JPS6220190B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel compounds that produce antipsychotic effects without extrapyramidal symptoms, novel pharmaceutical compositions containing the compounds as active ingredients, and antipsychotic effects produced by administering non-toxic, effective doses of the active ingredients to animals. Concerning how to do so. extrapyramidal symptoms
ESP (hereinafter referred to as ESP) is an extremely undesirable and common side effect caused by antipsychotics or neuroleptics. The compounds used as active ingredients in the compositions and methods of the invention exhibit antipsychotic activity, but have neuropharmacological characteristics that are substantially free from EPS-causing potential. The novel compounds of the present invention have the formula: It is a piperidylidene derivative of xanthene represented by Non-toxic pharmaceutically acceptable acid addition salts of compounds of formula [] are also useful in the compositions and methods of the invention. These salts can be easily produced by known methods. For example, the base can be reacted with an amount of an organic or inorganic acid in a water-compatible solvent such as acetone or ethanol, concentrated, cooled and separated, or an excess of the acid can be reacted with a water-compatible solvent such as ethyl ether or chloroform. The desired salt is separated directly by reaction in a non-aqueous solution of water. Examples of these organic acid salts include maleate, fumarate, benzoate, ascorbate, permate, succinate, bismethylene salicylate, methanesulfonate, ethanedisulfonate, acetic acid. salt, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, mandelate, cinnamate, citraconate, aspartate, stearate, palmitate, Mention may be made of itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulfonate and theophylline acetate and the salts of 8-halotheophyllin, such as 8-bromotheophylline. Examples of inorganic acid salts include hydrochloride, hydrobromide, sulfate, cyclohexylsulfamate, phosphate and nitrate. Of course, these salts can also be prepared by known classical methods by double decomposition of suitable salts. Compounds of formula [] are generally prepared by combining a suitably substituted xanthone with a halogen in an inert organic solvent such as an ether such as ethyl ether, dioxane or tetrahydrofuran for 30 minutes to 4 hours at room temperature to the reflux temperature of the solvent. The resulting tricyclic carbinol intermediate is dehydrated to form an olefin under acid or heating conditions. US Pat. Nos. 3,275,640 and 3,055,903 disclose piperidylidene thioxanthenes; South African Patent No. 67/04371 discloses piperidylidene dibenzoxepines; and US Pat. No. 3,470,188 discloses piperidylidene dibenzoxepines. Although piperidylidenexanthene and thioxanthene have been disclosed, these prior art do not disclose any unique feature of the compound of formula [], namely, that it exhibits antipsychotic activity without causing ESP. Belgian patent no.
No. 808347 describes di-nuclear substituted thioxanthenes with heterocyclic propyl or propylidene side chains as neuroleptics with low ESP. It has been shown that antipsychotic drugs cause ESP by interfering with neurotransmission in the dopaminergic pathway in the nigrostriatal body. This is thought to be due to the drug blocking dopamine receptors in the neostriatum. Therefore, the ability of a drug to block filamentous dopamine receptors is a measure of its susceptibility to ESP. To assess the ability of drugs to block filamentous dopamine receptors, a method developed by Ungerstedt [Ungerstedt and Arbuthnott, Brain Res. .,twenty four
Vol. 485 (1970): Ungerstedt, Acta
physiol.scand., Suppl., vol. 367, p. 49 (1971
)] was used. This treatment markedly reduces the dopamine content of the neostriatum on the lesion side and causes alteration of dopaminergic pathways in the nigrostriatal body. Animals with this lesion have asymmetrical posture and locomotion, which can be altered by drugs that affect dopaminergic activity. Amphetamine releases dopamine and norepinephrine from catecholaminergic nerves, causing these rats to make a unidirectional rotation toward the side of the lesion. Since the amount of dopamine that can be released by amphetamine from the normal substantia nigra filamentous nerves on the non-lesioned side is much greater than the amount remaining on the lesioned side, the rotational movement is clearly due to the release of filamentous dopamine receptors on the normal side. This is due to the preponderance of activity. Therefore, a drug's ability to counteract this rotational movement is a measure of its ability to block filamentous dopamine receptors and is an indicator of its ability to cause ESP. In order to express the ability of a drug to cause ESP, we investigated the resistance of amphetamine-induced rotation to ED ₅₀ (intraperitoneal) for acquired shock avoidance in rats, which is a method for evaluating antipsychotic effects.
Calculate the ED ₅₀ (intraperitoneal) ratio (R/A ratio).
ED ₅₀ and R/ in this avoidance and rotation test of several clinically established antipsychotics.
The A ratio is shown in Table 1. Chlorpromazine has an R/A ratio of 1.3. Antipsychotics that have a greater tendency to cause ESP than chlorpromazine, such as trifluoperazine, haloperidol, and pimozide,
with a ratio of 0.3-0.5. From chlorpromazine
Two antipsychotic drugs known to have a reduced tendency to cause ESP: thioridazine and clozapine.
have ratios of 2.7 and 3.8 respectively. Therefore,
A high R/A ratio indicates a low ability of the drug to cause ESP.

[Table] Next, formula 4-
The ED ₅₀ and R/A ratio of (2-chloro-9-xanthenylidene)-1-methylpiperidine in the avoidance learning ability and rotation test are shown in Table 2 below.

[Table] A novel pharmaceutical composition containing the compound of the present invention as an active ingredient comprises a non-toxic amount of the compound of formula [ ] or a pharmaceutically acceptable salt thereof sufficient to produce an antipsychotic effect in animals without ESP. , prepared in conventional unit dosage form by combining with a non-toxic pharmaceutical carrier according to accepted methods. Preferably, the composition contains about 1 to about 300 mg, advantageously about 5 to about 200 mg per dosage unit.
containing an active and non-toxic amount of the active ingredient selected from the range of . (The methanesulfonate salt of the compounds of Examples 1 and 2 below had an LD ₅₀ of 319.5 mg/Kg when administered orally to rats, and an LD ₅₀ of 79.8 when administered intraperitoneally.
mg/Kg, LD ₅₀ for intraperitoneal administration in mice is 56.8
mg/Kg. ) The pharmaceutical carrier used can be solid or liquid and can be in a variety of pharmaceutical forms. If a solid carrier is used, such as lactose, magnesium stearate, china clay, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia, etc., the composition may be in tablets, powders, hard gelatin capsules, or troches or lozenges. It can be done. The amount of solid carrier can vary, but is preferably from about 25 mg to about 1 g. If a liquid carrier is used, such as syrup, peanut oil, olive oil, sesame oil, water, etc., the composition can be encapsulated in soft gelatin, syrup, emulsion or liquid suspension. Also included in the carrier or diluent are delay substances such as glyceryl monostearate or glyceryl distearate alone or in combination with a wax. For parenteral administration, such as intramuscular administration, solution 1
It is obtained by dissolving a water-soluble salt of the active ingredient in water or physiological saline at a concentration containing from about 2 to about 50 mg of active ingredient per ml. According to the present invention, the compounds of formula [] or their non-toxic acid addition salts are combined with a pharmaceutical carrier, as required for antipsychotic action, preferably in a sufficient amount to produce antipsychotic action without causing ESP. Administered to animals in non-toxic doses. The active ingredient is preferably in unit dosage form from about 1 to about 300% of the parent compound of formula [ ].
It is administered orally or intravenously in an active, non-toxic amount selected from the range of mg. Advantageously, the same amount is administered two to three times a day until the desired effect is achieved.
The daily dose is selected from the range of about 2 to about 900 mg, preferably about 10 to about 600 mg of the active ingredient. When using this method, antipsychotic effects are obtained with minimal ESP. Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto. Formulation example 1 Ingredient % (W/V) 4-(2-chloro-9-xanthenylidene)-1-
Methylpiperidine (as water-soluble acid addition salt)
Equivalent to 20 mg of free base per ml Sodium tartrate 1 Tartaric acid 0.7 Water Adjust to 100% Dissolve the ingredients in approximately 95% of the final volume of water, mix, heat if necessary, and cool to room temperature to remove the remaining Add water. This solution is filtered and placed into ampoules. The solution obtained in Formulation Example 1 is administered to animals in need of antipsychotic action within the above dosage range. Example 1 Magnesium scraps slightly covered with dry tetrahydrofuran gently refluxing under nitrogen atmosphere
To 4.3 g (0.175 mol) is added 1 ml of a solution of base in tetrahydrofuran (ca. 50 ml of tetrahydrofuran) derived from 29.8 g (0.175 mol) of 4-chloro-N-methylpiperidine hydrochloride. , granular potassium hydroxide,
Trituration with 1 ml of water, extraction with ether and evaporation of the dry extract under vacuum to liberate it beforehand). A small amount of ethereal methylmagnesium bromide is added and once the reaction has started, the remaining base is diluted with about 150 ml of tetrahydrofuran while stirring. This solution is added dropwise over a period of 0.5 hour with slight heating, and the resulting reaction mixture is stirred and refluxed for 1 hour. Reflux gently,
2-chloroxanthone 27.0g while stirring
(0.117 mol) is gradually added. The reaction mixture is stirred and refluxed for 1 hour and cooled over an ice water-ammonium chloride mixture to give an oil. This oil solidifies.
Recrystallization from ethyl acetate gave 2-chloro-9-(1
-Methyl-4-piperidyl)xanthene-9-ol is obtained. Melting point 206-208℃ This xanthene-9
-ol 12.5 g (0.038 mol), o-sulfobenzoic anhydride 14.0 g (0.76 mol) and propionic acid
Reflux 380 ml for 3 hours. The reaction mixture is heated under vacuum at 100° C., the syrup obtained is dissolved in water, made strongly basic with 40% sodium hydroxide solution, extracted with ether and the dried extract is evaporated. The remaining free base is dissolved in ethyl acetate and 4.4 g of maleic acid is added to obtain 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine maleate. Melting point 206-207°C Example 2 4-(2-chloro-9-xanthenylidene)-1
- Treating a solution of methylpiperidine in acetonitrile with 1 equivalent of methanesulfonic acid to give the corresponding methanesulfonate salt. Melting point 225-228℃

Claims (1)

[Claims] 1 Formula: or a non-toxic pharmaceutically acceptable acid addition salt thereof. 2. The compound of item 1 above in free base form. 3. The compound of item 1 above, which is a methanesulfonate. 4 formula: 1. An antipsychotic pharmaceutical composition free from extrapyramidal symptoms, comprising a compound represented by the formula (1) or a non-toxic pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical carrier.