JPS647995B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ω-aminoalkoxybenzoylthiophenes and acid addition salts thereof. More specifically, the present invention relates to ω-aminoalkoxybenzoylthiophenes having anxiolytic or sedative effects and acid addition salts thereof. The compound of the present invention has the following general formula () It is indicated by. In the general formula (), n represents an integer of 2 to 5, and R represents the group shown below. [Formula] In the above formula, R ¹ and R ² each represent a hydrogen atom or a C ₁ to C ₃ alkyl group. Specific examples include an amino group, a dimethylamino group, a methylamino group, a dipropylamino group, and the like. [Formula] In the above formula, m represents an integer of 4 or 5, and the heterocyclic group may be substituted with one or both of a phenyl group and a hydroxyl group, which may be substituted with a halogen atom. Specifically, pyrrolidinyl group, piperidino group, 4-phenylpiperidino group, 3-hydroxy-1-pyrrolidinyl group, 4-phenyl-4-hydroxypiperidino group, 4-(4-chlorophenyl)piperidino group, 3-phenyl-1-pyrrolidinyl group, 4-
(4-chlorophenyl)-4-hydroxypiperidino group and the like. [Formula] In the above formula, R ³ represents an alkyl group which may be substituted with a hydroxyl group or a phenyl group which may be substituted with a halogen atom. Specifically, 4-methyl-1-piperazinyl group, 4-ethyl-1-piperazinyl group, 4-(β-hydroxyethyl)-1-piperazinyl group, 4-phenyl-1-piperazinyl group, 4-(4- fluorophenyl)-1-piperazinyl group, 4-(4-
chlorophenyl)-1-piperazinyl group, 4-
(3-chlorophenyl)-1-piperazinyl group and the like. Specific examples of the compounds of the present invention include the following compounds. 2-{2-(4-methylaminobutoxy)benzoyl}thiophene 2-{2-(4-ethylaminobutoxy)benzoyl}thiophene 2-{2-(4-dimethylaminobutoxy)benzoyl}thiophene 2-{2- (4-diethylaminobutoxy)benzoyl}thiophene 2-{2-(4-dipropylaminobutoxy)benzoyl}thiophene 2-{2-[4-(1-pyrrolidinyl)butoxy]
Benzoyl}thiophene 2-{2-(4-piperidinobutoxy)benzoyl}thiophene 2-{2-[4-(4-phenyl-4-hydroxypiperidino)butoxy]benzoyl}thiophene 2-{2-{ 4-[4-(4-chlorophenyl)-
4-Hydroxypiperidino]butoxy}benzoyl}thiophene 2-{2-[4-(4-phenyl-1-piperazinyl)butoxy]benzoyl}thiophene 2-{2-{4-[4-(4-chlorophenyl) −
1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(3-chlorophenyl)-
1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(2-chlorophenyl)-
1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(4-fluorophenyl)
-1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(3-fluorophenyl)
-1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(2-fluorophenyl)
-1-Piperazinyl]butoxy}benzoyl)thiophene 2-{2-[4-(4-methyl-1-piperazinyl)butoxy]benzoyl}thiophene 2-{2-[4-(4-ethyl-1-piperazinyl)butoxy [benzoyl}thiophene 2-{2-(2-methylaminoethoxy)benzoyl}thiophene 2-{2-(2-dimethylaminoethoxy)benzoyl}thiophene 2-{2-(2-diethylaminoethoxy)benzoyl}thiophene 2- {2-[2-(1-pyrrolidinyl)ethoxy]
Benzoyl}thiophene 2-{2-(2-piperidinoethoxy)benzoyl}thiophene 2-{2-[2-(4-phenyl-4-hydroxypiperidino)ethoxy]benzoyl}thiophene 2-{2-{ 2-[4-(4-chlorophenyl)-
4-Hydroxypiperidino]ethoxy}benzoyl}thiophene 2-{2-[2-(4-phenyl-1-piperazinyl)ethoxy]benzoyl}thiophene 2-{2-[2-(4-methyl-1-piperazinyl) ) Ethoxy]benzoyl}thiophene 2-{2-(5-methylaminopentyloxy)
Benzoyl}thiophene 2-{2-(5-dimethylaminopentyloxy)benzoyl}thiophene 2-{2-(5-diethylaminopentyloxy)benzoyl}thiophene 2-{2-[5-(1-pyrrolidinyl)pentyloxy] Benzoyl}thiophene 2-{2-(5-piperidinopentyloxy)benzoyl}thiophene 2-{2-[5-(4-phenyl-4-hydroxypiperidino)pentyloxy]benzoyl}thiophene 2-{2 -{5-[4-(4-chlorophenyl)-
4-Hydroxypiperidino]pentyloxy}benzoyl}thiophene 2-{2-[5-(4-phenyl-1-piperazinyl)pentyloxy]benzoyl}thiophene 2-{2-{5-[4-(4- Chlorophenyl-1
-piperazinyl]pentyloxy}benzoyl}
Thiophene 2-{2-{5-[4-(3-fluorophenyl)
-1-piperazinyl]pentyloxy}benzoyl}thiophene 2-{2-[5-(4-methylpiperazinyl)-1
-Pentyloxy]benzoyl}thiophene 2-{2-(3-methylaminopropoxy)benzoyl}thiophene 2-{2-(3-ethylaminopropoxy)benzoyl}thiophene 2-{2-(3-dimethylaminopropoxy)benzoyl }thiophene 2-{2-(3-diethylaminopropoxy)benzoyl}thiophene 2-{2-(3-dipropylaminopropoxy)
Benzoyl}thiophene 2-{2-[3-(1-pyrrolidinyl)propoxy]benzoyl}thiophene 2-{2-(3-piperidinopropoxy)benzoyl}thiophene 2-{2-[3-(4-phenyl- 4-Hydroxypiperidino)propoxy]benzoyl}thiophene 2-{2-{3-[4-(4-chlorophenyl)-
4-Hydroxypiperidino]propoxy}benzoyl}thiophene 2-{2-[3-(4-phenyl-1-piperazinyl)propoxy]benzoyl}thiophene 2-{2-{3-[4-(4-chlorophenyl) −
1-piperazinyl]propoxy}benzoyl}thiophene 2-{2-{3-[4-(3-chlorophenyl)-
1-piperazinyl]propoxy}benzoyl}thiophene 2-{2-{3-[4-(2-chlorophenyl)-
1-piperazinyl]propoxy}benzoyl}thiophene 2-{2-{3-[4-(4-fluorophenyl)
-1-piperazinyl]propoxy}benzoyl}
Thiophene 2-{2-{3-[4-(3-fluorophenyl)
-1-piperazinyl]propoxy}benzoyl}
Thiophene 2-{2-{3-[4-(2-fluorophenyl)
-1-piperazinyl)propoxybenzoyl}thiophene 2-{2-[3-(4-methyl-1-piperazinyl)propoxy]benzoyl}thiophene 2-{2-[3-(4-ethyl-1-piperazinyl)propoxy] benzoyl}thiophene 2-
{2-[3-(4-β-hydroxyethyl-1-piperazinyl)propoxy]benzoyl}thiophene 2-{2-[3-(4-propyl-1-piperazinyl)propoxy]benzoyl}thiophene In addition, the above compounds Pharmaceutically acceptable acid addition salts are also included within the scope of this invention. Acid addition salts of the above include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, succinic acid, adipic acid, propionic acid, tartaric acid, maleic acid, citric acid, benzoic acid, toluenesulfonic acid, Examples include acid addition salts such as methanesulfonic acid. Next, a method for producing the compound of the present invention will be explained. The ω-aminoalkoxybenzoylthiophenes of the compounds of the present invention have the following general formula () (In the above formula, X represents a halogen atom, and n has the same meaning as n in the general formula ().)
- Manufactured by reacting halogenoalkoxybenzoylthiophenes with amines represented by the following general formula () R-H ... () (In the above formula, R has the same meaning as R in the general formula ()) . To explain the above production method in detail, one of the raw materials, ω-halogenoalkoxybenzoylthiophenes (), is 2-(ω-halogenoalkoxy).
It is obtained by Friedel-Crafts reaction between benzoyl chloride and thiophene under a tin tetrachloride catalyst. (Organic Synthesis Collective Volume (OS colle., 2 , p. 8) The amount of amines () consumed in the above reaction is 1 mole per 1 mole of ω-halogenoalkoxybenzoylthiophene. The reaction rate can be further increased if
The amine is used in an amount of 1 to 100 mol per mol of the ω-halogenoalkoxybenzoylthiophene. Although the reaction proceeds satisfactorily even in the absence of a solvent, an inert solvent may be used to carry out the reaction in a homogeneous system. As the solvent, water, dioxane, tetrahydrofuran, dimethyl sulfoxide, lower alcohol, dimethylformamide, or a mixture of two or more of these solvents is used. The reaction temperature is not particularly limited, but usually ranges from room temperature to
The temperature is 150℃. The reaction time varies depending on the reaction temperature and the reactivity of the raw materials, but is usually 40 hours or less. Furthermore, bases may be added in order to collect hydrogen halide generated by the reaction and accelerate the reaction. As the bases, inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate, and tertiary amines such as pyridine and triethylamine are used. The amount of bases used is ω
-halogenoalkoxybenzoylthiophenes 1
It is usually 1 to 5 moles per mole. When the above-mentioned bases are not added, the ω-aminoalkoxybenzoylthiophenes further react with the hydrogen halide produced in the reaction and change into acid addition salts thereof. To obtain the desired acid addition salt, excess amines and solvent are distilled off, and a strong aqueous base such as sodium hydroxide or potassium hydroxide is added to free the acid addition salt of ω-aminoalkoxybenzoylthiophene. The ω-aminoalkoxybenzoylthiophenes are extracted with a solvent such as ether, chloroform, or benzene. Further, by neutralizing by adding a desired acid, the desired acid addition salt of ω-aminoalkoxybenzoylthiophene can be obtained. The ω-aminoalkoxybenzoylthiophenes and acid addition salts thereof obtained by the above reaction are purified by recrystallization using a suitable solvent such as alcohol-ether. The compounds of the present invention have anxiolytic or sedative effects. In the compound represented by the general formula (), R
When is [Formula] and the multi-ring group has a substituent, especially the following formula () (In the above formula, R ⁴ represents a phenyl group which may be substituted with a halogen atom.) A substituted piperidino group represented by the following is preferred. Preferred compounds having anxiolytic or sedative effects include the following compounds. 2-{2-(3-dimethylaminopropoxy)benzoyl}thiophene 2-{2-(3-diethylaminopropoxy)benzoyl}thiophene 2-{2-[3-(1-pyrrolidinyl)propoxy]benzoyl}thiophene 2-{ 2-(3-piperidinopropoxy)benzoyl}thiophene 2-{2-[3-(4-phenyl-4-hydroxypiperidino)propoxy]benzoyl}thiophene 2-{3-{4-[4-( 4-chlorophenyl)-
4-Hydroxypiperidino]propoxy}benzoyl}thiophene 2-{2-[3-(4-phenyl-1-piperazinyl)propoxy]benzoyl}thiophene 2-{3-[4-(4-chlorophenyl)-1- Piperazinyl]propoxy}benzoyl}thiophene 2-{2-{3-[4-(4-fluorophenyl)
-1-piperazinyl]propoxy}benzoyl}
Thiophene The pharmacological effects of the compound of the present invention are shown below. The anxiolytic effects of the compounds of the present invention were examined using the following method. Meprobamate, known as an anxiolytic drug, was used as a control drug. The results are 50% effective dose (ED ₅₀ , mg/
It is shown in Table 1 as Kg po). The animals used were ddy male mice (20-22 g).
Anti-fighting effect and anti-morphine as indicators of anxiolytic effect
The effect was investigated. In other words, the anti-fighting effect is
Developed by applying a 28VDC, 4-5mA, 3 minute electric shock to the foot via the grid.
The suppressive effect on fighting (taming effect) was investigated (RETedeschi,
DHTedeschi, A. Mucha, L. Cook, P.A.
Mattis, E.J.Fellows., Journal of Pharmacology and Experimental Therapy (J.Pharmacol.exp.Therap.),
125, 28 (1959)). The anti-morphine effect was measured by the inhibitory effect on the tail-raising reaction caused by administering morphine 20mg/Kgi.p. according to the method of Takagi et al. Journal, 66 , 107 (1970).
As shown in Table 1, the compounds of the present invention exhibited anxiolytic effects superior to meprobamate. [Table] Although the compound of the present invention can be administered by any method, the following method is preferably carried out. That is, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, and intraperitoneal injection, as well as oral administration are possible. The dosage is determined depending on the patient's age, health condition, weight, type of concurrent treatment, if any, frequency of treatment, nature of desired effect, etc. Generally, the daily dose of the active ingredient is 0.5-50mg/
Kg body weight, usually 1-30 mg/Kg body weight, administered in one or more doses. When the compound of the present invention is administered orally, it is in the form of tablets, capsules, powders, liquids, elixirs, etc.
In the case of parenteral administration, it is used in a sterilized liquid form such as a liquid or suspension. When used in such forms, solid or liquid non-toxic pharmaceutical carriers can be included in the composition. As an example of a solid carrier, conventional gelatin type capsules are used. The active ingredient may also be packaged as a tablet or powder, with or without adjuvants. These capsules, tablets, and powders generally contain 5 to
Contains 95% by weight of active ingredient, preferably 25-90%. That is, these dosage forms should contain 5 to 500 mg, preferably 25 to 250 mg of active ingredient. As the liquid carrier, water or oils of animal or plant origin or synthetic oils such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, etc. are used. Generally, physiological saline, dextrose or similar sucrose solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as liquid carriers, and in particular, in the case of injections using physiological saline, a suitable amount of 0.5
~20%, preferably 1-10% by weight of active ingredient. In the case of liquid preparations for oral administration, suspensions or syrups containing 0.5 to 10% by weight of the active ingredient are preferred. In this case, aqueous excipients such as fragrances, syrups, and pharmaceutical micelles are used as carriers. As explained above, the compounds of the present invention have excellent anxiolytic effects and can be effectively used as sedatives. Example (1) 2-{2-(3-chloropropoxy)benzoyl}thiophene Thiophene (7 g) and 2-(3-chloropropoxy)benzoyl chloride (boiling point 125-
8°/1 mmHg) (19.4 g) was dissolved in benzene (80 ml), and a solution of tin tetrachloride (21.7 g) in benzene (20 ml) was added dropwise while cooling. After completion of dripping, 1.5
The mixture was stirred under cooling for 1 hour, and then stirred for 1 hour at room temperature. After the reaction is complete, add 1N hydrochloric acid (100ml),
Extract with ether. The organic layer was diluted with water and 1N−
After washing with NaOH and drying with anhydrous sodium sulfate,
The solvent was distilled off, and the residue was separated by silica gel column chromatography (eluent: benzene).
Oily 2-{2-(3-chloropropoxy)benzoyl}thiophene (15 g) was obtained (yield 64
%). This was subjected to the next amination reaction. (2) 2-{2-[3-(4-phenyl-1-piperazinyl)propoxy]benzoyl}thiophene Dissolve 2-{2-(3-chloropropoxy)benzoyl}thiophene (2.0 g) in DMF (10 ml). Then, N-phenylpiperazine (1.25 g) and triethylamine (1.4 g) were added, and the mixture was heated at 50°C.
Stir for 17 hours. After the reaction is completed, 2N aqueous sodium hydroxide solution is added, extracted with ether, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in ether, and 20% hydrogen chloride/ethanol was added to crystallize it. 4-phenyl-1-piperazinyl)propoxy]benzoyl}thiophene hydrochloride is obtained. Yield: 2.9 g (yield 85%) Physical properties are shown in column No. 6 of Table-2. Other compounds were synthesized in a similar manner and are shown in Table 2. 【table】

Claims (1)

[Claims] 1. The following general formula {The above general formula n represents an integer of 2 to 5, and R represents [formula] (in the formula, R ¹ and R ² each represent a hydrogen atom or a C ₁ to C ₃ alkyl group), [formula] (formula m represents an integer of 4 or 5, and the heterocyclic group may be substituted with a phenyl group and/or a hydroxyl group which may be substituted with a halogen atom.) or [Formula] (in the formula R ³ represents an alkyl group optionally substituted with a hydroxyl group or a phenyl group optionally substituted with a halogen atom.)} ω-aminoalkoxybenzoylthiophenes and acid addition salts thereof.