JPS6048507B2 - 2-(ω-aminoalkoxy)diphenyl sulfides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 2-(ω aminoalkoxy) diphenyl sulfides and acid addition salts thereof.

The present invention also provides 2-1 (ω-
The present invention relates to central nervous system agents, particularly antidepressants, containing aminoalkoxy)diphenyl sulfide or its derivatives or acid addition salts.

Conventionally, certain 2-(ω-aminoalkoxy)diphenyl ethers and 2-(ω-aminoalco,oxy)diphenyl sulfides are known.

(For example, pr0tivaeta1 | CA45, 57
7a (1951) T0y0shimaata1, J｜P
harm, 50c | Jap, 89 | 1417-1425
(1970) However, the compounds described in the above-mentioned documents do not have any satisfactory pharmacological activity, especially useful pharmacological activity as a central nervous system agent (antireserpine action, etc.).

The present inventors have searched for a compound that has a strong antireserpine effect and is useful as a central nervous system drug, especially an antidepressant.
The present invention was completed by discovering that novel 2-(ω-ami/alkoxy)diphenyl sulfides and acid addition salts thereof have strong anti-reserpine effects and low toxicity.

To explain the present invention in detail, the 2-
(ω-Aminoalkoxy)diphenyl sulfides are represented by the following general formula (I).

O(CH2)nR-1s,i゛・tsu,,,■■■,>: ,,,,-' (I) In the above general formula (I), R is an amino group, C, ~ C, alkylamino group, C2-C6 dialkylamino group, morpholino group, 1-piperidyl group or 4-methyl-1-piperidinyl group, and n represents an integer of 3, 4 or 5.

Furthermore, as a preferable compound of the present invention, the above general formula (
In I), when n is 3, R is an alkylamino group of C1-3),
When n is 4), R is an amino group, a C1-C5 alkylamino group; a C2-C6 dialkylamino group or a morpholino group; and when n is 5, R is a C2-C55) dialkylamino group or morpholino group. The compound 7 is mentioned.

Next, specific examples of the compounds of the present invention will be given.

2-(3-Methylaminopropoxy) diphenyl sulfide 2-(3-dimethylaminopropoxy) diphenyl sulfide 2-(4-aminobutoxy) diphenyl sulfide 2-(4-methylaminobutoxy) diphenyl'L sulfide 2-(4 -dimethylaminobutoxy) diphenyl sulfide 2-(4-morpholinobutoxy) diphenyl sulfide'(2-[4-(4-methyl-1-piperazinyl)butoxy] diphenyl sulfide 2
-(5-Methylaminopentyloxy) diphenyl sulfide 2-(5-dimethylaminopentyloxy) diphenyl sulfide 2-[5-(1-piperidyl)pentyloxy] diphenyl sulfide Among the above compounds, the following have antireserpine activity. is more useful as a central nervous system drug.

2-(3-Methylaminopropoxy) diphenyl sulfide 2-(4-aminobutoxy) diphenyl sulfide 2-(4-methylaminobutoxy) diphenyl sulfide 2-(4-dimethylaminobutoxy) diphenyl sulfide 2-(4-morpholinobutoxy) ) diphenyl sulfide) 2-(5-dimethylaminopentyloxy)
Diphenylsulfide and pharmaceutically acceptable acid addition salts of the above compounds are also included within the scope of this invention.

2(ω-aminoalkoxy)diphenylsulfuric acid (i) according to claim 3, wherein the acid addition salt is represented by hydrochloric acid or hydrogen bromide.

6. 2-(ω aminoalkoxy) diphenyl sulfides according to claim 3, which are represented by the following formula.

7. 2-(ω-aminoalkoxy)diphenyl sulfides according to claim 3, which are represented by the following formula.

8 2-(ω-aminoalkoxy)diphenyl sulfides according to claim 3, represented by the following formula 9 2-(ω-) according to claim 3, represented by the following formula
aminoalkoxy) diphenyl sulfides.

10 The following general formula (I) (In the above general formula (I), R is an amino group, a C, to C5 alkylamino group, a C2 to C6 dialkylamino group,
A morpholino group represents a 1-piperidyl group or a 4-methyl-1-piperazinyl group, and n represents an integer of '03, 4 or 5.

) or an acid addition salt thereof. 11 In the central nervous system agent according to claim 10, when n is 3, R is a C, to C5 alkyl penta-amino group, and when n is 4, R is an amino group, a C1 to C5 alkyl group. 2-(ω-
A central nervous system drug containing diphphenylsulfide (aminoalkoxy) or an acid addition salt thereof.

12 Claim 1 in which the central nervous system drug is an antidepressant
The agent for the central nervous system according to item 0 or item 11.

13 The following general formula (■) (In the above general formula (■), X represents a halogen atom,
n represents an integer of 3, 4 or 5.

) and 2-(ω-halogenalkoxy)diphenyl sulfides represented by the following general formula (■) R -H (■) (In the above general formula (■), R is an amino group, C, to C5 alkylamino group, a C2-C6 dialkylamino group,
Morpholino group, 1-piperidyl group or 4-methyl61-
Represents a piperazinyl group.

) (In the above general formula (I), R is as defined in the above general formula (■), and n is 3,
Represents an integer of 4 or 5.

) A method for producing 2-(ω aminoalkoxy) diphenyl sulfides or acid addition salts.

5 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 2-(ω aminoalkoxy) diphenyl sulfides and acid addition salts thereof.

The present invention also provides 2-IC (ω
-Aminoalkoxy)diphenyl sulfide or its derivatives or acid addition salts.

Conventionally, certain 2-(ω-aminoalkoxy)diphenyl ethers and 2-(ω-aminoalkoxy)diphenyl sulfides are known.

(For example, PrOtivaetal, CA45,57
7a (1951) TOyOshimaatal, J, P
harm, SOc, Jap. 89,l4l7~1425
(1970) However, none of the compounds described in the above document are 2. None of these drugs has satisfactory pharmacological activity, especially useful pharmacological activity as a central nervous system agent (antireserpine effect, etc.).

The present inventors have searched for a compound that has a strong antireserpine effect and is useful as a central nervous system drug, especially an antidepressant.
The present invention was completed by discovering that novel 2-(ω-aminoalkoxy)diphenyl sulfides and their acid addition salts have strong anti-reserpine effects and low toxicity.

To explain the present invention in detail, the compound of the present invention. Ru2-
(ω-Aminoalkoxy)diphenyl sulfides are represented by the following general formula (I).

In the above general formula (I), R represents an amino group, a C, to C, alkylamino group, a C2 to C6 dialkylamino group, a morpholino group, a 1-piperidyl group, or a 4-methyl-1-piperidinyl group, and n is Represents an integer of 3, 4 or 5. Furthermore, preferred compounds of the present invention include, in the above general formula (I), when n is 3, R is an alkylamino group of C, ~, and when n is 4, R is an amino group;
a C1-C5 alkylamino; a C2-C6 dialkylamino group or a morpholy group; and when n is 5, R is C;

~C5) Compound 7 which is a dialkylamino group or a morpholino group can be mentioned. Next, specific examples of the compounds of the present invention will be given.

2-(3-Methylaminopropoxy) diphenyl sulfide 2-(3-dimethylaminopropoxy) diphenyl sulfide 2-(4-aminobutoxy) diphenyl sulfide 2-(4-methylaminobutoxy) diphenyl sulfide 2-(4-dimethylamino butoxy) diphenyl sulfide 2-(4-morpholinobutoxy) diphenyl sulfide 2-[4-(4-methyl-1-piperazinyl)butoxy] diphenyl sulfide 2-(5-methylaminopentyloxy) diphenyl sulfide 2-(5-dimethylamino Pentyloxy) diphenyl sulfide 2-[5-(1-piperidyl) pentyloxy] diphenyl sulfide Among the above compounds, the following compounds have a strong anti-reserpine effect and are more useful as agents for the central nervous system.

2-(3-Methylaminopropoxy) diphenyl sulfide 2-(4-aminobutoxy) diphenyl sulfide 2-(4-methylaminobutoxy) diphenyl sulfide 2-(4-dimethylaminobutoxy)
Diphenylsulfide 2-(4-morpholinobutoxy)diphenylsulfide 2-(5-dimethylaminopentyloxy)diphenylsulfide Also included within the scope of the present invention are pharmaceutically acceptable acid addition salts of the above compounds.

The above acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, maleic acid, taenoic acid, benzoic acid, toluenesulfonic acid, and methane acid. Examples include acid addition salts such as sulfonic acid.

Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention, 2-(ω-aminoalcooxy)diphenyl sulfide (I), has the following general formula (■) (in the above formula, X represents a halogen atom, and n represents an integer of 3, 4, or 5. represent.

) and 2-(ω-halogenoalkoxy)diphenyl sulfide represented by the following general formula (■)R-H (■) (In the above formula, R is as defined in the above general formula (I).

) can be produced by reacting with aminos represented by

To explain the above manufacturing method in detail, 2-
(ω-halogenoalkoxy) diphenyl sulfide (formerly 2-hydroxydiphenyl sulfide, 1,3-dihalogenopropane, 1,4-dihalogenobutane, 1,5-
It is obtained by reacting dihalogenopentane etc. in the presence of an alkali.

Another raw material, aminos, is represented by the above general formula (■), specifically ammonia; methylamine, ethylamine, sopropylamine! Secondary amines such as dimethylamine, diethylamine, N-methyl-N-ethylamine, etc.; piperidine, morpholine, 4-methylpiperazine, morpholine, 4-methylpiperazine, etc. are used. 3 Aminos (■) consumed in the above reaction are 1 mole of 2-(ω-halogenoalkoxy)diphenyl sulfide.
It is a mole.

The reaction rate can be further increased by using an excess of aminos. Usually, the amount of aminos is 1 to 1 per mole of 2-(ω-halogenoalco4(xy)diphenyl sulfide.
00 moles are used. Although the reaction proceeds satisfactorily even without 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, or a mixture of two or more of these solvents is used. The reaction temperature is not particularly limited, but is usually from room temperature to 5150°C.

The reaction time varies depending on the reaction temperature and the reactivity of the raw materials, but is usually in the range of 1 minute to 4 hours.

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 Ξ-class amines such as pyridine and triethylamine are used. The amount of the base used is usually 1 to 5 moles per mole of 2-(ω-halogenoalkoxy)diphenylsulfide 5. When the above-mentioned bases are not added, the 2-(aminoalkoxy)diphenyl sulfide further reacts with the hydrogen halide produced in the reaction and changes into its acid addition salt.

In order to obtain a desired acid addition salt, excess aminos and solvent are distilled off, and a strong base aqueous solution such as sodium hydroxide or potassium hydroxide is added to carry out the acid addition of 2-(ω-aminoalkoxy)diphenyl sulfide. The salts are converted into free 2-(ω aminoalkoxy) diphenyl sulfides, which are extracted with a solvent such as ether, chloroform, or benzene.
When further neutralized by adding a desired acid, the desired 2-
Acid addition salts of (ω-aminoalkoxy) diphenyl sulfides can be obtained. The 2-(ω-aminoalkoxy)diphenyl sulfides and acid addition salts thereof obtained by the above reaction are purified by recrystallization using a suitable solvent such as alcohol-ether.

Next, the compound of the present invention, 2-(ω-aminoalkoxy)
The pharmacological effects of diphenyl sulfides and their acid addition salts will be explained.

2-(ω-aminoalkoxy)diphenyl sulfides and their acid addition salts are used as central nervous system agents,
In particular, it has interesting activities such as antireserpine action and anticonvulsant action, which are unique to antidepressants.

Pharmacological tests were conducted using Ddy male mice regarding the following various effects.

The anti-reserpine effect is due to reserpine (5m9/K9i.p.
) was judged from the antagonism to the decrease in body temperature.

(P.S.J. Spencerin"Antidep
resientDru 倭”S.GaraUniand
M. N. G. Duhes, ed. ,ExcerptaM
edicaFOundatiOn, Amsterdam
, p. l94-204 (1967) LD5O is Litc
It was determined by the hfield-WilcOxOn method.

The central depressant effect was judged by examining the muscle relaxant effect and the amount of spontaneous movement. (S.CourvOisier, R.Ducr.
Ot, L. JulOu; ″PsychOtrOpic
-Drugs”Ed. by S. Garattini, V
．． Ghetti, P. 373, (1957)) Locomotor activity was measured with an ANIMEX device. Antagonistic convulsive effects were determined from the presence or absence of antagonism to tonic convulsions produced by applying electric shock to mice. (L.S.
COOdman, M. SinghGrewal, W. C
．． BrOwnandE. A. Swinyard, J. P
hArmacOl, Exptal. Therap. ,l
O&168 (1953)) Anti-tremolin effect was determined from the strength of suppression of tremor caused by administration of tremolin.
(G.M. Everett, L.E. BlOcusa
ndJ. M. Sheppard, Science 24
, 79 (1956) The results are shown in Tables 1 and 2.

For comparison, the pharmacological effects of amitriptyline, a known antidepressant, will also be described. ED.

O indicates the dose that inhibits each response by 50%. Table 1 shows that each test compound has an anti-reserpine effect and is less toxic than amitoptyline.

From Table 2 above, 2-(4-methylaminobutoxy)
Diphenylsulfide/hydrochloride's antitremolin effect, which is a muscle relaxant or central anticholinergic effect, is considerably weaker than that of amitriptyline, and the above-mentioned 2-(4-methylaminobutoxy) diphenyl sulfide is less effective than amitriptyline in terms of safety and side effects. It is considered to be superior. Compounds of the invention that have the effect of alleviating depression in warm-blooded animals can be administered in any manner.

That is, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or oral administration is also possible.

The dosage is determined depending on the patient's age, health condition, weight, degree of depression, type of concurrent treatment, if any, frequency of treatment, nature of desired effect, etc.

Generally, the daily dose of active ingredients is 0.5-50m9/K
9 body weight, usually 1-30 m9/K9 body weight, and is administered in one or more doses. When the compound of the present invention is administered orally, it is used in the form of a tablet, capsule, powder, liquid, elixir, etc., and when administered parenterally, it is used in a sterile 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 5-95%, preferably 25-90% by weight of active ingredient.

Thus, these dosage forms should contain between 5 and 500 mg of active ingredient, preferably between 25 and 250 mg.

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. In general, 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, usually 0. 5-20%,
Preferably it contains 1-10% by weight of the 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. Next, the production method of the present invention will be specifically explained in Examples, but the compounds included in the present invention are limited to the compounds synthesized according to the following Examples unless they go beyond the gist of the present invention. isn't it.

Example 1 2-(4-promobutoxy)diphenyl sulfide 5
．． 0g to 100ml of ethanol. Dissolved in L and 40% dimethylamine aqueous solution.

After standing at room temperature for 8 hours, ethanol and excess dimethylamine were distilled off under reduced pressure. Aqueous sodium hydroxide solution was added to the reaction product, and the mixture was extracted with ether.

Ether is distilled off, monohydrochloric acid is added, and the solvent is distilled off under reduced pressure to obtain 2-(4-dimethylaminobutoxy)diphenyl sulfide hydrochloride. Ethanol recrystallizes into ether. Yield 4.6g (91% yield), melting point 140~
146°C elemental analysis: C, 8H23NOS. CHN as HCe Example 2 2-(3-bromopropoxy)diphenyl sulfide 0
．． 5 g and 6 g of methylamine were dissolved in 100 ml of ethanol and reacted in a sealed tube at 50° C. for 2 hours.

Ethanol and excess methylamine were distilled off under reduced pressure, and 2N-
Sodium hydroxide is added and the reaction product is extracted with ether. Dry hydrogen chloride gas is blown into the ether solution, and the precipitate is collected by filtration. Reconsolidation from ethanol ether yields 2-(3-methylaminopropoxy)diphenyl sulfide. Obtain crystals of hydrochloride. Yield 4.1g (yield 86%), melting point 99-102'C Elemental analysis: C, 6H,
9NOS. Various 2-(ω-aminoalkoxy)diphenyl sulfides were synthesized as HCI according to the above examples.

Claims (1)

[Claims] 1 The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (I) (In the above general formula (I), R is an amino group, an alkylamino group of C_1 to C_5, C_2 ~C_6 dialkylamino group,
Morpholino group, 1-piperidyl group or 4-methyl-1-
It represents a piperazinyl group, and n represents an integer of 3, 4 or 5. ) 2-(ω-Aminoalkoxy)diphenyl sulfides or acid addition salts thereof. 2 In the 2-(ω-aminoalkoxy)diphenyl sulfides described in claim 1, when n is 3, R is C_1 to C_
5 alkylamino group, and when n is 4, R is an amino group, C_1 to C_5 alkylamino group, C_2 to C_
6 dialkylamino group or morpholino group, and when n is 5, R is a C_2 to C_6 dialkylamino group or morpholino group. 2-(ω-aminoalkoxy) diphenyl sulfides. 3 In the 2-(ω-aminoalkoxy) diphenyl sulfides described in claim 2, the alkylamino group is a methylamino group and the dialkylamino group is a dimethylamino group.
Diphenylsulfides. 4 2-(ω-Aminoalkoxy) diphenyl sulfides according to claim 3, which are represented by the following formula ▲ Numerical formulas, chemical formulas, tables, etc. are available. 5 2-(ω-Aminoalkoxy) diphenyl sulfides according to claim 3, which are represented by the following formula ▲ Numerical formulas, chemical formulas, tables, etc. are available. 6 2-(ω-aminoalkoxy) diphenyl sulfides according to claim 3, which are represented by the following formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼. 7. 2-(ω-aminoalkoxy) diphenyl sulfides according to claim 3, which are represented by the following formula ▲ Numerical formulas, chemical formulas, tables, etc. are available. 8 2-(ω-Aminoalkoxy)diphenyl sulfides according to claim 3, represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. 9 The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 2-(ω-aminoalkoxy)diphenyl sulfides according to claim 3. 10 The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above general formula (I), R is an amino group, an alkylamino group from C_1 to C_5, and a dialkylamino group from C_2 to C_6. ,
A morpholino group represents a 1-piperidyl group or a 4-methyl-1-piperazinyl group, and n represents an integer of 3, 4 or 5. ) or an acid addition salt thereof. 11. In the agent for the central nervous system according to claim 10, when n is 3, R is an alkylamino group of C_1 to C_5, and when n is 4, R is an amino group, C_1 to
2-(ω-aminoalkoxy)diphenyl sulfides or A central nervous system drug containing its acid addition salt. 12. The central nervous system agent according to claim 10 or 11, wherein the central nervous system agent is an antidepressant. 13 The following general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the above general formula (II), X represents a halogen atom, and n represents an integer of 3, 4, or 5.) 2-(ω-halogenalkoxy) diphenyl sulfides represented by the following general formula (III) R-H (III) (In the above general formula (III), R is an amino group, C_1 to C
It represents an alkylamino group of _5, a dialkylamino group of C_2 to C_6, a morpholino group, a 1-piperidyl group, or a 4-methyl61-piperazinyl group. ) The following general formula (I) is characterized by reacting with an amino compound represented by
III), where n represents an integer of 3, 4 or 5. ) A method for producing 2-(ω aminoalkoxy) diphenyl sulfides or acid addition salts.