JPH11199573A - 5ht3 receptor agonist and new benzothiazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agonist specifically acting on a neuronal 5-HT3 receptor in the intestinal canal nervous system, and useful for the treatment of e.g. diseases associated with digestive system disorders and pancreatic insufficiency, by using a specific benzothiazole derivative (salt) as active ingredient. SOLUTION: This 5-HT3 receptor against has, as its active ingredient, a compound of formula I [R is a group of formula II (R2 is H, a lower alkyl or the like; (n) is 1-4) or formula III (R3 is H, cyano, a lower alkyl or the like; R4 is H, a lower alkyl or the like); A is a single bond or methylene; R1 is H, a halogen, OH or the like; the nitrogen atom bound to R3 may represent a substituted quaternary ammonium] or a salt thereof [e.g. 2-(1-piperazinyl) benzothiazole]. The compound of formula I is prepared, for example, by condensation reaction between a compound of formula IV (X is a halogen or organic sulfonic acid residue) and a compound of the formula: RH.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION The present invention is useful as a medicament.
The present invention relates to a novel benzothiazole derivative or a salt thereof.

[0002]

[Prior art] The compound of the present invention may be administered to the intestinal nervous system or
A neuronal cell located in the primary afferent of the central nervous system
Effective and selective agonists of rotonin (5-HT) receptor
Act as This type of receptor is currently 5-HT₃Acceptance
It is considered a body. The compound of the present invention is useful for efferent nerve endings.
Release acetylcholine to exert its action.
Manifest. Stimulation of acetylcholine receptors in the gastrointestinal tract
To increase gastrointestinal motility and improve gastrointestinal dysfunction
(Goodman and Gilman's The Pharmacol
ogical Basis of Therapeutics 8th edition, p125, (199
0), Pergamon Press). Furthermore, in the central nervous system, 5-
HT₃Receptors are located at the presynaptic level and regulate their neural activity.
(J. Neurosci., 11, 1881 (19
91)). Therefore, 5-HT₃Receptor agonists, especially digestive
It may be useful for organ disorders. The inventor
Etc. are described in WO92 / 07849 and WO95 / 24406
Thiazole derivatives as disclosed, WO 94/0
6791, WO95 / 24399 or JP-A-7-701
No. 36, the condensed thiazole derivative disclosed in
5-HT₃Reported selective agonist activity of receptor
doing.

[0003] Further, 2- (4-methyl-1-piperazini)
B) benzoxazole and 2- (4-methyl-4-p)
Lopenenyl-1-piperazinyl) benzoxazole is 5
-HT₃Reported to have receptor agonist activity
(16th Medicinal Chemistry Symposium).
On the other hand, 5-HT₃2 as compounds having receptor affinity
-(4-acetyl-1-piperazinyl) benzothiazole
(Eur. J. Med. Chem., 30 (9), 715-9, 1995), 5-HT
₃2- (4-benzene) as a compound having a receptor antagonistic action
(Jil-1-piperazinyl) benzothiazole and the like are known.
(J. Med. Chem., 37 (9), 1320-5, 1994). In addition,
2- (1-homopiperazinyl) benzothiene as an intermediate
Azole (EP226842), 2 as an antiparasitic agent
-(4-methyl-1-piperazinyl) benzothiazole
(Eur. J. Med. Chem., 13 (2), 171-5, 197
8), 2- (1-piperazinyl) benzo represented by the following formula
The thiazole derivative has anti-coccidial activity in chickens
(J. Med. CHem., 15 (6), 693-4, 1972).

Embedded image

[0004]

[Problems to be solved by the invention] 5-HT₃Receptor activation
The above compounds are known as drugs, but they are more excellent
5-HT₃Drug discovery of receptor agonists is an important medical issue
It is. An object of the present invention is to provide a strong 5-HT₃Receptor agonist activity
To provide novel benzothiazole derivatives and salts thereof.
And to provide a medicine containing them.
And

[0005]

The present inventors have SUMMARY OF THE INVENTION Where conducted extensive studies to achieve the above problems, in that it has a newly synthesized benzothiazole derivative is 5-HT ₃ strong agonist activity in receptor The present invention has been completed. That is, the present invention provides 5-HT containing a benzothiazole derivative represented by the following general formula (I) or a salt thereof as an active ingredient.
₃ receptor agonists.

Embedded image (The symbols in the formula represent the following meanings.

Embedded imageA: single bond or methylene group R₁: Hydrogen atom, halogen, hydroxy, cyano, nitro
B, lower alkyl or lower alkenyl group R₂: Hydrogen atom, lower alkyl, lower alkenyl or lower
Group of Formula (1) -A₁-OR₅ (2) -A₁-CO-R₅ (3) -A₁-CO-OR₆ R₃: Hydrogen atom, cyano, lower alkyl, lower alkenyl
Cycloalkyl, cycloalkyl-lower alkyl,
Aryl, aryl-lower alkyl, pyridyl, or lower
Group of Formula (1) -A₁-OR₅ (2) -A₁-CO-R₅ (3) -A₁-CO-OR₆ (4) -A₁-CO-OA₂-O-CO-R₅ (5) -C (NH₂) = NA₁-OR₅ (6) -C (NH₂) = NA₁-CO-R₅ (7) -C (NH₂) = NA₁-CO-OR₆ (8) -C (R₇) = NA₁-OR₅ (9) -C (R₇) = NA₁-CO-R₅ (10) -C (R₇) = NA₁-CO-OR₆ R₄: Hydrogen atom, lower alkyl or R₃Together with
R which forms a 4- to 8-membered nitrogen-containing saturated ring₅: Hydrogen atom or lower alkyl group R₆: Hydrogen atom, lower alkyl or 2-oxo-4-me
Tyl-1,3-dioxolylmethyl group R₇: Hydrogen atom or lower alkyl group A₁: Single bond or lower alkylene group A₂: Lower alkylene group n: integer from 1 to 4  Provided that R in the R group₃The nitrogen atom to which the group is attached is a substituent
And quaternary ammonium. )

[0006] Further, the present invention is represented by the following general formula (I ′).
Benzothiazole derivatives or salts thereof.

Embedded image(Where A, R₁And R have the above-mentioned meaning. However, 2
-(1-piperazinyl) benzothiazole, 2- (1-
Homopiperazinyl) benzothiazole, 2- (4-methyl)
Ru-1-piperazinyl) benzothiazole, 2- (4-
(Acetyl-1-piperazinyl) benzothiazole, 2-
(4-benzyl-1-piperazinyl) benzothiazole
2- [4- (2-hydroxyphenyl) -1-pipe
Radinyl] benzothiazole, 2- [4- (2-methoxy)
Cyphenyl) -1-piperazinyl] benzothiazole,
2- [4- (2-ethoxyphenyl) -1-piperazini
Ru] benzothiazole, 2- [4- (3-chlorophenyl)
Ru) -1-piperazinyl] benzothiazole, 2- (4
-Piperonyl-1-piperazinyl) benzothiazole,
6- [2- [4- (2-benzothiazolyl) -1-pipe
Radinyl] ethyl] -3-methyl-2-benzothiazoly
Non, 6- [3- [4- (2-benzothiazolyl) -1
-Piperazinyl] propyl] -3-methyl-2-benzo
Thiazolinone, 6- [4- [4- (2-benzothiazoli)
L) -1-piperazinyl] butyl] -3-methyl-2-
Benzothiazolinone, 2- (4-formyl-1-pipera)
Dinyl) benzothiazole, 2- [4- (2-bromo-
3-propenyl) -1-piperazinyl] benzothiazolate
2- [4- (2,4-dichlorobenzyl) -1-pi
Perazinyl] benzothiazole, 2- (4-pentyl-
1-piperazinyl) benzothiazole, 6-nitro-2
-(1-piperazinyl) benzothiazole, 6-methoxy
C-2- (1-piperazinyl) benzothiazole, 6-
Methoxy-2- (4-methyl-1-piperazinyl) ben
Zothiazole, 6-methoxy-2- (4-benzyl-1
-Piperazinyl) benzothiazole, [4- (2-ben
Zothiazolyl) -1-piperazinyl] acetic acid, 2- [4-
(4-Chlorophenyl) -1-piperazinyl] benzothi
Azole, 2- [4- (2-hydroxyethyl) -1-
Piperazinyl] benzothiazole, 2- [4- (2,4
-Dinitrophenyl) -1-piperazinyl] benzothia
Zol, propyl [4- (2-benzithiazolyl) -1
-Piperazinyl] carboxylate. )

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION A compound represented by the general formula (I) or (I ')
These compounds are further described as follows.
In the definition of the general formula in this specification, unless otherwise specified
The term "lower" refers to a straight or branched chain having 1 to 6 carbon atoms.
Means a carbon chain. Therefore, "lower alkyl group"
An alkyl group having 1 to 6 carbon atoms.
Methyl, ethyl, propyl, butyl, pentyl (A
Mill), hexyl group or isopropyl group.
An isomer, preferably an alkyl having 1 to 3 carbon atoms
Group. "Lower alkenyl group" means having 2 to 2 carbon atoms.
6 alkenyl groups, specifically, for example, vinyl,
1-propenyl, 1-butenyl, 1-pentenyl, 1-
Hexenyl or allyl group, 1-methylethenyl group, etc.
And preferably has 2 to 3 carbon atoms.
Alkenyl groups. "Lower alkylene group" means charcoal
An alkylene group having a prime number of 1 to 6;
Methylene, ethylene, trimethylene, tetramethyle
, Pentamethylene, hexamethylene groups or their structures
And preferably has 1 to 3 carbon atoms.
It is an alkylene group.

[0008] “Cycloalkyl group” means 3 to 3 carbon atoms
8 saturated hydrocarbon ring groups, specifically, for example, cyclo
Propyl, cyclobutyl, cyclopentyl, cyclohexyl
A sil, cycloheptyl, cyclooctyl group, etc.
You. “Aryl” is the number of carbon atoms which may have a substituent
6 to 14 aromatic groups, preferably phenyl
No. As a substituent, a halogen atom, lower alkyl
, Lower alkyl-O-, hydroxyl group and the like.
May have 1 to 3 substituents. "4- to 8-membered nitrogen-containing
"Saturated ring" specifically refers to azetidine, pyrrolidine, pipet
Lysine, hexahydroazepine, octahydroazocine
Is mentioned. R4 group is integrated with R3 group to form 4 to 8
As the R group for forming a membered nitrogen-containing saturated ring,
In addition, the following groups are exemplified.

Embedded image “Halogen atom” includes fluorine atom, chlorine atom, odor
And an iodine atom.

The compound of the present invention may have an optical
Isomer (optically active substance, diastereomer, etc.) exists
You. Further, the compound of the present invention may be a compound having an amide bond.
There are also tautomers based on amide bonds. Departure
It is clear that these isomers are separated or mixed.
Compounds. The compound of the present invention forms a salt with an acid or a base.
I do. Hydrochloric acid, hydrobromic acid, hydrogen iodine as salts with acids
Inorganic acids such as acids, sulfuric acid, nitric acid, and mineral acids with phosphoric acid, formic acid,
Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,
Fumaric acid, maleic acid, lactic acid, malic acid, citric acid,
Tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethane
Acid addition salts with organic acids such as sulfonic acid and glutamic acid
I can do it. Sodium and potassium as salts with bases
Of lium, magnesium, calcium, aluminum, etc.
Inorganic bases, methylamine, ethylamine, meglumine,
Organic bases such as ethanolamine or lysine, arginine
Salts and ammonium with basic amino acids such as
Salt. Further, the compound of the present invention is a hydrate,
It can form solvates and polymorphs with ethanol.
Wear.

Manufacturing method (first manufacturing method)

Embedded image(Where A, n, R₁, R₂, R₃, R₄And R are as described above
Indicates the meaning of X is a halogen atom or an organic sulfonic acid residue
Represents a group. The compound (I) of the present invention is a compound represented by the general formula (II)
And a compound represented by the general formula (III) or (IV) or a compound thereof
Reacting with a salt to condense, then optionally₂Or
R₃Can be produced by converting This
The halogen atom represented by X is iodine, bromine, chlorine, etc.
And the organic sulfonic acid is methanesulfonyl
Alkylsulfurs such as oxy and ethanesulfonyloxy groups
Phonyloxy group, toluene (particularly p-toluene) sulfo
Arylsulfonyloxy groups such as nyloxy group;
I can do it. The reaction is carried out by reacting corresponding amounts of compound (II) and compound
(III) or (IV), or one of them as excess mole
Solvent-free or dimethylformamide, dimethyl sulf
Hoxide, ether, tetrahydrofuran, dioxa
Acetone, methyl ethyl ketone, methanol, ethanol
Knol, methylene chloride, dichloroethane, chloropho
In a solvent inert to the reaction, such as
, Picoline, dimethylaniline, N-methylmorpholine
, Trimethylamine, toluethylamine, hydrogenated nato
Lium, potassium carbonate, sodium carbonate, sodium bicarbonate
Of bases such as ium, sodium hydroxide and potassium hydroxide
In the presence, depending on the starting compound, from cooling to room temperature, room temperature
It is advantageous to carry out the reaction under heating or under reflux.

[0011] R₂Or R₃Depends on the type of substituent.
However, both are performed by applying a common method. example
For example, N-alkylation or N-alkylation of a primary or secondary amine compound
The silation reaction is carried out with the corresponding alkyl halide or acid halide.
Alkylation or acylating agent with acetonitrile, etc.
In a solvent inert to the reaction, potassium carbonate if necessary
Or in the presence of a base such as triethylamine.
In addition, the reductive alkylation reaction with a carbonyl compound
The corresponding primary or secondary amine derivative is reacted with a compound such as methylene chloride.
In an inert organic solvent, preferably in the presence of an acid catalyst such as acetic acid.
Carbonyl compounds such as benzaldehyde in the presence
Sodium ethoxy borohydride, cyano borohydride
Treatment with a suitable reducing agent such as sodium
Reduction treatment such as catalytic hydrogenation using
Can be performed. Also, with formalin
General reductive methylation using formic acid
it can. The deacylation reaction is carried out in the presence of an acid or an alkali.
Hydrolysis is preferred. N-amidination, N-imidoni
Reaction or N-cyanoation reaction is 3,5-dimethyl
-1-pyrazolecarboxamidine hydrochloride, ethyl acetate
Using cetimidate hydrochloride or bromocyanide
Solvents inert to the reaction in the presence of a base such as triethylamine
Performed in a medium. Also, R₃If there is an ester group in the
Hydrogenated in a suitable solvent such as tetrahydrofuran.
Treatment with an appropriate reducing agent such as
It can also lead to the corresponding alcoholic body. N-Hide
Roxyguanidine derivatives are salts of N-cyano-form
Reaction of hydroxylamine in a suitable solvent in the presence of a group
It can be manufactured by

[0012] Further, R in the R group₃The nitrogen source to which the group is attached
The compound whose quaternary ammonium is the corresponding tertiary ammonium
Reacting alkyl halides with alkyl halides, etc. in a conventional manner.
Can be manufactured more. Manufactured in this way
The compound of the present invention is free or as a salt thereof.
Separated and purified. Isolation and purification include extraction, concentration, distillation,
Normalization such as crystallization, filtration, recrystallization, and various types of chromatography
This is done by applying the chemical operation. Various isomers are isomers
It can be isolated by a conventional method utilizing the difference in physical properties between the two.
For example, by the racemic resolution method of a racemic compound (for example,
Diastereomers with common optically active acids (tartaric acid, etc.)
How to lead to salt and optical resolution etc.)
Can lead to sex. Also, a mixture of diastereomers
The compound can be prepared by a conventional method, for example, fractional crystallization or chromatography.
-Can be separated. Optically active compounds are suitable
Manufactured by using various optically active starting compounds.
Can also be.

[0013]

【The invention's effect】 The compound of the present invention is useful for the treatment of neurons in the intestinal nervous system.
5-HT₃By acting specifically on the receptor,
Digestive disorders, ie senile, flaccid, rectal, etc.
Constipation, sudden / chronic gastritis, gastric / duodenal ulcer, gastric neurosis, stomach
Ptosis, reflux esophagitis, pseudo ileus, non-ulcer dyspepsia,
Abdominal complaints, heartburn due to diseases such as diabetes, abdominal distention
Fullness, anorexia, upper abdominal discomfort, nausea, vomiting or abdominal pain
Gastrointestinal motility disorders, gastrointestinal dysfunction after anesthesia surgery, stomach
Useful in treating stasis, indigestion, bloating, etc.
is there. In addition, diseases associated with pancreatic insufficiency such as fat malabsorption
Can be used for the treatment of In addition, the compound of the present invention
-HT₃Cancer for the purpose of pain relief based on receptor agonist activity
Treatment of constipation symptoms induced by morphine administered to patients
It is also effective for treatment (PCT / JP97 / 02524).
In addition, the compounds of the present invention can be used to inhibit central nervous system inhibitory presynapses.
5-HT₃Acts like 5-HT on receptors
Psychiatric disorders (eg, schizophrenia and depression), anxiety,
For the treatment of symptoms such as memory impairment, dementia and extrapyramidal disorders
It is also useful. Further, the compound of the present invention, urinary tract obstruction,
Treatment of urinary difficulties associated with urinary calculi or prostatic hypertrophy
Can also be used.

The pharmacological action of the compound of the present invention is as follows.
More confirmed. The compound of the present invention is 5-HT₃Receptor activation
Remarkably active in guinea pig isolated colon
Show action. The effect is described below together with the measurement method. <5-HT₃Receptor agonist activity> Hartley male
The distal colon of a lumop (500-800 g) is removed and
20 mm sections were made. Longitudinal muscle direction in Magnus tube
And the contractile response was measured isometrically. 5-HT is
A dose-dependent contractile response occurs at a concentration of 0.1 to 30 μM.
The maximum reaction was shown at 10 to 30 μM. (5-HT
Action is 5-HT₃Via receptor: J.Pharmacol.Exp.Th
er., 259, 15-21, 1991). The effect of the compound on each sample
The relative values were shown by comparison with the action of 5-HT. Max.
The response is 100% of the maximum contraction response by 5-HT.
Is the percentage of the maximum response by the compound when
lative potency is based on 5-HT EC50 value (1)
And the relative value of the EC50 value of the compound. (Relative potency = EC50 value of 5-HT /% of compound
EC50 value)  The compound of the present invention has a concentration-dependent guinea pig concentration of 300 μM or less.
The isolated colon showed a contractile action. Further, the compound of the present invention
Guinea pig isolated colonic contractile action is selective 5-HT₃
JP-A-3-223278, which is a receptor antagonist
Antagonized by 0.3 μM of the compound described in Example 44. This
Thereby, the colonic contractile action of the compound of the present invention is increased by 5-HT.₃
It was confirmed that the activity was mediated by receptor action. that's all
From the results, it was found that the compound of the present invention has strong 5-HT₃Receptor
It was shown to be an agonist.

[0015] One or more of the compounds of the present invention or salts thereof
Preparations containing the above as an active ingredient are usually used for formulation.
Is prepared using carriers, excipients and other additives
You. No solid or liquid carrier or excipient
Such as lactose, magnesium stearate,
Starch, talc, gelatin, agar, pectin, arabi
Agum, olive oil, sesame oil, cocoa butter, ethylene
Glycols and the like can be used. Dosing
Tablets, pills, capsules, granules, powders, liquids, etc.
Oral administration, injections such as intravenous injection and intramuscular injection, suppositories, transdermal
And the like. Throw
Dosage may vary depending on the condition, age, sex, etc.
It is determined as appropriate depending on the case, but usually per adult,
1 to 1,000 mg, preferably 50 to 20 per day
It is orally administered once or several times a day in the range of 0mg
Or 1 to 500 mg per adult per day
Can be administered intravenously once to several times a day, or
Is administered intravenously for 1 hour to 24 hours per day
You. Of course, as mentioned above, the dosage varies under various conditions.
If the dose is less than the above dose range
There is also.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. , Mixed with magnesium aluminate. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium calcium glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Containing ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further include preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing agents (eg,
Adjuvants such as glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by producing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.

[0017]

【Example】 Next, the present invention will be described in more detail with reference to Examples.
Explain, but the invention is not limited to these examples
is not. In the examples, room temperature usually indicates about 10 to 30 ° C.
You. Example 1  500 mg of 2-chlorothiazole and 5.08 of piperazine
g of the mixture was stirred at 150 ° C. for 5 hours. Reaction solution
Extracted with chloroform, saturated aqueous sodium bicarbonate
After washing with water, it was dried over anhydrous sodium sulfate. Reaction
The solvent is distilled off, and the residue is subjected to silica gel column chromatography.
-(Chloroform / methanol / ammonia water)
And 0.70 g of 2- (1-piperazinyl) benzothia
The sol was obtained as the free base. Take 87mg from now
85m by treatment with fumaric acid in tanol / water
g of fumarate was obtained. Thereafter, in the same manner as in Example 1,
The compound of Example 2-19 was obtained.

Embodiment 20  70 mg of 2- (1-piperazinyl) benzothiazole,
A mixture of 2 ml of water and 24 μl of formic acid was added to a 35% form under ice cooling.
28 μl of a marine aqueous solution was added, and the mixture was added
Stirred at 0 ° C. for 14 hours. Reaction mixture with chloroform
After extraction and washing with saturated aqueous sodium hydrogen carbonate solution,
Dry over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure,
The residue is purified by silica gel column chromatography (chloropho
Lum / methanol / ammonia water) and 56mg
2- (4-methyl-1-piperazinyl) benzothiazole
Was obtained as the free base. This is methanol / acetic acid
65 mg of fumaric acid
The acid salt was obtained. Hereinafter, in the same manner as in Example 20,
1,22 compounds were obtained.

Embodiment 23  2- (1-piperazinyl) benzothiazole 100m
g, dichloroethane 5 ml, benzaldehyde 46μ
l, 26 μl of acetic acid to a mixture of
Add 123 mg of sodium arsenide and stir at room temperature for 2 hours
Was. The reaction mixture was extracted with chloroform, and saturated
After washing with aqueous thorium solution and saturated saline solution in that order, anhydrous
Dried over sodium sulfate. The solvent was distilled off under reduced pressure to give a residue.
To silica gel column chromatography (chloroform
/ Methanol / aqueous ammonia) and the resulting crystals
By washing with hexane / ether, 2- (4-
Benzyl-1-piperazinyl) benzothiazole 96m
g was obtained.

Embodiment 24  N- [1- (2-benzothiazolyl) -4-piperidini
[A] acetamide in 4 ml of 1N hydrochloric acid
Then, the mixture was stirred under reflux for 20 hours. 1N reaction mixture
After basifying with sodium hydroxide, chloroform
Extracted and dried over anhydrous sodium sulfate. Solvent under reduced pressure
The residue obtained is treated with fumaric acid in methanol.
To give 2- (4-aminopiperidinyl) benzo
67 mg of the 0.5 fumarate of thiazole were obtained. Below
In the same manner as in Example 24, the compounds of Examples 25 and 26 were obtained.
Was.

Embodiment 27  2- (1-piperazinyl) benzothiazole 600m
g, potassium carbonate 378 mg, acetonitrile 12 ml
303 μl of ethyl bromoacetate was added to the mixture of
Stirred for 10 hours. After distilling off the reaction solvent, chloroform
Extraction and washed with saturated aqueous sodium hydrogen carbonate solution.
Then, it was dried over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure
And the obtained crystals are washed with hexane / ethyl acetate.
By means of ethyl 4- (2-benzothiazolyl)-
601 mg of 1-piperazinyl acetate was obtained. Below
In the same manner as in Example 27, the compounds of Examples 28-31 were obtained.
Was.

Embodiment 32  Ethyl 4- (2-benzothiazolyl) -1-piperazine
Nyl acetate (300 mg) in ether (4 ml)
Dissolve in 4 ml of drofuran and add 15 parts of lithium borohydride
mg and stirred at room temperature for 21 hours.
Add 26mg sodium arsenide and stir at room temperature for 24 hours
Was. After distilling off the reaction solvent, extraction with chloroform, water,
After washing with saturated saline, dry over anhydrous sodium sulfate
did. The solvent is distilled off under reduced pressure, and the residue is
Chromatography (chloroform / methanol / ammonium
A)), and the obtained crystals are purified with hexane / ethyl acetate.
2- [4- (2-benzothiazo)
183 mg of lyl) -1-piperazine] ethanol were obtained.

Embodiment 33  2- (4-methyl-1-piperazinyl) benzothiazole
200 mg in 2 ml of dimethylformamide,
82 μl of allyl bromide was added under ice-cooling and the mixture was added at room temperature for 3 days.
Stirred. After distilling off the reaction solvent, acetone was added to the residue.
I got it. The precipitate to be purified is collected by filtration, washed with acetone and dried.
And 1-allyl-4- (2-benzothiazolyl) -1-
290 mg of methylpiperazinium bromide were obtained.

Embodiment 34  200 mg of 2- (1-piperazinyl) benzothiazole
Was dissolved in 6 ml of dimethylformamide, and
Cyl-1-pyrazolecarboxamidine hydrochloride 319
mg and 369 mg of triethylamine, and the mixture was added at room temperature for 1 week.
While stirring. After evaporating the reaction solvent, the residue was silica gel
Column chromatography (chloroform / methanol /
Ammonia water) and use 4N hydrochloric acid / ethyl acetate
And converted to the hydrochloride, and then added with methanol / ethyl acetate.
By recrystallization, 4- (2-benzothiazolyl
L) -1-Piperazinecarboxamidine dihydrochloride 1
20 mg were obtained. Hereinafter, in the same manner as in Example 34,
35 compounds were obtained.

Embodiment 36  500 mg of 2- (1-piperazinyl) benzothiazole
Was dissolved in 20 ml of ethanol, and triethylamine 63
5 μl, 558 mg of ethyl acetimidate hydrochloride
The mixture was stirred at room temperature for 20 hours. Add methanol and react
After homogenizing the mixture, the solvent was distilled off and the resulting residue was
The hydrochloride was prepared using 4N hydrochloric acid / ethyl acetate. this
After washing with methanol / ethyl acetate, 2- (4-acetoiyl
Midoyl-1-piperazinyl) benzothiazole disalt
720 mg of the acid salt were obtained. Hereinafter, in the same manner as in Example 36,
The compound of Example 37 was obtained.

Embodiment 38  400 mg of 2- (1-piperazinyl) benzothiazole
Was dissolved in 6 ml of acetone, and 232 mg of bromocyanine was dissolved.
Add 397 µl of diisopropylethylamine and cool under ice.
Stir for 3 hours. The reaction solution was extracted with ethyl acetate, saturated carbon
After washing with sodium hydrogen oxyacid aqueous solution, anhydrous sodium sulfate
Dried with lium. The solvent was distilled off under reduced pressure to obtain the obtained crystals.
Was washed with hexane / ethyl acetate to give 4-
(2-benzothiazolyl) -1-piperazine carbonate
402 mg of Lil were obtained. Hereinafter, in the same manner as in Example 38,
The compound of Example 39 was obtained.

Embodiment 40  4- (2-benzothiazolyl) -1-piperazinecarbo
200 mg of nitrile, 6 ml of 1,4-dioxane,
Dissolve in 5 ml of ethanol, and add
g and triethylamine (114 µl)
While stirring. The reaction solution was extracted with ethyl acetate, and saturated
After washing with aqueous sodium hydrogen chloride solution, anhydrous sodium sulfate
Dried. The solvent was distilled off under reduced pressure.
By washing with xane / ethyl acetate, 4- (2
-Benzothiazolyl) -N-hydroxy-1-piperazi
67 mg of carboxamidine were obtained. Example 40 below
In the same manner as in the above, the compound of Example 41 was obtained.

Embodiment 42  2- (4-acetimidoyl-1-piperazinyl) benne
158 mg of zothiazole dihydrochloride suspended in methylene chloride
Under turbidity, 54 μl of ethyl chloroformate, 0.2 N hydroxide
8.3 ml of thorium was added under ice cooling, and the mixture was stirred at room temperature for 6 hours.
Was. The reaction solution was extracted with chloroform, and saturated
After washing with an aqueous solution of lithium, dry over anhydrous sodium sulfate.
Dried. The solvent was distilled off under reduced pressure.
Washing with ethyl N-[(amino) [4
-(2-benzothiazolyl) -1-piperazinyl] methyl
54 mg of [len] carbamate were obtained. Example 42 and
Similarly, the compounds of Examples 43 to 48 were obtained.

Embodiment 49  Chloromethyl 4- (2-) obtained in the same manner as in Example 42.
Benzothiazolyl) -1-piperazinecarboxylate
Dissolve 0.37 g in 5 ml of dimethylformamide, and add
0.25 g of sodium acid was added and stirred at 80 ° C. for 20 hours.
Was. Add water and extract with chloroform.
Dried with calcium. The crude crystals obtained by evaporating the solvent under reduced pressure
Acetoxy washes by washing with ethyl acetate / hexane
Methyl 4- (2-benzothiazolyl) -1-piperazine
0.170 g of carboxylate was obtained.

Embodiment 50  3- (2-benzothiazolyl) octahydrate of Example 13
B-1H-pyrrolo [1,2-d] [1,4] diazepine
1.41 g of the racemic free base of L-(-)-diben
1.85 g of zoyltartaric acid treated in methanol / water
A salt was formed. This is recrystallized four times from methanol / water
After purification, saturated aqueous sodium hydrogen carbonate
Add the solution and extract with chloroform.
Dried with um. The resulting free base is converted into
(−)-3- (2-benzothiazolyl)
Octahydro-1H-pyrrolo [1,2-d] [1,4]
0.227 g of the fumarate salt of diazepine was obtained.

Embodiment 51  First two crystal mothers obtained in the purification process of Example 50
Combine the liquids, add a saturated aqueous sodium hydrogen carbonate solution,
Extract with loroform, dry over anhydrous magnesium sulfate
Was. 0.96 g of the obtained free base was added to D-(+)-diben
The same treatment as in Example 50 using 1.26 g of zoyltartaric acid
(+)-3- (2-benzothiazoly
L) octahydro-1H-pyrrolo [1,2-d] [1,
4] 0.287 g of diazepine fumarate was obtained.

[0032] The structure and physical properties of the example compounds
The results are shown in Tables 1 to 8. The symbols in the table have the following meaning. EX: Example number, Sal: salt, DATA: physical properties, mp:
Melting point, NMR: nuclear magnetic resonance spectrum (tetramethorsila
MS is mass spectrometry (FAB is fast atom
Impact method) Ac: acetyl, Bn: benzyl, cPro: cyclop
Ropyr, Et: ethyl, Me: methyl, MeO: methoxy, P
h: phenyl, Pyr: pyridyl

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

[Table 3]

[0036]

[Table 4]

[0037]

[Table 5]

[0038]

[Table 6]

[0039]

[Table 7]

[0040]

[Table 8]

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI C07D 277/82 C07D 277/82 417/04 207 417/04 207 211 211 417/06 211 417/06 211 417/12 213 417 / 12 213 317 317 487/04 140 487/04 140 152 152

Claims (2)

[Claims] 1. A 5-HT ₃ receptor agonist comprising, as an active ingredient, a benzothiazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image (The symbols in the formula represent the following meanings. A: Single bond or methylene group R ₁ : hydrogen atom, halogen, hydroxy, cyano, nitro, lower alkyl or lower alkenyl group R ₂ : hydrogen atom, lower alkyl, lower alkenyl or group of the following formula (1) -A ₁ − OR ₅ (2) -A ₁ -CO-R ₅ (3) -A ₁ -CO-OR ₆ R ₃ : hydrogen atom, cyano, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl ,
Aryl, aryl-lower alkyl, pyridyl, or a group represented by the following formula (1) -A ₁ -OR ₅ (2) -A ₁ -CO-R ₅ (3) -A ₁ -CO-OR ₆ ( _{4) -A 1 -CO-O-} A 2 -O-CO-R 5 (5) -C (NH 2) = N-A 1 -O-R 5 (6) -C (NH 2) = N- A ₁ -CO-R ₅ (7) -C (NH ₂ ) = N-A ₁ -CO-OR ₆ (8) -C (R ₇ ) = N-A ₁ -OR ₅ (9) —C (R ₇ ) = N—A ₁ —CO—R ₅ (10) —C (R ₇ ) = N—A ₁ —CO—O—R ₆ R ₄ : Integrated with hydrogen atom, lower alkyl or R ₃ R ₅ : hydrogen atom or lower alkyl group R ₆ : hydrogen atom, lower alkyl or 2-oxo-4-methyl-1,3-dioxolylmethyl Group R ₇ : hydrogen atom or lower alkyl group A ₁ : single bond or lower alkylene group A ₂ : lower alkylene group n: an integer of 1 to 4, provided that the nitrogen atom to which R ₃ group in R group is bonded is substituted. It can be a quaternary ammonium with a group. ) 2. A thiazole derivative represented by the general formula (I ′)
Or a pharmaceutically acceptable salt thereof. Embedded image(The symbols in the formula represent the following meanings.A: single bond or methylene group R₁: Hydrogen atom, halogen, hydroxy, cyano, nitro
B, lower alkyl or lower alkenyl group R₂: Hydrogen atom, lower alkyl, lower alkenyl or lower
Group of Formula (1) -A₁-OR₅ (2) -A₁-CO-R₅ (3) -A₁-CO-OR₆ R₃: Hydrogen atom, cyano, lower alkyl, lower alkenyl
Cycloalkyl, cycloalkyl-lower alkyl,
Aryl, aryl-lower alkyl, pyridyl, or lower
Group of Formula (1) -A₁-OR₅ (2) -A₁-CO-R₅ (3) -A₁-CO-OR₆ (4) -A₁-CO-OA₂-O-CO-R₅ (5) -C (NH₂) = NA₁-OR₅ (6) -C (NH₂) = NA₁-CO-R₅ (7) -C (NH₂) = NA₁-CO-OR₆ (8) -C (R₇) = NA₁-OR₅ (9) -C (R₇) = NA₁-CO-R₅ (10) -C (R₇) = NA₁-CO-OR₆ R₄: Hydrogen atom, lower alkyl or R₃Together with
R which forms a 4- to 8-membered nitrogen-containing saturated ring₅: Hydrogen atom or lower alkyl group R₆: Hydrogen atom, lower alkyl or 2-oxo-4-me
Tyl-1,3-dioxolylmethyl group R₇: Hydrogen atom or lower alkyl group A₁: Single bond or lower alkylene group A₂: Lower alkylene group n: integer from 1 to 4  In addition, R in the R group₃The nitrogen atom to which the group is attached is a substituent
And quaternary ammonium. However, 2- (1-
Piperazinyl) benzothiazole, 2- (1-homopipe
Radinyl) benzothiazole, 2- (4-methyl-1-)
Piperazinyl) benzothiazole, 2- (4-acetyl)
-1-piperazinyl) benzothiazole, 2- (4-be
Benzyl-1-piperazinyl) benzothiazole, 2-
[4- (2-hydroxyphenyl) -1-piperazini
Ru] benzothiazole, 2- [4- (2-methoxyphen)
Nyl) -1-piperazinyl] benzothiazole, 2-
[4- (2-ethoxyphenyl) -1-piperazinyl]
Benzothiazole, 2- [4- (3-chlorophenyl)
-1-piperazinyl] benzothiazole, 2- (4-pi
Peronyl-1-piperazinyl) benzothiazole, 6-
[2- [4- (2-benzothiazolyl) -1-piperazine
Nyl] ethyl] -3-methyl-2-benzothiazolino
, 6- [3- [4- (2-benzothiazolyl) -1-
Piperazinyl] propyl] -3-methyl-2-benzothi
Azolinone, 6- [4- [4- (2-benzothiazoli)
L) -1-piperazinyl] butyl] -3-methyl-2-
Benzothiazolinone, 2- (4-formyl-1-pipera)
Dinyl) benzothiazole, 2- [4- (2-bromo-
3-propenyl) -1-piperazinyl] benzothiazolate
2- [4- (2,4-dichlorobenzyl) -1-pi
Perazinyl] benzothiazole, 2- (4-pentyl-
1-piperazinyl) benzothiazole, 6-nitro-2
-(1-piperazinyl) benzothiazole, 6-methoxy
C-2- (1-piperazinyl) benzothiazole, 6-
Methoxy-2- (4-methyl-1-piperazinyl) ben
Zothiazole, 6-methoxy-2- (4-benzyl-1
-Piperazinyl) benzothiazole, [4- (2-ben
Zothiazolyl) -1-piperazinyl] acetic acid, 2- [4-
(4-Chlorophenyl) -1-piperazinyl] benzothi
Azole, 2- [4- (2-hydroxyethyl) -1-
Piperazinyl] benzothiazole, 2- [4- (2,4
-Dinitrophenyl) -1-piperazinyl] benzothia
Zol, propyl [4- (2-benzithiazolyl) -1
-Piperazinyl] carboxylate. ).