HK1081185B - Acyl derivatives of ziprasidone having neuroleptic activity - Google Patents

Description

Acyl derivatives of ziprasidone having neuroleptic activity

Background

The present invention relates to prodrugs, which are the compound 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazinyl) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one (hereinafter ziprasidone) and pharmaceutically acceptable acid addition salts thereof, processes for their preparation, and methods of their use. The compounds of the present invention have neuroleptic activity and are therefore useful as antipsychotics.

U.S. patent 5935960 discloses the compound 1- [2- (6-chloro-2, 3-dihydro-2-oxo-1H-indol-5-yl) ethyl ] -4- [ imino (2-mercaptophenyl) methyl ] piperazine as a prodrug of ziprasidone.

U.S. patent 5312925 discloses ziprasidone hydrochloride monohydrate, processes for its preparation, pharmaceutical compositions thereof and methods of treating psychosis.

U.S. patent 5206366 discloses an aqueous-based process for preparing ziprasidone. The above U.S. patents are incorporated by reference in their entirety.

Summary of the invention

The present invention relates to compounds of the formula

And pharmaceutically acceptable acid addition salts thereof, wherein R is¹Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, n-hexyl, n-heptanoic acid, n-octyl, n-nonyl, n-decyl, and n is an integer of 1 to 5.

Preferred pharmaceutically acceptable acid addition salts of the compound of formula 1 are selected from the group consisting of hydrochloride, mesylate, acetate, fumarate, succinate, maleate, besylate, citrate, tartrate and sulfate salts. The most preferred salt is the hydrochloride salt.

A preferred subgroup of compounds 1 is that wherein R¹Selected from methyl, ethyl, isobutyl and decyl and n is a subgroup of 2.

The most preferred compound that can be prepared according to the present invention is 4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid ethyl ester hydrochloride.

The invention also relates to a process for preparing a compound of formula I:

the process comprises reacting a compound of formula II:

according to the invention, the compound of formula II can be prepared by reacting a compound of formula III in the presence of concentrated hydrochloric acid

And formula R¹OH, wherein M is Ba or Ca; and R is¹Selected from hydrogen and C₁～C₁₀An alkyl group.

According to the invention, the compounds of the formula III can be prepared by reacting compounds of the formula IV

In the formula R²Is C₁-C₁₀Alkyl and n is an integer of 1 to 10, and a general formula M (OH)₂The inorganic base is reacted to obtain; m is Ba or Ca.

According to the invention, the compounds of the formula IV can be prepared by reacting compounds of the formula V

And its general formula R²O₂C-(CH₂)_n-C(＝O)-O-C(＝O)-(CH₂)_nCO₂R²By reaction with an acylating agent of an acid anhydride of the formula (II) wherein R is²Is C₁～C₁₀An alkyl group, and n is 1 to 5.

In the process for preparing the compounds of formula I, the preferred base is selected from alkali metal bicarbonates, alkali metal carbonates, tertiary amines such as tri-C₁～C₆Alkylamines, and heterocyclic weak bases such as pyridine, lutidine or picoline. The most preferred base is aqueous sodium bicarbonate.

Alcohol R¹R in OH¹Is selected from C₁～C₁₀An alkyl group. Preferred alcohols R¹R in OH¹Selected from methyl, ethyl and isobutyl. In the most preferred embodiment, R¹Is ethyl.

The diacylated compound of formula IV is hydrolytically converted to the monoacylated alkaline earth metal salt of formula III, at elevated temperature, in the presence of an alkaline earth metal hydroxide dissolved in water and an inert water-miscible organic solvent. Preferred alkaline earth metal hydroxides are calcium hydroxide or barium hydroxide. Preferred temperatures are from about 45 ℃ to about 80 ℃ and preferred solvents are selected from tetrahydrofuran, dioxane, dimethyl sulfoxide, alkyl ethers, N-dimethylformamide and other aprotic solvents, or ethers having a boiling point of from about 50 ℃ to about 200 ℃. The most preferred solvent is tetrahydrofuran.

The barium or calcium salt of formula III is a useful intermediate in the preparation of acyl derivatives of the invention. In a preferred embodiment of n-2, the acyl derivative is a succinyl derivative and the salt is a calcium salt.

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid barium salt,

in a most preferred embodiment, the compound having formula III is 4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid calcium salt.

The compounds of formula IV are useful intermediates in the preparation of acyl derivatives of the invention. Preferably n is 2, and R¹Is C₂～C₄An alkyl group.

In a most preferred embodiment, the compound of formula IV is succinic acid 5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-1- (3-ethoxycarbonyl-propionyl) -1H-indol-2-yl ester ethyl ester.

Inorganic base M (OH)₂With compound IV in a water-miscible organic solvent, preferably tetrahydrofuran.

Having the formula M (OH)₂Preferred bases of (b) are those wherein M is Ca or Ba. The most preferred base is calcium hydroxide.

Preferred acylating agents are aliphatic anhydride acylating agents of the formula:

in the formula R²Is ethyl.

The acylation is carried out in anhydrous dichloromethane in the presence of an organic base and a diethyl ether adduct of magnesium bromide.

In a preferred embodiment, the organic base is triethylamine.

The effective dosage of the ziprasidone prodrug of the invention will depend on the route of administration to be employed, the indication to be treated and other factors such as the age and weight of the subject being treated. In the dosage ranges below, the term "mgA" refers to the number of milligrams of the free base of the prodrug. The recommended oral dosage range is 6-400 mgA/day, preferably 50-250 mgA/day. Parenteral administration, e.g., injection, is recommended to be in the range of 3.0 to 200 mgA/day, preferably 6.0 to 100 mgA/day.

Detailed description of the invention

Acylated derivatives of ziprasidone were synthesized as shown in scheme 1 below. R in scheme 1¹And R²And n is as defined for formulae I, II, IV. Metal ions M of the formula III⁺²Is Ca⁺²And Ba⁺²。

Scheme 1

Ziprasidone (V) is acylated at both the 1-nitrogen and 2-oxo positions (of the indole ring) according to the method of Yamada et al Tetrahedron Letters, 43, 647, (2002) under completely anhydrous conditions with an acyl anhydride VI in the presence of magnesium bromide diethyl ether containing the adduct and triethylamine. The diacylated product is unexpectedly obtained by this method because when the oxindole is acylated with pivalic anhydride according to Yamada's method, only a single substitution is made at either the H or O atom.

The anhydride used for the acylation reaction was prepared according to scheme 2.

Scheme 2

According to scheme 2, the selected acid chloride is self-condensed with sodium hydroxide particles in anhydrous dichloromethane to form the desired acidAn anhydride. The acylation step of scheme 1 is carried out in two separate addition steps. The anhydride solution in dichloromethane was added to the previously prepared solution of ziprasidone in anhydrous tetrahydrofuran in magnesium bromide diethyl ether adduct (MgBr) under nitrogen₂·Et₂O) and triethylamine in anhydrous dichloromethane, the reaction temperature being controlled in the range of 0 ℃ to about 25 ℃.

The corresponding diacylated product IV is then hydrolyzed with calcium hydroxide or barium hydroxide in aqueous tetrahydrofuran to selectively remove the acyl group at the 2-oxo position, and the remaining ester is hydrolyzed to form the corresponding calcium or barium salt (III), which is isolated by filtration.

In the formula M⁺²The compounds of formula III, which are Ca or Ba cations, are novel compounds which can be hydrolyzed under selected conditions according to scheme 3 to give compounds II, VI or VII.

Scheme 3

With reference to scheme 3, compound III with selected alcohols R¹The OH is reacted in hydrochloric acid to form the acylated derivative of ziprasidone in the half ester hydrochloride (II) chemical form.

Compound III may also optionally be reacted with water and hydrochloric acid to form the carboxylic acid in zwitterionic VI or hydrochloride VII form.

Prodrugs of ziprasidone may be administered as a neuroleptic agent. It may be administered alone to the human being treated, preferably together with a pharmaceutically acceptable carrier or diluent in a pharmaceutical composition, in accordance with standard pharmaceutical practice. Prodrugs of ziprasidone can be administered orally or parenterally, including intravenously or intramuscularly. Suitable pharmaceutical carriers include solid diluents or fillers, as well as sterile aqueous solutions and various organic solvents. The pharmaceutical composition is easily administered in various dosage forms such as tablets, powders, lozenges, syrups and injections. These pharmaceutical compositions may, if desired, contain other ingredients such as flavouring agents, binders and excipients. Thus, for oral purposes, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used for tableting. Solid compositions of a similar type may also be used as fillers to soften and harden filled gelatin capsules. Preferred materials for this include lactose and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents together with diluents such as water, ethanol, propylene glycol, glycerin and mixtures thereof.

The effective dosage of the ziprasidone prodrug of the invention will depend on the route of administration to be employed, the indication to be treated, and other factors such as the age and weight of the subject being treated. In the dosage ranges below, the term "mgA" refers to the number of milligrams of the free base of the prodrug. The recommended oral dosage range is 6-400 mgA/day, preferably 50-250 mgA/day, and more preferably 50-100 mgA/day. Parenteral administration, e.g., injection, is recommended to be in the range of 3.0 to 200 mgA/day, preferably 6.0 to 100 mgA/day.

Because of their improved solubility in water compared to ziprasidone, the prodrugs of the invention can be formulated as gastrointestinal drugs. As another advantage, the prodrug is slowly hydrolyzed in vivo; thereby gradually releasing ziprasidone into the patient's body over a long period of time. Due to the lower utilization rate, the frequency of drug delivery to the patient is desirably reduced. For parenteral administration, solutions or suspensions of the ziprasidone prodrug in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent should first be rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed can readily be obtained by standard procedures well known to those skilled in the art.

The effective dose of ziprasidone prodrug will depend on the route of administration and other factors such as the age and weight of the subject generally known.

The following preparations and examples of prodrugs of the present invention are provided for the purpose of further illustration only and are not intended to limit the scope of the claimed invention. The industrial reagents are used without further purification. The melting point was not corrected. NMR data are reported in parts per million (δ) and are referenced to the deuterium lock signal from the sample solvent. All mass spectra were performed using electron impact (E1, 70eV) conditions unless otherwise indicated. Unless otherwise indicated, chromatography refers to column chromatography, performed on 32-63 μm silica gel, and performed under nitrogen pressure (flash chromatography). High Pressure Liquid Chromatography (HPLC) was performed on a Hewlett packard 1100 series HPLC. Analysis by HPLC (mobile phase: 1100ml acetonitrile, 1000ml water, 2ml H₃PO₄2ml TEA), using an Inertsil 5. mu.C 8150X 4.6mm (MetaChem, Technologies Inc.) column; the flow rate is 1.0 ml/min; a detector: UV 250 nm; an injector: 10 mu l of the mixture; the column temperature was 36 ℃.

Preparation 1

Succinic acid 5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) ethyl ] -6-chloro-1- (3-ethoxycarbonyl) -propionyl-1H-indol-2-yl ester ethyl ester

In situ formation of anhydrides

Part A

Ethyl succinyl chloride [ ethyl 3- (chloroformyl) propionate ] (57ml, 381 mmol, 2.5 molar equivalents) was dissolved in anhydrous dichloromethane (610ml) at 15-25 ℃ under nitrogen atmosphere. Sodium hydroxide particles (3.1g, 76 mmol, 0.5 molar equivalent) were then added and the resulting mixture was stirred thoroughly at 15-25 ℃ for 75 minutes under nitrogen, after which the mixture was kept for part B.

Acylation reaction

Part B

Under the nitrogen atmosphere, magnesium bromide diethyl ether adduct MgBr is added at the temperature of 15-25 DEG C₂·Et₂O (82.3g, 320 mmol, 2.1 mol ratio) was stirred into dry dichloromethane (1200ml) and a nitrogen atmosphere was maintained throughout. Triethylamine (54ml, 381 mmol, 2.5 mol ratio) was added and the resulting suspension was cooled to 6.5 ℃. To this cooled suspension was added a solution of ziprasidone (63.0g, 153 mmol, 1 mole ratio) in anhydrous tetrahydrofuran (1100ml) over 20 minutes while the reaction mixture temperature was maintained at 6.5 ℃. When the addition was complete, the reaction mixture was stirred at 6.5 ℃ for a further 40 minutes. The prepared anhydride solution described in section a above was then added under nitrogen over a period of 30 minutes such that atmospheric moisture could not come into contact with the reagents or reaction mixture. During the addition, the reaction temperature was increased from 6.5 ℃ to 14 ℃. After the addition was complete, the reaction mixture was stirred at 10 ℃ for 1 hour and at 15-25 ℃ for 6 hours. The reaction mixture was then quenched by the addition of distilled water (1000ml), the organic layer was separated and the remaining aqueous layer was extracted twice with dichloromethane (2X 250 ml). The dichloromethane layer and the extracts were combined and the volume reduced to about 800ml under reduced pressure. The combined concentrated dichloromethane solutions were washed twice with distilled water (2X 400ml), dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to give 100.6g of a cream brown solid product.

Preparation 2

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-barium butyrate salt

The product of preparation 1 (15.0g, 22.4 mmol, 1 mol), tetrahydrofuran (112ml), distilled water (280ml) and barium hydroxide (12.0g, 44.8 mmol, 2 mol) were stirred together to form a reaction mixture, and stirred at 69-71 ℃ for 24 hours to form a thick slurry during the reaction. When the reaction was complete, the reaction mixture was cooled to 15-30 ℃, water (200ml) was added and the quenched reaction mixture was stirred for 15 minutes. The precipitated product was separated by filtration, washed with distilled water (500ml), and dried in vacuo to give 29g of a white solid which was a mixture of barium salt and residual inorganic barium salt. This product was used in the second step described in example 3 without further purification.

Preparation 3

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid calcium salt

The product of preparation 1 (78.2g, 116.9 mmol) was mixed together with 95% pure calcium hydroxide (26.8g, 140 mmol), tetrahydrofuran (585ml) and water (1460ml) and stirred at 65 ℃ for 16 h. The resulting reaction mixture was cooled to room temperature and water (600ml) was added. The product began to precipitate and after at least 20 minutes of granulation at room temperature, precipitation was complete. The resulting calcium salt product was isolated by filtration, washed with water (400ml) and dried under vacuum at 90 ℃ for at least 16 hours. This product contains hydrated water and trace impurities.

Example 1

Preparation of 4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid ethyl ester hydrochloride

The product of preparation 1 (27.8g, 53.2 mmol), ethanol (530ml) and 32% concentrated hydrochloric acid (20ml, 4.5 equiv) were mixed together. The mixture was boiled under reflux at 79 ℃ for 2 hours. (the end of the reaction was carefully monitored by HPLC observing the product peak at-2.7 minutes and possible reaction by-products at-5.3 minutes). The reaction mixture was filtered at-70 ℃ and the residue washed with hot ethanol (50ml) at-70 ℃. The filtrate and washings were combined and cooled to room temperature. Water (100ml) was added to start crystallization and after a minimum of 15 minutes of granulation at room temperature, the product was isolated by filtration, washed with water (100ml) and dried in a vacuum oven at 75 ℃ for 1 day to give 19.8g of an off-white to light red brownish solid in 64.4% yield.

C₂₇H₃₀Cl₂N₄O₄S calculated value: c.56.15; h, 5.24; cl, 12.28; n, 9.70; s, 5.55. found: c, 55.51; h, 5.27; cl, 12.04; n, 9.67; and S, 5.28.

FT-IR：3149，2954，2508，2430，1728，1656，1624，1590，1561，1494，1474，1447，1377，1351，1290，1159，1038，1013，993，878，736，712，596，548.

¹H-NMR(DMSO，400MHz)：δ11.41(bs)，8.15-8.08(m)，7.64(s)，7.58(t)，7.45(t，)，6.95(bs)，4.02(q)，3.69(bs)，3.53(bs)，3.36(bs)，3.33-3.30(t，)，3.23-3.21(m)；2.65(t)，2.48(t)，1.15(t).

¹³C-NMR(DMSO，400MHz)：δ172.51，162.89，152.81，128.81，127.66，125.33，124.74，121.89，60.79，55.87；51.27，47.20，28.15，14.76.

Example 2

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid ethyl ester

The compound from preparation 1 (15.0g, 26.0 mmol), dichloromethane (150ml) and 5% w/v aqueous sodium bicarbonate solution (150ml) were mixed and the resulting mixture was stirred well for 25 minutes at 35 ℃. Dichloromethane (100ml) was then added and stirring continued for 20 minutes at 30 ℃. The reaction mixture was extracted with dichloromethane (2X 100ml), the aqueous layer was separated and the combined organic layers were washed with water (4X 200 ml). The washed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to about 100 ml. To the concentrate thus obtained was added acetonitrile (500ml), crystallization was started in the course of the addition, and the resulting crystal slurry was re-concentrated under vacuum to remove residual dichloromethane. The solid was filtered off and dried in a vacuum oven at 60 ℃.

And (3) recrystallization: the initially isolated product was dissolved in a minimum amount of hot dichloromethane and acetonitrile was added until crystallization began and the resulting crystallization slurry was reconcentrated under vacuum to remove residual dichloromethane. The purified solid was filtered and dried in a vacuum oven at 60 ℃.

C₂₇H₂₉ClN₄O₄S calculated value: c, 59.94; h, 5.40; cl, 6.55; n, 10.35; s, 5.93, found: c; 59.66, respectively; h, 5.71; cl, 6.72; n, 10.58; and S, 5.97.

FT-IR：2983，2839，2812，1730，1657，1638，1562，1490，1470，1462，1422，1386，1282，1263，1240，1153，1121，1037，1013，991，940，892，799，739，668，646，583.

¹H-NMR(DMSO，400MHz)：δ8.10-8.05(m)，7.69(s)，7.55(t)，7.43(t)，6.75(s)，4.01(q)，3.59(s)，3.13-3.08(m)，2.95(s)，2.54(t)，2.48(s)，1.14(t).

¹³C-NMR(DMSO，400MHz)：δ173.50，163.54，152.74，135.41，128.68，128.68，127.84，125.21，124.79，121.80，60.41，58.01，52.33，48.93，31.95，30.27，29.88，14.79.

Example 3

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid ethyl ester, hydrochloride

The barium salt (21.0g) produced in preparation 2, ethanol (550ml) and concentrated hydrochloric acid (6ml) were added together and the resulting reaction mixture was boiled under reflux at 78-80 ℃ for 4 hours. To the reaction mixture was added another portion of concentrated hydrochloric acid (4ml) and heating at reflux was continued for 1 hour. Ethanol (100ml) was added to the hot, uncooled reaction mixture and the resulting mixture was stirred for 10 minutes without further cooling. The precipitated barium salt was removed by hot filtration and washed with hot ethanol (200 ml). The ethanol filtrate and washings were combined and concentrated under reduced pressure. Ethane was added until the cloud point was reached until product solids precipitated out of solution. The precipitated solid was isolated by filtration and dried under vacuum to give the product 5.6g in 65% yield over two passes.

Example 4

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid isobutyl ester, hydrochloride

The product of example 3 (1.0g, 1.7 mmol, 1 molar equivalent) was dissolved in 2-methyl-1-propanol (27ml), concentrated hydrochloric acid (136 μ l, 1 molar equivalent) was added and the reaction mixture was heated at a temperature range of 98-100 ℃ for 4.5 hours. Cooling the reaction mother liquor to room temperature of 15-25 ℃, adding distilled water (10ml), granulating for 15 minutes, filtering and separating the product, and drying under vacuum. Yield 640mg (62% yield).

Example 5

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid methyl ester, hydrochloride

The product of preparation 2 (1.0g), methanol (26ml) and sufficient concentrated hydrochloric acid were added together until the reaction mixture was detected to be acidic. The resulting reaction mixture is boiled under reflux at 63-65 ℃ for 24 hours. The reaction mixture was cooled to a temperature range of 15-25 ℃, distilled water (25ml) was added and the mixture was stirred for 30 minutes at a temperature range of 15-25 ℃. The solid product precipitated from solution, was isolated by filtration and dried in vacuo to give 490mg (49% yield) of the product.

Example 6

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid ethyl ester, hydrochloride

The product of example 5 (611mg, 1.1 mmol) was mixed with ethanol (27ml) and concentrated hydrochloric acid (0.5ml) and the mixture was boiled under reflux at a temperature range of 78-80 ℃ for 24 h, distilled water (20ml) was added to the hot reaction mixture and the solid was removed during hot filtration. The filtrate was cooled again and the solid product isolated by filtration, washed with distilled water (20ml) and dried under vacuum to give 200mg (32% yield).

Example 7

Preparation of 4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid ethyl ester hydrochloride

The product calcium salt of preparation 3 (27.8g, 53.2 mmol), ethanol (530ml) and 32% concentrated hydrochloric acid (20ml,. about.4.5 equiv) were mixed together and the mixture was boiled under reflux at 79 ℃ for 2 hours (the end of the reaction was carefully monitored by HPLC to see the peak of the product at 2.7 minutes and possible reaction by-products at 5.3 minutes) the reaction mixture was filtered at-70 ℃ and the residue was washed with 70 ℃ hot ethanol (50 ml). The filtrate and washings were combined, allowed to cool to room temperature, water (100ml) was added to start crystallization, and after a minimum of 15 minutes of granulation at room temperature, the product was isolated by filtration, washed with water (100ml) and dried in a vacuum oven at 75 ℃ for 1 day to give 19.8g of an off-white to light red brownish solid in 64.4% yield.

C₂₇H₃₀Cl₂N₄O₄S calculated value: c, 56.15; h, 5.24; cl, 12.28; n, 9.70; s, 5.55. found: c, 55.51; h, 5.27; cl, 12.04; n, 9.67; and S, 5.28.

FT-IR：3149，2954，2508，2430，1728，1656，1624，1590，1561，1494，1474，1447，1377，1351，1290，1159，1038，1013，993，878，736，712，596，548.

¹H-NMR(DMSO，400MHz)：δ11.41(bs)，8.15-8.08(m)，7.64(s)，7.58(t)，7.45(t，)，6.95(bs)，4.02(q)，3.69(bs)，3.53(bs)，3.36(bs)，3.33-3.30(t，)，3.23-3.21(m)，2.65(t)，2.48(t)，1.15(t).

¹³C-NMR(DMSO，400MHz)：δ172.51，162.89，152.81，128.81，127.66，125.33，124.74，121.89，60.79，55.87，51.27，47.20，28.15，14.76.

Example 8

Preparation of 4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid ethyl ester

The product of example 1 or example 7 (15.0g, 26.0 mmol), dichloromethane (150ml) and 5% w/v aqueous sodium bicarbonate solution (150ml) were mixed and the resulting mixture was stirred well for 25 minutes at 35 ℃. Dichloromethane (100ml) was then added and stirring was continued for 20 minutes at 30 ℃. The reaction mixture was extracted with dichloromethane (2X 100ml), the aqueous layer was separated and the combined organic layers were washed with water (4X 200 ml). The washed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to about 100 ml. To the concentrate thus obtained was added acetonitrile (500ml), crystallization commenced during the addition, and the resulting crystalline slurry was reconcentrated under vacuum to remove residual dichloromethane, the solid was filtered off and dried in a vacuum oven at 60 ℃.

And (3) recrystallization: the initially isolated product was dissolved in a minimum amount of hot methylene chloride, acetonitrile was added until crystallization began, the resulting crystallization slurry was reconcentrated under vacuum to remove residual methylene chloride, and the purified solid was filtered and dried in a vacuum oven at 60 ℃.

C₂₇H₂₉ClN₄O₄S calculated value: c, 59.94; h, 5.40; cl, 6.55; n, 10.35; s, 5.93, found: c, 59.66; h, 5.71; cl, 6.72; n, 10.58; and S, 5.97.

FT-IR：(cm^-1)2983，2839，2812，1730，1657，1638，1562，1490，1470，1462，1422，1386，1282，1263，1240，1153，1121，1037，1013，991，940，892，799，739，668，646，583.

¹H-NMR(DMSO，400MHz)：δ8.10-8.05(m)，7.69(s)，7.55(t)，7.43(t)，6.75(s)，4.01(q)，3.59(s)，3.13-3.08(m)，2.95(s)，2.54(t)，2.48(s)，1.14(t).

¹³C-NMR(DMSO，400MHz)：δ173.50，163.54，152.74，135.41，128.68，128.68，127.84，125.21，124.79，121.80，60.41，58.01，52.33，48.93，31.95，30.27，29.88，14.79.

Example 9

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid, hydrochloride salt

The calcium salt product of preparation 3 (20g, 37.6 mmol) was mixed together with concentrated hydrochloric acid (7.9ml, 2.5 equiv.) and water (750ml) and stirred at 50 ℃ overnight. The resulting reaction mixture was a slurry, which was cooled to room temperature and water (250ml) was added. The product was granulated at room temperature for at least 15 minutes. The resulting product was isolated by filtration, washed with water (100ml) and dried under vacuum at 70 ℃ for at least 16 hours. 15.2g of an off-white to light brown solid are obtained in 74% yield.

¹H-NMR(DMSO，400MHz)：δ10.24(bs)，9.55(bs)，8.07-8.03(m)，7.73(s)，7.55(t)，7.42(t，)，7.27(bs)，6.84(bs)，6.63(bs)，3.47(bs)，3.20(bs)，2.95-2.84(m)，2.73(bs)，2.59(bs)，2.49(bs)，2.39(bs).

Example 10

4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-butyric acid, mesylate.

The calcium salt product of preparation 3 (10g, 19.5 mmol), tetrahydrofuran (75ml), water (75ml) and methanesulfonic acid (9.5ml, 7.5 eq) were mixed together and stirred at ambient temperature overnight. The resulting product was isolated by filtration, washed with tetrahydrofuran/water (30ml of each) and dried under vacuum at 45 ℃ for at least 16 hours. 5.4g of an off-white to light brown solid are obtained in 54% yield.

¹H-NMR(DMSO，300MHz)：δ9.85(bs)，8.20-8.12(m)，7.65-7.60(m)，7.50(t)，6.98(bs)，4.17(d)，3.84-3.73(m)，3.50-3.33(m)，3.24-3.12(m)，2.63-2.57(m)，2.53-2.50(m)，2.43(s)，2.35(s)，2.09(s)，1.36(s).

Example 11

Preparation of 4- {5- [2- (4-benzo [ d ] isothiazol-3-yl-piperazin-1-yl) -ethyl ] -6-chloro-2-oxo-2, 3-dihydro-indol-1-yl } -4-oxo-decyl butyrate hydrochloride

The product of example 9 (4.0g, 7.28 mmol), 4-dimethylaminopyridine (800mg, 6.55 mmol, 0.9 equiv.), N, N "-dicyclohexylcarbodiimide (2.0g, 9.46 mmol, 1.3 equiv.) and dichloromethane (25ml) were added together to form a dark solution. To the dark solution obtained above was then added 1-decanol (1.5ml, 8.0 mmol, 1.1 equiv). The resulting reaction mixture was heated to 40 ℃ for 3 days. To the reaction mixture were added dichloromethane (40ml) and water (20ml) to isolate the product. The organic layer was separated and washed with water (2X 20 ml). The washed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness in a vacuum rotary evaporator. The resulting black gum (6.43g) was dried under vacuum overnight.

Purification by column chromatography:

stationary phase: silica gel 60A, mobile phase: ethyl acetate

Fractions 1 to 7 were collected and concentrated to about 50ml ethyl acetate by rotary evaporation. Hexane was added until solid precipitated. Granulated for 4 hours and filtered. The solid was washed with 50ml of hexane. Drying in a vacuum oven at 80 ℃ for 18 h gave the product as a purplish-brown fine solid (2.3 g).

FT-IR(cmu^-1)：ν3320，2924，2850，1724，1609，1473，1454，1420，1381，1350，1258，1162，1024，907，863，735，703，666，584.

¹H-NMR(DMSO，400MHz)：δ10.29(bs)，8.04(d)，7.70(bs)，7.54(t)，7.41(t，)，7.25(bs)，7.19(s)6.82(bs)，6.62(bs)，5.58(d)，3.93(bs)，3.47(s)，3.35(bs)，2.99-2.96(m)，2.87(bs)，2.73(bs)，2.62(bs)，2.49(s)，1.71(d)，1.59(d).1.49(bs).1.17(bs)，0.81(t).

Claims (13)

1. A compound of formula I

Or a pharmaceutically acceptable acid addition salt thereof, wherein R¹Selected from hydrogen and C₁-C₁₀An alkyl group; and wherein n is an integer of 1 to 5.

2. A compound according to claim 1, wherein R¹Is ethyl.

3. A process for the preparation of a compound of formula I,

comprising reacting a compound II of the formula with a base,

in the formula R¹Selected from hydrogen and C₁-C₁₀An alkyl group; and wherein n is an integer of 1 to 5.

4. The process of claim 3 wherein the compound of formula II is prepared by reacting a compound of formula III with water or formula R in the presence of concentrated hydrochloric acid¹Alcohol reaction of OH to obtain:

wherein M is calcium or barium; r¹Is C₁-C₁₀An alkyl group; and wherein n is an integer of 1 to 5.

5. The process of claim 4, wherein the compound of formula III is prepared by reacting a compound IV of the formula:

in the formula R²Is C₁～C₁₀An alkyl group, n is an integer of 1 to 5.

6. The process of claim 5 wherein the compound of formula IV is prepared by reacting a compound of the formula V:

7. the process of claim 6 wherein the acylating agent is an anhydride acylating agent having the formula VI:

in the formula R²Is C₁～C₁₀An alkyl group, n is an integer of 1 to 5.

8. The process of claim 6 wherein the anhydride acylating agent is reacted with the compound of formula V in the presence of magnesium bromide-diethyl etherate and an organic base.

9. The process of claim 7 wherein the anhydride acylating agent is an anhydride having the formula VII:

10. the process of claim 8, wherein the organic base is triethylamine.

11. The process of claim 3, wherein the base is selected from the group consisting of alkali metal bicarbonates, alkali metal carbonates, C₁-C₆Trialkylamines; and heterocyclic bases selected from pyridine, lutidine and picoline.

12. The method of claim 11, wherein the base is sodium bicarbonate.

13. A pharmaceutical composition having neuroleptic activity comprising a psychotropic effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.