BG107357A

BG107357A - Thiazolidinedione salt fore treatment of diabetes mellitus

Info

Publication number: BG107357A
Application number: BG107357A
Authority: BG
Inventors: Andrew Craig; Tim HO
Original assignee: Smithkline Beecham P.L.C.
Priority date: 2000-06-08
Filing date: 2002-12-05
Publication date: 2003-08-29
Also published as: GB0014006D0; BR0111536A; CZ20023966A3; AP2002002673A0; NO20025883L; JP2003535862A; EA200300005A1; NO20025883D0; IL153279A0; HUP0301137A2; WO2001094344A1; ZA200209954B; PL360592A1; AU2001264078A1; DZ3382A1; OA12284A; CN1443186A; MA25753A1; CA2411065A1; MXPA02012100A

Abstract

A novel pharmaceutical compound 5-[4-2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4 -dione hydrobromide or a solvate thereof, a process for preparing such a compound, a pharmaceutical composition comprising such a compound are the use of such a compound in medicine. 10 claims, 4 figures

Description

ТЕХНИЧЕСКА СЪЩНОСТ НА ИЗОБРЕТЕНИЕТОSUMMARY OF THE INVENTION

Изобретението се отнася до ново фармацевтично средство, до метод за получаването на фармацевтичното средство и до използването на фармацевтичното средство в медицината.The invention relates to a new pharmaceutical agent, to a method for the preparation of a pharmaceutical agent, and to the use of the pharmaceutical agent in medicine.

ПРЕДШЕСТВАЩО СЪСТОЯНИЕ НА ТЕХНИКАТАBACKGROUND OF THE INVENTION

Европейска патентна заявка, номер на публикацията ЕР 0,306,228 се отнася до определени тиазолидиндионови производни, разкрити като притежаващи хипогликемична и хиполипидемична активност. Съединението от пример 30 на ЕР 0,306,228 е 5-[4-[2-(Ν-Μβτππ-Ν-(2пиридил)амино)етокси]бензил]тиазолидин-2,4-дион (по-нататък в описанието се отнася като “Съединение (I)”).European Patent Application Publication Number EP 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycemic and hypolipidemic activity. The compound of Example 30 of EP 0,306,228 is 5- [4- [2- (N-ββπππ-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter referred to as "Compound (I) ”).

Международна патентна заявка, номер на публикацията WO 94/05659 разкрива определени соли на съединенията от ЕР 0,306,228, включващи соли, образувани от минерални киселини, като бромоводородна, хлороводородна и сярна киселини и органични киселини, като соли на метансулфонова, винена и по-специално малеинова киселина.International Patent Application Publication Number WO 94/05659 discloses certain salts of the compounds of EP 0,306,228, including salts formed from mineral acids such as hydrobromic, hydrochloric and sulfuric acids and organic acids such as salts of methanesulfonic, tartaric and in particular maleic acid.

Сега беше открито, че Съединение (I) образува нова сол на бромоводородната киселина (тук също се отнася като “Хидробромид”), която е особено стабилна и подходяща за обемно получаване и обработване. Хидробромидът също има висока точка на топене, показва особено добра водоразтворимост и притежава добри обемни свойства на потока. Следователно, хидробромидът е изненадващо податлив на фармацевтично преработване в голям мащаб и специално на едромащабно смилане.It has now been found that Compound (I) forms a new salt of hydrobromic acid (also referred to herein as "Hydrobromide"), which is particularly stable and suitable for bulk preparation and treatment. The hydrobromide also has a high melting point, exhibits particularly good water solubility and has good flow properties. Therefore, the hydrobromide is surprisingly susceptible to large-scale pharmaceutical processing and in particular large-scale milling.

Новата форма може да бъде получена чрез ефективен, икономичен и възпроизводим метод, особено подходящ за едро мащабно получаване.The new form can be obtained by an efficient, economical and reproducible method, particularly suitable for large-scale production.

Новият Хидробромид също има полезни фармацевтични свойства и по-специално се посочва, че е полезен за лечението и/или профилактиката на захарен диабет, състояния, свързани със захарния диабет и определени негови усложнения.The new Hydrobromide also has useful pharmaceutical properties and is particularly indicated to be useful for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof.

Съобразно с това, настоящото изобретение осигурява 5-[4-[2-(Nметил-М-(2-пиридил)амино)етокси]бензил]тиазолидин-2,4-дион хидробромид или негов солват.Accordingly, the present invention provides 5- [4- [2- (Nmethyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof.

Подходящо е хидробромидът да е монохидробромид.The hydrobromide is suitably monohydrobromide.

В един предпочитан аспект, Хидробромидът осигурява инфрачервен спектър в съответствие с Фигура I.In one preferred aspect, the Hydrobromide provides the infrared spectrum in accordance with Figure I.

В предпочитан аспект, Хидробромидът осигурява Раманов спектър в съответствие с Фигура II.In a preferred aspect, the Hydrobromide provides the Raman spectrum in accordance with Figure II.

В предпочитан аспект, Хидробромидът осигурява рентгенова дифракционна диатрама на прахов образец (дебайграма) (XRPD) в съответствие с Таблица I или Фигура III.In a preferred aspect, the Hydrobromide provides an X-ray powder diffraction pattern (XRPD) in accordance with Table I or Figure III.

В предпочитан аспект Хидробромидът осигурява ¹³С NMR спектър в твърдо състояние в съответствие с Фигура IV.In a preferred aspect, the Hydrobromide provides a ¹³ C solid state NMR spectrum in accordance with Figure IV.

Благоприятно е също е, че Хидробромидът има точка на топене в обхвата от 175 до 185°С, специално 180 до 185°С, например 181 °C.It is also advantageous that the hydrobromide has a melting point in the range of 175 to 185 ° C, especially 180 to 185 ° C, for example 181 ° C.

Също, Хидробромидът има Т_{начална} в обхвата от 180 до 186°С, например 182.5°С.Also, the hydrobromide has a T _initial in the range of 180 to 186 ° C, for example 182.5 ° C.

Така в предпочитан аспект, Хидробромидът се характеризира по това, че той осигурява един или повече от:Thus, in a preferred aspect, the Hydrobromide is characterized in that it provides one or more of:

(i) инфрачервен спектър в съответствие с Фигура I;(i) infrared spectrum in accordance with Figure I;

(й) Раманов спектър в съответствие с Фигура II;(j) Raman spectrum according to Figure II;

(iii) Рентгенова диаграма на прахов образец (дебайграма) в съответствие с Таблица I или Фигура III;(iii) X-ray powder pattern (debig) in accordance with Table I or Figure III;

(iv) ¹³С NMR спектър в твърдо състояние в съответствие с Фигура IV; и (ν) точка на топене в обхвата от 175°С до 185°С, специално 180 до(iv) ¹³ C solid state NMR spectrum according to Figure IV; and (ν) a melting point in the range of 175 ° C to 185 ° C, in particular 180 to

185°С, например 181 °C.185 ° C, for example 181 ° C.

Настоящото изобретение обхваща Хидробромидът или негов солват, изолирани в чиста форма или когато се смесят с други материали. Така, в един аспект се осигурява Хидробромида или негов ?*- солват в изолирана форма.The present invention encompasses the Hydrobromide or solvate thereof, isolated in pure form or when mixed with other materials. Thus, in one aspect, the Hydrobromide or its? * Solvate in isolated form is provided.

В друг аспект се осигурява Хидробромида или негов солват в пречистена форма.In another aspect, the Hydrobromide or solvate thereof is provided in purified form.

Допълнително в друг аспект се осигурява Хидробромида или негов солват в кристална форма.In another aspect, the hydrobromide or solvate thereof is provided in crystalline form.

Също така, изобретението осигурява Хидробромида или негов солват в твърда фармацевтично приемлива форма, като например твърда дозирана форма, особено когато е приспособена за орално прилагане.The invention also provides the Hydrobromide or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.

Освен това, изобретението също осигурява Хидробромида или негов солват във фармацевтично приемлива форма, специално в обемна форма, такава форма, която да бъде подходяща за смилане.In addition, the invention also provides the Hydrobromide or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, in a form suitable for milling.

Следователно, изобретението осигурява Хидробромида или негов солват във фармацевтично приемлива форма, специално в обемна форма, такава форма, която да има добри свойства на потока, специално добри обемни свойства на потока.Accordingly, the invention provides the Hydrobromide or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, such as to have good flow properties, especially good bulk flow properties.

Подходящ солват е хидрат.A suitable solvate is a hydrate.

Изобретението също осигурява метод за получаване на Хидробромида или негов солват, характеризиращ се с това, че 5-[4-[2-(Nметил-М-(2-пиридил)амино)етокси]бензил]тиазолидин-2,4-дион (Съединение I) или негова сол, за предпочитане диспергирани или разтворени в подходящ разтворител, взаимодейства с източник на бромоводород и ако се изисква, солват на Хидробромида се получава; и Хидробромидът или неговия солват се възстановява.The invention also provides a process for the preparation of the Hydrobromide or solvate thereof, characterized in that 5- [4- [2- (Nmethyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione ( Compound I) or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a hydrobromide source and, if required, a hydrobromide solvate is obtained; and the hydrobromide or solvate is recovered.

Подходящ реакционен разтворител е алканол, например пропан-гол или въглеводород, като толуен, кетон, като ацетон, естер, като етилацетат, етер, като тетрахидрофуран, нитрил, като ацетонитрил, или халогениран въглеводород, като дихлорметан, вода, органична киселина, като оцетна киселина или техни смеси.A suitable reaction solvent is alkanol, for example propane-gol or hydrocarbon, such as toluene, ketone, such as acetone, ester, such as ethyl acetate, ether, such as tetrahydrofuran, nitrile, such as acetonitrile, or halogenated hydrocarbon, such as dichloromethane, water, organic acid. acid or mixtures thereof.

Подходящо, източникът на бромоводород се осигурява посредством воден разтвор на бромоводород, например, 48% w/w разтвор във вода. Алтернативно, източникът на бромоводород е разтвор на бромоводород в подходящ разтворител, евентуално реакционният разтвор, например, пропан-2-ол. В допълнение, бромоводородът може да бъде добавен директно към разтвор или суспензия на Съединение (I) в избрания реакционен разтворител.Suitably, the source of hydrogen bromide is provided by an aqueous solution of hydrogen bromide, for example, a 48% w / w solution in water. Alternatively, the source of hydrogen bromide is a solution of hydrogen bromide in a suitable solvent, optionally the reaction solution, for example, propan-2-ol. In addition, hydrogen bromide can be added directly to a solution or suspension of Compound (I) in the chosen reaction solvent.

Алтернативен източник на бромоводород се осигурява чрез основна сол на бромоводородна киселина, например амониев бромид или сол на бромоводордната киселина на амина, например, етиламин или диетиламин.An alternative source of hydrobromic is provided by a basic salt of hydrobromic acid, for example ammonium bromide or a salt of hydrobromic acid of an amine, for example, ethylamine or diethylamine.

Реакцията обикновено се провежда при околна температура или при повишена температура, например при температурата на флегмата на разтворителя, въпреки че може да бъде използвана всяка подходяща температура, която осигурява необходимия продукт.The reaction is usually carried out at ambient temperature or at elevated temperature, for example at the reflux temperature of the solvent, although any suitable temperature that provides the required product may be used.

Солвати, като хидрати на Хидробромида, се получават съгласно конвенционални методи.Solvates, such as hydrobromide hydrates, are prepared according to conventional methods.

Оползотворяване на изискваното съединение общо включва кристализация из подходящ реакционен разтворител, обикновено чрез охлаждане до температура в обхвата от 0°С до 60°С, например, 20 доUtilization of the required compound generally involves crystallization from a suitable reaction solvent, typically by cooling to a temperature in the range of 0 ° C to 60 ° C, for example, 20 to

25°С или от 40 до 50°С. Например, Хидробромидът може да бъде изкристализирам из алкохол, като пропан-2-ол или кетон, като ацетон.25 ° C or 40 to 50 ° C. For example, the hydrobromide may be crystallized from an alcohol such as propan-2-ol or a ketone such as acetone.

В една предпочитана форма оползотворяването се състои в първоначално охлаждане до начална температура, като такава в обхвата от 40 до 50°С, при което настъпва първоначалнална кристализация и след това охлаждане до вторична температура, подходяща е в обхвата от 0 до 25°С.In one preferred embodiment, the recovery consists of initial cooling to an initial temperature, such as in the range of 40 to 50 ° C, whereby an initial crystallization occurs and then cooling to a secondary temperature, suitable in the range of 0 to 25 ° C.

Кристализацията може също да бъде инициирана чрез зараждане на кристали с кристали от Хидробромид или негов солват, но това не е крайно необходимо.Crystallization can also be initiated by the formation of crystals with crystals of Hydrobromide or a solvate thereof, but this is not absolutely necessary.

w Солвати се получават чрез използване на подходящи конвенционални методи.w Solvates are prepared using appropriate conventional methods.

Съединение (I) се получава съгласно известни методи, такива, които са разкрити в ЕР 0,306,228 и WO 94/05659. Разкритията в ЕР 0,306,228 и WO 94/05659 са дадени от литературата.Compound (I) is prepared according to known methods, such as those disclosed in EP 0,306,228 and WO 94/05659. The disclosures in EP 0,306,228 and WO 94/05659 are given in the literature.

Когато тук се използва, изразът “Т_начална” се определя от Диференциалната Сканираща Калориметрия и има общоизвестно значение в науката, както за примера, изразен в “Pharmaceutical Thermal Analysis, Techniques and Applications”, Ford and Timmins, 1989 като “The temperature corresponding to the intersection of the pre-transition baseline w with extrapolated edge of the transition”.When used herein, the term "T _- helical" is defined by Differential Scanning Calorimetry and is of common knowledge in science, as in the example expressed in "Pharmaceutical Thermal Analysis, Techniques and Applications", Ford and Timmins, 1989 as "The temperature corresponding to the intersection of the pre-transition baseline w with the extrapolated edge of the transition ”.

Когато тук се използва изразът “добри свойства на поток” във връзка с определени съединения подходящо се охарактеризира от споменатото съединение, имащо Hausner коефициент по-малък от или равен на 1.5, специално по-малък от или равен на 1.25.When used herein the term "good flow properties" in relation to particular compounds is suitably characterized by said compound having a Hausner coefficient of less than or equal to 1.5, especially less than or equal to 1.25.

“Hausner коефициент” е възприет термин в науката."Hausner coefficient" is an accepted term in science.

Когато тук се използва изразът “профилактика на състояния, свързани със захарен диабет” включва лечението на състояния, такива като устойчивост на инсулин, понижен глюкозен толеранс, хиперинсулинизъм и гестационен диабет.When used herein, the term "prevention of diabetes-related conditions" includes the treatment of conditions such as insulin resistance, decreased glucose tolerance, hyperinsulinism, and gestational diabetes.

Ч&де·'·H & where

Захарен диабет, за предпочитане, означава захарен диабет Тип II.Diabetes mellitus preferably means type II diabetes mellitus.

Състояния, свързани с диабет включват хипергликемия и устойчивост на инсулин и пълнота. Други състояния, свързани с диабет включват повишено кръвно налягане, сърдечно съдови заболявания, специално атеросклероза, определени храносмилателни разтройства, по-специално регулирането на апетита и приемането на храна при пациенти, страдащи от разтройства, свързани с недостатъчно хранене, като анорексия на нервна почва и разтройства, свързани с преяждане, като напълняване и анорексия булемия. Допълнителни състояния, свързани с диабет, включват синдром на поликистозни яйчници и инсулинова устойчивост, индуцирана от стероид.Diabetes-related conditions include hyperglycemia and insulin resistance and fullness. Other conditions related to diabetes include high blood pressure, cardiovascular disease, especially atherosclerosis, certain digestive disorders, in particular regulation of appetite and food intake in patients suffering from malnutrition disorders such as anorexia nervosa and overeating disorders such as bulking and anorexia bulemia. Additional conditions associated with diabetes include polycystic ovary syndrome and steroid-induced insulin resistance.

Усложненията на състоянията, свързани със захарния диабет, обхванати тук, включват бъбречно заболяване, специално бъбречно заболяване, свързано с развитието на диабет Тип II, включващо диабетна нефропатия, гломерулонефрит, гломеруларна склероза, нефритен синдром, хипертензивна нефросклероза и краен стадий на бъбречно заболяване.The complications of the diabetes mellitus conditions covered herein include kidney disease, a particular kidney disease associated with the development of Type II diabetes, including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephritic syndrome, hypertensive nephrosclerosis.

Както се споменава по-горе съединението от изобретението има полезни терапевтични свойства. Настоящото изобретение осигурява Хидробромида или негов солват за използване като активна терапевтична субстанция.As mentioned above, the compound of the invention has useful therapeutic properties. The present invention provides the Hydrobromide or solvate thereof for use as an active therapeutic substance.

По-специално, настоящото изобретение осигурява Хидробромида или негов солват за използване при лечението и/или профилактиката на захарен диабет, състоянията, свързани със захарния диабет и негови определени усложнения.In particular, the present invention provides the Hydrobromide or solvate thereof for use in the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof.

Хидробромидът или неговия солват може да бъдат приложен сам по себе си или за предпочитане като фармацевтичен състав също съдържащ фармацевтично приемлив носител. Подходящи методи да приготвянето на Хидробромида или неговия солват, общо всето са тези, разкрити за Съединение (I) в гореспоменатите публикации.The hydrobromide or solvate thereof may be administered alone or preferably as a pharmaceutical composition also containing a pharmaceutically acceptable carrier. Suitable methods for preparing the Hydrobromide or solvate thereof are generally those disclosed for Compound (I) in the aforementioned publications.

Съобразно с това настоящото изобретение също осигурява фармацевтичен състав, съдържащ Хидробромида или неговия солват и негов фармацевтично приемлив носител.Accordingly, the present invention also provides a pharmaceutical composition comprising the Hydrobromide or solvate thereof and a pharmaceutically acceptable carrier thereof.

Хидробромидът или негов солват нормално се прилагат в единица дозирана форма.The hydrobromide or solvate thereof is normally administered in unit dosage form.

Активното съединение може да бъде приложено, чрез който и да е подходящ начин, но обикновено чрез оралните или парентерални начини. За такова използване, съединението обикновено ще бъде използвано във формата на фармацевтичен състав заедно с фармацевтичен носител, разредител и/или ексципиент, въпреки че точната форма на съединението ще зависи от начина на прилагане.The active compound can be administered by any suitable route, but usually by oral or parenteral routes. For such use, the compound will typically be used in the form of a pharmaceutical composition together with a pharmaceutical carrier, diluent and / or excipient, although the exact form of the compound will depend on the route of administration.

Съединения се приготвят чрез смесване и са подходящо приспособени за орално, парентерално или местно прилагане и като такива могат да бъдат във формата на таблетки, капсули, орално течни състави, прахове, гранули, перли, пастили, възстановяеми прахове, разтвори за инжектиране и вливане, или суспензии, супозитории и трансдермални начини. Предпочитат се съединения, които могат да се прилагат орално, по-специално оформени орални състави, тъй като те са по-удобни за общо използване.Compounds are prepared by blending and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, orally liquid compositions, powders, granules, pearls, pastilles, recoverable powders, injection and infusion solutions, or suspensions, suppositories and transdermal routes. Compounds which can be administered orally, in particular shaped oral compositions, are preferred, since they are more convenient for general use.

Таблетки и капсули за орално прилагане обикновено са в единица w доза и съдържат обичайни ексципиенти, такива като свързващи вещества, пълнители, разредители, таблетиращи вещества, омазващи вещества, дезинтегранти, оцветители, ароматизатори и омокрящи вещества. Таблетките могат да бъдат покрити в съответствие с известни методи в науката.Tablets and capsules for oral administration are usually in unit w dose and contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavors and wetting agents. The tablets may be coated according to known methods in the art.

Подходящи пълнители за използване включват целулоза, манитол, лактоза и други подобни вещества. Подходящи дезинтегранти включват нишесте, поливинилпиролидон и производни на нишестето, като натриево нишестен гликолат. Подходящи омазнители включват, например, магнезиев стеарат. Подходящи фармацевтични омокрящи вещества включват натриев лаурил сулфат.Suitable fillers for use include cellulose, mannitol, lactose, and the like. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutical wetting agents include sodium lauryl sulfate.

Твърди орални състави могат да бъдат получени чрез конвенционални методи на смесване, пълнене, таблетиране или подобните. Могат да бъдат използвани повторни операции на смесване, за да се разпредели активното вещество през тези състави, използвайки големи количества пълнители. Такива операции, разбира се, са конвенционални в науката.Solid oral compositions may be prepared by conventional methods of mixing, filling, tabletting or the like. Repeated mixing operations can be used to distribute the active substance through these compositions using large amounts of fillers. Such operations, of course, are conventional in science.

Орални течни състави могат да бъдат във формата, например, на водни или маслени суспензии, разтвори, емулсии, сиропи или елексири, ^w или могат да бъдат представени като сух продукт за възстановяване с вода или други подходящи носители преди употреба. Такива течни състави могат да съдържат конвенционални добавки, такива като суспендиращи вещества, например сорбитол, сироп, метилцелулоза, желатин, хидроксиетил целулоза, карбоксиметил целулоза, гел на алуминиев стеарат или хидрогенирани ядливи мазнини, емулгатори, например лецитин, сорбитан моноолеат, или акация; безводни носители (които могат да включват ядливи масла), например бадемово масло, фракционирано кокосово масло, маслени естери, такива като естери на глицерин, пропилен гликол или етилов алкохол, консерванти, например ** метил или пропил р-хидроксибензоат или сорбинова киселина и ако се желае обичайни ароматизиращи или оцветяващи вещества.Oral liquid compositions may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, ^w or may be presented as a dry product for reconstitution with water or other suitable carriers before use. Such liquid compositions may contain conventional additives, such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, emulsifiers, e.g. anhydrous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerol esters, propylene glycol or ethyl alcohol, preservatives, for example ** methyl or propyl p-hydroxybenzoate or sorbic acid, and if conventional flavoring or coloring agents are desired.

За парентерално прилагане се приготвят течни единица дозирани форми, съдържащи съединение от настоящото изобретение и стерилен носител. Съединението, зависейки от носителя и концентрацията, може или да бъде суспендирано или разтворено. Парентералните разтвори обикновено се приготвят чрез разтваряне на активното съединение в носител и пълнител, стерилизиране преди напълване в подходящ флакон или ампула и херметизиране. Благоприятно е, че прибавки, като местни анестезиращи, консервиращи и буфериращи вещества също се разтварят в носителя. За да се повиши стабилността съставът може да бъде замразен след напълване във флакона и водата да се отстрани под вакуум.For parenteral administration, a liquid unit dosage form containing a compound of the present invention and a sterile carrier is prepared. The compound, depending on the carrier and the concentration, can either be suspended or dissolved. Parenteral solutions are usually prepared by dissolving the active compound in vehicle and vehicle, sterilizing it prior to being filled into a suitable vial or ampoule and sealing. Advantageously, additives such as topical anesthetic, preservative and buffering agents are also dissolved in the carrier. In order to increase stability, the composition may be frozen after filling in the vial and the water removed in vacuo.

Парентералните суспензии се приготвят по същия начин, освен че активното съединение се суспендира в носителя вместо да бъде разтворено и стерилизирано чрез подлагане на етиленов оксид преди суспендирането в стерилния носител. Благоприятно е, че повърхностно активното вещество или омокрящото вещество се включва в състава, за да се улесни еднаквото разпределяне на активното съединение.Parenteral suspensions are prepared in the same way, except that the active compound is suspended in the vehicle instead of dissolved and sterilized by subjecting ethylene oxide before suspension in the sterile vehicle. Advantageously, the surfactant or wetting agent is incorporated into the composition to facilitate uniform distribution of the active compound.

Както е общоприето, съставите обикновено трябва да бъдат ft*' придружени с написани или отпечатани напътствия за употребата при съответното медицинско лечение.As generally accepted, the compositions should usually be ft * 'accompanied by written or printed instructions for use in appropriate medical treatment.

Така както се използва тук, изразът “фармацевтично приемлив” обхваща съединения, състави и ингредиенти за двете използвания при човека и ветеринарията: например, изразът “фармацевтично приемлива сол” обхваща ветеринарно приемлива сол.As used herein, the term "pharmaceutically acceptable" encompasses compounds, compositions, and ingredients for both human and veterinary use: for example, the term "pharmaceutically acceptable salt" encompasses a veterinarily acceptable salt.

Настоящото изобретение допълнително осигурява метод за лечението и/или профилактика на захарен диабет, състаяния, свързани със захарния диабет и негови определени усложнения при човека или друго млекопитаещо, което включва прилагане на ефективно, нетоксично w количество от Хидробромид или негов солват към човек или друго млекопитаещо при необходимост от това.The present invention further provides a method for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof in humans or other mammals, which includes administering an effective, non-toxic amount of Hydrobromide or a solvate thereof to a human or other mammal if necessary.

Обикновено, активният ингредиент може да бъде приложен като фармацевтичен състав, така както е дефиниран тук преди това, и това формира особен аспект на настоящото изобретение.Typically, the active ingredient can be administered as a pharmaceutical composition as defined herein before, and this forms a particular aspect of the present invention.

В друг аспект на настоящото изобретение се осигурява използването на Хидробромид или негов солват за производството на лекарствен препарат за лечението и/или профилактиката на захарен диабет, състояния, свързани със захарен диабет и определени негови усложнения.In another aspect of the present invention there is provided the use of Hydrobromide or a solvate thereof for the manufacture of a medicament for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof.

При лечението и/или профилактиката на захарен диабет, състояния, свързани със захарен диабет и определени негови усложнения, Хидробромидът или негов солват може да бъде поеман в количества, така че да осигури Съединение (I) в подходящи дози, такива каквито са разкрити в ЕР 0,306,228, WO 94/05659 и WO 98/55122.In the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof, the hydrobromide or solvate thereof may be administered in amounts to provide Compound (I) at appropriate doses such as disclosed in EP 0,306,228, WO 94/05659 and WO 98/55122.

Не са отбелязани никакви странични токсични ефекти при гореспоменатите лечения за съединението, съгласно изобретението.No adverse toxic effects were noted in the above-mentioned treatments for the compound of the invention.

Следващите примери илюстрират изобретението, но по никакъв начин не го ограничават.The following examples illustrate the invention but are by no means limited thereto.

ПРИМЕРИ ЗА ИЗПЪЛНЕНИЕ НА ИЗОБРЕТЕНИЕТОEXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

Пример 1: 5-[4-[2-(Ν-ΜθΤΗΠ·Ν-(2пиридил)амино)етокси]бензил]тиазолидин-2,4-дион хидробромидExample 1: 5- [4- [2- (Ν-ΜθΤΗΠ · Ν- (2pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

Смес на 5-[4-[2-(Ν-Μβτππ-Ν-(2пиридил)амино)етокси]бензил]тиазолидин-2,4-дион (1.0 д) и пропан-2-ол (50 ml) се разбърква и нагрява под обратен хладник в продължение на период от 10 минути, при което се наблюдава точка на бистър разтвор. Бромоводородна киселина (48% w/w разтвор във вода, 0.31 ml) след това се прибавя на капки и реакционната смес се разбърква в продължение на 10 минути под обратен хладник и после се охлажда до 21 °C. Продуктът се събира чрез филтриране и се промива с пропан-2-ол (10 ml) като се получава 5-[4-[2-(М-метил-М-(2-пиридил)амино)етокси]бензил]тиазолидин-A mixture of 5- [4- [2- (N-ββπππ-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione (1.0 g) and propan-2-ol (50 ml) was stirred and reflux for 10 minutes, at which point a clear solution is observed. Hydrobromic acid (48% w / w solution in water, 0.31 ml) was then added dropwise and the reaction mixture was stirred for 10 minutes under reflux and then cooled to 21 ° C. The product was collected by filtration and washed with propan-2-ol (10 ml) to give 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-

2,4-дион хидробромид (0.41 д) като бяло кристално твърдо вещество.2,4-dione hydrobromide (0.41 g) as a white crystalline solid.

Пример 2: 5-[4-[2-(Ν-μθτηπ·Ν-(2пиридил)амино)етокси]бензил]тиазолидин-2,4-дион хидробромидExample 2: 5- [4- [2- (N-μθτηπ · N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

Смес на 5-[4-[2-(Ν-ΜθτΜη-Ν-(2пиридил)амино)етокси]бензил]тиазолидин-2,4-дион (3.0 д) и ацетон (100 ml) се разбърква и нагрява под обратен хладник в продължение на период от 15 минути, при което се наблюдава точка на бистър разтвор. Бромоводородна киселина (48% w/w разтвор във вода, 0.95 ml) след това се прибавя и реакционната смес се разбърква в продължение на 15 минути под обратен хладник и после се охлажда до 21 °C. След престояване в продължение на 120 часа майчината луга се декантира и кристалният продукт се промива с ацетон (10 ml) и се изсушава под вакуум в продължение на 3 часа, като се получава 5-[4-[2-(Ν-Μβτππ-Ν-(2пиридил)аминоетокси]бензил]тиазолидин-2,4-дион хидробромид (3.7 д) ¹H-NMR (d₆-DMSO): съвместимо с 5-[4-[2-(М-метил-М-(2пиридил)аминоетокси]бензил]тиазолидин-2,4-дион хидробромид, съдържащ ацетон, 0.5% wt/wt.A mixture of 5- [4- [2- (Ν-ΜθτΜη-Ν- (2pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (3.0 g) and acetone (100 ml) was stirred and refluxed. for a period of 15 minutes, at which point a clear solution is observed. Hydrobromic acid (48% w / w solution in water, 0.95 ml) was then added and the reaction mixture was stirred for 15 minutes under reflux and then cooled to 21 ° C. After standing for 120 hours, mother liquor was decanted and the crystalline product was washed with acetone (10 ml) and dried in vacuo for 3 hours to give 5- [4- [2- (Ν-Μβτππ-Ν - (2-pyridyl) aminoethoxy] benzyl] thiazolidine-2,4-dione hydrobromide (3.7 g) ¹ H-NMR (d ₆ -DMSO): compatible with 5- [4- [2- (N-methyl-N- (2-pyridyl) ) aminoethoxy] benzyl] thiazolidine-2,4-dione hydrobromide containing acetone, 0.5% wt / wt.

Пример 3: 5-[4-[2-(Ν-μθτηπ-Ν-(2пиридил)амино)етокси]бензил]тиазолидин-2,4-дион хидробромидExample 3: 5- [4- [2- (Ν-μθτηπ-Ν- (2pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

Смес на 5-[4-[2-(М-метил-М-(2-пиридил)амино)етокси]бензил]тиазолидин-Mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-

2,4-дион (15.0 д) и ацетон (230 ml) се разбърква и нагрява под обратен хладник в продължение на 15 минути, при което се наблюдава точка на бистър разтвор. Бромоводородна киселина (48% w/w разтвор във вода,2,4-dione (15.0 g) and acetone (230 ml) were stirred and refluxed for 15 minutes, at which point a clear solution was observed. Hydrobromic acid (48% w / w solution in water,

4.75 ml) след това се прибавя и сместа се охлажда до 45°С и се разбърква в продължение на 1 час, след което се охлажда до 21 °C. Белият твърд продукт се събира чрез филтриране и се промива с ацетон (100 ml) като се получава 5-[4-[2-(1\1-метил-М-(2 пиридил)амино)етокси]бензил]тиазолидин-2,4-дион хидробромид (17.7 д) като бяло кристално твърдо вещество.4.75 ml) is then added and the mixture is cooled to 45 ° C and stirred for 1 hour, then cooled to 21 ° C. The white solid was collected by filtration and washed with acetone (100 ml) to give 5- [4- [2- (1'-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2, 4-dione hydrobromide (17.7 g) as a white crystalline solid.

ХАРАКТЕРИЗИРАЩИ ДАННИ ЗА ХИДРОБРОМИДА (1) РЕГИСТРИРАНИ ЗА ПРОДУКТА ОТ ПРИМЕР 3 Разтворимост на хидробромидаHYDROBROMIDE CHARACTERISTICS (1) REGISTERED FOR THE PRODUCT OF EXAMPLE 3 Hydrobromide Solubility

Разтворимостта на материала се определя чрез прибавяне на вода на аликвотни части от 1 до 1000 ml приблизително до 100 mg на лекарствена субстанция докато прахът се разтвори. Видимита разтворимост се потвърждава чрез HPLC опит на наситен разтвор.The solubility of the material is determined by adding water in aliquots of 1 to 1000 ml to approximately 100 mg of drug substance until the powder is dissolved. The apparent solubility was confirmed by HPLC test of a saturated solution.

Разтворимост: 6 mg/mlSolubility: 6 mg / ml

Разтворимост в твърдо състояние на хидробромидаSolid solubility of the hydrobromide

Разтворимостта в твърдо състояние на лекарствената субстанция се определя чрез съхраняване приблизително на 1.0 g от материала в стъклена бутилка при I) 40°С/75% относителна влажност (RH), открито излагане в продължение на 1 чесец и Ь) при 50°С, затворена в продължение на 1 месец. Материалът се изпитва чрез HPLC за крайно съдържание и продукти на разпадане при двата случая.The solubility of the solid substance of the drug substance is determined by storing approximately 1.0 g of the material in a glass bottle at I) 40 ° C / 75% relative humidity (RH), open exposure for 1 month and b) at 50 ° C. closed for 1 month. The material was tested by HPLC for final content and degradation products in both cases.

a) 40°С/ 75% RH: не се наблюдава изразено разпадане (HPLC опит 98% първоначално).a) 40 ° C / 75% RH: no pronounced decay was observed (HPLC experiment 98% initially).

b) 50°С: : не се наблюдава изразено разпадане (HPLC опит 98% първоначално).b) 50 ° C: no pronounced decay was observed (HPLC experiment 98% initially).

Свойства на потока на хидробромидаHydrobromide flow properties

Съотношението между обемното тегло и получено обемно тегло (коефицинет на Hausner) на Хидробромида се определя, използвайки стандартни методи (“Pharmaceutics-The Science of Dosage Form Desing”, editor M.AIton, 1988, published by:Churchill Livingstone).The ratio of the volume weight to the obtained body weight (Hausner coefficient) of the Hydrobromide was determined using standard methods ("Pharmaceutics-The Science of Dosage Form Desing", editor M.Aton, 1988, published by: Churchill Livingstone).

Коефициент на Hausner: 1.3Hausner coefficient: 1.3

Тначална HS ХИДробрОМИДаInitial HS HYDROBROMIDE

Тначална на лекарствената субстанция се определя от Диференциалната Сканираща Калориметрия, използвайки устройството на Perkin-EI;er DSC7.Initial drug substance was determined by Differential Scanning Calorimetry using the Perkin-EI; er DSC7 device.

Тначална 182.5 СOriginal 182.5 C

Точка на топене на хидробромидаHydrobromide melting point

Точката на топене на лекарствената субстанция се определя визуално чрез микроскоп.за определяне на температурата на топене.The melting point of the drug substance was determined visually by microscope to determine the melting temperature.

Температура на топене : 181 °C (2) РЕГИСТРИРАНИ ЗА ПРОДУКТА ОТ ПРИМЕР 2Melting point: 181 ° C (2) REGISTERED FOR EXAMPLE 2 PRODUCT

Спектърът на инфрачервено поглъщане на минерално маслена дисперсия на продукта се получава, използвайки спектрометър Nicolet 710 FT-IR при 2 cm'¹ дисперсия (Фигура I). Данните се дигитализират при 1 cm'¹ интервали. Ивици се наблюдават при:The infrared absorption spectrum of the mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at 2 cm < -1 ^> dispersion (Figure I). Data were digitized at 1 cm ^'1 intervals. The bands are observed at:

2923, 2854, 2749, 1745, 1698, 1643, 1610, 1544, 1515, 1459, 1419, 1378, 1327, 1313, 1287, 1256, 1240, 1228, 1203, 1185, 1151, 1071, 1054, 1032, 1014, 985, 906, 803, 771,738, 712, 524 cm’¹.2923, 2854, 2749, 1745, 1698, 1643, 1610, 1544, 1515, 1459, 1419, 1378, 1327, 1313, 1287, 1256, 1240, 1228, 1203, 1185, 1151, 1071, 1054, 1032, 1014, 985, 906, 803, 771.738, 712, 524 cm ^'1.

IR спектъра на твърдия продукт се регистрира, използвайки универсално съоръжение ATR. Ивици се наблюдават при: 2929, 2859, 2749, 1745, 1694, 1641, 1608, 1543, 1514, 1445, 1419, 1382, 1358, 1326, 1311, 1287, 1255, 1240, 1202, 1184, 1148, 1070, 1053, 1031, 1014, 985, 906, 862, 844, 802, 768, 737, 710, 657 cm'¹. Рамановият спектър на продукта (Фигура I) се регистрира с пробата в NMR тръба, използвайки Nicolet 960 E.S.P.FTраманов спектрометър, при дисперсия 4 cm'¹ с възбуждане от Nd:V04 лазер (1064 nm) с изходна мощност 400 mW. Ивици се наблюдават при:The IR spectrum of the solid product is recorded using a universal ATR facility. The bands are observed at: 2929, 2859, 2749, 1745, 1694, 1641, 1608, 1543, 1514, 1445, 1419, 1382, 1358, 1326, 1311, 1287, 1255, 1240, 1202, 1184, 1148, 1070, 1053 , 1031, 1014, 985, 906, 862, 844, 802, 768, 737, 710, 657 cm ' ¹ . The Raman product spectrum (Figure I) was recorded with the sample in an NMR tube using a Nicolet 960 ESPFT Raman spectrometer at 4 cm < ¹ ^> dispersion with a Nd: V04 laser (1064 nm) with a power output of 400 mW. The bands are observed at:

3067, 2997, 2926, 2884, 2860, 1747, 1611, 1588, 1545, 1445, 1382, 1360, 1315, 1287, 1240, 1213, 1185, 1070, 1016, 986, 917, 826, 769, 740, 712, 659, 636, 620, 605, 506, 470, 405, 332, 303, 134, 99 cm’¹.3067, 2997, 2926, 2884, 2860, 1747, 1611, 1588, 1545, 1445, 1382, 1360, 1315, 1287, 1240, 1213, 1185, 1070, 1016, 986, 917, 826, 769, 740, 712, 659, 636, 620, 605, 506, 470, 405, 332, 303, 134, 99 cm ¹ .

XRPD диаграмата на продукта (Фигура III) се регистира, използвайки следните постигнати условия: Анодна тръба: Си, напрежение на генератор: 40 kV, ток на генератор 40 mA, начален ъгър 2.0°2Θ, краен ъгъл: 35.0°2Θρ размер на стъпка 0.02°2Θ, време за стъпка 2.5 секунди. Характерните XRPD ъгли и относителни интензитети са записани в Таблица 1.The XRPD product diagram (Figure III) is recorded using the following conditions achieved: Anode tube: C, generator voltage: 40 kV, generator current 40 mA, start angle 2.0 ° 2Θ, end angle: 35.0 ° 2Θρ step size 0.02 ° 2Θ, time step 2.5 seconds. The characteristic XRPD angles and relative intensities are recorded in Table 1.

Таблица 1Table 1

Ъгъл Angle Интензитет Intensity 2-тета* 2-Theta * % % 10.0 10.0 2.9 2.9 11.7 11.7 2.7 2.7 12.4 12.4 0.8 0.8 13.2 13.2 8.9 8.9 13.4 13.4 9.6 9.6 13.8 13.8 1.1 1.1 14.4 14.4 1.8 1.8 14.8 14.8 5.6 5.6 15.9 15.9 7.4 7.4 16.3 16.3 23.5 23.5 17.1 17.1 17.2 17.2

17.6 17.6 15.5 15.5 18.1 18.1 21.1 21.1 19.4 19.4 15.1 15.1 20.3 20.3 6.8 6.8 20.7 20.7 2.4 2.4 21.3 21.3 7.3 7.3 22.1 22.1 36.3 36.3 22.5 22.5 20.8 20.8 22.8 22.8 3 3 23.4 23.4 100 100 23.7 23.7 18 18 24.0 24.0 19.7 19.7 24.5 24.5 18.1 18.1 24.9 24.9 25.2 25.2 25.7 25.7 10.6 10.6 26.3 26.3 12 12 26.8 26.8 11.8 11.8 27.0 27.0 15.8 15.8 27.3 27.3 6.6 6.6 27.8 27.8 15.4 15.4 28.2 28.2 5 5 29.2 29.2 12.4 12.4 29.4 29.4 6.8 6.8 29.9 29.9 5.9 5.9 30.4 30.4 11.5 11.5 30.7 30.7 21.9 21.9 31.1 31.1 2.9 2.9 31.8 31.8 7.2 7.2 32.2 32.2 8.3 8.3

32.3 32.3 8.8 8.8 32.5 32.5 11.9 11.9 33.0 33.0 7.3 7.3 33.9 33.9 7 7 34.3 34.3 9 9 34.7 34.7 5.5 5.5

Claims

Patent Claims

1. Compound 5- [4- [2- (N-ββππη-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof.

2,4-dione (15.0 g) and acetone (230 ml) were stirred and refluxed for 15 minutes, at which point a clear solution was observed. Hydrobromic acid (48% w / w solution in water,

2,4-dione hydrobromide (0.41 g) as a white crystalline solid.

Example 2: 5- [4- [2- (N-ββ · N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

A mixture of 5- [4- [2- (N-ββπππ-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (3.0 g) and acetone (100 ml) was stirred and refluxed. for a period of 15 minutes, at which point a clear solution is observed. Hydrobromic acid (48% w / w solution in water, 0.95 ml) was then added and the reaction mixture was stirred for 15 minutes under reflux and then cooled to 21 ° C. After standing for 120 hours, mother liquor was decanted and the crystalline product was washed with acetone (10 ml) and dried in vacuo for 3 hours to give 5- [4- [2- (Ν-Μβτππ-Ν - (2-pyridyl) aminoethoxy] benzyl] thiazolidine-2,4-dione hydrobromide (3.7 g) ¹ H-NMR (d ₆ -DMSO): compatible with 5- [4- [2- (N-ββπππ-N- (2-pyridyl) ) aminoethoxy] benzyl] thiazolidine-2,4-dione hydrobromide containing acetone, 0.5% wt / wt.

Example 3: 5- [4- [2- (Ν-μθτηπ-Ν- (2pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

Mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-

2-Theta scale

FIGURE IV: Solid state NMR spectrum of hydrobromide, ^ ···

THIAZOLIDINDINE TREATMENT SALT

Diabetes mellitus

2400/02-RS

SUMMARY OF THE INVENTION

The invention relates to a new pharmaceutical agent, to a method for the preparation of a pharmaceutical agent, and to the use of the pharmaceutical agent in medicine.

BACKGROUND OF THE INVENTION

European Patent Application Publication Number EP 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycemic and hypolipidemic activity. The compound of Example 30 of EP 0,306,228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter referred to as " Compound (I) ”).

International Patent Application Publication Number WO 94/05659 discloses certain salts of the compounds of EP 0,306,228, including salts formed from mineral acids such as hydrobromic, hydrochloric and sulfuric acids and organic acids such as salts of methanesulfonic, tartaric and in particular maleic acid.

SUMMARY OF THE INVENTION

It has now been found that Compound (I) forms a new salt of hydrobromic acid (also referred to herein as "Hydrobromide"), which is particularly stable and suitable for bulk preparation and treatment. The hydrobromide also has a high melting point, exhibits particularly good water solubility and has good flow properties. Therefore, the hydrobromide is surprisingly susceptible to large-scale pharmaceutical processing and in particular large-scale milling.

The new form can be obtained by an efficient, economical and reproducible method, particularly suitable for large-scale production.

The new Hydrobromide also has useful pharmaceutical properties and is particularly indicated to be useful for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof.

Accordingly, the present invention provides 5- [4- [2- (Nmethyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof.

The hydrobromide is suitably monohydrobromide.

In one preferred aspect, the Hydrobromide provides the infrared spectrum in accordance with Figure I.

In a preferred aspect, the Hydrobromide provides the Raman spectrum in accordance with Figure II.

In a preferred aspect, the Hydrobromide provides an X-ray powder diffraction pattern (XRPD) in accordance with Table I or Figure III.

In a preferred aspect, the Hydrobromide provides a ¹³ C solid state NMR spectrum in accordance with Figure IV.

It is also advantageous that the hydrobromide has a melting point in the range of 175 to 185 ° C, especially 180 to 185 ° C, for example 181 ° C.

Also, the hydrobromide has a T _h in the range from 180 to 186 ° C, for example 182.5 ° C.

Thus, in a preferred aspect, the Hydrobromide is characterized in that it provides one or more of:

(i) infrared spectrum in accordance with Figure I;

(H) Raman spectrum according to Figure II;

(iii) X-ray powder pattern (debig) in accordance with Table I or Figure III;

(iv) ¹³ C solid state NMR spectrum according to Figure IV; and (ν) a melting point in the range of 175 ° C to 185 ° C, in particular 180 to

185 ° C, for example 181 ° C.

The present invention encompasses the Hydrobromide or solvate thereof, isolated in pure form or when mixed with other materials. Thus, in one aspect, the Hydrobromide or solvate thereof is provided in an isolated form.

In another aspect, the Hydrobromide or solvate thereof is provided in purified form.

In another aspect, the hydrobromide or solvate thereof is provided in crystalline form.

The invention also provides the Hydrobromide or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.

In addition, the invention also provides the Hydrobromide or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, in a form suitable for milling.

Accordingly, the invention provides the Hydrobromide or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, such as to have good flow properties, especially good bulk flow properties.

A suitable solvate is a hydrate.

The invention also provides a process for the preparation of the Hydrobromide or solvate thereof, characterized in that 5- [4- [2- (N -methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione ( Compound I) or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a hydrobromide source and, if required, a hydrobromide solvate is obtained; and the hydrobromide or solvate is recovered.

A suitable reaction solvent is alkanol, for example propane-gol or hydrocarbon, such as toluene, ketone, such as acetone, ester, such as ethyl acetate, ether, such as tetrahydrofuran, nitrile, such as acetonitrile, or halogenated hydrocarbon, such as dichloromethane, water, organic acid. acid or mixtures thereof.

Suitably, the source of hydrogen bromide is provided by an aqueous solution of hydrogen bromide, for example, a 48% w / w solution in water. Alternatively, the source of hydrogen bromide is a solution of hydrogen bromide in a suitable solvent, optionally the reaction solution, for example, propan-2-ol. In addition, hydrogen bromide can be added directly to a solution or suspension of Compound (I) in the chosen reaction solvent.

An alternative source of hydrobromic is provided by a basic salt of hydrobromic acid, for example ammonium bromide or a salt of hydrobromic acid of an amine, for example, ethylamine or diethylamine.

The reaction is usually carried out at ambient temperature or at elevated temperature, for example at the reflux temperature of the solvent, although any suitable temperature that provides the required product may be used.

Solvates, such as hydrobromide hydrates, are prepared according to conventional methods.

Utilization of the required compound generally involves crystallization from a suitable reaction solvent, typically by cooling to a temperature in the range of 0 ° C to 60 ° C, for example, 20 to

25 ° C or 40 to 50 ° C. For example, the hydrobromide may be crystallized from an alcohol such as propan-2-ol or a ketone such as acetone.

In one preferred embodiment, the recovery consists of initial cooling to an initial temperature, such as in the range of 40 to 50 ° C, whereby an initial crystallization occurs and then cooling to a secondary temperature, suitable in the range of 0 to 25 ° C.

Crystallization can also be initiated by the formation of crystals with crystals of Hydrobromide or a solvate thereof, but this is not absolutely necessary.

4 * Solvates are prepared by the use of suitable conventional methods.

Compound (I) is prepared according to known methods, such as those disclosed in EP 0,306,228 and WO 94/05659. The disclosures in EP 0,306,228 and WO 94/05659 are given in the literature.

When used herein, the term "T _initial " is defined by Differential Scanning Calorimetry and is of common knowledge in science, as in the example expressed in "Pharmaceutical Thermal Analysis, Techniques and Applications", Ford and Timmins, 1989 as "The temperature corresponding to the intersection of the pre-transition baseline Mon with the extrapolated edge of the transition ”.

When used herein the term "good flow properties" in relation to particular compounds is suitably characterized by said compound having a Hausner coefficient of less than or equal to 1.5, especially less than or equal to 1.25.

"Hausner coefficient" is an accepted term in science.

When used herein, the term "prevention of diabetes-related conditions" includes the treatment of conditions such as insulin resistance, decreased glucose tolerance, hyperinsulinism, and gestational diabetes.

Diabetes mellitus preferably means type II diabetes mellitus.

Diabetes-related conditions include hyperglycemia and insulin resistance and fullness. Other conditions related to diabetes include high blood pressure, cardiovascular disease, especially atherosclerosis, certain digestive disorders, in particular regulation of appetite and food intake in patients suffering from malnutrition disorders such as anorexia nervosa and overeating disorders such as bulking and anorexia bulemia. Additional conditions associated with diabetes include polycystic ovary syndrome and steroid-induced insulin resistance.

The complications of the diabetes mellitus conditions covered herein include kidney disease, a particular kidney disease associated with the development of Type II diabetes, including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephritic syndrome, hypertensive nephrosclerosis.

As mentioned above, the compound of the invention has useful therapeutic properties. The present invention provides the Hydrobromide or solvate thereof for use as an active therapeutic agent.

In particular, the present invention provides the Hydrobromide or solvate thereof for use in the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof.

The hydrobromide or solvate thereof may be administered alone or preferably as a pharmaceutical composition also containing a pharmaceutically acceptable carrier. Suitable methods for preparing the Hydrobromide or solvate thereof are generally those disclosed for Compound (I) in the aforementioned publications.

Accordingly, the present invention also provides a pharmaceutical composition comprising the Hydrobromide or solvate thereof and a pharmaceutically acceptable carrier thereof.

The hydrobromide or solvate thereof is normally administered in unit dosage form.

The active compound can be administered by any suitable route, but usually by oral or parenteral routes. For such use, the compound will typically be used in the form of a pharmaceutical composition together with a pharmaceutical carrier, diluent and / or excipient, although the exact form of the compound will depend on the route of administration.

Compounds are prepared by blending and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, orally liquid compositions, powders, granules, pearls, pastilles, recoverable powders, injection and infusion solutions, or suspensions, suppositories and transdermal routes. Compounds which can be administered orally, in particular shaped oral compositions, are preferred, since they are more convenient for general use.

Tablets and capsules for oral administration are usually in unit dose and contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavors and wetting agents. The tablets may be coated according to known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose, and the like. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutical wetting agents include sodium lauryl sulfate.

Solid oral compositions may be prepared by conventional methods of mixing, filling, tabletting or the like. Repeated mixing operations can be used to distribute the active substance through these compositions using large amounts of fillers. Such operations, of course, are conventional in science.

Oral liquid compositions may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable carriers before use. Such liquid compositions may contain conventional additives, such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, emulsifiers, e.g. anhydrous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and if desired common flavoring or coloring matter.

For parenteral administration, a liquid unit dosage form containing a compound of the present invention and a sterile carrier is prepared. The compound, depending on the carrier and the concentration, can either be suspended or dissolved. Parenteral solutions are usually prepared by dissolving the active compound in vehicle and vehicle, sterilizing it prior to being filled into a suitable vial or ampoule and sealing. Advantageously, additives such as topical anesthetic, preservative and buffering agents are also dissolved in the carrier. In order to increase stability, the composition may be frozen after filling in the vial and the water removed in vacuo.

Parenteral suspensions are prepared in the same way, except that the active compound is suspended in the vehicle instead of dissolved and sterilized by subjecting ethylene oxide before suspension in the sterile vehicle. Advantageously, the surfactant or wetting agent is incorporated into the composition to facilitate uniform distribution of the active compound.

As is generally accepted, compositions should usually be accompanied by written or printed instructions for use in appropriate medical treatment.

As used herein, the term "pharmaceutically acceptable" encompasses compounds, compositions, and ingredients for both human and veterinary use: for example, the term "pharmaceutically acceptable salt" encompasses a veterinarily acceptable salt.

The present invention further provides a method for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof in a human or other mammal, which includes administering an effective, non-toxic amount of Hydrobromide or solvate to a human or other mammal in the need for this.

Typically, the active ingredient can be administered as a pharmaceutical composition as defined herein before, and this forms a particular aspect of the present invention.

In another aspect of the present invention there is provided the use of Hydrobromide or a solvate thereof for the manufacture of a medicament for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof.

In the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof, the hydrobromide or solvate thereof may be administered in amounts to provide Compound (I) at appropriate doses such as disclosed in EP 0,306,228, WO 94/05659 and WO 98/55122.

No adverse toxic effects were noted in the above-mentioned treatments for the compound of the invention.

The following examples illustrate the invention but are by no means limited thereto.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

Example 1: 5- [4- [2- (Ν-ββτΗΠ · Ν- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

A mixture of 5- [4- [2- (N-ββπππ-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione (1.0 g) and propan-2-ol (50 ml) was stirred and reflux for 10 minutes, at which point a clear solution is observed. Hydrobromic acid (48% w / w solution in water, 0.31 ml) was then added dropwise and the reaction mixture was stirred for 10 minutes under reflux and then cooled to 21 ° C. The product was collected by filtration and washed with propan-2-ol (10 ml) to give 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-

A compound according to claim 1, characterized in that it provides two or more of:

(i) infrared spectrum in accordance with Figure I;

(ii) Raman spectrum according to Figure II;

(iii) X-ray powder pattern (debig) in accordance with Table I or Figure III;

(iv) ¹³ C solid state NMR spectrum according to Figure IV; and (ν) a melting point in the range of 175 ° C to 185 ° C, in particular 180 to 185 ° C, for example 181 ° C.

A compound according to claim 1 or claim 2 in purified form.

4. Compound according to each one from the claim 1 TO 3, characterized in that it is in solid dosage form 5. Compound according to each one from the claim 1 TO 3, characterized in that is in pharmaceutical acceptable grindable shape. 6. Compound according to each one from the claim 1 TO 3, characterized in that is in pharmaceutical acceptable

form having good flow properties.

7. A process for the preparation of 5- [4- [2- (N-μθτηπ-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof, characterized in that 5- [4- [2- (Ν-μθτηπ-Ν- (2pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione or a salt thereof is reacted with a hydrobromide source and then, if required, a hydrobromide solvate is obtained and the hydrobromide or solvate thereof is recovered.

8. A pharmaceutical composition comprising 5- [4 [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof, and a pharmaceutically acceptable carrier.

9. Compound 5- [4- [2- (N-ββπππ-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof for use as an active therapeutic substance.

Use of 5- [4- [2- (N-ββπππ-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof for the manufacture of a medicament for the treatment and / or prevention of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications of diabetes mellitus.

Thiazolidinedione salt for the treatment of diabetes mellitus

ABSTRACT

The invention relates to a new pharmaceutical composition 5- [4- [2- (Nmethyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or solvate thereof, to a process for the preparation of the compound, to a pharmaceutical composition containing this compound and to the use of the compound in medicine.

FIGURE I: Infrared spectrum of hydrobromide

FIGURE II: Raman spectrum of hydrobromide

FIGURE III: X-ray powder pattern of hydrobromide

4.75 ml) is then added and the mixture is cooled to 45 ° C and stirred for 1 hour, then cooled to 21 ° C. The white solid was collected by filtration and washed with acetone (100 ml) to give 5- [4- [2- (N-ββππ-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4 -dione hydrobromide (17.7 g) as a white crystalline solid.

HYDROBROMIDE CHARACTERISTICS (1) REGISTERED FOR THE PRODUCT OF EXAMPLE 3 Hydrobromide Solubility

The solubility of the material is determined by adding water in aliquots of 1 to 1000 ml to approximately 100 mg of drug substance until the powder is dissolved. The apparent solubility was confirmed by HPLC test of a saturated solution.

Solubility: 6 mg / ml

Solid solubility of the hydrobromide

The solubility of the solid substance of the drug substance is determined by storing approximately 1.0 g of the material in a glass bottle at I) 40 ° C / 75% relative humidity (RH), open exposure for 1 month and b) at 50 ° C. closed for 1 month. The material was tested by HPLC for final content and degradation products in both cases.

a) 40 ° C / 75% RH: no pronounced decay was observed (HPLC experiment 98% initially).

b) 50 ° C: no pronounced decay was observed (HPLC experiment 98% initially).

Hydrobromide flow properties

The ratio of the volume weight to the obtained body weight (Hausner coefficient) of the Hydrobromide was determined using standard methods ("Pharmaceutics-The Science of Dosage Form Desing", editor M.Aton, 1988, published by: Churchill Livingstone).

Hausner coefficient: 1.3

Hydrobromide Initial

Initial drug substance was determined by Differential Scanning Calorimetry using the Perkin-EI; er DSC7 device.

Initial: 182.5 ° C

Hydrobromide melting point

The melting point of the drug substance was determined visually by microscope to determine the melting temperature.

Melting point: 181 ° C (2) REGISTERED FOR EXAMPLE 2 PRODUCT

The infrared absorption spectrum of the mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at 2 cT ¹ dispersion (Figure I). Data are digitized at 1 cm @ ^-1 intervals. The bands are observed at:

2923, 2854, 2749, 1745, 1698, 1643, 1610, 1544, 1515, 1459, 1419, 1378, 1327, 1313, 1287, 1256, 1240, 1228, 1203, 1185, 1151, 1071, 1054, 1032, 1014, 985, 906, 803, 771.738, 712, 524 cm ^'1.

The IR spectrum of the solid product is recorded using a universal ATR facility. The bands are observed at: 2929, 2859, 2749, 1745, 1694, 1641, 1608, 1543, 1514, 1445, 1419, 1382, 1358, 1326, 1311, 1287, 1255, 1240, 1202, 1184, 1148, 1070, 1053 , 1031, 1014, 985, 906, 862, 844, 802, 768, 737, 710, 657 cm ' ¹ . The Raman product spectrum (Figure I) was recorded with the sample in an NMR tube using a Nicolet 960 ESPFT Raman spectrometer at a 4 cm ^-1 dispersion with an excitation of a Nd: V04 laser (1064 nm) with a power output of 400 mW. The bands are observed at:

3067, 2997, 2926, 2884, 2860, 1747, 1611, 1588, 1545, 1445, 1382, 1360, 1315, 1287, 1240, 1213, 1185, 1070, 1016, 986, 917, 826, 769, 740, 712, 659, 636, 620, 605, 506, 470, 405, 332, 303, 134, 99 cm ¹ .

The XRPD product diagram (Figure III) is recorded using the following conditions achieved: Anode tube: C, generator voltage: 40 kV, generator current 40 mA, start angle 2.0 ° 2Θ, end angle: 35.0 ° 2Θρ step size 0.02 ° 2Θ, time step 2.5 seconds. The characteristic XRPD angles and relative intensities are recorded in Table 1.