JPS5826754B2 - Sankanshikikagobutsunopiperigylideneyudotainoseihou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel pharmaceutical compositions containing as active ingredients compounds that produce antipsychotic effects without extrapyramidal symptoms, and antipsychotic drugs obtained by administering non-toxic, effective doses of the active ingredients to animals. It relates to a method of producing an effect.

extrapyramidal symptoms
ptom (hereinafter referred to as EPS) 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 active ingredients used in the compositions and methods of the invention are the compounds shown below.

This compound is a new compound.

Non-toxic pharmaceutically acceptable acid addition salts of compounds of formula CI') 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 ferric 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 water compatible solvent.

Examples of these organic acid salts include maleate, fumarate, benzoate, ascorbate, permoate,
Succinate, bismethylene salicylate, methanesulfonate, ethanedisulfonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, mandelate , cinnamate, citraconate, aspartate, stearate, palmitate, itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulfonate and theophylline acetate and 8- Salts of roteophyllin, such as 8-bromotheophylline, are mentioned.

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.

The compound of formula [I] is prepared by preparing 2-chloro-9-xanthone in an inert organic solvent such as an ether such as ethyl ether, dioxane or tetrahydrofuran.
It is obtained by reacting with N-methylpiperidyl-4-magnesium chloride at room temperature to the reflux temperature of the solvent for 30 minutes to 4 hours, and dehydrating the resulting carbinol intermediate under acid or heating conditions to form an olefin.

US Pat. Nos. 3,275,640 and 3,055,903 disclose piperidylidene thioxanthenes, South African Patent No. 6,7104371 discloses piperidylidene dibenzoxepines, and US Pat. No. 3,470,188 discloses piperidylidene thioxanthenes. Although lydenxanthene and thioxanthin have been disclosed, these prior art do not disclose the unique feature of the compound of formula [■], namely, that it exhibits antipsychotic activity without causing EPS.

Belgian Patent No. 808347 describes di-substituted thioxanthins with heterocyclic propyl or propylidene side chains as low EPS neuroleptics.

It has been shown that antipsychotic drugs interfere with neurotransmission in the dopaminergic pathway of the striatum, causing EPS.

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 EPS.

To evaluate the ability of drugs to block filamentous dopamine receptors, a method developed by Ungerstedt (Ungerstedt and Arbuthnott, BrainRes. 2
Volume 4, page 485 (1970); Ungerstedt
, Acta physiol, 5cand, 5u
pp1. ．． 367, p. 49 (1971)] was used.

This treatment markedly reduces the dopamine content of the neostriatum on the lesion side and causes alterations in dopaminergic pathways in the malignant striatum.

Animals with this lesion have asymmetrical posture and locomotion, which is altered by drugs that affect dopaminergic pathways.

Amphetamine releases dopamine and norepinephrine from catecholminergic 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 normal malignant filamentary 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 activity of filamentous dopamine receptors on the normal side. This is due to the dominance of

Therefore, a drug's ability to antagonize this rotational movement is a measure of its ability to block filamentous dopamine receptors and is an indicator of its ability to cause EPS.

To express the ability of a drug to induce EPS, the ED5o (intraperitoneal) for antagonism of amphetamine-induced rotation is compared with the ED60 (intraperitoneal) for antagonism of shock avoidance acquisition in rats, which is a method for evaluating antipsychotic effects. Calculate the ratio (R/A ratio).

ED in this avoidance and rotation test of several clinically established antipsychotics.

and R/A ratio are shown in Table 1.

Chlorpromazine
has an R/A ratio of 1.3.

Antipsychotics that have a greater tendency to cause EPS than chlorpromazine, such as trifluoperazine (trifluop
erazine), haloperidol (haloper)
idol) and pimozide
Ha has a ratio of 0.3 to 0.5.

Two antipsychotics are known to have a lower tendency to cause EPS than chlorpromazine: thioridazine and clozapine.
clozapine) have ratios of 2.7 and 3.8, respectively.

Therefore, a high R/A ratio indicates a low ability of the drug to induce EPS.

4-(2-chloro-9-xanthenylidene)-1-methylpiperidine of formula (I') has a high R/A ratio of 12.2 and is virtually free from the risk of causing EPS.

Compound of formula [■] and other similar formulas: Table 2 shows the ED5o and its R/A ratio in the avoidance learning ability and rotation test of the compound represented by *.

As shown in Table 2, the compound of formula (I') has a highly desirable high R/A ratio compared to other similar compounds.

The composition of the present invention comprises administering a non-toxic amount of the compound of formula [■] or a pharmaceutically acceptable salt thereof, which is sufficient to produce an antipsychotic effect in animals without EPS, in accordance with an accepted method. Combined with a pharmaceutical carrier, it is prepared into conventional unit dosage forms.

Preferably, the composition contains about 1 to about 30
0.7%, advantageously from about 5 to about 200% of the active ingredient.

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 support can vary, but is preferably from about 25 m9 to about 11 m9.

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 materials such as glyceryl monostearate or glyceryl distearate alone or in combination with a wax.

Dosage forms for parenteral administration, such as intramuscular administration, may be prepared by dissolving a water-soluble salt of the active ingredient in water or saline at a concentration of from about 2 to about 50 μl of active ingredient per ml of solution. It will be done.

According to the method of the present invention, the compound of formula [■] or a non-toxic acid addition salt thereof is preferably combined with a pharmaceutical carrier as required for antipsychotic action, and is capable of exerting antipsychotic action without causing EPS. is administered to the animal in a non-toxic amount sufficient to cause

The active ingredient is administered orally or intramuscularly in an active and non-toxic amount selected from the range of about 1 to about 3007Q of the parent compound of formula CI'), preferably in unit dosage form.

Advantageously, 2-3 times a day until the desired effect is achieved.
Administer equal amounts.

The daily dosage is selected from the range of about 2 to about 900 μ, preferably from about 10 to about 600 μ of the active ingredient.

Using this method, antipsychotic effects are obtained with minimal EPS.

Next, the pharmaceutical composition of the present invention and its use will be explained with reference to Examples, but the present invention is not limited thereto.

Example 1 Component % (W/V) 4-(2-
Chloro-9-xane (per IWL, free tenylidene)
-1-Methylpipe Add 20% base to lysine (as a water-soluble acid addition salt) Sodium tartrate Aqueous tartrate Adjust to 0.7 ioo% This ingredient is dissolved in water in an amount of about 95% of the final volume and mixed, Heat if necessary, cool to room temperature and add remaining water.

Filter this solution into an ampul.

The solution of Example 1 is administered to animals in need of antipsychotic effects in the above dosage range.

Example 2 Magnesium scraps 4,3 P (
0,175 mol) of a base derived from 29.8 f (0,175 mol) of 4-chloro-N-methylpiperidine hydrochloride (a solution of the base in about 50 ml of tetrahydrofuran) is added (this base (preliminarily liberated by trituration with ether, granulated potassium hydroxide, 1 ml of water, extraction with ether and evaporation of the dry extract under vacuum).

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.

With slight heating, this solution is added dropwise over a period of 0.5 hours, and the resulting reaction mixture is stirred and refluxed for 1 hour.

2-Chloroxanthone 27. Reflux gently and do not stir. Of (0,117 mol) is slowly 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 gives 2-chloro-9-(1-methyl-4-piperidyl)xanthene-9-ol.

Melting point: 206-208°C This xanthine-9-ol 12.5 P (0,03
8 mol), 0-sulfobenzoic anhydride 14. (1(0,
76 mol) oyohyfurohionic acid 38o7711 was refluxed for 3 hours.

The reaction mixture was heated at 100 °C under vacuum, the resulting syrup was dissolved in water and 40% hydroxylated), made strongly basic with IJum solution, extracted with ether, and the dried extract was evaporated. let

The remaining free base was dissolved in ethyl acetate and the maleic acid 4.
41 to obtain 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine maleate.

Melting point 206-207°C Example 3 A solution of 4-(2-chloro-9-xanthenyritene)-1-methylpiperidine in acetonitrile is treated with 1 equivalent of methanesulfonic acid to give the corresponding methanesulfonic acid salt.

Claims (1)

[Claims] A compound represented by the formula: characterized by reacting 12-chloro-9-xanthone with N-methylpiperidyl-4-magnesium chloride and then dehydrating the produced carbinol intermediate; and A method for preparing a non-toxic pharmaceutically acceptable acid addition salt thereof.