JPS6323969B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a new pharmaceutical use of 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole. Conventionally, the following formula In the _formula , X is sulfur or imino; n is ₁ or _{2 ;} fluoromethyl or hydroxy, A is a 5-membered heterocyclic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur and having two adjacent carbon atoms in common with the benzene ring; However, the nucleus is benzo-2,1,
other than 3-thiadiazole, and R ₂ and R ₃ are substituents that can be present in ring A, where R ₂ is bonded to a carbon atom of the ring and hydrogen, halogen, alkyl (C _{1- 4} ), alkoxy (C _1-4 ),
alkylthio (C _1-4 ), trifluoromethyl or hydroxy, and R ₃ is bonded to the nitrogen atom of the ring and is hydrogen or alkyl (C _1-4 ), with the proviso that A is [c]pyrrole. , the nitrogen atom of A is substituted with alkyl (C _1-4 ), and the compound of formula ′ (in the formula) R′ is the formula Here, each of R ₁ ′, R ₂ ′ and R ₃ ′ independently represents hydrogen, halogen, alkyl (C _1-4 ), alkoxy (C _1-4 ), nitro, cyano, hydroxy or alkylthio (C _{1 -4} ) and is a group of or ) R′ is the formula where each of A and B is =CH-, or one of A and B is =CH-, and the other of A and B is =N-,
Y ₁ and Y ₂ are independently hydrogen, halogen, alkyl (C _1-4 ), alkoxy (C _1-4 ), nitro, trifluoromethyl, cyano, hydroxy or alkylthio (C _1-4 ); and Y ₃ is hydrogen, alkyl (C _1-4 ) or alkoxy (C _1-4 ), is a group of , compounds of are known. Compounds of the formula are generally known, for example from DE 2800062, DE 2653005 and DE 2416024. These compounds are said to have various pharmacological activities, such as muscle relaxant activity. Compounds of formula ', where R' is a radical of formula, are also generally known. They are US patents
3843668 and DE 2636309 and is said to be useful as an anticonvulsant and an antirigor. Compounds of formula ', where R' is a group of formula, are generally known, for example from British Patent Specification 1381979, and are said to be active as antihypertensive agents. Now, unexpectedly, formula I and '
It has been found that the said compounds exhibit tranquilizing and sedative activity, for example for the treatment of neuroses. Therefore, according to the present invention, 5-chloro-
4-12-imidazolin-2-yl-amino)-
Tranquilizing and sedative compositions containing 2,1,3-benzothiadiazole are provided. The tranquilizing and sedative activity of the above compounds has been demonstrated in clinical trials and standard animal experiments. For example, in a double-blind clinical trial, 5-chloro-4-(2-imidazoline-2
Hypochondriasis and psychosomatic disorders with 2,1,3-amino)-2,1,3-benzothiadiazole in unit dosage form at a daily dose of 3 mg three times a day and 6 mg/day for 14 days. Significant tranquilizing effects were observed when administered orally to patients suffering from neurosis. This result is before the test.
3rd, 6th, 10th and 14th day of treatment
It corresponded to Mehnert's 20 symptom scale on day 1. The psycholeptic activity of the above compounds is confirmed in standard animal tests. That is, these compounds suppress activity as demonstrated in mice. In one study, two groups (one group was a control group) of 4 mice each were dosed with 0.01 mg/Kg to 0.1 mg/Kg.
Kg of test compound was administered orally and an electronic cage (Motron-Productor, Stockholm, Sweden) illuminated with red light was used.
Motility Testing). The number of times the mouse interrupts the light beam is counted alectronically every 15 minutes over a 60 minute period. Additionally, these compounds reduce defensive dual tendency behavior (a form of circular behavior) and increase social contact in standard animal induction studies. In one study, male mice administered 0.1-1 mg/Kgp.o. (orally) of compound were placed in an isolated, aggressive male mouse home cage (tome cdge).
for 6 minutes. The behavior of the introduced mice was then evaluated by AKDixon and JHMackintosh, Anim.
Behav. 19 , 138–140 (1971), “Das
Tier im Experiment”, edited by W. Weihe, Hans
Huber Verlag, Bern, 1978, AK in
Dixon “Rodent Social Behavior in Relation
to Biomedical Research”, such as non-social activity, social snobbery and mating, aggression, defensive duality, escape or retreat, and feeding behavior. In addition, H. Kleinlogel et al., Huropean J.
An increase in naps is observed when rats are administered 0.3-3 mg/Kgp.o. of the compound in a sleep/wake cycle carried out according to the principles of Pharmacol. 33 , 159-163 (1975). EEG was recorded over 8 hours. The above compounds are therefore useful as tranquilizers. For the novel uses described above, the dosage will, of course, vary depending on the compound used, the method of administration and the treatment desired. However, in general, satisfactory results are obtained using daily doses of about 0.01 to about 3 mg/Kg animal body weight (e.g. 0.01 to 1 mg/Kg), preferably 2 to 4 times/day. or given in the form of delayed release. For large mammals, the total daily dose is from about 0.25 to about 16 mg, preferably from about 0.125 mg to
It is administered in unit dosage form containing about 8 mg of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent in two to four divided doses per day. For 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole, the total daily dose is preferably 1 to 12 mg;
Preferably it is 2 to 8 mg. The compounds can be administered in free base form or in the form of pharmaceutically acceptable acid addition salts. Such salt forms are known, for example hydrochloride.
The free base form and the acid addition salt form exhibit comparable activity. The compounds can be administered orally as pharmaceutical compositions in the form of tablets, powders, granules, capsules, suspensions, syrups and elixirs, or parenterally in the form of injectable solutions or suspensions. .
Apart from the compounds of formula, the compositions can contain pharmaceutically inert organic or inorganic auxiliaries, optionally granulating agents, binders, lubricants, dispersants, wetting agents and preservatives. Additionally, the pharmaceutical compositions can contain coloring, flavoring, and sweetening agents. Adjuvants for tablet manufacturing can be calcium carbonate, lactose, microcrystalline cellulose, mannitol or talc. Starch and alginic acid or microcrystalline cellulose can be used as granulating and disintegrating agents, starch, polyvinylpyrrolidone and gelatin as binders, and magnesium stearate, stearic acid, colloidal silicon dioxide and talc as lubricants. The tablet formulation may be coated or uncoated;
The coating can be applied in a manner known per se and delays disintegration and absorption in the gastrointestinal tract,
This has the purpose of providing a delayed relief effect over a long period of time. Suspending agents suitable for the preparation of liquid dosage forms are, in particular, methylcellulose, tragacanth and sodium alginate. Suitable wetting agents are, for example, polyoxyethylene stearate and polyoxyethylene sorbitan-
It is monooleate. Additionally, preservatives such as p-hydroxy-benzoic acid alkyl esters can be used. Capsule formulations may include the above compound itself or the compound as an inert solid diluent;
For example, it can be included along with calcium phosphate, starch, lactose, mannitol, colloidal silicon dioxide and microcrystalline cellulose. Solid formulations, especially tightly-filled capsules and tablets, are preferred because they are easy to manufacture and convenient to administer. The present invention also provides a package containing instructions for using a compound of formula or ' as a tranquilizer or sedative. Example 1 Tablets Suitable for Oral Administration Tablets containing the ingredients listed below can be prepared by conventional techniques and are administered in doses of two tablets four times a day.

[Table] If desired, the tablet can be shaped so that it is easily divided into two parts. Example 2 Capsules Suitable for Oral Administration Capsules containing the ingredients listed below can be prepared by conventional techniques and administered in a dosage of one capsule two to four times a day.

Table 1 Example 3 Sterile Injectable Solutions Injectable solutions containing the ingredients shown below can be prepared by conventional techniques including the buffering shown below and subsequent sterilization by conventional methods. The solution can be injected once a day.

【table】

[Table] Amount of distilled water to make 1ml
Buffer to pH 5. If desired, the solution can be sealed in ampoules. In the above animal test, 5-chloro-4-(2
-imidazolin-2-yl-amino)-2,1,
The following results were obtained using 3-benzothiadiazole. Activity test: ED ₅₀ 0.06 mg/Kgp.o. ED ₅₀ is the dose at which the locomotor activity (indicated by the number of light beams interrupted) in mice is half that of the control. Sleep test: 113% nap of control nap at 0.32 mg/Kgp.o.

[Table] Diazole

Claims (1)

[Claims] 1 5-chloro-4-(2-imidazoline-2-
A tranquilizing and sedative composition characterized in that it contains 2,1,3-benzothiadiazole (amino)-2,1,3-benzothiadiazole, in the form of free base or pharmaceutically acceptable acid addition salt. 2 5-chloro-4-(2-imidazoline-2-
2. The composition of claim 1 in unit dosage form containing from about 0.125 to about 8 mg of the free base of 2,1,3-benzothiadiazole (amino)-2,1,3-benzothiadiazole.