MXPA00000511A - A crystalline dibenzothiazepine derivative and its use as an antipsychotic agent - Google Patents

A crystalline dibenzothiazepine derivative and its use as an antipsychotic agent

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Publication number
MXPA00000511A
MXPA00000511A MXPA/A/2000/000511A MXPA00000511A MXPA00000511A MX PA00000511 A MXPA00000511 A MX PA00000511A MX PA00000511 A MXPA00000511 A MX PA00000511A MX PA00000511 A MXPA00000511 A MX PA00000511A
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Mexico
Prior art keywords
hydroxyethoxy
piperazinyl
dibenzo
thiazepine
ethyl
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Application number
MXPA/A/2000/000511A
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Spanish (es)
Inventor
Evan William Snape
Original Assignee
Zeneca Limited
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Publication of MXPA00000511A publication Critical patent/MXPA00000511A/en

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Abstract

Crystalline 11-(4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine (I) may be prepared by crystallising 11-(4-[2-(2-hydroxyethoxy)ethyl]-1- piperazinyl)-dibenzo[b,f][1,4]thiazepine from a non-aromatic solvent such as ethyl acetate, isobutyl acetate, methyl iso-butylketone or methyl tert-butyl ether, preferably in the absence of water. The crystalline material produced may be converted into a pharmaceutically acceptable salt such as a fumarate. The crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1- piperazinyl)-dibenzo[b,f][1,4]thiazepine may be used to treat psychoses.

Description

A DERIVATIVE OF DIBENZODIACEPINE CRYSTALINE AND ITS USE AS AN ANTIPSYCHOTIC AGENT DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of diazepine derivatives and, in particular, to the preparation of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f ] [1,4] thiazepine and salts thereof. The compound, 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine (Formula I) shows antidopaminergic activity useful, for example, as an antipsychotic agent with a substantial reduction in potential causes side effects such as acute dystonia, acute dyskinesia, pseudo-Parkinsonism and tardive dyskinesia. The compound of the formula I is described in the European Patent issued EP 240,228. This patent describes the properties of the compound of the formula I and its synthesis of dibenzofb, f] [1,] thiazepine-11 (10-H) -one. In this synthetic route it is necessary to prepare and purify the compound 2- (2-hydroxyethoxy?) Ethyl-1-piperazine (HEEP). The European patent granted EP 282,236 describes an improved process for the preparation of the compound of the formula I which obviates the need to prepare and purify the compound 2- (2-hydroxyethoxy) ethyl-1-piperazine since this improved process does not it uses 2- (2-hydroxyethoxy) ethyl-1-piperazine. The need to use carboxyethyl piperazine which is useful for preparing 2- (2-hydroxyethoxy) ethyl-1-piperazine is also obvious. Various pharmaceutical compounds develop as salts of pharmacologically acceptable acids or bases. This is usually done if the biologically active substance itself has a physical form that makes it unsuitable for handling in manufacturing processes. Most of . Manufacturing processes involve materials that can be handled in mixtures and formulation, which is facilitated by the active materials being either a liquid or a highly fusible, free-flowing solid. Although salts can be made with suitable acids or bases, these sometimes do not add anything to the therapeutic benefit of the compounds, pharmaceuticals and are therefore biologically redundant. This should be better if the pharmaceutical compound can be manufactured as the pure active substance. - The reported synthesis of 1- (4- [2- (2-hydroxyethoxy) ethyl] -l-piperazinyl) -dibenzo [b, f] [1,4] thiazepine provides 11- (4- [2- (2- hydroxyethoxy) ethyl] -1-piperazonyl) -dibenzo [b, f] [1,4] thiazepine as a fumarate salt from this has been necessary to prepare the salt to efficiently obtain a sufficiently pure product. However, preparing the fumarate salt has been necessary to first prepare the hydrogen fumarate salt and substantially convert it to fumarate. The present invention is based, at least in part, on an improved method of purifying the compound of the formula I, and in particular in a method of purifying the compound of the formula I such that the compound of the formula, I is obtained in a crystalline form. According to the present invention, it is provided 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] crystalline thiazepine. 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -. dibenzo [b, f] [1,4] crystalline thiazepine can be converted to one of its pharmaceutically acceptable salts and thus the present invention also provides 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) crystalline dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt prepared therefrom.
The 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-pipera? Nyl; -dibenzo [b, f] [1,4] crystalline thiazepine is generally provided in a substantially pure form.This is generally preferred that 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] crystalline thiazepine is greater than 90% pure, more preferably 99% or more preferred 99% pure According to the present invention it is also possible to provide a process for preparing 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b], f] [1,4] crystalline isothiazepine a pharmaceutically acceptable salt thereof comprising crystallizing 11- (4- [2- (2-hydroxyethoxy) and yl] -1-piperazinyl) -dibenzo [b, f] [1 , 4] thiazepine from a non-aromatic solverme, and from, where a pharmaceutically acceptable salt is required, reacts 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f ] [1,] thiazepine with an acid that facilitates a pharmaceutically acceptable linkage. According to the present invention there is also a process provided to prepare 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] crystalline thiazepine or a salt pharmaceutically acetable comprising crystallizing 11- (4 - [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine from a non-aromatic solvent substantially in the absence of water; and from where, when a pharmaceutically acceptable salt is required, 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine reacts with an acid que- provides a pharmaceutically acceptable anion. The crystallization can be initiated with the help of a seed crystal. The salts of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine will generally comprise acid addition salts. Suitable salts can be selected from those pharmaceutically acceptable salts known in the art. This can be obtained by any conventional salt preparation method known in the art For example, salts can be obtained by the reaction of 11- (4- [2- (2-hydroxyethoxy) and yl] -1-piperazinyl ) -dibenzo [b, ~ f ~] Tl \ 4] thiazepine with a convenient acid, such as hydrochloric acid, maleic acid, fumaric acid, citric acid, phosphonic acid, methanesulfonic acid and sulfuric acid. fumarate and in particular hemi-fumarate salt It is generally preferred that the fumarate salt of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1, 4] thiazepine is bis- [11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine] fumarate.
It is generally preferred, for example, that the solvent be dry. It is further preferred that 11- (4- [2- (2-hydroxy-oxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] thiazepine is also dry so that the solution formed in the solution of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine in the solvent is substantially free of water. More specifically, the solution formed in the crystallization process must be free of water. Thus, in a preferred embodiment there is a process provided to prepare 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine, or a pharmaceutically acceptable salt thereof, which comprises crystallizing 11- (4 - [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine from a solution of 11- (4 - [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [T, ~ 4] thiazepine in a non-aromatic solvent that is free of water. The 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] crystalline thiazepine may, if desired, be converted to a pharmaceutically acceptable salt, as mentioned before. Examples of such solvents include, for example, esters such as those of the formula R.xCO "R 'wherein R1 and R" are alkyl groups, ethers of the formula RJOR4 wherein RJ and R4 are alkyl groups; the formula R ^ COR6 wherein R 5 and R 6 are alkyl groups.
The particular values of R1, R ', R', R4, R'J and R6 include, for example, C? _ Alkyl? such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl. Conveniently, R1, R :, R1, and R are selected from C? _ Alkyl. Specific examples of the suitable solvent include, for example, ethyl acetate, isobutyl acetate, methyl iso-butyl ketone and methyl tert-butylether. Solvents of particular interest include, for example, ethers. Thus, a solvent of particular interest is methyl tert-butyl ether. The temperature of the solution contains 11- (4- [2- (2-hydroxyet i) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine which can be decreased during crystallization. In general, the temperature will be lowered to approximately 0 ° C. Conveniently, the temperature is gradually decreased over a period of time. Thus, in a specific example, the temperature is lowered to room temperature (approximately 25 ° C) and then further decreased to approximately 0 ° C for a period greater than 1 hour and generally greater than 2 hours. In particular, the temperature is decreased from room temperature to 0 ° C for a period of 2 to 4 hours, preferably about 3 hours. Where a seed crystal is used this will generally be added to the crystallization mixture when the mixture is at room temperature. In the case where the temperature is lowered, the seed crystal will, in general, be added just before the temperature is lowered (from room temperature). The amount of solvent used to crystallize 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine will vary according to the precise solvent selected. In particular, the amount of solvent is such that, when 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine is dissolved in it gives a concentration (before crystallization) of about 120_- to 160mg / ml, more particularly 130 to 150mg / ml. It is generally preferred that the amount of the solvent be such that it gives a concentration (before crystallization.) Of about 135 to 145 mg / ml. In a particular embodiment of the invention there is provided a purification method 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] thiazepine which comprises crystallizing 11- (- [2- (2-hydroxyethoxy) and yl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine-methyl-tert-butyl ether in the absence of water. Particular and specific, preferred conditions include those mentioned in the above.
As mentioned before, the crystalline product. it may, if desired, be converted to a pharmaceutically acceptable salt. - In a further embodiment of the present invention there is provided a method for preparing the fumarate of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1, 4] thiazepine, which method comprises reacting 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzofb, f] [1,4] crystalline thiazepine with fumaric acid. ~~~~ The 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazin? L) -dibenzo [b, f] [1,4] crystalline thiazepine will generally be prepared as defined above at the moment. The 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazyl) -dibenzo [b, f] [1,4] crystalline thiazepine will generally be reacted with the fumaric acid in a solvent such as an alcohol . Examples of such alcohols will include methanol and ethanol. A particularly suitable solvent is ethanol which may conveniently be in the form of industrial methylated spirits (IMS). The present invention also provides a method for preparing crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] thiazepine, or a pharmaceutically acceptable salt of the same, - ~ of a solution of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] thiazepine in an aromatic solvent whose process comprises: a) add water and an acid to the solution of 11- (4- [2- (2- * hydroxyethoxy) ethyl] -1-pipera3myl) -dibenzo [b, f] [1,4] thiazepine -in the aromatic solvent; b) separate the aqueous and organic phases; c) adding a non-aromatic solvent and a base to the aqueous phase; d) separating the aqueous and non-aromatic solvent phases e) drying the non-aromatic solvent phase; f) crystallizing 11- (4- [2- (2-hydroxyethoxy) ethyl] -l-pi? < -razi-nil) -dibenzo [b, f] [1,4] thiazepine from non-aromatic solvent; and from where, if a pharmaceutically acceptable salt is desired, 11- (4- [2- (2-hydroxyethoxy) -ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] is reacted. thiazepine with the acid that provides a pharmaceutically acceptable anion. The particular, preferred and specific values: include the aforementioned values. The aromatic solvent is preferably toluene. It will be appreciated that the amount / strength of the acid added in step (a) will be such that the aqueous is made acidic and the amount / strength of the aggregate phase in step (c) will be such that the aqueous phase will be makes basic. The compound of this invention is a central nervous depressant system and can be used as a tranquilizer for the relief of hyperactivity states, for example, in mice, gratos, rats, dogs and other mammalian species, and additionally for the management of psychotic conditions in man, in the same way as chlorpromazine. For this purpose 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine, or the physiologically acceptable acid addition salt thereof, it can be administered orally or parenterally in a conventional dosage form such as tablets, pills, capsules, injectables or the like. The dose in ml / kg of body weight of a compound of the present invention in mammals will vary according to the size of the animal and particularly with respect to the brain / body weight ratio. In general, a higher dose of mg / kg for a small animal such as a cat will have the same effect as a lower dose of mg / kg in an adult human. A minimum effective dose for the compound of the formula I will be at least about 1.0 mg / kg of body weight per day for mammals with a maximum dose for a small mammal - such as a dog of approximately 200 mg / kg per day. For humans, a dose of approximately 1.0 to 40 mg / kg per day will be effective, for example, approximately 50 to 200 mg / day for a person of 50 kg average weight. The dose can be given once daily or in divided doses, for example, 2 to 4 daily doses. The dose may be conventionally formulated in an oral or parenteral dosage form by the combination of about 25 to 500 mg per unit dose of the conventional vehicle, excipient, binder, preservative, stabilizer, flavoring or the like as called by pharmaceutically acceptable practice. , for example, as described in US Patent 3,755,340. The compound of the formula I (or salt) can be used in pharmaceutical compositions as previously described or be contained in or co-branched with one or more other known drugs. Thus, according to the present invention there is also provided a pharmaceutical composition comprising 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] -thiazepine crystalline or a pharmaceutically acceptable salt prepared therefrom, together with a pharmaceutically acceptable diluent or carrier. In particular, a "pharmaceutical composition comprising 11- (4- [2- (2-hydroxyethoxy) et il] -1-piperaxazinyl) -dibenzo [b, f] [1,4] crystalline thiazepine and a diluent or pharmaceutically acceptable carrier The present invention also provides a method for treating neuropsychiatric disorders (in particular, a method of treating psychosis, more particularly schizophrenia) using 11- (- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) - dibenzo [b, f] [1,4] crystalline thiazepine, or a pharmaceutically acceptable salt prepared therefrom In particular, the present invention provides a method for treating neuropsychiatric disorders, which comprises administering an effective amount of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine crystalline to a warm-blooded mammal such as a human, In particular, the present invention provides a method treat psychosis, more particularly Schizophrenia The present invention also provides the use of crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine in the manufacture of a medicament to treat neuropsychiatric disorders and in particular psychoses such as schizophrenia. As mentioned above, the present invention offers advantages over known methods for preparing- 11- (4- [2- (2-hydroxylethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] - thiazepine and its salts. First, the present invention provides crystalline 11- (- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] -thiazepine. In particular the invention provides processes for the preparation rJe 11- (4- [2- (2-hydroxyet i) ethyl] -1-piperazinyl) -dibenzo [b, E] [1 *, 4] crystalline thiazepine which is high purity. In general, the crystalline material has a high melting point consistent with a crystalline solid of high purity and good quality. Previously, pure 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine "has been obtained by the provision of a purified salt, the This has required the preparation of the hydrogen fumarate salt followed by subsequent conversion to the fumarate salt.This conversion is a resulting process of low relativity which requires the use of relatively dilute reaction mixtures to ensure the formation of the desired fumarate salt greater than a mixture of forms of hydrogen fumarate and fumarate salt.With the use of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzofb, f] [1, 4] purified crystalline thiazepine, the fumarate salt can be prepared in a relatively high resulting process from the difficulties associated with obtaining the correct salt form are minimized.The present invention also provides processes for the preparation of 11- (4- [2- ( 2-hydroxyethoxy?) Ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine and its salts in a more productive form than previously reported using materials and / or plants such as more efficient solvents.
This invention will be illustrated by the following non-limiting examples in which, otherwise stated: (i) the temperature is given in degrees Celsius (C): the operations are carried out at room temperature, that is, that It is a temperature in the range of 18-25 ° C. (ii) evaporation of the solvent is carried out using a rotary evaporator under reduced pressure (600 ^ 4000 pascal, 4.5-30 mmHg) with a bath temperature above 60 ° C; (iii) in general, the course of the reactions are followed by TLC and / or HPLC and reaction times are only for illustration; ~~~ (iv) the melting points are uncorrected and (dec) indicates decomposition; the melting points given are those obtained by the materials prepared as described; the polymorphism may result from the isolation of materials with different melting points in the same preparations; ~~ (v) all final products were essentially pure through TLC and / or HPLC and had microanalytical data and satisfactory nuclear magnetic resonance (NMR) spectrum; (vi) returns are given for illustration only; ~ (vii) the reduced pressure is given as absolute pressures in pascals (Pa); other pressures are given as pressures calibrated in bars; (viii) chemical symbols have their usual meaning; The following abbreviations are also used: v (volume), p (weight), mp (melting point), L (liters), mi (milliliters), g (grams), mmoles (millimoles), mg (milligrams), min (minutes), h (hours), IMS (industrial methylated spirits); and La 11- (4- [2- (2-hydrox-ethoxy) ethyl] -1-piperazyl) -dibenzo [b, f] [1,4] thiazepine was prepared as described in European Patent No. EP 282,236. This compound can also be prepared as described in European Patent No. 240,228. Example 1 (a) Water (106ml) is added to a stirred mixture of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] t Ace-pina (59 g) in toluene at 40 ° C. Concentrated hydrochloric acid, - (21.4ml) is added to the mixture and the mixture is stirred vigorously for 15 minutes at 40 ° C. The phases are separated. Methyl tert-butyl ether (25 ml) is added to the phase. watery Aqueous sodium hydroxide solution (15.4 ml, density 1.5 g / cm 3) is added and the mixture is heated to 45 ° C and stirred vigorously for 15 minutes. The mixture was allowed to settle and the phases separated. The organic phase was washed with water (2 x 25 ml) at 45 ° C and then dried by distillation at 55 ° C using a Dean and StarK separator. The dry mixture was allowed to cool to 25 ° C. It was sown and stirred overnight to give a solid. The mixture was cooled to 0 ° C and kept at 0 ° C for 4 hours. The solid was collected by filtration, washed with methyl ter-butylétei and dried "in a vacuum oven at 50 ° C overnight, then 11- (4 - [2- (2-hydroxyethoxy) tyl] -1-piperazinyl was obtained. ) -dibenzo [b, f] [1,4] thiazepine (46.7 g) as a white crystalline solid, mp 82-84 ° C. (b) IMS (35 ml) was added to the free base- (30.0 g) and the stirred mixture was heated to 60 ° C. in a 100 ml flask to give a solution.This solution was transferred to a 500 ml reactor vessel by a sinter.The 100 ml flask was washed with heat (60 ° C) IMS (10 ml) and washing was added to the reaction vessel. The mixture in the reactor vessel was heated to 60 ° C with stirring. Fumaric acid (4.65 g) and IMS (60 ml) were added to the 100 ml flask. The mixture was heated to 60 ° C, with stirring to give a solution containing a small number of solid masses of material. The mixture was added to the reaction vessel by the sinter as well as the mixture was filtered and the masses were removed. The resulting mixture in the reaction vessel was stirred to give the crystalline material. IMS (10 ml) was added to the 100 ml flask, heated to 60 ° C and transferred to the reaction vessel. The thick crystalline mass in the reaction vessel was heated to reflux and then allowed to cool to room temperature, to give a solid. The stirred mixture was cooled to 0 ° C and the temperature of the mixture was kept at this temperature for 1 hour.The solid was collected by filtration and washed with cold IMS (30 ml) (0 to 5 ° C). IMS had to be used to wash out the reaction vessel.The solid was dried in a vacuum oven at 55 ° C overnight to give 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] thiazepine as a white crystalline solid (32.7 g); 94.4 ^ of performance. Example 2 Using a method similar to that described in Example 1, 11- (4- [2- (2-hydroxy-ethoxy) and yl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine was crystallized to give the listed solvents instead of methyl tert-butyl ether.
Solvent Resistance (%) Performance (%) P.F. (° C) Acetate of 100 39.7 .-) ethyl111 Acetate of iso31, 5 70.1 83-86 butyl Methyl iso- 99.4 69.7 83-86 butyl ketone Methyl iso- 99.3 67.8 85-86 butyl ketone1 'Methyl ter- 100 86 83-86 butyl ether Methyl ter- 99 J-W6 butyl ether [1] crystallized from 11- (4 - [2- (2-hydroxyethyl) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] iazepine - previously isolated [2] ] suitable solid [3] load 80 ', Resistance is a measure of purity. He ? of resistance is the t, of the desired ingredient, 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, £] [1,] iazepine, in the weight of the isolated material. EXAMPLE 3 The following illustrates pharmaceutically representative dosage forms containing a compound of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine and salts of the same, for example as illustrated in any of the above Examples (hereinafter referred to as "compound -X"), for therapeutic or prophylactic use in humans: (a) Table ta mg / tablet Compound X 50.0 Mannitol . USP 223.75 Croscarmellose sodium. . . . '6.0 Corn starch 15.0 Hydroxypropylmethylcellulose (HPMC), 2.25 Magnesium stearate ~' 3.0 (b) Capsule Compound X 10.0 Mannitol. USP 488.5 Croscarmellose sodium 15.0 Magnesium stearate. . . . . . ~ "™ ~" 1.5 The above formulations can be obtained, by the conventional procedure well known in the pharmaceutical art. The tablets may be enteric coated by conventional means, for example to provide a cellulose acetate phthalate coating.

Claims (22)

  1. CLAIMS 1- A compound that is 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] 11, 4] crystalline thiazepine.
  2. 2. The compound according to claim 1, characterized in that the crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine is greater 90% pure.
  3. 3. The compound according to claim 2, characterized in that the. 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] tiac "crystalline pina is greater than 99% pure
  4. 4. A process for preparing 11 - (crystalline 4-12- (2-hydroxyethoxy) and yl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine or the pharmaceutically acceptable salt thereof, which comprises crystallizing 11- (4 - [2- (2-hydroxyethoxy) tyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine of a non-aromatic solvent, and from which a pharmaceutically acceptable salt is required, is reacted 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,] thiazepine with an acid providing a pharmaceutically acceptable anion
  5. 5. A process for plowing " 11- (4- (2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzofb, f] [1, Itiazepine or the pharmaceutically acceptable salt thereof, which comprises crystallizing 11- (4- [2- ( 2-hydroxyethoxy) and yl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine from a solution of 11- (4- [2- (2 -hydroxyethoxy) ethyl] -1-piperazinyl) -diben [b, f] [1,4] thiazepine in a non-aromatic solvent and in which the solution is substantially free of water.
  6. 6. The process according to any of claims 4 or 5, characterized in that the non-aromatic solvent is selected from an ester of the formula R1COR wherein R1 and R ~ are alkyl groups; an ether of the formula R ^ OR'1 wherein R3 and R4 are alkyl groups; and a ketone of the formula R ° CORr 'wherein R 5 and R 6 are alkyl groups.
  7. 7. The process according to claim 6, characterized in that R1, R2, R ', and R4 are selected from C1-4 alkyl.
  8. 8. The process according to claim 6, characterized in that the non-aromatic solvent is selected from ethyl acetate, isobutyl acetate, methyl iso-butyl ketone and methyl tert-butyl ether.
  9. 9. The process according to any of claims 4 to 8, characterized in that the solvent is selected from methyl tert-butyl ether.
  10. 10. A process for purifying 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, £] [1,4] thiazepine comprising crystallizing 11- (4- [2- (2-hydroxyethoxy) etii] -1-piperazinyl) -dibenzo [b, f] [1,4] thiacep a of methyl tert-butyl ether in the absence of water. The process according to any of claims 4 to 10, characterized in that 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine - and the non-aromatic solvent are heated to a solution and the temperature of the solution contains 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1 , 4] thiazepine is decreased at room temperature and then further decreased to about 0 ° C for a longer period of time.
  11. I hour
  12. 12. The process according to claim 11, characterized in that the temperature is lowered from room temperature to 0 ° C for a period of about 2 to 4 hours.
  13. 13. The process in accordance with the claim
    II or 12, characterized in that the temperature is lowered from an environment at 0 ° C for a period of about 3 hours. -
  14. 14. The process according to any of claims 4 to 13, characterized in that the amount of the non-aromatic solvent is that which, when 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) - dibenzo pi / J "[1, 4] thiacepme is dissolved therein to give a concentration (before crystallization) of about 120 to 160 mg / ml.
  15. 15. The process according to claim 14, characterized in that the amount of a non-aromatic solvent gives 135 to 145 mg / ml.
  16. 16. The process- in accordance with any <; Ue claims 4 to 15, characterized in that it comprises reacting 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazomyl) -dibenzo [b, f] [1,4] crystalline thiazepine with acid fumaric to give the fumarate salt of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-pipe azinyl) -dibenzo [b, f] [1,4] thiazepine.
  17. 17. The process for preparing crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzofb, f] [1,] thiazepine or a pharmaceutically acceptable salt thereof, of a solution of 11- (4 - [2- (2-hydroxy-toxy) and il] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine - in an aromatic solvent whose process is characterized in that it comprises: a ) adding water and an acid to the solution 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzofb, f] [1,4] thiazepine in the aromatic solvent; b) separate the aqueous and organic phases; - • _ c) adding a non-aromatic solvent and a base to the aqueous phase; d) separating the aqueous and non-aromatic solvent phases; e) drying the non-aromatic solvent phase; f) crystallizing 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazyl-nyl) -dibenzo [b, f] [1,4] thiazepine from the non-aromatic solvent; and from where, if a pharmaceutically acceptable salt is desired, react 11- (4 - [2- (2-yl-hydroxyethoxy-tyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine with a acid that provides a pharmaceutically acceptable anion
  18. 18. The process according to the claim
    17, characterized in that the aromatic solvent is toluene.
  19. 19. The process according to claim 17 or 18, characterized in that step (f) is carried out as claimed in any of claims 4 to 17. ~
  20. 20. A pharmaceutical composition comprising 11- (4) - [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] thiazepine crystalline and a pharmaceutically acceptable diluent or carrier
  21. 21. The use of 11- (4- [2- (2-hydroxyethoxy) et il] -1-piperazinyl) -dibenzo [b, f] [1,4] crystalline thiazepine in the manufacture or a medicament for treating neuropsychiatric disorders. - (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) -dibenzo [b, f] [1,4] crystalline thiazepine in the manufacture of a medicament for treating psychoses.
MXPA/A/2000/000511A 1997-08-01 2000-01-13 A crystalline dibenzothiazepine derivative and its use as an antipsychotic agent MXPA00000511A (en)

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Application Number Priority Date Filing Date Title
GB9716161.6 1997-08-01

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MXPA00000511A true MXPA00000511A (en) 2001-05-07

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