- {N'-methyl-N '-[2- (3,5- Dimethoxy) phenethyl] amino} butyl]]-{[6- (N-methylureidyl)] indan-2-yl} carboxamide (10) N-[[4- {N'-methyl-N '-[2 -(3,5-Dimethoxy) phenethyl] amino} butyl]]-[4- (N-methylureidyl)] benzamide (11) (1 2) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-{3- [4- (N-ethylureidyl)] phenyl} propion Amide (13) (14) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-{3- [N-methylcarbamoyl- ( 1,
2,3,4-Tetrahydroquinolin-6-yl)]} propionamide

Here, the pharmacologically acceptable salt of the present invention is not limited as long as it forms a salt with the free form of the compound of the present invention. Specifically, for example, hydrochloride,
Inorganic acid addition salts such as hydrobromide, perchlorate, sulfate, nitrate, phosphate, etc., organic acids such as oxalate, succinate, maleate, fumarate, tartrate etc. Examples thereof include addition salts, methane sulfonates, ethane sulfonates, benzene sulfonates, toluene sulfonates, camphor sulfonates, and other sulfonic acid addition salts.

The dosage forms of the compound of the present invention include oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, ointments, patches, external preparations such as suppositories, and injections. Formulations for use. In the case of formulation, it can be produced by a conventional method using an ordinary formulation carrier.

That is, in order to produce an oral preparation, an aralkylaminoalkylamide derivative or a pharmacologically acceptable salt thereof and an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, After adding a flavoring agent and the like, powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared by a conventional method.

As the excipient, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, etc., and as the binder,
For example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc. For example, starch, agar, gelatin powder,
Crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium, etc., and examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, etc. As for the flavoring agent, cocoa powder, peppermint brain, aroma powder, peppermint oil, dragon brain, cinnamon powder and the like are used as the flavoring agent. Needless to say, these tablets and granules may be sugar-coated or may be appropriately coated if necessary.

When producing an injectable preparation, the aralkylaminoalkylamide derivative or a pharmacologically acceptable salt thereof is mixed with a pH adjusting agent, a solubilizer, an isotonicity agent, etc., and if necessary, a solubilizing aid. Add agents, stabilizers, etc., and formulate by a conventional method.

The method for producing the external preparation is not limited,
It can be produced by a conventional method. That is, as the base material used for formulation, pharmaceuticals, quasi drugs,
It is possible to use various raw materials commonly used for cosmetics and the like.

Specific examples of the base material to be used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols. Raw materials such as alcohols, water-soluble polymers, clay minerals, and purified water are added, and if necessary, pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, etc. are added. But you can
The base material for the external preparation according to the present invention is not limited to these. In addition, if necessary, other components having an action of inducing differentiation,
Components such as a blood flow promoter, a bactericidal agent, an anti-inflammatory agent, a cell activator, vitamins, amino acids, a moisturizer, and a keratolytic agent can also be added. The amount of the above-mentioned base material added is such that the concentration is usually set in the production of the external preparation.

The clinical dose of the aralkylaminoalkylamide derivative or a pharmacologically acceptable salt thereof according to the present invention is not limited depending on the symptoms, severity, age, complications, etc., and the kind and administration route of the salt. It is usually 0.01 mg to 2000 mg, preferably 0.1 mg to 1500 mg, and more preferably 1 mg to 1000 mg per day for an adult, although it varies depending on the case. Oral, intravenous, suppository or transdermal administration To do. The LD ₅₀ value of the compound of the present invention is extremely high, and the safety is extremely high.

Next, in order to specifically describe the present invention,
Manufacturing Examples and Examples are listed below, but it goes without saying that the present invention is not limited to these.

[Production Example] Production Example 1 N-methyl-N- (3,5-dimethoxyphenethyl) -1,
Synthesis of 4-diaminobutane

[0039]

[Chemical 13]

10.0 g of N-methyl- (3,5-dimethoxyphenethyl) amine was dissolved in DMF (130 ml), and anhydrous potassium carbonate 1
0.63 g, 4-bromobutyronitrile 6.12 ml were added, and at room temperature
The reaction was carried out for 12 hours. Water was added and the mixture was extracted with ethyl acetate.
After washing with water and saturated saline, drying over anhydrous potassium carbonate,
The solvent was distilled off under reduced pressure. Ethanol (150 m
l), concentrated hydrochloric acid (11 ml) and 1 g of platinum oxide were added, and hydrogenated at room temperature at 3 Kg / cm ² for 12 hours. The catalyst was filtered off, extracted with chloroform and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to give the title compound as a colorless oil 1
0.85g was obtained. (Yield; 80%)

Boiling point: 165-168 ° C. (0.5 to 0.9 mmHg) ¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 1.3-1.9 (6 H, m), 2.2-2.
8 (11H, m), 3.75 (6H, s), 6.2-6.4 (3H, m).

[0042]

EXAMPLES Synthesis Method Each carboxylic acid (5 mmol), the above amine (5 mmol) and 1,3-dicyclohexylcarbodiimide (DCC, 10 mmol) were suspended in anhydrous acetonitrile (10 ml) and heated under reflux for 5 hours, The solvent was evaporated, and the obtained residue was purified by silica gel chromatography to give the title compound. This was dissolved in acetonitrile and made into an oxalate salt by a conventional method.

Example 1 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]]-(4-fluoro)
Cinamide oxalate

[0044]

Embedded image

Yield: 72% Melting point: 151-152 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 8.3 (1 H, m), 7.6 (2 H,
m), 7.4 (1H, d), 7.2 (2H, t), 6.6 (1H, d), 6.5 (2H, s), 6.4 (1H,
s), 3.7 (6H, s), 3.2 (4H, m), 3.1 (2H, m), 2.9 (2H, m), 2.8 (3H,
s), 1.7 (2H, m), 1.5 (2H, m).

Example 2 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]]-(3,4-methyle
Ndioxy) cinnamide oxalate

[0047]

[Chemical 15]

Yield: 85% Melting point: 135-140 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 8.2 (1H, m), 7.4 (1H, m
d), 7.2 (1H, s), 7.1 (1H, d), 6.9 (1H, d), 6.5 (3H, m), 6.4 (1H,
m), 6.05 (2H, s), 3.8 (6H, s), 3.2 (4H, m), 3.1 (2H, m), 2.9 (2
H, m), 2.8 (3H, s), 1.7 (2H, m), 1.5 (2H, m).

Example 3 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]]-[4- (1H-imi
Dazol-1-yl)] cinnamide oxalate

[0050]

Embedded image

Yield: 86% Melting point: 134-135 ° C. ¹ H-NMR (400MHz, DMSO-d ₆ ); δ (ppm) 8.4 (1H, s), 8.3 (1H,
t), 7.8 (1H, s), 7.7 (4H, s), 7.4 (1H, d), 7.1 (1H, s), 6.7 (1H,
d), 6.5 (2H, m), 6.4 (1H, s), 3.7 (6H, s), 3.2 (4H, m), 3.1 (2H, m
m), 2.9 (2H, m), 2.8 (3H, s), 1.7 (2H, m), 1.5 (2H, m).

Example 4 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]] cinnamide
Oxalate

[0053]

[Chemical 17]

Yield: 75% Melting point: 131-132 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 8.2 (1H, m), 7.6 (2H, m)
d), 7.4 (4H, m), 6.6 (1H, d), 6.45 (2H, s), 6.4 (1H, m), 3.7 (6
H, s), 3.2 (4H, m), 3.0 (2H, m), 2.9 (2H, m), 2.7 (3H, s), 1.6 (2
H, m), 1.45 (2H, m).

Example 5 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]]-[(6-fluor
B) Indan-2-yl] carboxamide oxalate

[0056]

Embedded image

Yield: 75% Melting point: 155-156 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.1 (1H, m), 7.0 (1H, m
d), 6.8 (1H, t), 6.5 (1H, bs), 6.4 (2H, m), 6.3 (1H, m), 3.8 (6
H, s), 3.3-3.1 (7H, m), 2.7 (2H, m), 2.6 (2H, m), 2.4 (2H, m),
2.3 (3H, s), 1.6 (4H, m).

Example 6 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]]-(indan-2-
Ill) carboxamide oxalate

[0059]

[Chemical 19]

Yield: 81% Melting point: 152-153 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 8.0 (1H, m), 7.2 (2H, m)
M), 7.1 (2H, m), 6.5 (2H, m), 6.4 (1H, m), 3.7 (6H, s), 3.2-2.9
(11H, m), 2.8 (3H, s), 1.6 (2H, m), 1.4 (2H, m).

Example 7 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]]-benzamide
・ Oxalate

[0062]

Embedded image

Yield: 83% Melting point: 148-150 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.8 (2H, m), 7.5-7.3 (3
H, m), 6.3 (3H, m), 3.8 (6H, s), 3.5 (2H, m), 2.8 (4H, s), 2.6 (2
H, m), 2.4 (3H, s), 1.7 (4H, m).

Example 8 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]]-[4- (methyla
Mino) cyanoiminoamino] cinnamide oxalate

[0065]

[Chemical 21]

Example 9 N-[[4- {N'-methyl-N '-[2- (3,5-
Dimethoxy) phenethyl] amino} butyl]]-[4- (N-methyl
Ureisil)] Cinnamide oxalate

[0067]

[Chemical formula 22]

Example 10 N-[[4- {N'-methyl-N '-[2- (3,
5-dimethoxy) phenethyl] amino} butyl]]-{3- [4- (N-
Methyl uredyl)] phenyl} propionamide

[0069]

[Chemical formula 23]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.44 (4
H, m), 2.27 (3H, s), 2.36-2.42 (4H, m), 2.59-2.66 (2H, m), 2.
68-2.75 (2H, m), 2.79 (3H, d, J = 4.6Hz), 2.87 (2H, t, J = 7.5H
z), 3.13-3.19 (2H, m), 3.77 (6H, s), 5.28 (1H, m), 6.31 (1H,
t, J = 2.2Hz), 6.34 (2H, d, J = 2.2Hz), 6.50 (1H, t, J = 5.5Hz),
7.02-7.07 (2H, m), 7.10-7.18 (3H, m).

Example 11 N-[[4- {N'-methyl-N '-[2- (3,
5-dimethoxy) phenethyl] amino} butyl]]-{[6- (N-me
Chillureidyl)] indan-2-yl} carboxamide
Oxalate

[0072]

[Chemical formula 24]

NMR of free form ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.52-1.58 (4 H, m), 2.2
1 (3H, s), 2.43 (2H, m), 2.60-2.67 (2H, m), 2.68-2.76 (2H, m
m), 2.80 (3H, d, J = 4.6Hz), 2.98-3.19 (5H, m), 3.22-3.28 (2
H, m), 5.03 (1H, m), 6.31 (1H, t, J = 2.3Hz), 6.34 (2H, d, J = 2.3
Hz), 6.57 (1H, t, J = 4.5Hz), 6.64 (1H, br-s), 6.97 (1H, dd, J =
1.6Hz, 7.6Hz), 7.03-7.07 (3H, m).

Example 12 N-[[4- {N'-methyl-N '-[2- (3,
5-dimethoxy) phenethyl] amino} butyl]]-[4- (N-methyl
Lurazil)] Benzamide oxalate

[0075]

[Chemical 25]

NMR of free form ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.55-1.70 (4 H, m), 2.2
5 (3H, s), 2.43 (2H, t, J = 6.6Hz), 2.57-2.63 (2H, m), 2.64-2.
70 (2H, m), 2.80 (3H, d, J = 4.6Hz), 3.35-3.42 (2H, m), 3.74 (6
H, s), 5.91 (1H, m), 6.28 (1H, t, J = 2.4Hz), 6.31 (2H, d, J = 2.4)
Hz), 7.28-7.33 (2H, m), 7.44 (1H, t, J = 5.1Hz), 7.53-7.58 (2
H, m), 8.11 (1H, br-s).

Example 13 N-Methyl-N- (3,5-dimethoxy
Phenethyl) -N- {N '-[4- (N-methylureizyl)] pheneti
Luraysil} Butylamine

[0078]

[Chemical formula 26]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.44-1.
53 (4H, m), 2.27 (3H, s), 2.40 (2H, t, J = 6.8Hz), 2.57-2.64 (4
H, m), 2.68-2.74 (2H, m), 2.80 (3H, d, J = 4.6Hz), 3.06-3.13
(2H, m), 3.21-3.28 (2H, m), 3.77 (6H, s), 4.92 (1H, m), 5.51
(1H, m), 5.72 (1H, m), 6.30 (1H, t, J = 2.2Hz), 6.35 (1H, d, J =
2.2Hz), 6.88-6.93 (2H, m), 7.01-7.05 (2H, m), 7.49 (1H, br-
s).

Example 14 N-[[4- {N'-methyl-N '-[2- (3,
5-dimethoxy) phenethyl] amino} butyl]]-{3- [4- (N-
Ethylureidyl)] phenyl} propionamide

[0081]

[Chemical 27]

¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 1.03
(3H, t, J = 7.2Hz), 1.36-1.45 (2H, m), 1.55-1.66 (2H, m), 1.6
8-1.78 (2H, m), 2.05 (2H, t, J = 8.0Hz), 2.45 (2H, t, J = 8.0H
z), 2.73 (3H, s), 2.84.2.91 (2H, m), 2.98-3.13 (6H, m), 3.15
-3.23 (2H, m), 3.73 (6H, s), 6.18 (1H, t, J = 5.5Hz), 6.38 (1H,
t, J = 2.2Hz), 6.46 (2H, m), 7.00 (2H, d, J = 8.4Hz), 7.28 (2H,
d, J = 8.4Hz), 7.83 (1H, t, J = 5.7Hz), 8.42 (1H, s).

Example 15 N-[[4- {N'-methyl-N '-[2- (3,
5-dimethoxy) phenethyl] amino} butyl]]-[4- (N-ethyl)
Luurezil)] Styrylacetic acid amide oxalate

[0084]

[Chemical 28]

¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 1.74-
1.84 (2H, m), 2.62 (3H, d, J = 4.6Hz), 2.73 (3H, s), 2.82-2.90
(2H, m), 2.98-3.06 (4H, m), 3.09-3.23 (4H, m), 3.73 (6H, s),
6.10-6.19 (1H, m), 6.20-6.26 (1H, m), 6.32-6.40 (2H, m), 6.
43-6.47 (2H, m), 7.23 (2H, d, J = 8.6Hz), 7.35 (2H, d, J = 8.6H
z), 8.04 (1H, t, J = 5.7Hz), 8.72 (1H, s).

Example 16 N-[[4- {N'-methyl-N '-[2- (3,
5-dimethoxy) phenethyl] amino} butyl]]-{3- [N-methyl]
Lucarbamoyl- (1,2,3,4-tetrahydroquinoline-6-a
)]} Propionamide oxalate

[0087]

[Chemical 29]

Example 17 N-[[4- {N'-methyl-N '-[2- (3,
5-Dimethoxy) phenethyl] amino} butyl]]-[4- (1H-I
Midazol-1-yl)] styryl acetic acid amide oxalate

[0089]

Embedded image

NMR of free form ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.5-1.8 (2 H, m), 2.17
(3H, s), 2.3-2.5 (6H, m), 3.01 (2H, d, J = 5.4Hz), 3.1-3.5 (2
H, m), 3.72 (6H, s), 6.0-6.3 (4H, m), 6.40 (1H, d, J = 15.5Hz),
7.1-7.5 (7H, m), 7.78 (1H, s).

Finally, the usefulness of the compounds of the present invention will be listed as the effects of the invention.

【The invention's effect】

Pharmacological Test Example 1 The dopamine D ₃ receptor-specific antagonism of the compounds of the present invention was evaluated.

(1) Method 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 2 mM CaC
An assay buffer having a composition of l ₂ and 1 mM MgSO ₄ was used. D
₂ , Cultured mammalian cells expressing each D ₃ receptor protein were suspended in a buffer solution, and a membrane fraction prepared by centrifugation was used as a receptor. The radioligand is [ ³
H] spiperone was used. The test compound was dissolved in dimethyl sulfoxide (DMSO) and then diluted 10-fold with the assay buffer before use. Assay buffer (20 μl), test compound (20 μl), 7.5 nM radioligand (20 μl) and receptor solution (160 μl) were added, and a total of 200 μl was mixed and incubated at room temperature for 1 hour. After incubation, B / F separation was performed using a cell harvester. Filtermat B was used as the filter paper. After that, the radioactivity of the filter paper was changed to β scintillation coun
It was measured by ter. The effect of each test compound was calculated according to the following formula.

[0094]

[Equation 1]

The IC ₅₀ value was determined by the probit method. Further, using the Kd value obtained for each lot of the receptor, the Ki value of each test compound was obtained according to the following formula.

[0096]

[Equation 2]

(2) Results The following table shows the results of the affinity evaluation of the representative examples of the compounds of the present invention for the dopamine D ₂ and D ₃ subtype receptors and the affinity ratio (D ₂ / D ₂ D ₃ ).

[0098]

[Table 1]

From the above table, the compounds of the present invention are dopamine D ₃
It is clear that it has a specific affinity for the receptor.

Pharmacological Test Example 2 Binding experiment with rat striatal membrane preparation using [ ³ H] spiperone as a ligand.

(1) Method [0100] In a binding experiment using a rat striatal membrane preparation using [ ³ H] spiperone as a ligand, the inhibition curve of dopamine agonist was increased by the addition of guanosine triphosphate (hereinafter, GTP). Apparently by shifting to IC ₅₀
It is known that, while the value becomes high, the antagonist does not show a shift in the inhibition curve even when GTP is added. As shown in the table below, it is a dopamine agonist
quinpirole [RBI (ResearchBiochemicals Internationa
l) CAS registration number: 85760-74-3] or (±) -7-Hyd
For roxy-N, N-Di- (n-propyl) -2-aminotetralin, which is a typical example of the present invention, the IC ₅₀ value was increased by adding 2 mM-GTP to the reaction system of the binding experiment. In the compound of Example 11, the dopamine antagonist haloperidol
The IC ₅₀ value did not change as in (Haloperidol).

[0102]

[Table 2]

From the above table, the compounds of the present invention are dopamine D ₃
It is clear that it is a dopamine antagonist with high selectivity for the receptor and a new anti-schizophrenia drug that avoids the side effects of conventional dopamine D ₂ receptor antagonists.

As described above, the compound of the present invention is a preventive / therapeutic / ameliorating agent for a disease for which a dopamine D ₃ receptor antagonism is effective, and preferably a clinically safe and highly useful preventive / therapeutic agent for schizophrenia. -It was shown that it could be an improving agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/47 A61K 31/47 C07C 233/62 9547-4H C07C 233/62 233/78 9547-4H 233/78 275/38 9451-4H 275/38 275/40 9451-4H 275/40 279/28 9451-4H 279/28 C07D 215/14 C07D 215/14 233/60 104 233/60 104 317/68 317 / 68 (72) Inventor Atsushi Kuroki 1881-75 Ami, Ami Town, Inashiki District, Ibaraki Prefecture

Claims (5)

[Claims] 1. An aralkylaminoalkylamide derivative (I) represented by the following general formula or a pharmaceutically acceptable salt thereof. Embedded image {In the formula, R ¹ and R ² represent the same or different groups selected from a lower alkoxy group, a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a lower alkyl group, and R ¹ and R ^{2 represent} a ring. May be formed. R ³ represents a hydrogen atom or a lower alkyl group. R ⁴ means a group represented by the following general formula. Embedded image [In the formula, R ⁵ and R ⁶ are a hydrogen atom, a halogen atom, a lower alkyl group, a heteroaryl group, a group represented by the following chemical formula, [In formula, R < ⁷ > means the group represented by an oxygen atom or a formula (= N-CN). ] R means 0 or 1. ] N
Means an integer of 1 to 3. m means an integer of 2 to 4. The bond represented by the following chemical formula is It means a single bond or a double bond. ｝ 2. An aralkylaminoalkylamide derivative (II) represented by the following general formula or a pharmaceutically acceptable salt thereof. Embedded image [In the formula, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , n, m and r have the same meanings as described above. ] The bond represented by the following chemical formula is as follows: It means a single bond or a double bond. ] 3. The aralkylaminoalkylamide derivative according to claim 1, which is one selected from the following compounds, or a pharmaceutically acceptable salt thereof. (1) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-(4-fluoro) cinnamide (2) N-[[4 -{N'-Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-(3,4-methylenedioxy) cinnamide (3) N-[[4- {N' -Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-[4- (1H-imidazol-1-yl)]
Cinnamide (4) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]] cinnamide (5) N-[[4- {N'- Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-[(6-Fluoro) indan-2-yl]
Carboxamide (6) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-(indan-2-yl) carboxamide (7) N-[[4- {N'-Methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-benzamide (8) N-[[4- {N'-methyl-N '-[2- (3,5-Dimethoxy) phenethyl] amino} butyl]]-[4- (methylamino) cyanoiminoamino] cinnamide (9) N-[[4- {N'-methyl-N'- [2- (3,5-Dimethoxy) phenethyl] amino} butyl]]-[4- (N-methylureidyl)] cinnamide (10) N-[[4- {N'-methyl-N '-[2 -(3,5-Dimethoxy) phenethyl] amino} butyl]]-{3- [4- (N-methylureidyl)] phenyl} propionamide (11) N-[[4- {N'-methyl-N '-[2- (3,5-Dimethoxy) phenethyl] amino} butyl]]-{[6- (N-methylureidyl)] indan-2-yl} carboxamide (12) N-[[4- { N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl]]-[4- (N-methyl Ureijiru)] benzamide (13) N-methyl-N-(3,5-dimethoxy-phenethyl)-N-{N'
[4- (N-Methylureidyl)] phenethylureidyl} butylamine (14) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl] ]-{3- [4- (N-Ethylureidyl)] phenyl} propionamide (15) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} Butyl]]-[4- (N-Ethylureidyl)] styryl acetic acid amide (16) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl] ]-{3- [N-methylcarbamoyl- (1,
2,3,4-Tetrahydroquinolin-6-yl)]} propionamide (17) N-[[4- {N'-methyl-N '-[2- (3,5-dimethoxy) phenethyl] amino} butyl ]]-[4- (1H-Imidazol-1-yl)]
Styryl acetic acid amide 4. A preventive / therapeutic / ameliorating agent for a disease for which a dopamine D ₃ receptor antagonism is effective, which comprises the aralkylaminoalkylamide derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. . 5. The prevention / treatment of a disease for which a dopamine D ₃ receptor antagonism is effective according to claim 4, which is an anti-schizophrenia drug.
Improver.