MXPA98009242A - Salt mesylate trihydrate 5 - (- 2- (4- (1,2-benzoisotiazol-3-il) -1-piperazinil) ethyl) -6-chlorine-1,3-dihydro-2h-indol-2- - Google Patents

Abstract

The invention relates to the mesylate trihydrate salt of 5- (2- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) et il) -6-chloro-1-3-dihydro-2H- indolo-2-one, to pharmaceutical compositions containing said mesylate trihydrate salt and to methods of using said mesylate trihydrate salt to treat psychotic disorders

Description

BALES MESYLATE OF 5- (2- (4- <1,2-BENZ0IS0TIA2Q ~ 3-I) -1 ~ PIPERAZIUI) ETHYL) -β-CHLORINE-, 3 ~ DIHYDRON ~ 2H ~ IMDO -2-OMA DIHYDRATES (ZIPRASIDONE ), ITS PREPARATION AND ITS USE AS AN ANTAGONIST OF DOPAMINE D2 sq > ? AND.? OF THE INVENTION The invention relates to the mesylate salts of 5- < 2- (4- (1'-2-benzisothiazol-3-yl) -l-piperazinyl> ethyl> -6-chloro-1,3-dihydro-2H-indol-2-one dihydrate (hereinafter "ziprasidone mesylate dihydrate") to pharmaceutical compositions containing one or both zxprasidone mesylates dihydrate and to procedures for the administration of ziprasidone mesylates dihydrate to treat psychotic diseases Ziprasidone is a potent antipsychotic agent and is therefore useful for the treatment of various disorders including schizophrenia »anxiety and migrainous pain U.S. patent 5,312,925 refers to ziprasidone hydrochloride monohydrate and states that ziprasidone hydrochloride monohydrate is practically hygroscopic stable» which avoids possible problems associated with weight changes of the active ingredient during the manufacture of capsules and tablets US Patent 5,312,925 is incorporated herein by reference in its entirety However, ziprasidone hydrochloride monohydrate has a low solubility in water and »as a result» is more suitable for formulation in capsules or tablets than for injectable dosage forms. Ziprasidone mesylates dihydrate also possess hygroscopic stability. Ziprasidone dihydrate mesylates have the additional advantage of having significantly greater solubility in water than monohydrate hydrochloride, which makes the mesylate dihydrate salts more suitable for injectable dosage forms than the hydrochloride monohydrate.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to mesylate dihydrate salts of 5- (2- < 4- < l-2-benzisothiazol-3-yl > -l-piperazinyl) ethyl) -6-chloro-l »3-dihydro 2H-indol-2-one. This invention also relates to a pharmaceutical composition for the treatment of a psychotic disorder »such as schizophrenia, anxiety or migrainous pain» comprising a quantity of mesylate salts dihydrate of 5- < 2- < 4- < 1.2-benzoisothiazol-3-yl > -l-piperazinyl) ethyl > -6-chloro-i.3-dihydro-2H-indol-2-na which is effective for the treatment of said psychotic disorder "and a pharmaceutically acceptable carrier. This invention further relates to a method of treating a psychotic disorder »such as schizophrenia» migraine anxiety or pain »in a mammal» including a human »comprising administering to said mammal an amount of mesylate salts dihydrate of S- (2) - (4- (1'-2-benzisothiazol-3-yl) -l-piperazinyl) ethyl) -6-chloro-l-3-dihydro-2H-indol-2-one which is effective in the treatment of said disorder.

DESCRIPTION OF THE DRAWINGS Figure 1 represents the diffraction spectrum of X-ray powder of ziprasidone mesylate dihydrate (elongated crystal) expressed as the intensity (Cps) versus the diffraction angle (degrees 2T> Figure 2 represents the powder diffraction spectrum X-ray of ziprasidone mesylate dihydrate (needle crystal) expressed as intensity (Cps) versus diffraction angle (degrees 2T> Figure 3 represents the X-ray powder diffraction spectrum of anhydrous ziprasidone mesylate (crystal elongate) expressed as the intensity (Cps) versus the diffraction angle (degrees 28) Figure 4 shows a photomicrograph of ziprasidone mesylate dihydrate (elongated crystal) Figure 5 shows a photomicrograph of ziprasidone mesylate dihydrate (acicular crystal) Figure 6 shows a photomicrograph of anhydrous ziprasidone mesylate (elongated crystal). Tables 1 to 3 below »identify peak selection. of the spectra of Figures 1 to 3 »respectively» by the diffraction angle < 2T) > separation d »maximum intensity (Max. Int.) and relative intensity (Int. Ret.).

TABLE 1 DIFFUSION DATA OF RAYS POWDER FOR DIBTDRATED ZIPRASIDONE MESILATE (LONG CRYSTALS) TABLE 1 (CONTIMUACTOW.

TABLE 2 DATA OF DIFFUSION OF RAY DUST FOR MESILATE OF ZIPRASIDONE DIHYDRATED (ACICULAR CRYSTALS) TABLE 2 (CONTINUED) TABLE 3 DIFFUSION DATA OF RAYS POWDER FOR ZIPRASIDONE ANHYDRO MESYLATE (LONGER CRYSTALS) s TABLE 3 (CONTINUED) DETAILED DESCRIPTION OF THE INVENTION Ziprasidone mesylate exists in four different crystalline forms: ziprasidone mesylate anhydrous (elongated crystal) »ziprasidone mesylate dihydrate (elongated crystal)» ziprasidone mesylate dihydrate (acicular crystal) and ziprasidone mesylate trihydrate. Each crystalline form has different characteristics such as a different X-ray powder diffraction pattern and a different crystalline form that can be observed by photomicrography. The elongated (Figure 4) and acicular (Figure 5) crystals of ziprasidone mesylate dihydrate are relatively long and thin »in contrast to the prismatic crystals of ziprasidone mesylate trihydrate. The crystals of anhydrous ziprasidone mesylate (Figure 6) are different »although in a similar way to the elongated crystals of the dihydrated form. The photomicrographs of Figures 4 to 6 were obtained using an Olympus polarization microscope (model BH-2) equipped with a halogen lamp »binoculars» polarization filter and Sony 3ccd video camera with Sony color printer. The X-ray powder diffraction pattern characteristic of the ziprasidone mesylates dihydrate is depicted in Figures 1 and 2. Although the crystals of ziprasidone mesylate anhydrous (Figure 6) may have a shape similar to the elongated crystals of the dihydrate (FIG. 4) »the X-ray powder diffraction spectrum of the ziphydrate mesylate anhydrous (Figure 3) is clearly distinct from the X-ray powder diffraction spectrum of the ziprasidone mesylates dihydrate (Figure 1 and 2). The X-ray powder diffraction spectra of Figures 1 to 3 were obtained on a Siemens R3RA / V diffractometer. The ziprasidone mesylates dihydrate are also characterized by their water content "which is indicated by the Karl Fissher (KF) value of 6» 4 ± 1 »0. Ziprasidone trihydrate mesylate is the subject of a co-pending U.S. patent application filed with the present patent entitled "Methanesulfonated 5- (2- (4- (l» 2-benzisothiazol-3-yl) - l-piperazinyl) ethyl) -6-chloro-l »3-dihydro-2H-indol-2-one trihydrate" (Pfizer file number PC9277) "presented jointly with the present. The former interim application of the United States "in process with this" is incorporated herein by reference in its entirety. Ziprasidone mesylates dihydrate are significantly more soluble in aqueous medium than ziprasidone hydrochloride monohydrate »which has a solubility of O» OS mg / ml in water at room temperature. The aqueous solubility of the four forms of ziprasidone mesylate is indicated below in Table 4.

TABLE 4 SOLUBILITY IN WATER OF POLYMORPHOSES OF MSSILATE OF ZIPRASIDONE The hydrated ziprasidone mesylates can be prepared from the free base (ziprasidone) which is prepared as described in column 4 »lines 22 to 43 of the aforementioned U.S. patent 5,312,925. The free base can also be prepared as described in U.S. Patent 5,338 B46, the disclosure of which is incorporated herein by reference in its entirety. When it is desired to use as an injectable formulation, it is preferred to carry out the preparation under pyrogen-free and particle-free conditions. The solvents and reagents free of particles can be prepared by filtering them in a Millipore1 * nylon filter of O »45 μm. The acicular crystals of ziprasidone mesylate dihydrate are prepared by mixing the free base with a mixture of water and organic solvent »by adding dilute methanesulfonic acid and heating to reflux as described above for the preparation of the trihydrate. The acicular crystals of the dihydrate are prepared by adding an acicular polymorph initiation crystal to the reaction solution after the solution has been stirred at reflux for about thirty minutes. A suspension "rssácea" indicating the formation of crystals will begin to form. The reaction solution is then allowed to cool slowly with stirring. During cooling to approximately 50 ° C »water can be added to the solution to lighten the suspension. The needle crystals can be filtered out of the composition through a multilayer filter and then washed successively with suitable volumes of a THF / water solution (65:35 v / v) and water. When allowed to dry at room temperature, the water content of needle crystals has a KF value ranging from 6 to 0 to 6., 8% (the theoretical KF value for the trihydrate is 6.4). The elongated crystals of ziprasidone dihydrate are prepared by mixing the free base with water and heating the resulting suspension at 50 ° C to 55 ° C. Methanesulfonic acid is then added and the mixture is heated to reflux ». After about 1 to 6 hours, preferably 2 hours, the solution is cooled to give the eluted crystals dihydrate. The resulting suspension is stirred for about 2 hours at room temperature and the crystals of the composition are then filtered and washed as described above for the needle crystals. When they are allowed to dry at room temperature, the water content of the elongated crystals has a Karl Fischer value ranging from 6 »0? 4 to 6» 8 >; í (the theoretical KF value for the dihydrate is 6 »4«). Ziprasidone mesylates dihydrate can be administered as psychotic agents as described in U.S. Patent 5,312,925, cited above. The administration of ziprasidone mesylate dihydrate is preferably carried out in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition "according to conventional pharmaceutical practice and as described in U.S. Patent 5,312,925" cited above. Suitable pharmaceutical carriers include solid diluents or fillers and sterile aqueous solutions »various organic solvents and excipients known to those skilled in the art. Ziprasidone mesylates dihydrate can be administered orally or parenterally »including the intravenous or intramuscular form. For parenteral administration * it is preferred »when the use of water is desired» to use sterile water for injection (AEI). Administration by intramuscular injection is preferred. A preferred composition for intramuscular injection is ziprasidone mesylate dihydrate (acicular or elongate) or both) in combination with sulfoxybutyl β-cyclodextrin as a carrier, preferably in a ratio of 1:10 (w / w) dihydrate to vehicle. Compositions containing ziprasidone mesylate dihydrate (acicular or elongate) in combination with sul xi ß-cyclodextrin can be prepared as described in the co-pending United States provisional patent applications, entitled "Method of Making Inclusion Co plexes "(file number of Pfizer PC 9563)» presented jointly with the present »and" Inclusion Complexes of Aryl-Heterocyclic Compounds "(file number of Pfizer PC S83B)» presented jointly with this. The previous interim US applications * being processed together with the present "both are hereby incorporated by reference in their entirety. The effective dose of ziprasidone mesylates dihydrate depends on the desired route of administration, the indication to be treated and other factors such as age and weight of the patient. In the following dosing intervals "the term" mgA "refers to milligrams of free base (ziprasidone). A recommended range of oral dosage ranges from 5 to 300 mgA / day »preferably from 40-200 mgA / day» more preferably 40-S0 mgA / day »in single or divided doses. A recommended range for parenteral administration "such as injection" is from 2 »5 mgA / day to 160 mgA / day and preferably 5-80 mgA / day. The present invention is illustrated by the following examples, although it is not limited to the details thereof. Unless otherwise indicated, the preparations described in the following examples were carried out in particulate-free and pyrogen-free conditions. As used in the following examples »THF refers to tetrahydrofuran and AEI refers to sterile water for injection.

EXAMPLE 1 Purification of 5-C2-C4 ~ (1,2-benzisothiazol-3-yl) -l- Piperazinyl-lethyl-3-6-sloro-l »3-dihydro-2H-indol-2-one They were loaded in a glass-lined tank »clean and dry. 46.8 Kg of 5-C2-C4- (1,2-benzoisothiazol-3-yl) -1- piperazinyl3ethyl-6-chloro-l »3-dihydro-2H-indol-2-one and 2816» 4 1 of THF. The suspension was heated to reflux and maintained for forty-five minutes to form a cloudy solution. The solution was filtered through an 83.82 cm rotary filter precoated with a filter aid and supported on a Fulflo ** filter (manufactured by Parker Hannifin Corp. Lebanon, Indiana) to a clean, dry, glass-lined reservoir in a lower level. The filtered solution was concentrated by vacuum distillation, cooled to 5 ° C and allowed to stir for two hours. The product was collected by filtration in a centrifuge and washed with cold THF (0-5 ° C). The product was collected and dried under vacuum at 45 ° C »providing 40» 5 kg of product. The product had a purity of 101 »5« (within the txpiso range of 100 ± 2 μm vs. the standard) as determined by HLPC assay.

EXAMPLE 2 5-C2-C4- (l-benzisothiazol-3-yl) -l-pjperazinyl-yl-3-6-chloro- »3-dihxdrcr-2H-indol-2-one trihydrate anosulfonate A suspension was produced by charging l.OOO g of 5-C2-C4- (1'-2-benzisothiazol-3-yl) -l-piperazinyl-3-ethyl-3-6-chloro-l »3-dihydro-2H-indol-2-one» 7,500 ml of AEI and 4,000 ml of THF in a 22-liter three-neck round-bottom flask »equipped with a heating mantle» a mechanical stirrer on top »a condenser and a temperature probe. The contents of the flask were protected from light with a cover of aluminum foil. The suspension was heated to 50 ° C while stirring. Dilute ethanesulfonic acid was prepared by combining 188 ml of methanesulonic acid with 812 ml of AEI. The diluted methanesulfonic acid was added slowly by means of an addition funnel to the reaction mixture. The reaction was heated to reflux (about 65 ° C) and a dark red solution formed upon heating the reaction mixture. The reaction mixture was allowed to stir under reflux conditions for about thirty minutes. After the thirty minute period »the heating blanket was switched off to allow cooling of the reaction mixture with stirring. The mixture was allowed to cool with stirring overnight (approximately 18 hours). When the reaction mixture was cooled »the product crystallized as large" yellowish "hexagonal prismatic crystals. The mixture was left stirring for one hour at ambient conditions. The product was isolated in a Bushner funnel with a filter of several fabrics and washed successively with l.OOOO of THF / AEI (65:35 »v / v) and 1,000 ml of AEI. The crystals were dispersed on glass trays and allowed to dry under ambient conditions to a Karl Fischer value of about 9 »6%. The product was sieved in a Mikro-Sa plmill * »(manufactured by Pulverizing Mashinery Division of Mikropul Copr.» Summit »New Jersey) equipped with a plate of 0» 027 H at a speed of 14.O00 rm. The product yield was 945 g. The structure of the product was confirmed by NMR as methanesulfonate of 5-C2-E4- (1'-2-benzisothiazol-3-yl) -piperazinyl-lethyl 3-6-chloro-l, 3-dihydro-2H-indole-2 -one trihydrate. A3C NMR (DMSO-dβ): é, 177.1 (O), 163 »O (O). 153 »0 (O). 145 »0 (O)» 132.4 (O). 129.0 (1), 127.8 (O), 127.7 (1), 127.1 (O). 126.5 (O) »125.6 (1), 124» 9 (1) »122.1 (1). 110.6 (1), 55.9 (2), 51 »7 (2), 47.5 (2)» 40 »7 (3), 36.2 (2)» 27.9 (2). NMR of AH (DMS0-dβ): U 10.5 (S, 1H), 9.8 (broad s, 1H), 8.2 (d, J = 8 »2 Hz, 1H), 8.1 (d »J = 8.2 Hz, 1H), 7.6 μm, 1H), 7.5 (, 1H)» 7.3 (s »1H). 6 »9 (2, 1H), 4.2 (m, 2H). 3.7 (m, 2H), 3.5 (m, 2H) »3.4 (m» 2H), 3.1 (m, 2H), 2.4) S, 3H). Analysis of the product by HPLC showed a peak with a retention time corresponding to that of a standard. The HPLC conditions are summarized below in Table 5.

TABLE 5 EXAMPLE 3 Metanosulonate of 5-r2-C4- (1,2-benzoigothiazol-3-yl) -l- Piperazinyl ethyl-6-sloro-l > Anhydrous 3-dihydro-2H-indol-2-one A suspension was produced by charging 350 g of 5-C2-C4- (1'-2-benzisothiazol-3-yl) -l-piperazinyl-3-ethyl-3-6-chloro-l, 3-dihydro-2H-indol-2-one and 7,000 ml. of isopropanol in a 12-liter, three-necked round-bottomed flask, fitted with a heating mantle »a mechanical stirrer on top», a condenser and a temperature probe. The suspension was heated to 50 ° C while stirring. 65.9 ml of methanesulphonic acid were added slowly by means of an addition funnel to the reaction mixture at 50 ° C. A slight exotherm up to 55 ° C was observed along with a thickening of the suspension and clearance of the suspension color. The reaction was distilled at atmospheric pressure to remove 2554 volume (1,750 ml). The suspension was cooled to room temperature and left stirring overnight. The product was isolated in a sintered glass funnel and washed with fresh isopropanol. The solids were dispersed on glass trays and allowed to dry under ambient conditions to a Kari Fischer value of 0 »5". The yield was 420.3 g of product. Analysis of the product by HPLC showed a peak with a retention time corresponding to that of a standard. The purity of the product »determined by HPLC (conditions in Table 5). it was 99 * 854.

EXAMPLE 4 5-C2-C4 ~ (l-benzisothiazol-3-yl) -l-pjperazinyl ethyl -6-chloro-l »3-dihydro-2H-indol-2-one methanediol dihydrate (acicular crystals) A suspension was produced by charging 5 g of 5-C2-C4- (1'-2-benzisothiazol-3-yl) -l-piperazinyl-3-ethyl-3-6-chloro-1,3-dihydro-2H-indol-2-one »37 * 5 ml of water and 20 ml of THF in a 150 ml three-necked round-bottom flask equipped with a heating mantle »a mechanical stirrer on top» a condenser and a temperature probe. The contents of the flask were protected from light with a cover of aluminum foil. The suspension was heated to 65 ° C while stirring. Dilute methanesulfonic acid was prepared by combining 1 ml of methanesulfonic acid with 4 ml of AEI. The dilute raetanesulfonic acid was added slowly by means of an addition funnel to the reaction mixture. The reaction was heated to reflux (about 65 ° C) and a dark red solution formed. The reaction mixture was allowed to stir under reflux conditions for about thirty minutes. After a period of thirty minutes, an acicular polymorph initiation crystal was added to the reaction solution. The formation of crystals was started »and the heat was removed to allow a slow cooling of the reaction with stirring. During cooling to 50 ° C, a thick "rosacea" suspension was observed in the flask. Water (20 ml) was added to the flask to rinse the suspension. The product was left stirring at ambient conditions for one hour. The product was isolated in a Buchner funnel with a filter paper and the solids were allowed to dry at ambient conditions up to a Kari Fischer value of 6 »6%. The product yield was 6 »03 g. The purity of the product, determined by HPLC (conditions in Table 5), was 99.8K.

EXAMPLE 5, 5-C2-C4- (l-benzisothiazol-3-yl) -l-jperazinyl-3-ethyl-3-6-chloro-1,3-dihydro-2H-indol-2-one methanesulfonate dihydrate (elongated crystals ) A suspension was produced by charging 25 g of 5-C2-C4- (1 »-benzoisothiazol-3-y1) -l-piperazinyl-3-ethyl-13 -6-chloro-1-dihydro-2H-indol-2-one and 375 ml. of water in a 500 ml three-necked round bottom flask equipped with a heating mantle »a mechanical stirrer in the upper part» a condenser and a temperature probe. The contents of the flask were protected from light with a cover of aluminum foil. The suspension was heated at 50-55 ° C while stirring. Methanesulfoniso acid (5 ml) was added slowly by means of an addition funnel to the reaction mixture. Thickening of the suspension and the color of the suspension were observed. The reaction was heated to reflux (about 100 ° C) and allowed to stir for about 1 hour. The product was isolated in a Buchner funnel with a filter paper and the solids were allowed to dry under ambient conditions to a Kari Fissher value of 6.254. The product yield was 32.11 g. The purity of the product »determined by HPLC (conditions in Table 5) was 98» 754.

Claims (5)

NOVELTY OF THE INVENTION CLAIMS

1. - A mesylate salt of 5- (2- (4- (1,2-benzoisothiazole- 3-yl) -l-piperazinyl) ethyl) -6-sloro-l »3-dihydro-2H-indol-2-one dihydrate.

2. The compound according to claim 1 »in the form of elongated crystals.

3. The compound according to claim 1 »in the form of acicular crystals.

4. A pharmaceutical composition for the treatment of a psychotic disorder "comprising an amount of the compound according to claim 1 which is effective in the treatment of said psychotic disorder and a pharmaceutically acceptable carrier. 5.- The use of a mesylate salt of 5- (2- (4-1,2-benzisothiazol-3-yl) -l-piperazinyl) ethyl) -6-chloro-l-3-di-dro-2H- indole-2-one dihydrate for the preparation of a medicament for treating a psychotic disorder in a mammal. & The use according to claim 5, wherein said disorder is schizophrenia »anxiety or migrainous pain. 7. The use according to claim 5 »wherein said disorder is schizophrenia. R SUDE DE LA TN / ENCIQff The invention relates to the mesylate salts of 5- (2- (4- (1 »2-benzisothiazol-3-yl) -l-piperazinyl) ethyl) -6-chloro-l, 3-dihydro-2H-indole 2-one dihydrate. to pharmaceutical compositions containing said mesylate dihydrate salts "and to methods of using said mesylate dihydrate salts to treat psychotic disorders. P98 / 1160F