Risperidone, method thereof, antipsychotic composition based on it and how you can get


(57) Abstract:

Risperidonum formula I is obtained by processing 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-it Mamonovo acid in an inert solvent. The advantage of the compounds of formula I that providing prolonged isolation of risperidone from poorly soluble in water pamiatnik salts, they are dopamine antagonists for long periods. 4 c. and 5 C.p. f-crystals, 1 table.

The present invention relates to a new risperidonum, possessing valuable pharmacological properties, and method thereof, pharmaceutical compositions and method of reception.

EP-0196132 reveals the connection 3-[2-[4-(6-fluoro-1,2 - benzisoxazol-3-yl)-1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2 - methyl-4H-pyrido[1,2-a]pyrimidine-4-one, commonly known as risperidone and which is strong antipsychotic agent. Unfortunately, modern formulations of risperidone provide effective levels in plasma only during a limited time interval. Dosage forms of risperidone long acting, which can be introduced by injection, would be very valuable in maintenance therapy and analeptic long-term actions include oil solutions, for example, sesame oil, slightly soluble in water, ether derivatives of neuroleptic compounds. Attempts to prolong the activity of some phenothiazine neuroleptics through the use of poorly water-soluble salts, such as pamoate, turned out to be really successful (for example, Florence et al. , 1976, J. Pharm. Sci., 65(11), 1665-1668). Found that the use of pamoate salt of risperidone on dogs significantly lengthens the period allocation of risperidone, giving levels of risperidone and its active metabolite in plasma, which is effective against caused by apomorphine vomiting for several weeks.

In accordance with this present invention relates to salts of joining Mamonovo acid to risperidone. In particular, the invention relates to a compound having the formula

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The period during which supported effective plasma levels depend on the physical characteristics of the powder sample risperidonum, such as particle size and shape of the crystal.

Risperidone, its preparation and pharmacological activity described in EP-0196132. Pamoate salt of risperidone produced by processing of risperidone Mamonovo acid or its salt, for example dinatrium the statutory solvent, for example ethanol, to the solution Mamonovo acid in a suitable solvent, N,N-dimethylformamide, and stirring the mixture until you fall precipitate pamoate salt of risperidone. The reaction product is separated from the environment and, if necessary, purified by methods widely known in the art, for example by extraction, crystallization and chromatography. Micronized form compounds that are the subject of the invention, produced using the methods micronisation, known in the art, for example by grinding in a suitable mill and sieving in suitable sieve.

In one specific aspect the invention relates to mixed pamoate salts accession of risperidone, for example monosodium pamoate salt of risperidone.

The compounds forming the subject of the present invention are strong antagonists of neurotransmitters, particularly dopamine. The antagonism of these neurotransmitters inhibit a number of symptoms caused by selection, and, in particular, excessive secretion of dopamine. The Central antagonists of the dopamine receptor, known to have neuroleptic properties, for example, they counteract the positive symptoms of schizophrenia, such as hallucin is ispolzovanie this connection, in particular as a strong antipsychotic drugs and especially as tools that are useful in the treatment of chronic psychosis, lie mainly in the field of Central nervous system (CNS).

These compounds also show Central serotonin antagonism. Centrally acting serotonin antagonists, presumably, improve negative symptoms of schizophrenia, for example, energy, fatigue, autism, and depressive mood, and also reduce the scope of extrapyramidal side effects (EPS) during maintenance therapy of classical neuroleptics, i.e. dopamine antagonists. Combined dopamine-serotonin antagonists are particularly interesting because they give the weakening of both positive and negative symptoms of schizophrenia with low propensity for EPS.

The advantage of the compounds of the present invention is that, providing prolonged isolation of risperidone from poorly soluble in water pamiatnik salts, they are dopamine antagonists for long periods. This may be evidenced, for example, measurement of plasma levels after intramuscular or subcutaneous giving it to the dogs and long protease dopamine agonist. Thus, the compounds of the subject invention, allow to cure at relatively large intervals, for example a few weeks, and the actual time of the giving of the medication depends on the physical nature of the used connections and the condition of the patient. Therefore, the claimed compounds allow for more effective therapy: prolonged isolation facilitates the maintenance of a stable plasma concentrations at non-toxic effective level, and the route of administration contributes to a more strict patient compliance with the regimen and the regimen prescribed medicines.

Unlike most currently available antipsychotics long-term effects, which are usually cooked in oil for intramuscular injection, the compounds that are the subject of the present invention have the advantage that they can be prepared as in lipophilic (e.g., oil) and lipophobic (e.g., water) solvents, and introduce different ways, for example subcutaneously or intramuscularly.

Taking into account their useful pharmacological properties, the inventive compounds can be prepared in various pharmaceutical forms for a number of the claimed compounds as the active substance is thoroughly mixed with a pharmaceutically acceptable carrier, the media may take a variety of forms depending on the form of the drug intended for injection. These pharmaceutical compositions are desirable in unit dosage form suitable, for example, for subcutaneous or intramuscular injection. For the last route of administration of the inventive compounds are preferably suspended in an aqueous solvent, which may further include a wetting agent, such as polyoxyethylene derivatives of esters of sorbent, for example Polysorbate 80 (= Tween 80), and Polysorbate 20 (= Tween 20), lecithin, polyoxyethylene and polyoxypropylene esters, deoxycholate sodium and the like; suspendisse agent, such as a derivative of cellulose, such as methylcellulose, sodium carboxymethyl cellulose and hydroxypropyl-methylcellulose, polyvinylpyrrolidone, alginates, chitosan, dextrans, gelatin, polyethylene glycols, polyoxyethylene and polyoxypropylene esters and the like; acid, for example hydrochloric acid, and the like; a base, for example sodium hydroxide and the like; a buffer comprising a mixture of suitable amounts of acid, such as phosphoric, succinic, tartaric, lactic, acetic, maleic or lemon is Yu acid, benzyl alcohol, bottled hydroxyanisol, bottled hydroxytoluene, chlorobutanol, gallate, hydroxybenzoate, ethylenediaminetetraacetic acid, phenol, chlorocresol, metacresol, chloride benzothia, chloride myristyl -- piccoline, acetate finalstate (II), thimerosal and the like; a means of adjustment of tonicity such as sodium chloride, dextrose, mannitol, sorbitol, lactose, sodium sulfate, and the like.

Alternative compounds forming the subject of the present invention can be introduced into the mixture with oil. The correct oil for this purpose include non-volatile oils, such as peanut oil, sesame oil, cottonseed oil, corn oil, safflower oil, castor oil, etiloleat, soybean oil, synthetic esters of glycerol with long-chain fatty or medium chain acids and mixtures of these and other oils.

The composition can also be added thickeners, for example, aluminum monostearate, ethylcellulose, triglycerides, hydrogenated castor oil and the like.

Taking into account the usefulness of the compounds according to the present invention, in the treatment of psychotic diseases, it is obvious that the present invention oami, moreover, this method includes the introduction of pharmaceutically effective amounts of compounds according to the invention in a mixture with a pharmaceutical carrier. In another aspect, the present invention relates to the use of the claimed compounds as medicines, in particular as antipsychotics. In General it is believed that an effective amount is from 0.05 to 50 mg/kg body weight, preferably from 0.5 to 10 mg/kg body weight.

The following examples are intended to illustrate but not to limit the scope of the present invention.

Example 1.

The solution 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2 - a] pyrimidine-4-it (0,048 mol) in ethanol (600 ml) are added to a solution Mamonovo acid (0,048 mol) in N, N-dimethylformamide (400 ml). The mixture is stirred for 3 hours the precipitate is filtered off with suction, washed with ethanol and dried, obtaining 31 g (81%) 4,4'-Methylenebis[3-hydroxy-2 - naphthaleneacetic[3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-it (1:1); so pl. 269,2oC.

q.s. - quantum satis (enough).

Example 2.

BR> purified water - q.s. 1 ml

Risperidonum, Polysorbate 20, benzyl alcohol and purified water are thoroughly mixed and homogenized, thus obtaining the aqueous suspension.

Similarly prepared:

F 2: water suspension

risperidonum 50 mg

Polysorbate - 2 mg

benzyl alcohol 15 mg

carboxymethylcellulose sodium 20 mg

purified water - q.s. 1 ml

F 3: suspension in oil

risperidonum 50 mg

sesame oil - q.s. 1 ml

Example 3.

Prolonged action monoamine salt of risperidone versus risperidone in the form of a free base set as follows.

Apomorfina test on dogs.

Used the method described by P. A. J. Janssen and C. J. E. Niemegeers in Arzneim. Forschang (Drug. Res. 9, 765-767 (1959). Suspension of risperidone in the form of the free base in sesame oil and reperitonealization composition F 1, F 2 and F 3 enter the three dogs (short-legged hounds) in doses of 2 to 2.5 mg/kg of Risperidone in the form of free base, and F 1 and F 2 is injected intramuscularly, and F 3 is injected subcutaneously. Then after some time introducing provocative standard dose 0,31 mg/kg (subcutaneously) of apomorphine, the cue is used as an indicator of its activity.

The table presents data on the average activity period (days) obtained for the three experimental animals.

From the table it is clear that the introduction of risperidonum has resulted in a significantly longer period of activity in comparison with the introduction of risperidone in the form of free base.

1. Risperidonum formula I

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2. Antipsychotic composition comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient used risperidonum in an effective amount.

3. The composition according to p. 2, characterized in that it represents a form suitable for injection.

4. The composition according to p. 3, characterized in that it is an aqueous suspension.

5. The composition according to p. 4, characterized in that it further comprises benzyl alcohol, ester sorbitan and water.

6. The composition according to p. 5, characterized in that it further contains a derivative of cellulose.

7. The method of obtaining antipsychotic composition comprising risperidonum as defined in any of paragraphs.2 to 5, characterized in that an effective amount of rispe the p. 1 as a drug.

9. The method of receiving risperidonum formula I, wherein 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-one process Mamonovo acid in an inert solvent.


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wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

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EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex