TR201806945T4 - 2-amino-1-hydroxyethyl-8-hydroxyquinoline-2 (1H) -one derivatives having both SS2 adrenergic receptor agonist and m3 muscarinic receptor antagonist activities. - Google Patents

2-amino-1-hydroxyethyl-8-hydroxyquinoline-2 (1H) -one derivatives having both SS2 adrenergic receptor agonist and m3 muscarinic receptor antagonist activities. Download PDF

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TR201806945T4
TR201806945T4 TR2018/06945T TR201806945T TR201806945T4 TR 201806945 T4 TR201806945 T4 TR 201806945T4 TR 2018/06945 T TR2018/06945 T TR 2018/06945T TR 201806945 T TR201806945 T TR 201806945T TR 201806945 T4 TR201806945 T4 TR 201806945T4
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methyl
amino
salt
cyclohexyl
ethylamino
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Carrera Carrera Francesc
Pajuelo Lorenzo Francesca
Antonio Perez Andres Juan
Prat Quiñones Maria
Puig Duran Carlos
Julia Jane Montserrat
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Almirall Sa
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Abstract

Mevcut buluş, (i) 2-amino-1-hidroksietil-8-hidroksikinolin-2(1H)-on türevleri ve (ii) bir hidroksikarboksilik asit, bir sülfonik asit veya bir sülfimid türevinin spesifik farmasötik olarak kabul edilebilir kristalin katılma tuzları ile, ya da bunların farmasötik olarak kabul edilebilir bir solvatı ile ilgilidir. Mevcut buluş, söz konusu tuzları içeren farmasötik bileşimler ile, ikili SS2 adrenerjik reseptör agonist ve M3 muskarinik reseptör antagonist aktiviteleri ile ilişkili solunum hastalıklarının tedavisinde kullanılmaya yönelik bu tuzlar ile ve bu tip tuzları hazırlamaya yönelik prosedürler ve ara ürünler ile de ilgilidir.The present invention relates to (i) derivatives of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2 (1H) -one, and (ii) specific pharmaceutically acceptable crystalline addition salts of a hydroxycarboxylic acid, a sulfonic acid or a sulfimide derivative, or a pharmaceutically acceptable solvate thereof. The present invention also relates to pharmaceutical compositions comprising said salts, to those salts for use in the treatment of respiratory diseases associated with dual SS2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities, and to procedures and intermediates for preparing such salts.

Description

TARIFNAME HEM ß2 ADRENERJIK RESEPTOR AGONIST HEM DE M3 MUSKARINIK RESEPTOR ANTAGONIST AKTIVITELERINE SAHIP 2-AMINO-1-HIDROKSIETIL-ß- HIDROKSIKINOLIN-2(1H)-ON TUREVLERI BULUS SAHASI Mevcut bulus, (i) 2-amin0-1-hidroksietil-8-hidroksikinolin-2(1H)-on türevleri ve (ii) bir hidroksikarboksilik asit, bir sülfonik asit veya bir sülfimid türevinin Spesifik farmasötik olarak kabul edilebilir kristalin katilma tuzlari ile, ya da bunlarin farmasötik olarak kabul edilebilir bir solvati ile ilgilidir. Mevcut bulus, söz konusu tuzlari içeren farmasötik bilesimler ile, ikili [32 adrenerjik reseptör agonist ve M3 muskarinik reseptör antagonist aktiviteleri ile iliskili solunum hastaliklarinin tedavisinde kullanilmaya yönelik bu tuzlar ile ve bu tip tuzlari hazirlamaya yönelik prosedürler ve ara ürünler ile de ilgilidir. DESCRIPTION BOTH ß2 ADRENERGIC RECEPTOR AGONIST AND M3 MUSCARINIC REceptOR WITH ANTAGONIST ACTIVITIES 2-AMINO-1-HYDROXIETIL-ß- HYDROXYKINOLIN-2(1H)-ON DERIVATIVES FIELD OF INVENTION The present invention includes (i) 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives and (ii) a Specific pharmaceutical use of hydroxycarboxylic acid, a sulfonic acid or a sulphimid derivative with acceptable crystalline addition salts, or a pharmaceutically acceptable It is related to solvati. The present invention relates to pharmaceutical compositions containing these salts, with dual [32] Respiration associated with adrenergic receptor agonist and M3 muscarinic receptor antagonist activities with these salts for use in the treatment of diseases and to prepare such salts. It also relates to procedures and intermediates for

BULUSUN ARKA PLANI reseptör antagonist aktivitesine sahip oldugu bilinen bilesikler açiklanir. Ancak bu bilesiklerin çogu, bir kuru toz olarak inhalasyon yoluyla yapilacak etkin uygulamalar için formüle edilememektedir. Kuru toz olarak inhalasyon uygulamalari zorlu bir istir. Içe solunacak olan tozun parçacik boyutunun ve parçacik boyutu dagiliminin dikkatli sekilde kontrol altinda tutulmasini gerektirir. Dahasi, parçacik topaklanmasi veya kümelenmesini önlemek de önemlidir. ilaveten, bu tip aletlerde kullanilacak farmasötik bilesimler ve formülasyonlar hazirlanirken, ne higroskopik olan ne de nemle eriyebilen ve göreli yüksek (yani yaklasik erime noktasina sahip olan ve böylece materyalin önemli ayrisma veya kristallik kaybi olmaksizin mikronize edilmesine imkan veren bir terapötik ajanin kristalin formuna sahip olunmasi çokça arzu edilir. türevleri yeterli farmakolojik davranis göstermis olmakla birlikte bunlarin, mikronizasyona imkan vermek üzere göreli yüksek bir erime noktasina sahip, ne higroskopik ne de nemle eriyebilen kristalin bir tuz formunda elde edilmelerinin zor oldugu ortaya koyulmustur. bilesiklerin herhangi birinin kristalin tuzu bildirilmemistir. BACKGROUND OF THE INVENTION Compounds known to have receptor antagonist activity are described. However, these compounds Most are formulated for effective administration by inhalation as a dry powder. not possible. Inhalation applications as dry powder are a challenging task. to be inhaled carefully control the particle size and particle size distribution of the powder requires retention. Moreover, it is also possible to prevent particle aggregation or aggregation. is important. In addition, pharmaceutical compositions and formulations for use in such devices being neither hygroscopic nor soluble and having a relatively high (i.e., approximate melting point) It has the crystalline form of a therapeutic agent that allows it to be micronized without loss of it is highly desirable. Although its derivatives have shown adequate pharmacological behavior, their micronization It has a relatively high melting point, neither hygroscopic nor moist It has been demonstrated that it is difficult to obtain them in the form of a soluble crystalline salt. The crystalline salt of any of the compounds is not reported.

Dolayisiyla bu bilesiklerin, kabul edilebilir seviyelerde higroskopiklik ve göreli yüksek erime noktalarina sahip en az birinin, nemle erimeyen stabil tuz formlari için bir ihtiyaç söz konusudur BULUSUN KISA AÇIKLAMASI Mevcut bulus, asagidakilerin birine karsilik gelen, farmasötik olarak kabul edilebilir bir kristalin katilma tuzunu saglamaktadir: iI)etiIamino)metiI)-5-metoksifenilamino)-3-0ksopropil)(metil)amino)-sikloheksil hidroksi(di- 2-tienil)asetat etandisülfonat, iI)etilamino)-metil)-5-met0ksifenilkarbamoiloksi)etiI)-(metil)amin0)-sikloheksil 2-hidroksi- 2,2-di(tiofen-2-il)asetat disakkarinat ve iI)etilamino)-metil)-5-met0ksifenilkarbamoiloksi)etiI)-(metil)amino)sikloheksil 2-hidroksi- 2,2-di(tiofen-2-il)asetat L-tartrat ve bunlarin farmasötik olarak kabul edilebilir solvatlari. Therefore, these compounds have acceptable levels of hygroscopicity and relatively high melting. there is a need for stable salt forms that do not dissolve with moisture subject of BRIEF DESCRIPTION OF THE INVENTION The present invention is a pharmaceutically acceptable crystalline crystal corresponding to one of the following. provides the joining salt: ii)ethylamino)methyl)-5-methoxyphenylamino)-3-Oxopropyl)(methyl)amino)-cyclohexyl hydroxy(di- 2-thienyl)acetate ethanedisulfonate, ii)ethylamino)-methyl)-5-methoxyphenylcarbamoyloxy)ethyl-(methyl)amino)-cyclohexyl 2-hydroxy- 2,2-di(thiophen-2-yl)acetate disaccharinate and ii)ethylamino)-methyl)-5-methoxyphenylcarbamoyloxy)ethyl-(methyl)amino)cyclohexyl 2-hydroxy- 2,2-di(thiophen-2-yl)acetate L-tartrate and their pharmaceutically acceptable solvates.

Bu bulus, bulus konusu bir tuzun terapötik olarak etkili bir miktarini ve farmasötik olarak kabul edilebilir bir tasiyici içeren bir farmasötik bilesimi de saglamaktadir. The present invention provides a therapeutically effective amount and pharmaceutically acceptable amount of a salt of the invention. It also provides a pharmaceutical composition comprising an acceptable carrier.

Bu bulus, bulus konusu bir tuzu ve bir veya daha fazla baska terapötik madde içeren bir kombinasyon da saglamaktadir. This invention includes a salt of the invention and one or more other therapeutic agents. combination as well.

Bu bulus, hem [32 adrenerjik reseptör agonist hem de M3 muskarinik reseptör antagonist aktivitesi ile iliskili bir patolojik durum veya hastaligin tedavisinde kullanilmaya yönelik olarak, bahsedilen patolojik durum veya hastaligin astim, akut veya kronik bronsit, amfizem, ya da kronik obstruktif akciger hastaligi (KOAH) oldugu bulus konusu bir tuzu, bulus konusu bir farmasötik bilesimi veya bulus konusu bir kombinasyonu da saglamaktadir. This invention is both a [32 adrenergic receptor agonist and an M3 muscarinic receptor antagonist]. for use in the treatment of a pathological condition or disease associated with its activity, the pathological condition or disease mentioned is asthma, acute or chronic bronchitis, emphysema, or chronic obstructive pulmonary disease (COPD), the subject of the invention is salt, the subject of the invention is a salt pharmaceutical composition or a combination according to the invention.

SEKILLERIN KISA AÇIKLAMASI il)etilamino)metil)-5-metoksifeniIamin0)-3-oksopropil)(metil)amino)sikloheksil hidroksi(di-2- tienil)asetata yönelik Fourier dönüsümlü kizilötesi (FTIR) spektrumunu gösterir. il)etilamino)metil)-5-metoksifenilamino)-3-oksopropil)(metil)amino)sikloheksil hidroksi(di-2- tienil)asetat etandisülfonata yönelik toz X isini kirinim (PXRD) desenini gösterir. il)etilamin0)metil)-5-met0ksifeniIamin0)-3-0ksopropil)(metil)amino)sikloheksil hidroksi(di-2- tienil)asetat etandisülfonata yönelik 1H-NMR ( verilerini gösterir. il)etilamino)metiI)-5-metoksifeniIamin0)-3-oksopr0pil)(metil)amin0)sikl0heksil hidroksi(di-2- tienil)asetat etandisülfonatin diferansiyel taramali kalorimetri (DSC) analizini gösterir. il)etilamino)metil)-5-metoksifeniIamin0)-3-0ksopropil)(metil)amino)sikloheksil hidroksi(di-2- tienil)asetat etandisülfonatin termogravimetrik (TG) analizini gösterir. il)etilamin0)metil)-5-metoksifeniIamin0)-3-0ksopropil)(metil)amino)sikl0heksil hidroksi(di-2- tienil)asetat etandisülfonata yönelik Fourier dönüsümlü kizilötesi (FTIR) spektrumunu gösterir. il)etilamino)metil)-5-metoksifeniIkarbam0il0ksi)etil)(metil)amino)sikl0heksil 2-hidr0ksi-2,2- di(ti0fen-2-il)asetata yönelik Fourier dönüsümlü kizilötesi (FTIR) spektrumunu gösterir. il)etilamino)metiI)-5-met0ksifeniIkarbam0iloksi)etiI)(metil)amino)sikl0heksil 2-hidr0ksi-2,2- di(tiofen-2-il)asetat disakkarinata yönelik toz X isini kirinim (PXRD) desenini gösterir. il)etilamino)metiI)-5-met0ksifeniIkarbam0iI0ksi)etiI)-(metil)amin0)sikloheksil 2-hidr0ksi-2,2- di(ti0fen-2-il)asetat disakkarinata yönelik 1H-NMR spektrumudur (. il)etilamino)metil)-5-metoksifeniIkarbamoiloksi)etil)-(metil)amino)sikloheksil 2-hidr0ksi-2,2- di(ti0fen-2-il)asetat disakkarinata yönelik DSC analizini gösterir. il)etilamino)metiI)-5-met0ksifeniIkarbam0il0ksi)etiI)-(metil)amin0)sikloheksil 2-hidr0ksi-2,2- di(ti0fen-2-il)asetat disakkarinata yönelik TG analizini gösterir. il)etilamin0)metiI)-5-metoksifenilkarbam0il-0ksi)etil)(metil)amino)sikl0heksil 2-hidr0ksi-2,2- di(tiofen-2-il)asetat disakkarinata yönelik FTIR spektrumunu gösterir. il)etilamino)metiI)-5-metoksifenilkarbam0iIoksi)etiI)(metiI)amino)sikl0heksil 2-hidr0ksi-2,2- di(ti0fen-2-il)asetat L-tartrata yönelik toz X isini kirinim (PXRD) desenini gösterir. il)etilamino)metil)-5-metoksifeniIkarbamoiloksi)etil)-(metil)amino)sikloheksil 2-hidr0ksi-2,2- di(tiofen-2-il)asetat L-tartratin 1H-NMR spektrumudur (. il)etilamino)metiI)-5-metoksifenilkarbam0iloksi)etiI)-(metil)amino)sikloheksil 2-hidr0ksi-2,2- di(tiofen-2-il)asetat L-tartrata yönelik DSC analizini gösterir. il)etilamino)metil)-5-metoksifenilkarbamoiloksi)etil)-(metil)amino)sikloheksil 2-hidr0ksi-2,2- di(tiofen-2-il)asetat L-tartrata yönelik TG analizini gösterir. il)etilamin0)metil)-5-metoksifeniIkarbamoiI-oksi)etil)(metil)amin0)sikloheksil 2-hidr0ksi-2,2- di(tiofen-2-il)asetat L-tartrata yönelik FTIR spektrumunu gösterir. BRIEF DESCRIPTION OF THE FIGURES yl)ethylamino)methyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2- shows the Fourier transform infrared (FTIR) spectrum for thienyl)acetate. yl)ethylamino)methyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)cyclohexylhydroxy(di-2- Shows the powder X-ray diffraction (PXRD) pattern for thienyl)acetate ethanedisulfonate. yl)ethylamino)methyl)-5-methoxyphenylamino)-3-0xopropyl)(methyl)amino)cyclohexylhydroxy(di-2- Shows 1H-NMR data for thienyl)acetate ethanedisulfonate. yl)ethylamino)methyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2- Shows differential scanning calorimetry (DSC) analysis of thienyl)acetate ethanedisulfonate. yl)ethylamino)methyl)-5-methoxyphenylamino)-3-0xopropyl)(methyl)amino)cyclohexyl hydroxy(di-2- Shows thermogravimetric (TG) analysis of thienyl)acetate ethanedisulfonate. yl)ethylamino)methyl)-5-methoxyphenylamino)-3-Oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2- thienyl)acetate shows the Fourier transform infrared (FTIR) spectrum for ethanedisulfonate. yl)ethylamino)methyl)-5-methoxyphenylcarbam0yloxy)ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2- Shows the Fourier transform infrared (FTIR) spectrum for di(thiOphenyl-2-yl)acetate. yl)ethylamino)methyl)-5-methoxyphenylcarbamyloxy)ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2- Shows the powder X-ray diffraction (PXRD) pattern for di(thiophen-2-yl)acetate disaccharinate. yl)ethylamino)methyl)-5-methoxyphenylcarbam0yloxy)ethyl-(methyl)amino)cyclohexyl 2-hydroxy-2,2- 1H-NMR spectrum for di(thiOphenyl-2-yl)acetate disaccharinate (. yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2- Shows DSC analysis for di(thiOphenyl-2-yl)acetate disaccharinate. yl)ethylamino)methyl)-5-methoxyphenylcarbam0yloxy)ethyl-(methyl)amino)cyclohexyl 2-hydroxy-2,2- Shows the TG analysis for di(thiOphenyl-2-yl)acetate disaccharinate. yl)ethylamino)methyl)-5-methoxyphenylcarbam0yl-oxy)ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2- Shows the FTIR spectrum for di(thiophen-2-yl)acetate disaccharinate. yl)ethylamino)methyl)-5-methoxyphenylcarbamyloxy)ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2- The powder shows the X-ray diffraction (PXRD) pattern for di(thiOphenyl-2-yl)acetate L-tartrate. yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2- 1H-NMR spectrum of di(thiophen-2-yl)acetate L-tartrate (. yl)ethylamino)methyl)-5-methoxyphenylcarbamyloxy)ethyl-(methyl)amino)cyclohexyl 2-hydroxy-2,2- Shows DSC analysis for di(thiophen-2-yl)acetate L-tartrate. yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2- Di(thiophen-2-yl)acetate shows the TG analysis for L-tartrate. yl)ethylamino)methyl)-5-methoxyphenylcarbamoyl-oxy)ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2- Di(thiophen-2-yl)acetate shows the FTIR spectrum for L-tartrate.

BULUSUN DETAYLI AÇIKLAMASI Bulus konusu tuzlar, bilesimler ve metotlar tarif edilirken, asagida verilen terimler aksi belirtilmedigi sürece asagidaki anlamlara sahip olacaktir. gerçeklestirmeye yeterli bir miktar anlamina gelir. DETAILED DESCRIPTION OF THE INVENTION In describing the salts, compounds and methods of the invention, the following terms are otherwise shall have the following meanings unless specified. means an amount sufficient to realize

Burada kullanildigi haliyle "tedavi" terimi, bir insan hastadaki bir hastalik veya bir tibbi durumun asagidaki hususlari içeren bir tedavisini ifade eder: (a) hastalik veya tibbi durumun meydana gelmesinin önlenmesi, yani bir hastanin profilaktik olarak tedavi edilmesi; (b) hastalik veya tibbi durumunun iyilestirilmesi, yani bir hastadaki hastalik veya tibbi durumunun geriletilmesinin saglanmasi; (c) hastalik veya tibbi durumunun baskilanmasi, yani bir hastadaki hastalik veya tibbi durumunun gelismesinin yavaslatilmasi; veya (d) bir hastadaki hastalik veya tibbi duruma ait semptomlarin yatistirilmasi. hastalik veya durum" ifadesi, hem [32 adrenerjik reseptör agonist ve M3 muskarinik antagonist reseptör aktivitesi ile iliskili olarak halihazirda kabul edilmis olan veya gelecekte bulunacak olan her hastaligi ve/veya durumu ihtiva eder. Bu tip hastaliklar, bunlarla sinirli olmamak 'üzere pulmoner hastaliklar, örnegin astim ve kronik obstruktif akciger hastaligi (kronik bronsit ve amfizem de dahil) ve ayrica nörolojik rahatsizliklar ve kalp rahatsizliklarini ihtiva eder. [32 adrenerjik reseptör agonist aktivitesinin, erken dogum (bkz. Uluslararasi Patent Basvurusu Yayini No WO 98/09632), glokoma ve bazi enflamasyon tipleri (bkz. Uluslararasi Patent oldugu da bilinmektedir. The term "treatment" as used herein refers to a disease or medical condition in a human patient. It refers to a treatment that includes the following: (a) prevention of disease or medical condition occurring, i.e. prophylactic treatment of a patient be treated as (b) amelioration of illness or medical condition, i.e. illness or medical condition in a patient ensuring regression of his condition; (c) suppression of illness or medical condition, i.e. illness or medical condition in a patient slowing the development of his condition; or (d) alleviating the symptoms of a disease or medical condition in a patient. "disease or condition" means both [32 adrenergic receptor agonist and M3 muscarinic antagonist already accepted or to be found in the future in relation to receptor activity Includes any disease and/or condition These types of diseases include but are not limited to pulmonary diseases, for example asthma and chronic obstructive pulmonary disease (chronic bronchitis and emphysema) as well as neurological and heart conditions. [32 adrenergic receptor agonist activity, preterm birth (see International Patent Application Publication No. WO 98/09632), glaucoma and certain types of inflammation (see International Patent is also known.

Diger taraftan M3 reseptör antagonist aktivitesi, gastrointestinal sistem rahatsizliklari ile, örnegin irritabl bagirsak sendromu (IBS) (bkz. örnegin U85397800), GI ülserleri, spastik kolit (bkz. örnegin US 4556653); idrar kanali rahatsizliklari, örnegin idrar kaçirma (bkz. örnegin J. bradikardisi ile iliskilidir. veya farmasötik olarak kabul edilebilir bir tuzu ile bir solventin bir veya daha fazla molekülü tarafindan olusturulan bir kompleks veya bir agregayi ifade eder. Bu tip solvatlar tipik olarak kristal yapili katilardir ve solüt ve solvent arasinda esasen sabit bir molar orana sahiptir. On the other hand, M3 receptor antagonist activity, with gastrointestinal system disorders, eg irritable bowel syndrome (IBS) (see eg U85397800), GI ulcers, spastic colitis (see for example US 4556653); urinary tract disorders, eg urinary incontinence (see eg J. associated with bradycardia. or one or more molecules of a solvent with a pharmaceutically acceptable salt It refers to a complex or an aggregate formed by These types of solvates are typically are crystalline solids and have an essentially constant molar ratio between solute and solvent.

Temsili solventler örnegin su, etanol, izopropanol ve benzerlerini içerir. Tercih edilen solvat, bir hidrat olmaktadir. Representative solvents include, for example, water, ethanol, isopropanol, and the like. Preferred solvate, becomes a hydrate.

Genel sentez prosedürleri Bulus konusu tuzlar, burada tarif edilen metotlar ve prosedürler ile veya benzer metotlar ve prosedürler kullanilarak hazirlanabilir. Tipik veya tercihli proses sartlarinin (yani reaksiyon sicakliklari, süreler, reaktiflerin mol oranlari, çözücüler, basinçlar vs.) verildigi yerlerde, aksi belirtilmedigi sürece diger proses sartlarinin kullanilabilecegi de takdir edilecektir. Optimum reaksiyon sartlari, kullanilan belirli reaktifler veya çözücülere göre degistirilebilir, ancak bu tip sartlar ilgili teknigin uzmanlari tarafindan rutin optimizasyon prosedürleri üzerinden tayin edilebilecektir. General synthesis procedures The salts of the invention can be used by the methods and procedures described herein or by similar methods and can be prepared using procedures. Typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reagents, solvents, pressures etc.) It will also be appreciated that other process conditions may be used unless specified. Optimum The reaction conditions may be changed according to the particular reagents or solvents used, but this type conditions are determined by experts in the relevant art through routine optimization procedures. can be done.

Bulus konusu tuzlari hazirlamaya yönelik prosedürler, bulusun diger yapilanmalari olarak saglanir ve asagidaki prosedürler ile gösterilir. Procedures for preparing the salts of the invention are referred to as other embodiments of the invention. provided and illustrated by the following procedures.

Bulus konusu tuzlar, burada tarif edilen bilesiklerden ve genel olarak piyasadan temin edilebilen (örnegin Aldrich) uygun hidroksikarboksilik asit, sülfonik asit veya sülfimid türevlerinden sentezlenebilir. The salts of the invention are commercially available from the compounds described herein and in general. suitable hydroxycarboxylic acid, sulfonic acid or sulphimide, which can be obtained (for example Aldrich) can be synthesized from its derivatives.

Ilgili reaksiyonlari gerçeklestirmeye yönelik uygun solventler, uzman kimyaci tarafindan seçilebilir ve olusturulacak olan spesifik tuza bagli olabilir. Istege göre su içeren, uygun solventlerin karisimlari kullanilabilir. Ornegin uygun solventler; metanol, etanol, diklorometan, tetrahidrofuran, su veya bunlarin bir karisimindan seçilebilir. Appropriate solvents for carrying out the respective reactions must be prepared by a qualified chemist. can be selected and depend on the specific salt to be created. optionally containing water, suitable Mixtures of solvents can be used. For example suitable solvents; methanol, ethanol, dichloromethane, tetrahydrofuran, water or a mixture thereof.

Yukaridaki reaksiyonlarin herhangi birinin tamamlanmasi üzerine tuz, reaksiyon karisimindan çökeltme, konsantre etme, santrifüjleme ve benzeri konvansiyonel yollarla izole edilebilir. Upon completion of any of the above reactions, the salt is removed from the reaction mixture. It can be isolated by conventional means such as precipitation, concentration, centrifugation and the like.

Spesifik proses sartlarinin (yani reaksiyon sicakliklari, süreler, reaktiflerin mol oranlari, çözücüler, basinçlar vs.) verildigi yerlerde, aksi belirtilmedigi sürece diger proses sartlarinin kullanilabilecegi de takdir edilecektir. Specific process conditions (i.e. reaction temperatures, times, mole ratios of reagents, solvents, pressures, etc.), other process conditions must be met unless otherwise stated. use would be appreciated.

Mevcut bulusun tuzlarini hazirlamak üzere serbest baz, tipik olarak uygun bir solvent içerisinde çözülür ve bahsedilen solvent ise bazi örneklere göre yaklasik olarak 60-80°C'ye isitilir. Daha sonra uygun hidroksikarboksilik asit veya sülfonik asit veya bir sülfimidin uygun bir solvent içerisindeki, tercih edildigi haliyle, serbest bazin içerisinde çözüldügü ile ayni olan solvent içerisindeki bir çözeltisi, isitilan çözeltiye ilave edilir. Karisim daha sonra istege göre 60- 80C`de veya oda sicakliginda 15-300 dakika karistirilir. Karisim daha sonra tipik olarak örnegin 20-25“C'ye veya O-5C'ye so gutulur. Olusan çökelti ürünü filtre edilerek ayrilir, uygun bir solvent ile yikanir ve örnegin vakum içerisinde kurutulur. The free base, typically in a suitable solvent, to prepare the salts of the present invention dissolved and the said solvent is heated to approximately 60-80°C according to some examples. More then suitable hydroxycarboxylic acid or sulfonic acid or a sulphimidine with a suitable solvent. solvent in which it is preferably the same as that dissolved in the free base A solution in it is added to the heated solution. The mixture is then optionally 60- It is stirred for 15-300 minutes at 80C or room temperature. The mix is then typically For example, it is cooled to 20-25“C or O-5C. The precipitate product formed is filtered off, suitable washed with a solvent and dried, for example in vacuo.

Farmasötik bilesim/er Bu bulus, bulus konusu bir tuzun terapötik olarak etkili bir miktarini veya bunun bir enantiyomeri veya farmasötik olarak kabul edilebilir bir solvatini ve farmasötik olarak kabul edilebilir bir tasiyi içeren farmasötik bilesimleri de kapsamaktadir. pharmaceutical composition/er The present invention provides a therapeutically effective amount of a salt of the invention or a combination thereof. enantiomer or a pharmaceutically acceptable solvatin and a pharmaceutically acceptable It also includes pharmaceutical compositions containing an acceptable carrier.

Tipik oldugu üzere farmasötik bilesim, inhalasyon yoluyla, tercihen bir kuru toz olarak uygulanacak sekilde formüle edilir. Typically, the pharmaceutical composition is administered by inhalation, preferably as a dry powder. formulated to be applied.

Tipik oldugu üzere farmasötik bilesim, bir veya daha fazla baska terapötik maddenin terapötik olarak etkili bir miktarini da içerir. Typically, the pharmaceutical composition consists of one or more other therapeutic agents. contains an effective amount.

Farmasötik formülasyonlar uygun olarak birim dozaj formu halinde sunulabilir ve eczacilik alaninda layikiyla bilinen yöntemlerin herhangi birine göre hazirlanabilir. Tüm metotlar, etkin maddenin / maddelerin tasiyici ile bir araya getirilmesi adimina yer verir. Söz konusu formülasyonlar genel olarak etkin madde ile sivi tasiyicilari veya inceltilerek bölünmüs kati tasiyicilari veya her ikisini tekdüze ve derinlemesine birlestirerek ve daha sonra gerekli görüldügü takdirde elde edilen ürünü arzu edilen formülasyon halinde sekillendirerek hazirlanabilir. Pharmaceutical formulations may conveniently be presented in unit dosage form and It may be prepared according to any of the methods well known in the art. All methods are active It includes the step of bringing the substance(s) together with the carrier. Aforementioned Formulations are generally composed of active substance and liquid carriers or thinned solids. by combining carriers or both uniformly and deeply, and then necessary by shaping the obtained product into the desired formulation can be prepared.

Akcigerlere inhalasyon yoluyla topikal sekilde ulastirilacak kuru toz bilesimleri, inhaler veya insuflatörlerde kullanilmak üzere örnegin jelatinden mamul kapsüllerde ve kartuslarda veya örnegin lamine alüminyum folyodan yapilan blisterlerde takdim edilebilir. Formülasyonlar genellikle bulus konusu tuzun ve laktoz veya nisasta gibi uygun bir toz bazinin (tasiyici madde) inhalasyonu için bir toz matrisi içerir. Laktoz kullanilmasi tercih edilir. Toz bazi, örnegin koruyucular, stabilizörler, emilim artiricilar veya aerodinamik degistiriciler gibi ilave bilesenler ihtiva edebilir. Dry powder compositions to be delivered topically to the lungs by inhalation, inhaler or in capsules and cartridges made of, for example, gelatin for use in insufflators or For example, it can be presented in blisters made of laminated aluminum foil. Formulations Generally, the salt of the invention and a suitable powder base such as lactose or starch (carrier) Contains a powder matrix for inhalation. The use of lactose is preferred. Powder base, for example additional components such as preservatives, stabilizers, absorption enhancers or aerodynamic modifiers may contain.

Her bir kapsül veya kartus genellikle her bir terapötik etkin maddeden 0.1 pg ve 9000 pg arasi bir miktari içerir. Alternatif olarak etkin madde(ler) eksipiyanlar olmaksizin takdim edilebilir. Each capsule or cartridge is usually between 0.1 pg and 9000 pg of each therapeutically active substance. contains an amount. Alternatively, the active ingredient(s) may be presented without excipients.

Formülasyonun ambalaji, tek dozlu veya çok dozlu uygulamalar için uygun olabilir. Çok dozlu uygulamalar durumunda formülasyon önceden ölçülmüs olabilir veya kullanim esnasinda ölçülebilir. Dolayisiyla kuru toz inhalerler, asagidaki gibi üç sinif halinde siniflandirilabilir: (a) tek dozlu, (b) çoklu birim dozlu ve (c) çok dozlu aletler. The packaging of the formulation may be suitable for single-dose or multi-dose administration. multidose In the case of applications, the formulation may be pre-measured or during use. measurable. Therefore, dry powder inhalers can be classified into three classes as follows: (a) single dose, (b) multiple unit dose and (c) multidose devices.

Birinci tipteki inhalerler için tekli dozlar, üretici tarafindan tartilarak, çogunlukla kartuslar veya sert jelatin kapsüller seklindeki küçük kaplar içerisine konulmus olur. Bir kartus söz konusu oldugunda tek dozlu Inhaler, bu sekilde inhalasyon tozunu içeren bir kartustan meydana gelir ve tekli dozajlar ölçülü olarak uygulanir. Inhalasyon tozu, kartusun tabanindaki bir hazneye, tabanda bir ölçülü slayt ve tepede bir kapak olacak sekilde, kalici olarak yerlestirilir. Bir kapsül, bir kap olarak kullanilacak oldugunda kapsülün ayri bir kutudan veya kaptan alinmasi ve inhalerin bir hazne alanina sokulmasi gerekir. Daha sonra kapsül'un. içe solunacak hava akimina ait bir kismin kapsül içerisinden geçerek tozu sürüklemesine imkan vermek veya inhalasyon esnasinda merkezkaç kuvvet etkisinde tozu kapsülden bu delikler vasitasiyla bosaltmak amaciyla igneler veya kesiciler ile açilmasi veya delinmesi gerekir. Inhalasyondan sonra bosalan kapsülün inhalerden tekrar çikarilmasi gerekir. Çogu durumda kapsülün sokulmasi ve çikarilmasi için inhalerin sökülmesi lazimdir, ki bu islem bazi hastalar için zor ve zahmetli bir islem olabilir. For inhalers of the first type, single doses are usually used in cartridges or cartridges, weighed by the manufacturer. It is placed in small containers in the form of hard gelatin capsules. It's a cartridge The single-dose Inhaler thus consists of a cartridge containing the inhalation powder. and single dosages are administered in moderation. Inhalation powder into a chamber at the base of the cartridge, It is permanently placed, with a metered slide at the bottom and a cover at the top. a capsule, taking the capsule from a separate box or container when it is to be used as a container, and The inhaler must be inserted into a chamber area. Then the capsule. air to breathe to allow a part of the current to pass through the capsule to drag the powder, or During inhalation, under the effect of centrifugal force, the powder is removed from the capsule through these holes. It should be opened or pierced with needles or cutters in order to empty it. from inhalation then the empty capsule must be removed from the inhaler again. In most cases, the capsule insertion and removal requires disassembly of the inhaler, which is difficult and difficult for some patients. can be a difficult task.

Inhalasyon tozlarina yönelik sert jelatin kapsüller kullanmakla ilgili diger dezavantajlar (a) ortam havasindan nem alinmasina karsi zayif koruma saglanmasi, (b) kapsüllerin Önceden asiri nispi neme maruz kalmis olmasindan sonra, ki bu durum parçalanma veya kertilmeye yol açar, kapsüllerin açilmasi veya delinmesi ile ilgili problemler ve (c) kapsül parçalarinin muhtemel olarak içeri solunmasidir. Dahasi birkaç kapsül inhaleri için eksik çekis de bildirilmistir (örnegin Nielsen ve ark., 1997). Other disadvantages associated with using hard gelatin capsules for inhalation powders (a) providing poor protection against moisture absorption from the ambient air, (b) pre-packaging of the capsules after exposure to excessive relative humidity, which may result in splintering or chipping. opens, problems with the opening or perforation of capsules, and (c) capsule fragments possibly inhaled. Moreover, for several capsule inhalers, there is also a lack of traction. has been reported (eg Nielsen et al., 1997).

Bazi kapsül inhalerleri, WO 92/03175 içerisinde tarif edildigi gibi, tekli kapsüllerin, delme ve bosaltma islemlerinin gerçeklestigi bir alis haznesine aktarilabildigi bir yuvaya sahiptir. Diger kapsül inhalerleri ise, doz bosaltimi için hava kanali ile hizali hale getirilebilen kapsül veya bir serit üzerinde saglanan sinirli sayida birim dozlar içeren blister inhalerler ile birlikte çoklu birim doz inhalerleri tipini içerir. Some capsule inhalers, as described in WO 92/03175, contain single capsules, piercing and It has a slot where it can be transferred to a receiving chamber where unloading processes take place. Other capsule inhalers, on the other hand, are capsule inhalers that can be aligned with the air duct for dose delivery. or with blister inhalers containing a limited number of unit doses supplied on a strip includes the type of multiple unit dose inhalers.

Blister inhalerleri, kapsül inhalerlerine göre ilaci neme karsi daha iyi korur. Toza erisim, kapagin ve ayrica blister folyonun delinmesi ile, ya da kapak folyosunun soyulmasi ile saglanir. Blister inhalers protect the drug against moisture better than capsule inhalers. Access to dust It is achieved by puncturing the lid and also the blister foil, or by peeling the lid foil off.

Bir disk yerine bir blister seridi kullanildiginda, dozlarin sayisi artirilabilir, ancak bosalan seridi degistirilmesi hastalar için nahos bir durumdur. Dolayisiyla bu tip aletler, seridi tasimak ve blister ceplerini açmak için kullanilan mekanizma da dahil olmak üzere, içerdikleri doz sistemi ile birlikte bir sefer kullanildiktan sonra atilir. Çok dozlu inhalerler, toz formülasyonunun önceden ölçülmüs miktarlarini içermez. Bunlar, nispeten büyük bir kaptan ve hasta tarafindan çalistirilmasi gereken bir doz 'ölçüm mekanizmasindan olusur. Kap, toz yiginindan volümetrik deplasman yoluyla tekli sekilde izole edilen çoklu dozlar içerir. Tamami, kaptaki toz ile doldurulmasi gereken bosluklara sahip olan, mekanizmalari mevcuttur. Diger çok dozlu aletler, belirli hacimdeki tozu kaptan bir uygulama haznesine veya bir hava kanalina tasimak 'üzere lokal veya çevresel girintiye sahip ölçülü basvurulari içerisinde tarif edilen Genuair® aleti (önceden Novolizer SD2FL olarak bilinirdi) Ilave terapötik ajanlar Bulus konusu tuzlar, yukarida belirtilen hastaliklar veya bozukluklarin tedavisinde etkili olduklari bilinen baska ilaçlar ile kombinasyon halinde de kullanilabilir. Mevcut bulusun tuzlari, örnegin asagida sayilanlar ile birlestirilebilir: (a) kortikosteroitler, ya da glukokortikoitler, (b) antihistaminler, (c) kemokin reseptör antagonistleri, mesela maravirok veya enfuvirtid, (e) CRth2 antagonistleri, (f) Iökotrien reseptör antagonistleri, (g) JAK inhibitörleri, mesela tofasitinib veya INCBO18424, (h) Syk inhibitörleri (i) fosdiesteraz lV inhibitörleri (j) p38 inhibitörleri, mesela ARRY- 5-Iipoksigenaz aktiflestirici protein inhibitörleri, mesela veliflapon, (m) 5-Iipoksigenaz inhibitörleri, (n) CYSLTR1 antagonistleri, (o) CYSLTR2 antagonistleri, (p) BLT1 antagonistleri, (q) BLT2 antagonistleri, (r) tromboksan A2 antagonistleri, mesela ramatroban, (s) DP1 reseptör antagonistleri, mesela laropiprant, (t) DP1 reseptör agonistleri, mesela BW-245C, (u) IP reseptör agonistleri, mesela RO-1138452, (v) Anti-IgE, mesela omalizumab, (w) IL5 antikor, mesela mepolizumab, (x) Iökotrien formasyon inhibitörleri, (y) dekongestanlar, mesela efedrin, psödoefedrin, sinefrin veya tetrahidrozolin; (z) mukolitikler, mesela asetilsistein, ambroksol, bromheksin, karbosistein, domiodol, eprazinon, erdostein, letostein, nelteneksin, sobrerol, stepronin ortiopronin; (aa) antitussifler, mesela dekstrometorfan, (bb) analjezikler, mesela aspirin, parasetamol, rofekoksid, selekoksib, morfin, kodein, oksikodon, hidrokodon, dihidromorfin veya flupirtin; ve (cc) ekspektoranlar, mesela antimon pentasi'ilf'ür, guaiakolsülfonat, guaifenesin, potasyum iyodür veya tiloksapol. When using a blister strip instead of a disc, the number of doses can be increased, but the empty strip Changing it is unpleasant for patients. Therefore, such tools are used to carry the strip and dosing system included, including the mechanism used to open the blister pockets It is discarded after one use with it. Multi-dose inhalers do not contain pre-measured amounts of the powder formulation. These, a dose 'measurement' that must be operated by a relatively large container and patient of the mechanism. The container is individually isolated from the dust pile by volumetric displacement. Contains multiple doses. Having cavities that need to be completely filled with the powder in the container, mechanisms are available. Other multi-dose devices are an application from a certain volume of powder. Measured with local or circumferential recess for 'carrying' into a reservoir or an air duct Genuair® instrument (formerly known as Novolizer SD2FL) described in its references Additional therapeutic agents The salts of the invention are effective in the treatment of the above-mentioned diseases or disorders. It can also be used in combination with other known drugs. The salts of the present invention, For example, it can be combined with: (a) corticosteroids, or glucocorticoids, (b) antihistamines, (c) chemokine receptor antagonists, such as maraviroc or enfuvirtide, (e) CRth2 antagonists, (f) Iukotriene receptor antagonists, (g) JAK inhibitors, eg tofacitinib or INCBO18424, (h) Syk inhibitors (i) fosdiesterase IV inhibitors (j) p38 inhibitors, such as ARRY-5-Lipoxygenase activating protein inhibitors, eg veliflapon, (m) 5-Lipoxygenase inhibitors, (n) CYSLTR1 antagonists, (o) CYSLTR2 antagonists, (p) BLT1 antagonists, (q) BLT2 antagonists, (r) thromboxane A2 antagonists, eg ramatroban, (s) DP1 receptor antagonists such as laropiprant, (t) DP1 receptor agonists such as BW-245C, (u) IP receptor agonists such as RO-1138452, (v) Anti-IgE, such as omalizumab, (w) IL5 antibody, eg mepolizumab, (x) Iukotriene formation inhibitors, (y) decongestants, eg ephedrine, pseudoephedrine, synephrine or tetrahydrozoline; (z) mucolytics such as acetylcysteine, ambroxol, bromhexine, carbocysteine, domiodol, eprazinone, erdosteine, letostein, neltenexin, sobrerol, stepronin orthiopronin; (aa) antitussives, eg dextromethorphan, (bb) analgesics, eg aspirin, paracetamol, rofecoxide, celecoxib, morphine, codeine, oxycodone, hydrocodone, dihydromorphine or flupirtine; and (cc) expectorants such as antimony pentacylf, guaiacolsulfonate, guaifenesin, potassium iodide or tyloxapol.

Dolayisiyla bulusun bir baska yapilanmasi, insan veya hayvan bedeninin tedavisinde eszamanli, ayri veya sirali sekilde kullanilmak 'üzere, (i) yukarida tanimlanan en az bir tuz bilesigi; ve (ii) yukarida tarif edilen bir veya daha fazla etkin madde içeren bir kombinasyon olmaktadir. Thus, another embodiment of the invention is in the treatment of the human or animal body. (i) at least one salt as defined above, for simultaneous, separate or sequential use compound; and (ii) a combination of one or more of the above-described active ingredients is happening.

Mevcut bulusun tercih edilen bir yapilanmasi, hem B2 adrenerjik reseptör agonist hem de M3 antimuskarinik aktivitesi ile iliskili patolojik durumlar, hastaliklar ve bozukluklarin tedavisinde veya bnlenmesine yönelik olarak, bahsedilen patolojik durum veya hastaligin astim, akut veya kronik bronsit, amfizem, ya da kronik obstruktif akciger hastaligi (KOAH) ve tercihen astim ve KOAH arasindan seçildigi, yukarida tanimlanan bir kombinasyon `ürünü olmaktadir. A preferred embodiment of the present invention is both a B2 adrenergic receptor agonist and an M3 in the treatment of pathological conditions, diseases and disorders associated with its antimuscarinic activity for the prevention or prevention of said pathological condition or disease as asthma, acute or chronic bronchitis, emphysema, or chronic obstructive pulmonary disease (COPD), preferably asthma and It is a combination product described above, selected from COPD.

Yukarida belirtildigi 'üzere mevcut bulusun tuzlari, yukarida tanimlanan bir baska terapötik etkin madde ile birlikte kullanilmaya da yöneliktir. As noted above, the salts of the present invention may be based on another therapeutic method described above. It is also intended to be used together with the active substance.

Terap'otik etkiye ulasmak için gerekli olan her bir etkin madde miktari elbette ki ilgili etkin maddeye, uygulama sekline, tedavi edilen bireye ve tedavi edilen ilgili rahatsizliga veya hastaliga bagli olarak degisecektir. Of course, the amount of each active substance required to achieve the therapeutic effect is of course the relevant active substance. the substance, the route of administration, the individual being treated, and the relevant condition being treated or It will change depending on the disease.

Etkin maddeler, istenen aktiviteyi sergilemek için yeterli olacak sekilde günde 1 ila 6 kere uygulanabilir. Tercih edildigi üzere etkin maddeler günde bir veya iki kere uygulanir. The active ingredients are administered 1 to 6 times a day, sufficient to exhibit the desired activity. applicable. Preferably, the active ingredients are applied once or twice a day.

Mevcut bulusun tuzlari ile birlestirilebilen uygun PDE4 inhibitörlerinin örnekleri, asagidaki gibidir: benafentrin dimaleat, etazolat, denbufillin, rolipram, sipamfillin, zardaverin, arofillin, filaminast, tipelukast, tofimilast, piklamilast, tolafentrin, mesopram, drotaverin hidroklorür, purin hidroklorür (V-1 1294A), 6-[3-(N,N-dimetilkarbamoil)fenilsüIfonil]-4-(3- siklopropilmetoksi-4-diflorometoksifenil)sikloheksan-1-ol, CDC-801 ve 5(S)-[3- Mevcut bulusun tuz bilesigi ile birlestirilebilen uygun kortikosteroitler ve glukokortikoitlerin örnekleri, asagidaki gibidir: prednizolon, metilprednizolon, deksametazon, deksametazon sipesilat, naflokort, deflazakort, halopredon asetat, budesonid, beklometazon dipropionat, hidrokortizon, triamsinolon asetonid, flosinolon asetonid, flusinonid, klokortolon pivalat, metilprednizolon aseponat, deksametazon palmitoat, tipredan, hidrokortizon aseponat, prednikarbat, alclometazon dipropionat, halometazon, metilprednizolon süleptanat, mometazon, mometazon furoat, rimeksolon, prednizolon farnesilat, siklesonid, bütiksokort propionat, RPR-i 06541, deprodon propionat, flutikazon, flutikazon propionat, flutikazon furoat, halobetasol propionat, Ioteprednol etabonat, betametazon b'L'itirat propionat, flunisolid, prednizon, deksametazon sodyum fosfat, triamzinolon, betametazon 17-valerat, betametazon, betametazon dipropionat, 21 -kIoro-1 1 beta-hidroksi-17alfa-[2-(metilsülfaniI)aset0ksi]-4- pregnen-3,20-dion, desizobütirilsiklezonid, hidrokortizon asetat, hidrokortizon sodyum süksinat, NS-126, prednizolon sodyum fosfat ve hidrokortizon probutat, prednizolon sodyum metas'ülfobenzoat ve klobetasol propionat. Examples of suitable PDE4 inhibitors that can be combined with the salts of the present invention are as follows: as: benafentrine dimaleate, etazolate, denbufillin, rolipram, cypamfillin, zardaverine, arofillin, filaminast, tipelukast, tofimilast, piclamilast, tolafenthrin, mesopram, drotaverine hydrochloride, purine hydrochloride (V-1 1294A), 6-[3-(N,N-dimethylcarbamoyl)phenylsulfonyl]-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol, CDC-801 and 5(S)-[3- Suitable corticosteroids and glucocorticoids that can be combined with the salt compound of the present invention examples are as follows: prednisolone, methylprednisolone, dexamethasone, dexamethasone sipesylate, naflocort, deflazacort, halopredon acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, flocinolone acetonide, flucinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredan, hydrocortisone aceponate, prednicarbate, alclomethasone dipropionate, halomethasone, methylprednisolone suleptanate, mometasone, mometasone furoate, rimexolone, prednisolone farnesilate, ciclesonide, butixocort propionate, RPR-i 06541, deprodon propionate, fluticasone, fluticasone propionate, fluticasone furoate, halobetasol propionate, Ioteprednol etabonate, betamethasone b'L'itrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamzinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate, 21-chloro-1 1 beta-hydroxy-17alpha-[2-(methylsulfanyl)acetoxy]-4- pregnen-3,20-dione, desisobutyrylciclesonide, hydrocortisone acetate, hydrocortisone sodium succinate, NS-126, prednisolone sodium phosphate and hydrocortisone probutate, prednisolone sodium metas'ulfobenzoate and clobetasol propionate.

Mevcut bulusun tuzlari ile birlestirilebilen uygun anti-histaminlerin 'örnekleri, asagidaki gibidir: metapirilen, mekitazin, azelastin hidroklorür, akrivastin, emedastin difumarat, emedastin fumarat, Ioratadin, siproheptadin hidroklorür, difenhidramin hidroklorür, doksepin hidroklor'ür, prometazin hidroklorür, Ievokabastin hidroklorür, desloratadin, sinnarizin, setastin hidroklorür, mizolastin, ebastin, setirizin hidroklor'ür, epinastin hidroklorür, olopatadin hidroklor'ür, bepotastin besilat, triprolidin hidroklorür, rupatadin fumarat, feksofenadin hidroklor'ür, 1334H. Examples of suitable anti-histamines that can be combined with the salts of the present invention are as follows: metapyrylene, mechitazine, azelastine hydrochloride, acrivastine, emedastine difumarate, emedastine fumarate, Ioratadine, cyproheptadine hydrochloride, diphenhydramine hydrochloride, doxepin hydrochloride, promethazine hydrochloride, Ievokabastine hydrochloride, desloratadine, cinnarizine, cetastin hydrochloride, mizolastine, ebastine, cetirizine hydrochloride, epinastine hydrochloride, olopatadine hydrochloride, bepotastine besylate, triprolidine hydrochloride, rupatadine fumarate, fexofenadine hydrochloride, 1334H.

Mevcut bulusun tuzlari ile birlestirilmesi mümkün olan uygun I'okotrien antagonistleri, asagidaki gibidir: CYSLTR1 antagonistleri, mesela montelukast, pranlukast veya zafirlukast; veya CYSLTR2 antagonistleri, mesela pranlukast, zafirlukast veya tipilukast. Suitable I'okotriene antagonists, which can be combined with the salts of the present invention, are as follows: such as: CYSLTR1 antagonists such as montelukast, pranlukast or zafirlukast; or CYSLTR2 antagonists such as pranlukast, zafirlukast, or tipilukast.

Mevcut bulusun tuzlari ile birlestirilmesi mümkün olan uygun CRTH2 antagonisti örnekleri, asagidaki gibidir: ramatroban, AMG-009, OC-000459. Examples of suitable CRTH2 antagonists, which can be combined with the salts of the present invention, as follows: ramatroban, AMG-009, OC-000459.

Mevcut bulusun tuzlari ile birlestirilmesi mümkün olan uygun Syk kinaz inhibitörleri örnekleri, asagidaki gibidir: fosfamatinib (Rigel), R-, pikeatannol, 2-(2-aminoetilamin0)-4-[3-(triflorometil)fenilamino]pirimidin-5-karboksamid, R-, 6- metoksifenil)ethan-1-on, N-[4-[6-(siklobütilamino)-9H-purin-2-ilamino]fenil]-N-metilasetamid dimetoksifenil)imidazo[1,2-c]pirimidin-5-ilamino]piridin-3-karb0ksamid dihidroklor'ur (BAY-61- Hem adrenerjik reseptör agonist ve M3 antimuskarinik aktivitesi ile iliskili patolojik durumlarin veya hastaliklarin tedavisi Mevcut bulusun tuzlari, mevcut bulusun farmasötik bilesimleri ve kombinasyonlari, hem ß2 adrenerjik reseptör agonist ve MS antimuskarinik aktivitesi ile iliskili patolojik durumlarin veya hastaliklarin ve tipik olarak solunum hastaliklarinin tedavisinde kullanilmaya yönelik olabilir. Examples of suitable Syk kinase inhibitors which can be combined with the salts of the present invention are: as follows: phosfamatinib (Rigel), R-, pikeatannol, 2-(2-aminoethylamino)-4-[3-(trifluoromethyl)phenylamino]pyrimidine-5-carboxamide, R-, 6- methoxyphenyl)ethan-1-one, N-[4-[6-(cyclobutylamino)-9H-purin-2-ylamino]phenyl]-N-methylacetamide dimethoxyphenyl)imidazo[1,2-c]pyrimidin-5-ylamino]pyridine-3-carboxamide dihydrochlor (BAY-61- Associated with both adrenergic receptor agonist and M3 antimuscarinic activity treatment of pathological conditions or diseases Salts of the present invention, pharmaceutical compositions and combinations of the present invention, both ß2 pathological conditions associated with adrenergic receptor agonist and MS antimuscarinic activity or may be for use in the treatment of diseases and typically respiratory diseases.

Solunum hastaliklari ile kastedilen astim, akut veya kronik bronsit, amfizem, ya da kronik obstruktif akciger hastaligidir (KOAH). Astim veya kronik obstruktif akciger hastaligi daha fazla tercih edilir. Respiratory diseases mean asthma, acute or chronic bronchitis, emphysema, or chronic obstructive lung disease (COPD). More asthma or chronic obstructive pulmonary disease preferable.

Kombinasyonda bulunan etkin maddeler ve yukarida tanimlandigi gibi ikinci terapötik madde, ayni farmasötik bilesimde veya ayni ya da farkli yoldan olmak üzere ayri, eszamanli, birlikte veya sirali sekilde uygulanmaya yönelik tasarlanmis farkli bilesimlerde uygulanabilir. The active ingredients in the combination and the second therapeutic agent as defined above, in the same pharmaceutical composition or by the same or different route separately, simultaneously, together or in different compositions designed for sequential application.

Tüm etkin maddelerin ayni zamanda veya zamansal olarak çok yakin sekilde uygulanmasi öngörülür. Alternatif olarak bir veya iki etkin madde sabah saatinde ve diger(ler)i ise günün daha geç bir saatinde verilebilir. Veya baska bir senaryoya göre bir veya iki etkin madde günde iki kere uygulanirken diger etkin madde(ler) günde bir kere ve gerek günde iki kere verilenin yapildigi zamanda veya ayri sekilde verilebilir. Etkin maddelerin tercihen en az ikisi ve daha çok tercih edildigi haliyle tamami ayni zamanda verilebilecektir. Etkin maddelerin tercihen en az ikisi ve daha çok tercih edildigi haliyle tamami bir karisim formunda verilebilecektir. Application of all active substances at the same time or very close in time foreseen. Alternatively, one or two active ingredients in the morning and the other(s) of the day may be given at a later time. Or in another scenario, one or two active substances per day It is administered twice, while the other active ingredient(s) are administered once a day or twice a day. May be given at the same time or separately. Preferably at least two or more of the active ingredients it can be given at the same time as it is very preferred. Most of the active ingredients at least two of them and more preferably the whole may be given in the form of a mixture.

Mevcut bulusun etkin madde bilesimleri tercihen inhalerler ve özellikle kuru toz inhalerleri yardimiyla uygulanan inhalasyon bilesimleri formunda uygulanir; ancak parenteral veya oral uygulama gibi baska formlar da olanaklidir. Burada bilesimlerin içe solunacak sekilde uygulanmasi, `özellikle obstruktif akciger hastaliklarinin tedavisi ve astim tedavisi için tercih edilen uygulama seklidir. The active ingredient compositions of the present invention are preferably inhalers and especially dry powder inhalers. administered in the form of inhalation compositions administered with its help; but parenteral or oral Other forms such as application are also possible. Here your compositions will be inhaled It is preferred especially for the treatment of obstructive pulmonary diseases and the treatment of asthma. is the application form.

Etkin madde / maddelerin formülasyonlari genellikle ya MDI uygulamasina yönelik bir itici, ya da bir nebulizor ile uygulanmak üzere su olabilen uygun bir tasiyici içerir. Söz konusu formülasyon ayrica ilave bilesenler, mesela koruyucular (örnek olarak benzalkonyum klorür, potasyum sorbat, benzil alkol); pH stabilizörleri (örnek olarak asidik ajanlar, bazik ajanlar, tampon sistemleri); izotonik stabilizörler (örnek olarak sodyum klorür); yüzey aktifler ve islatici ajanlar (örnek olarak polisorbatlar, sorbitan esterler); ve/veya emilim artiricilar (örnek olarak kitosan, hyaluronik asit, yüzey aktifler) ihtiva edebilir. Söz konusu formülasyon ayrica bulus konusu tuz ile karistirildiginda baska etkin maddelerin çözünürlügünü iyilestirmek üzere katki maddeleri ihtiva edebilir. Çözünürlük artiricilar, mesela siklodekstrinler, Iipozomlar veya ko- solventler, mesela etanol, gliserol ve propilen glikol gibi bilesenler ihtiva edebilir. Formulations of the active ingredient(s) are usually either a propellant for MDI application, or and a suitable carrier, which may be water for administration with a nebulizer. Aforementioned The formulation may also contain additional ingredients, eg preservatives (eg benzalkonium chloride, potassium sorbate, benzyl alcohol); pH stabilizers (e.g. acidic agents, basic agents, buffer systems); isotonic stabilizers (eg sodium chloride); surfactants and wetting agent agents (eg, polysorbates, sorbitan esters); and/or absorption enhancers (eg. chitosan, hyaluronic acid, surfactants). The formulation in question is also in accordance with the invention. Additives to improve the solubility of other active substances when mixed with the salt in question. may contain substances. Solubility enhancers such as cyclodextrins, liposomes or co- solvents, such as ethanol, glycerol and propylene glycol.

Mevcut bulusun etkin tuzlarinin formülasyonlarina yönelik uygun ilave tasiyicilar için bkz. For suitable additive carriers for formulations of the active salts of the present invention, see Supplementary Fig.

Remington: The Science and Practice of Pharmacy, 20. Baski, Lippincott Williams & Wilkins, Philadelphia, Pa., 2000. Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2000.

Kuru toz formundaki bir farmas'otik bilesime yönelik tasiyici, tipik olarak nisastalar veya farmasötik olarak kabul edilebilir bir seker, mesela Iaktoz veya glukoz arasindan seçilir. Etkin maddenin tasiyiciya göre miktari genel itibariyla %0.001 ila %99 arasinda degisiklik gösterecektir. The carrier for a pharmaceutical composition in dry powder form, typically starches or a pharmaceutically acceptable sugar, such as Iactose or glucose. Effective The amount of the substance according to the carrier generally varies between 0.001% and 99%. will show.

Ornekler Reaktifler, baslangiç materyalleri ve solventler ticari tedarikçilerden satin alinmis ve alindiklari gibi kullanilmistir. Examples Reagents, starting materials and solvents were purchased from commercial suppliers and used as.

Burada tarif edilen bilesiklere ait tuzlarin, farmasötik olarak kabul edilebilir genis yelpazedeki asitler ile (digerlerinin yani sira fumarik, süksinik, sülfürik, hidroksi-Z-naftoik, L-tartarik, hidrobromik, 4-asetamidobenzoik, sorbik, hidroklorik, oksalik, trifenilasetik, metansülfonik, etandisülfonik, p-tolüensülfonik, naftalen-sülfonik, sakkarin, L-mandelik, maleik, 1S-kamfur- -sülfonik, L-malik, L-piroglutamik ve naftalen-1,5-disülf0nik asitler), farmasötik olarak kabul edilebilir çok farkli solventler (digerlerinin yani sira aseton, etil asetat, izopropanol, 2-bütan0l, etanol, kloroform, metanol, tetrahidrofuran ve su veya bunlarin karisimlari) içerisinde kristalizasyon testleri gerçeklestirilmistir. 4-Asetamid0benzoik asit ve sorbik asidin tuzlari ya yaglari ya da amorf katilari vermistir. The salts of the compounds described herein have a wide range of pharmaceutically acceptable with acids (among others fumaric, succinic, sulfuric, hydroxy-Z-naphthoic, L-tartaric, hydrobromic, 4-acetamidobenzoic, sorbic, hydrochloric, oxalic, triphenylacetic, methanesulfonic, ethanedisulfonic, p-toluenesulfonic, naphthalene-sulfonic, saccharine, L-mandelic, maleic, 1S-camphor- -sulfonic, L-malic, L-pyroglutamic and naphthalene-1,5-disulfonic acids), pharmaceutically acceptable available in a wide variety of solvents (among others acetone, ethyl acetate, isopropanol, 2-butanol, ethanol, chloroform, methanol, tetrahydrofuran and water or mixtures thereof) crystallization tests were carried out. Salts of 4-acetamidobenzoic acid and sorbic acid gave either oils or amorphous solids.

Sülfürik asidin tuzu bir kati olarak, ancak çok düsük bir kristalinite ile elde edilmistir. Diger taraftan hidroklorik asit ve hidrobromik asidin tuzlari, kararsiz olmustur. The salt of sulfuric acid was obtained as a solid, but with a very low crystallinity. Other On the other hand, salts of hydrochloric acid and hydrobromic acid were unstable.

Sadece mevcut bulusun tuzlari, çok kristalindir. Dahasi bu kristalin tuzlar ne higroskopiktir ne de nemle eriyebilmistir ve göreli yüksek bir erime noktasi sergileyerek mikronize edilmelerine ve uzun dönemli stabilite sergilemelerine imkan vermistir. Only the salts of the present invention are very crystalline. Moreover, these crystalline salts are neither hygroscopic nor It also melts with moisture and exhibits a relatively high melting point, allowing them to be micronized. and allowed them to exhibit long-term stability.

Bulus konusu katilma tuzlarini hazirlamaya yönelik özellikle iyi metotlar asagidaki örneklerde gösterilmistir. Particularly good methods for preparing the addition salts of the invention are illustrated in the following examples. shown.

FTIR spektrumlari, ya bir Bruker Diamond tek yansitmali ATR sistemi, uyarim kaynagi olarak bir orta-kizilötesi kaynagi ve bir DTGS detektörü ile donatili bir Bruker Alpha spektrometre kullanilarak, ya da bir Diamond tek yansitmali ATR sistemi, uyarim kaynagi olarak bir orta- kizilötesi kaynagi ve bir DTGS detektörü ile donatili bir Perking Elmer, Spectrum one çözünürlügünde 32 taramada elde edilmistir. FTIR spectra, either a Bruker Diamond single-reflection ATR system, as the excitation source a Bruker Alpha spectrometer equipped with a mid-infrared source and a DTGS detector or a Diamond single-reflection ATR system with a mid-range as the excitation source. A Perking Elmer, Spectrum one equipped with an infrared source and a DTGS detector It was obtained in 32 scans at resolution.

DSC analizleri, ya bir Mettler Toledo DSC822e ile, ya da bir DSO-821 Mettler-Toledo (seri durumunda 1-3 mg'lik örnekler tartilarak (MX5 mikro tarti, Mettler), küçük deligi bulunan kapaklara sahip 40 pL alüminyum krozeler içerisine konulmus ve azot akimi (50 ml / dk) altinda oC/dk'lik bir isitma hizinda 30'dan 300 °C'ye is itilmistir. Verilerin toplanmasi ve degerlendirilmesi, STARe yazilimi ile yapilmistir. Bir DSO-821 Mettler-Toledo (seri numarasi delikli alüminyum kapaklar örneklerin üzerine yerlestirilmis ve bir pirinç çubuk ile sikistirilmistir. DSC analyzes can be performed either with a Mettler Toledo DSC822e or with a DSO-821 Mettler-Toledo (serial Weighing 1-3 mg samples (MX5 microweigher, Mettler) 40 pL aluminum crucibles with lids and under nitrogen flow (50 ml / min) The heat was pushed from 30 to 300 °C at a heating rate of oC/min. Data collection and Evaluation was done with STARe software. A DSO-821 Mettler-Toledo (serial number perforated aluminum caps were placed over the samples and tightened with a brass rod.

Ornekler 25“C'de dengelenmis ve 10“C/dk hizinda 300°C'ye isitilmi stir. Cihaz indiyum ve çinko standartlar kullanilarak kalibre edilmistir. The samples were equilibrated at 25°C and heated to 300°C at a rate of 10°C/min. The device is indium and calibrated using zinc standards.

Termogravimetrik analizler, bir Mettler Toledo SDTA851e ile kaydedilmistir. 1 - 3 mg'lik örnekler tartilarak (MX5 mikro tarti, Mettler), küçük deligi bulunan kapaklara sahip 40 pL alüminyum krozeler içerisine konulmus ve azot akimi (50 ml / dk) altinda 10 cC/dk'lik bi r isitma hizinda 30'dan 300 cC'ye isitilmi stir. Verilerin toplanmasi ve degerlendirilmesi, STARe yazilimi ile yapilmistir. Thermogravimetric analyzes were recorded with a Mettler Toledo SDTA851e. 1 - 3 mg by weighing samples (MX5 microweigher, Mettler), 40 pL with caps with small hole placed in aluminum crucibles and heated at 10 cC/min under nitrogen flow (50 ml/min). It is heated from 30 to 300 cc at speed. Data collection and evaluation, STARe software was made with

Proton nükleer manyetik rezonans analizleri, bir Bruker Avance 500 Ultrashield NMR spektrometre ve soguk problu bir Varian VNMRS 600 MHz ile, döteryumlanmis dimetils'ulfoksit (DMSO-dö) içerisinde kaydedilmistir. Spektrumlar, 8-10 mg örnekler 0.5 ml döteryumlanmis solvent içerisinde çözülerek elde edilmistir. Proton nuclear magnetic resonance analyzes, a Bruker Avance 500 Ultrashield NMR Deuterated dimethylsulfoxide with a spectrometer and a Varian VNMRS 600 MHz with cold probe (DMSO-d). Spectra, 8-10 mg samples 0.5 ml deuterated obtained by dissolving in solvent.

Elde edilen katinin bir toz kirinim desenini 'üretmek amaciyla, islemden geçirilmemis örneklerin yaklasik 20'ser mg'i, poliasetat folyolar kullanilarak standart örnek yuvalari içerisinde hazirlanmistir. In order to produce a powder diffraction pattern of the resulting solid, untreated samples are approximately 20 mg each in standard sample slots using polyacetate foils. has been prepared.

Toz kirinim desenleri, transmisyon geometrisinde CuKcd radyasyonu (1.54060 Ã) kullanilarak bir Bruker D8 Advance Series 2Theta/Theta toz kirinim sistemi `üzerinde üretilmistir. Bu sistem bir VANTEC-1 tekli foton sayaci PSD, bir Germanium monokromatör, doksan pozisyonlu otomatik doldurmali bir örnek kademesi, sabit saptirma yariklari ve bir radyal soller ile donatilidir. Kullanilan programlar: Veri toplama için DIFFRAC arti XRD Commander V.2.4.1 ve degerlendirme için EVA V.12.0. Powder diffraction patterns using CuKcd radiation (1.54060 Ã) in transmission geometry Built on a Bruker D8 Advance Series 2Theta/Theta powder diffraction system. This system a VANTEC-1 single-photon counter PSD, a Germanium monochromator, ninety-position with an auto-fill sample stage, fixed deflection slots and a radial soller is equipped. Programs used: DIFFRAC plus XRD Commander V.2.4.1 for data collection and EVA V.12.0 for evaluation.

Toz kirinim desenleri, bir Cu X-isini kaynagina sahip, D2 Phaser modeli bir Brucker X-isini toz difraktometre 'üzerinde de gerçeklestirilmistir. Bu metot, bir Lynxeye detektör kullanilarak, 0.01 derece 2-Teta adim boyutu ile ve her bir adimda 04 saniyelik bir toplama süresiyle 5 dereceden 40 derece 2-Teta araliginda çalisir. -iI)etilamino)metiI)-5-metoksifenilamino)-3-oksopropil)(metiI)amino)-sikloheksiI hidroksi(di-2-tienil)asetat etandis'ülfonat hazirlama. il)etilamino)metil)-5-metoksifenil-amino)-3-oksopropiI)(metil)-amino)sikloheksiI hidroksi(di-2-tienil)asetat serbest bazini bunun hidroflor'ür tuzundan hazirlama. süspansiyonuna, asiri miktarda doymus NaHCOa sulu çözeltisi ilave edildi. Karisim oda sicakliginda bes dakika karistirildi. Kati, bir yag haline geldi ve çözünme gözlenene kadar CHCI3/MeOH ( çözeltisi ile yeniden ekstrakte edildi. Organik fazlar birlestirildi, MgSO4 altinda kurutuldu, filtrelendi ve sari renkli kuru köpük formunda 1.09 9 serbest baz elde etmek üzere solventler, düsük basinç altinda konsantre edildi. (Verim: %97.17). il)etilamin0)metil)-5-metoksifeniIamin0)-3-0ksopropil)(metil)amino)sikloheksil hidroksi(di-2- tienil)asetat serbest bazina yönelik FTIR spektrumunu gösterir. Serbest bazi bilesigine yönelik 1'de görüldü. il)etilamino)-metiI)-5-metoksifenilamino)-3-oksopropil)(metiI)amino)-sikloheksiI hidroksiI-(di-2-tienil)asetat serbest bazindan kristalin etandisülfonat tuzunu dogrudan hazirlama. 1.2.1 Solvent olarak metanol kullanilarak. 105 mg serbest baz (0.132 mmol), manyetik karistirma esliginde ve zaman zaman sonikasyon altinda 14 ml metanol içerisinde çözüldü. Bu çözelti, açik sari bulanikliklari ortadan kaldirmak üzere 0.45 um'lik bir siringali filtre içerisinden filtrelendi ve daha sonra buraya, orta siddetli karistirma esliginde, 1 ml metanol içerisinde 27.6 mg'lik (0.145 mmol) bir etandisülfonik asit çözeltisi damla damla eklendi. Ekleme yapildiktan sonra berrak bir çözelti elde edildi. Birkaç dakika sonra beyaz bir bulaniklik gerçeklesti ve daha sonra çökeltinin miktari adim adim artti. Powder diffraction patterns, a Brucker X-ray model D2 Phaser with a Cu X-ray source was also carried out on the 'diffractometer'. This method is 0.01 using a Lynxeye detector. 5 with degree 2-Theta step size and a collection time of 04 seconds per step It works in the 2-Theta range from degrees 40 degrees. -II)ethylamino)methyl-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)-cyclohexyl Preparation of hydroxy(di-2-thienyl)acetate ethanedissulfonate. yl)ethylamino)methyl)-5-methoxyphenyl-amino)-3-oxopropyl)(methyl)-amino)cyclohexyl preparing the hydroxy(di-2-thienyl)acetate free base from its hydrofluoride salt. An excess of saturated NaHCOa aqueous solution was added to the suspension. my wife room stirred for five minutes at temperature. The solid became an oil and until dissolution was observed. CHCl3/MeOH ( re-extracted with the solution. The organic phases were combined, dried under MgSO4, filtered and solvents to obtain 1.09 9 free bases in the form of a yellow dry foam, concentrated under low pressure. (Yield: 97.17%). yl)ethylamino)methyl)-5-methoxyphenylamino)-3-0xopropyl)(methyl)amino)cyclohexylhydroxy(di-2- shows the FTIR spectrum for the thienyl)acetate free base. For free base compound seen in 1. yl)ethylamino)-methyl-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)-cyclohexyl directly from the free base of hydroxyI-(di-2-thienyl)acetate to the crystalline ethanedisulfonate salt. preparation. 1.2.1 Using methanol as solvent. 105 mg of free base (0.132 mmol), with magnetic stirring and occasional sonication dissolved in 14 ml of methanol under This solution is intended to eliminate light yellow blurs. was filtered through a 0.45 µm syringe filter and then poured there with stirring, 27.6 mg (0.145 mmol) of ethanedisulfonic acid in 1 ml of methanol solution was added dropwise. After addition, a clear solution was obtained. A few After a minute, a white haze occurred and then the amount of precipitate increased step by step.

Karistirmaya 1 saat devam edildi ve daha sonra karisim oda sicakliginda 24 saat beklemeye birakildi. Beyaz renkli kati filtrelendi, bir kere metanol/izopropil eter (121) çözeltisi ve üç kere etil eter ile yikandi ve böylece ve kurutma yapildiktan sonra, baslikta belirtilen tuzdan 76 mg elde edildi. (Verim: %585). 1.2.2 Solvent olarak CHzCIz/EIOH kullanilarak. 105 mg serbest baz (0.132 mmol), manyetik karistirma esliginde 3 ml diklorometan içerisinde çözüldü ve 3 ml etanol eklendi. Bu çözelti, çok açik sari bulanikliklari ortadan kaldirmak üzere 0.45 um'lik bir siringali filtre içerisinden filtrelendi ve daha sonra buraya, orta siddetli karistirmaya devam edilerek, 1 ml etanol içerisinde 27.6 mg'lik (0.145 mmol) bir etandisülfonik asit çözeltisi damla damla eklendi. Asit çözeltisinin ilk damlalari eklendikten sonra derhal beyaz renkli bir bulaniklik meydana geldi ve daha sonra çökelti adim adim çogaldi. Karistirmaya 1 saat devam edildi ve daha sonra karisim oda sicakliginda 24 saat beklemeye birakildi. Beyaz renkli kati filtrelendi, bir kere etanol/izopropil eter (111) çözeltisi ve üç kere etil eter ile yikandi ve böylece ve kurutma yapildiktan sonra, baslikta belirtilen tuzdan 99 mg elde edildi. (Verim: Sekil 2, etandisülfonat tuzuna yönelik toz X isini kirinim (PXRD) desenini gösterir. Çok sayida pik gözlendi ve tuzun kristalligi bu sekilde teyit edildi. XRPD açilarinin ve göreli yeginliklerin özeti, Tablo 1 içerisinde verilir. Mixing was continued for 1 hour and then the mixture was allowed to stand at room temperature for 24 hours. was abandoned. The white solid was filtered, once with methanol/isopropyl ether (121) solution and three times. washed with ethyl ether and thus and after drying, 76 mg of the salt mentioned in the title obtained. (Yield: 585%). 1.2.2 Using CH2Cl2/EIOH as solvent. 105 mg of free base (0.132 mmol) in 3 ml of dichloromethane with magnetic stirring dissolved and 3 ml of ethanol was added. This solution is used to remove very light yellow turbidity. It was filtered through a 0.45 µm syringe filter and then inserted here into medium With continued stirring, a solution of 27.6 mg (0.145 mmol) of ethanedisulfonic in 1 ml of ethanol was added. acid solution was added dropwise. White immediately after adding the first drops of acid solution a colored turbidity occurred and then the precipitate gradually increased. mix 1 hours were continued and then the mixture was left to stand at room temperature for 24 hours. White The colored solid was filtered off, washed once with an ethanol/isopropyl ether (111) solution and three times with ethyl ether. and thus and after drying, 99 mg of the title salt was obtained. (Yield: Figure 2 shows the powder X-ray diffraction (PXRD) pattern for the ethanedisulfonate salt. Numerous peak was observed and the crystallinity of the salt was thus confirmed. XRPD angles and relative intensities summary is given in Table 1.

Kirinim Açisi (? 9) d degeri (A) Gbreli Yeginlik (%) 9.22 9.58 49.3 Kirinim Açisi (“2 6) d degeri (A) Göreli Yeginlik (%) 1,2-dihidrokinolin-5-il)etilamino)-metil)-5-metoksifenilamino)-3-oksopr0pil)(metil)amin0)- sikloheksil hidroksil-(di-2-tienil)asetatin etandisülfonat tuzu, 19.95 ± 0.2'lik 26 degerlerinde piklere sahip bir X isini toz kirinim (XRPD) deseni ile karakterize edilir. Diffraction Angle (? 9) d value (A) Fertilizer Density (%) 9.22 9.58 49.3 Diffraction Angle (“2 6) d value (A) Relative Intensity (%) 1,2-dihydroquinolin-5-yl)ethylamino)-methyl-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)- cyclohexyl hydroxyl-(di-2-thienyl)acetatine ethanedisulfonate salt at 26 values of 19.95 ± 0.2 It is characterized by an X-ray powder diffraction (XRPD) pattern with peaks.

Sekil 3, etandisülfonat tuzunun 1H-NMR spektrumuna karsilik gelir. Asidin etilen grubuna karsilik gelen protonlarin ve ana yapiya ait kinolon grubundaki bir tek protonun tam degerleri arasindaki karsilastirmadan görüldügü üzere, serbest baz/ etandisülfonik asit arasinda 1:1'Iik stokiometrik oran açik sekilde görülmektedir. 1H NMR (, 1.99 - Sekil 4, 206 cC'de bir maksimum deger ile yogun bir endotermik egri sergileyen, ki bu durum tuzun olasi bir füzyonu / ayrismasina isaret edebilir, etandisülfonat tuzuna yönelik DSC analizini gösterir. Figure 3 corresponds to the 1H-NMR spectrum of the ethanedisulfonate salt. The ethylene group of the acid the exact values of the corresponding protons and a single proton in the quinolone group of the main structure 1:1 ratio between free base/ethanedisulfonic acid, as can be seen from the comparison between stoichiometric ratio is clearly visible. 1H NMR (, 1.99 - Figure 4 exhibits a dense endothermic curve with a maximum value of 206 cC, which is may indicate a possible fusion/separation of the salt, DSC for ethanedisulfonate salt displays the analysis.

Sekil 5, etandisülfonat tuzunun TG analizini gösterir. Bu spektrum, 40 ve 90 “C arasinda hafif bir kütle kaybi sergiler. Tuzun ayristigi yaklasik 250 °C'ye kadar anlamli de gisimler gözlenmez. Figure 5 shows the TG analysis of the ethanedisulfonate salt. This spectrum is light between 40 and 90°C. exhibits a mass loss. No significant changes are observed up to about 250 °C, where the salt decomposes.

Sekil 6, etandisülfonat tuzunun FTIR spektrumunu gösterir. Etandisülfonat tuzuna yönelik -il)eti'lamino)metiI)-5-metoksifenilkarbamoiloksi)-etil)(metil)amino)sikloheksil 2- hidroksi-Z,2-di(tiofen-2-il)asetat disakkarinat hazirlama dihidrokinolin-5-il)etilamino)metiI)-5-metoksifenilkarbamoiloksi)- etil)(metil)amino)si'kloheksil 2-hidroksi-2,2-di(tiofen-2-il)asetat serbest bazini hazirlama. 2-0kso-1,2-dihidrokinolin-5-il)etilamin0)metil)-5-met0ksifenilkarbamoiloksi)etil)- Ornek 12) süspansiyonuna, asiri miktarda doymus NaHCOs sulu çözeltisi ilave edildi. Karisim oda sicakliginda 1 saat karistirildi. Sulu katman, kloroform ile iki kere ekstrakte edildi. Figure 6 shows the FTIR spectrum of the ethanedisulfonate salt. For ethanedisulfonate salt -yl)ethylamino)methyl-5-methoxyphenylcarbamoyloxy)ethyl)(methyl)amino)cyclohexyl 2- Preparation of hydroxy-Z,2-di(thiophen-2-yl)acetate disaccharinate dihydroquinolin-5-yl)ethylamino)methyl-5-methoxyphenylcarbamoyloxy)- Preparation of ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetate free base. 2-Oxo-1,2-dihydroquinolin-5-yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)- An excess of saturated NaHCO3 aqueous solution was added to the suspension of Example 12). Mixture stirred for 1 hour at room temperature. The aqueous layer was extracted twice with chloroform.

Birlestirilen organik fazlar N82804 altinda kurutuldu, filtrelendi ve sari renkli kuru köpük formunda 1.2 9 serbest baz elde etmek üzere solventler, düsük basinç altinda konsantre edildi. il)etilamin0)metiI)-5-met0ksifenilkarbamoiloksi)etil)(metil)amin0)sikloheksil 2-hidroksi-2,2- di(tiofen-2-il)asetat serbest bazina yönelik Fourier dönüsümlü kizilötesi (FTIR) spektrumunu il)etilamino)metil)-5-metoksifenilkarbamoiI-oksi)etiI)(metiI)-amino)sikloheksil 2- hidroksi-2,2-di(ti0fen-2-il)asetat disakkarinat amorf formunu hazirlama. dihidrokinolin-5-il)etilamino)metiI)-5-metoksifenilkarbamoiI-oksi)etil)(metil)-amin0)sikloheksil 2-hidroksi- içinde bulunan bir sakkarin (18 mg, 0.1 mmol) çözeltisi eklendi. Karisim 1 saat karistirildi ve elde edilen çökelti filtrelendi ve baslikta belirtilen üründen 95 mg vermek üzere vakum altinda kurutuldu (verim %75). dihidrokinolin-5-il)etilamino)metiI)-5-metoksifeniI-karbamoiIoksi)etiI)(metil)- amino)sikloheksil 2-hidroksi-2,2-di(tiofen-2-il)asetat disakkarinat kristalin tuzu hazirlama. il)etilamino)metiI)-5-metoksifeniIkarbam0iI-oksi)etil)(metiI)-amino)sikloheksil 2-hidr0ksi-2,2- di(tiofen-2-il)asetatin kristalin yapida olmayan disakkarinat tuzu (25 mg, 0.031 mmol), etanol (0.5 ml) içinde süspansiyon haline getirildi ve 70 °C'de 2 saat kari stirildi. Süspansiyon, oda sicakligina sogumaya birakildi ve elde edilen kirli beyaz renkli toz filtrelendi ve gece boyu 60 ”C'de vakum altinda kurutuldu. Verim 10 mg (%40). Verim 10 mg (%40). il)etilamino)metiI)-5-metoksifenilkarbamoiloksi)etiI)(metiI)-amino)sikloheksil 2- hidroksi-2,2-di(ti0fen-2-il)asetat disakkarinat kristalin tuzunu dogrudan hazirlama. dihidrokinolin-5-il)etilamino)-metil)-5-metoksifeniIkarbamoiI-oksi)etil)(metiI)-amino)sikl0heksil 2-hidroksi-2,2-di(tiofen-2-il)asetatin (500 mg in etanol içerisindeki sicak (70 C) bir çözeltisine direkt olarak eklendi. Çözeltisi 1 saat siddetli sekilde karistirildi ve böylece kivamli, kirli beyaz renkli bir süspansiyona dönüstü. Balonun duvarlari, bir spatula ile kazindi ve süspansiyon 15 dakika daha karistirildi. Katilar daha sonra filtrelendi ve etanol ile iki kere yikanarak, 500 mg (%70 verim) sarimsi bir kati elde edildi. Bu sakkarinat tuzu istege göre 6 mL su içerisinde 30 dakika çamur haline getirildi. The combined organic phases were dried under N82804, filtered and dried to yellow dry foam. The solvents were concentrated under reduced pressure to obtain 1.2 9 free bases in the form of. yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2- Fourier transform infrared (FTIR) spectrum for di(thiophen-2-yl)acetate free base. yl)ethylamino)methyl)-5-methoxyphenylcarbamoyl-oxy)ethyl)(methyl)-amino)cyclohexyl 2- Preparation of hydroxy-2,2-di(thiOphenyl-2-yl)acetate disaccharinate amorphous form. dihydroquinolin-5-yl)ethylamino)methyl-5-methoxyphenylcarbamoyl-oxy)ethyl)(methyl)-amino)cyclohexyl 2-hydroxy- A solution of saccharin (18 mg, 0.1 mmol) contained in it was added. The mixture was stirred for 1 hour and The resulting precipitate was filtered off and under vacuum to yield 95 mg of the title product. dried (yield 75%). dihydroquinolin-5-yl)ethylamino)methyl-5-methoxyphenyl-carbamoyloxy)ethyl)(methyl)- amino)cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetate disaccharinate crystalline salt preparation. yl)ethylamino)methyl)-5-methoxyphenylcarbamyl-oxy)ethyl)(methyl)-amino)cyclohexyl 2-hydroxy-2,2- non-crystalline disaccharinate salt of di(thiophen-2-yl)acetatin (25 mg, 0.031 mmol), ethanol (0.5 ml) and stirred at 70 °C for 2 hours. suspension, chamber allowed to cool to temperature, and the resulting off-white powder was filtered and overnight at 60 It was dried under vacuum at ”C. Yield 10 mg (40%). Yield 10 mg (40%). yl)ethylamino)methyl-5-methoxyphenylcarbamoyloxy)ethyl(methyl)-amino)cyclohexyl 2- Direct preparation of hydroxy-2,2-di(thiOphenyl-2-yl)acetate disaccharinate crystalline salt. dihydroquinolin-5-yl)ethylamino)-methyl-5-methoxyphenylcarbamoyl-oxy)ethyl)(methyl)-amino)cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetatin (500mg in hot (70 C) was added directly to a solution. The solution was stirred vigorously for 1 hour so that changed into a thick, off-white suspension. The walls of the balloon were scraped off with a spatula and the suspension was stirred for an additional 15 minutes. The solids were then filtered and rinsed twice with ethanol. washing gave 500 mg (70% yield) of a yellowish solid. This saccharinate salt optionally It was turned into a sludge in 1 mL of water for 30 minutes.

Sekil 8, disakkarinat tuzuna yönelik toz X isini kirinim (PXRD) desenini gösterir. Çok sayida pik gözlendi ve tuzun kristalligi bu sekilde teyit edildi. XRPD açilarinin ve göreli yeginliklerin özeti, Tablo 2 içerisinde verilir. Figure 8 shows the powder X-ray diffraction (PXRD) pattern for the disaccharinate salt. Numerous peak was observed and the crystallinity of the salt was thus confirmed. XRPD angles and relative intensities summary is given in Table 2.

Kirinim Açisi (°2 6) d degeri (A) Göreli Yeginlik (%) Kirinim Açisi (2 6) d degeri (Ã) Gbreli Yeginlik (%) 26.74 3.33 42 27.38 3.25 35 1,2-dihidrokinolin-5-il)etilamino)metil)-5-metoksifenilkarbamoiloksi)etil)(metil)- önemli piklere sahip bir X isini toz kirinim (XRPD) deseni ile karakterize edilir. Diffraction Angle (°2 6) d value (A) Relative Intensity (%) Diffraction Angle (2 6) d value (Ã) Ferrous Density (%) 26.74 3.33 42 27.38 3.25 35 1,2-dihydroquinolin-5-yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)(methyl)- It is characterized by an X-ray powder diffraction (XRPD) pattern with significant peaks.

Sekil 9, disakkarinat tuzunun 1H-NMR spektrumuna karsilik gelir. Sakkarin molekülünün aromatik halkasina karsilik gelen protonlarin ve ana yapiya ait hidroksil radikalinde bulunan bir tek protonun tam degerleri arasindaki karsilastirmadan görüldügü üzere, serbest baz / sakkarin arasinda 1:2'lik stokiometrik oran açik sekilde görülmektedir. 1H NMR (, Sekil 10, 197 °C'de bir maksimum deger ile yogun bir endotermik egri sergileyen, ki bu durum tuzun olasi bir füzyonu / ayrismasina isaret edebilir, disakkarinat tuzuna yönelik DSC analizini gösterir. Figure 9 corresponds to the 1H-NMR spectrum of the disaccharinate salt. of the saccharin molecule found in the protons corresponding to the aromatic ring and the hydroxyl radical of the main structure. As can be seen from the comparison between the exact values of a single proton, the free base / The stoichiometric ratio of 1:2 between saccharin is clearly seen. 1H NMR (, Figure 10 shows an intense endothermic curve with a maximum value at 197 °C, which is may indicate a possible fusion/segregation of the salt, check the DSC analysis for the disaccharinate salt. shows.

Sekil 11, disakkarinat tuzunun TG analizini gösterir. Bu spektrum, 40 ve 80 cC arasinda çok hafif bir kütle kaybi sergiler. Tuzun ayristigi yaklasik 160 °C'ye kadar anlamli degisimler gözlenmez. Figure 11 shows the TG analysis of the disaccharinate salt. This spectrum is very good, between 40 and 80 cC. exhibits a slight loss of mass. Significant changes up to about 160 °C where the salt decomposes not observed.

Sekil 12, disakkarinat tuzunun FTlR spektrumunu gösterir. Serbest baz bilesigi ile karsilastirildiginda disakkarinatin kizilötesi spektrumu, önemli farkliliklara sahiptir. Her iki spektrumun bir karsilastirmasi, Sekil 12'ye de dahil edilmistir. Disakkarinata yönelik önemli -il)etilamino)metiI)-5-metoksifenilkarbamoiloksi)-etil)(metil)amino)sikloheksil 2- hidroksi-Z,2-di(ti'0fen-2-il)asetat L-tartrat hazirlama mL metanol içinde bulunan 115 mg'lik bir L-tartarik asit çözeltisine, 20 ml metanol içinde dihidrokinolin-5-il)etilamino)metil)-5-met0ksifenilkarbamoiIoksi)etil)-(metil)amino)sikloheksil 2- hidroksi-2,2-di(tiofen-2-il)asetat serbest baz çözeltisi (hazirlama sekli için bkz. yukari, 2.1) ilave edildi. Karisim oda sicakliginda 4 saat karistirildi. Meydana gelen çökelti filtrelendi ve gece boyu vakum altinda 40 “C'de kurutuldu. Verim %80. Figure 12 shows the FTlR spectrum of the disaccharinate salt. With free base compound In comparison, the infrared spectrum of disaccharinate has significant differences. Both A comparison of the spectrum is also included in Figure 12. Important for disaccharinate -yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)-ethyl)(methyl)amino)cyclohexyl 2- Preparation of hydroxy-Z,2-di(thi'Ophenyl-2-yl)acetate L-tartrate To a solution of 115 mg of L-tartaric acid in mL of methanol, in 20 ml of methanol dihydroquinolin-5-yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2- Addition of hydroxy-2,2-di(thiophen-2-yl)acetate free base solution (see above, 2.1 for preparation method) was done. The mixture was stirred at room temperature for 4 hours. The resulting precipitate was filtered and overnight. length was dried under vacuum at 40 °C. Yield 80%.

Sekil 13, L-tartrat tuzuna yönelik toz X isini kirinim (PXRD) desenini gösterir. Çok sayida pik gözlendi ve tuzun kristalligi bu sekilde teyit edildi. XRPD açilarinin ve göreli yeginliklerin özeti, Tablo 3 içerisinde verilir. Figure 13 shows the powder X-ray diffraction (PXRD) pattern for the L-tartrate salt. lots of peaks was observed and the crystallinity of the salt was thus confirmed. Summary of XRPD angles and relative intensities, It is given in Table 3.

Kirinim Açisi (? 9) d degeri (A) Gbreli Yeginlik (%) 13.20 6.70 35 Kirinim Açisi (“2 6) d degeri (A) Gbreli Yeginlik (%) 27.48 3.24 29 1,2-dihidrokinolin-5-il)etilamino)metil)-5-metoksifenilkarbamoiloksi)etiI)(metil)- piklere sahip bir X isini toz kirinim (XRPD) deseni ile karakterize edilir. Diffraction Angle (? 9) d value (A) Fertilizer Density (%) 13.20 6.70 35 Diffraction Angle (“2 6) d value (A) Fertilizer Density (%) 27.48 3.24 29 1,2-dihydroquinolin-5-yl)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)(methyl)- It is characterized by an X-ray powder diffraction (XRPD) pattern with peaks.

Sekil 14, L-tartrat tuzunun 1H-NMR spektrumuna karsilik gelir. L-tartarik asit molekülünün hidroksil radikaline karsilik gelen protonlarin ve ana yapiya ait hidroksil radikalinde bulunan bir tek protonun tam degerleri arasindaki karsilastirmadan görüldügü üzere, serbest baz / L- tartarik asit arasinda 1:1'lik stokiometrik oran açik sekilde görülmektedir. 1H NMR (, Sekil 15, 173 °C'de bir maksimum deger ile yogun bir endotermik egri sergileyen, ki bu durum tuzun olasi bir füzyonu / ayrismasina isaret edebilir, L-tartarat tuzuna yönelik DSC analizini gösterir. Figure 14 corresponds to the 1H-NMR spectrum of the L-tartrate salt. L-tartaric acid molecule one of the protons corresponding to the hydroxyl radical and the hydroxyl radical of the main structure. As can be seen from the comparison between the exact values of the single proton, the free base / L- The stoichiometric ratio of 1:1 between tartaric acid is clearly seen. 1H NMR (, Figure 15 exhibits a dense endothermic curve with a maximum value of 173 °C, which is may indicate a possible fusion/segregation of the salt, check the DSC analysis for the L-tartarate salt shows.

Sekil 16, L-tartrat tuzunun TG analizini gösterir. Bu spektrum 37 ve 90 CC arasinda, muhtemelen su molekülüne karsilik gelen hafif bir kütle kaybi sergiler. Tuzun ayristigi yaklasik 173 Sekil 17, L-tartart tuzunun FTIR spektrumunu gösterir. L-tartrat tuzuna yönelik önemli sinyaller 623 ve 524 cm4'de görülür. Figure 16 shows the TG analysis of the L-tartrate salt. This spectrum is between 37 and 90 CC, it probably exhibits a slight mass loss corresponding to the water molecule. The salt separates approx. 173 Figure 17 shows the FTIR spectrum of the L-tartart salt. Important signals for L-tartrate salt It is seen at 623 and 524 cm4.

Asagidaki preparat formlari bilesim (formülasyon) örnekleri olarak verilmistir: BILESIM ORNEGI 1 Formülasyon Örnegi 1 (kuru toz inhaler ile inhalasyon için formülasyon) Bilesen Miktar dihidrokinolin-S-il)etilamin0)-metiI)-5-metoksifenilkarbamoiloksi)etil)- (metil)amino)sikloheksil 2-hidroksi-2,2-di(tiofen-2-il)asetat L-tartrat tuzu (mikronize) Laktoz 3000 mg Formülasyon Örnegi 2 (kuru toz inhaler ile inhalasyon için formülasyon) Bilesen Miktar dihidrokinolin-S-il)etilamino)-metil)-5-metoksifeniI- karbamoiloksi)etil)-(metil)amin0)-sikloheksil 2-hidroksi-2,2-di(tiofen- 2-il)asetat disakkarinat (mikronize) Laktoz 3000 mg Formülasyon Örnegi 3 (kuru toz inhaler ile inhalasyon için formülasyon) Bilesen Miktar dihidrokinolin-S-il)etilamin0)metil)-5-met0ksifenilamin0)-3- oksopropil)(metiI)amin0)-sik|0heksil hidroksi(di-2-tienil)asetat etandis'ülfonat (mikronize) Laktoz 3000 mg Formülasyon Örnegi 4 (ölçülü dozlu inhaler için formülasyon) Bilesen Miktar dihidrokinolin-S-il)etilamino)-metil)-5-metoksifeniIkarbamoiloksi)etil)- (metil)amin0)sikloheksil 2-hidroksi-2,2-di(ti0fen-2-il)asetat L-tartrat tuzu (mikronize) 200 ml'ye 1 ,1,1,2,3,3,3-heptafl0ro-n-pr0pan tamamlayacak kadar Formülasyon Örnegi 5 (ölçülü dozlu inhaler için formülasyon) 1 ,1,1,2,3,3,3-heptafl0ro-n-propan Bilesen Miktar dihidrokinolin-S-il)etilamino)-metiI)-5-metoksifeniI- karbamoiloksi)etiI)-(metiI)amin0)-sikl0heksil 2-hidr0ksi-2,2-di(tiofen- 2-il)asetat disakkarinat (mikronize) 200 ml'ye tamamlayacak kadar Formülasyon Örnegi 6 (ölçülü dozlu inhaler için formülasyon) Bilesen Miktar dihidrokinolin-S-il)etilamin0)metil)-5-met0ksifenilamin0)-3- oksopropil)(metiI)amin0)-sik|0heksil hidroksi(di-2-tienil)asetat etandisülfonat (mikronize) 200 ml'ye 1 ,1,1,2,3,3,3-heptafl0ro-n-propan tamamlayacak kadar iI)etiIamino)metiI)-5-metoksifenilamin0)-3-oksopr0pil)(metil)amin0)-sikl0heksil hidroksi(di-2-tienil)asetat FTIR spektrumu. metoksifenilamin0)-3-0ksopr0pil)-(metiI)amin0)sikl0heksil hidroksi(di-2-tienilJasetat etandisülfonat X-isini kirinim (PXRD) deseni.. il)etilamino)metil)-5-metoksifenilamino)-3-0ksopropil)(metil)amino)sikl0heksiI hidroksi(di-2- tienil)asetat etandisülfonat 1H-NMR verileri (. 191:" ' sinyaller(-4H) - - ~°- I .g\l`.__._.›`__. _.,` _ o › . u..- I.. H., .._._- __w-__i __... `MJ-_- 4 '.i ' *tlh- _ .. . H iIJetiIamin0)metiI)-5-met0ksifenilamin0)-3-oksopr0pil)(metiI)amino)-sikl0heksil hidroksi(di-2- tienil)asetat etandisülfonat DSC analizi. 61 __fi - ,4111 8- _f_ 5 iI)etiIamin0)metiI)-5-metoksifeniIamino)-3-oksopr0piI)(metil)amino)-sikl0heksil hidroksi(di-2- tienil)asetat etandisülfonat TGA analizi -Ö-Q-Ö- 0-6_0--- O 0 1 J 0 --+-L--+-_f-+-q '- s-O-o-b--i 4-Q-Q ç -o---› il)etilamino)metil)-5-metoksifenilamino)-3-0ksopr0pil)(metil)amin0)-sikl0heksil hidroksi(di-2-tienil)asetat etandis'ülfonat FTIR spektrumu 1 \ I i 1 , I' I I i .. iv 1.' n rs" ç'i'.? Y" n'xl 'Mi ...I M." :ini- III u metil)-5-metoksifeniIkarbamoiloksi)etil)-(metiI)amino)sikloheksil 2-hidr0ksi-2,2-di(ti0fen-2- Geçirim [%1 335.11: il)asetat FTIR spektrumu. The following preparation forms are given as composition (formulation) examples: COMPOSITION SAMPLE 1 Formulation Example 1 (formulation for inhalation with dry powder inhaler) Component Quantity dihydroquinolin-S-yl)ethylamino)-methyl-5-methoxyphenylcarbamoyloxy)ethyl)- (methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetate L-tartrate salt (micronized) Lactose 3000mg Formulation Example 2 (formulation for inhalation with dry powder inhaler) Component Quantity dihydroquinolin-S-yl)ethylamino)-methyl-5-methoxyphenyl- carbamoyloxy)ethyl)-(methyl)amino)-cyclohexyl 2-hydroxy-2,2-di(thiophene- 2-yl)acetate disaccharinate (micronized) Lactose 3000mg Formulation Example 3 (formulation for inhalation with dry powder inhaler) Component Quantity dihydroquinolin-S-yl)ethylamino0)methyl)-5-methoxyphenylamino0)-3- oxopropyl)(methyl)amino)-cyclohexyl hydroxy(di-2-thienyl)acetate ethandis'ulfonate (micronized) Lactose 3000mg Formulation Example 4 (formulation for metered dose inhaler) Component Quantity dihydroquinolin-S-yl)ethylamino)-methyl-5-methoxyphenylcarbamoyloxy)ethyl)- (methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiOphenyl-2-yl)acetate L-tartrate salt (micronized) to 200 ml 1 ,1,1,2,3,3,3-heptafl0ro-n-pr0pan to complete Formulation Example 5 (formulation for metered dose inhaler) 1 ,1,1,2,3,3,3-heptafluoro-n-propane Component Quantity dihydroquinolin-S-yl)ethylamino)-methyl-5-methoxyphenyl- carbamoyloxy)ethyl)-(methyl)amino)-cyclohexyl 2-hydroxy-2,2-di(thiophene- 2-yl)acetate disaccharinate (micronized) to 200 ml to complete Formulation Example 6 (formulation for metered dose inhaler) Component Quantity dihydroquinolin-S-yl)ethylamino0)methyl)-5-methoxyphenylamino0)-3- oxopropyl)(methyl)amino)-cyclohexyl hydroxy(di-2-thienyl)acetate ethanedisulfonate (micronized) to 200 ml 1 ,1,1,2,3,3,3-heptafluoro-n-propane to complete ii)ethylamino)methyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)-cyclohexyl FTIR spectrum of hydroxy(di-2-thienyl)acetate. methoxyphenylamin0)-3-0xopropyl)-(methyl)amino0)cyclohexyl hydroxy(di-2-thienylJacetate ethanedisulfonate X-isine diffraction (PXRD) pattern.. yl)ethylamino)methyl)-5-methoxyphenylamino)-3-Oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2- thienyl)acetate ethanedisulfonate 1H-NMR data (. 191:" ' signals(-4H) - - ~°- I .g\l`._._.›`__. _.,` _ o › . u..- I.. H., .._._- __w-__i __... `MJ-_- 4 '.i ' *tlh- _ .. . H iJetylamino)methyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)-cyclohexyl hydroxy(di-2- thienyl)acetate ethanedisulfonate DSC analysis. 61 __fi - ,4111 8- _f_ 5 ii)ethylamino)methyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)-cyclohexyl hydroxy(di-2- thienyl)acetate ethanedisulfonate TGA analysis -Ö-Q-Ö- 0-6_0--- O 0 1 J 0 --+-L--+-_f-+-q '- s-O-o-b--i 4-Q-Q ç -o---› yl)ethylamino)methyl)-5-methoxyphenylamino)-3-0xopropyl)(methyl)amino)-cyclohexyl FTIR spectrum of hydroxy(di-2-thienyl)acetate ethanedissulfonate 1 \ I i 1 , I' I I i ..iv 1.' n rs" ç'i'.? Y"n'xl'Mi ...I M." :ini- III u methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophene-2- Permeability [%1 335.11: il) acetate FTIR spectrum.

Dalga sayisi cm-1 Lin (sayim) iI)etiIamino)metiI)-5- metoksifenilkarbamoiIoksi)etil)(metil)amin0)sikl0heksil 2-hidroksi-2,2- di(ti0fen-2- il)asetat disakkarinat X isini kirinim (PXRD) deseni. 2-Teta Olçegi il)etilamino)-metil)-5-metoksifenilkarbamoiloksi)etiI)-(metil)amino)sikl0heksil 2-hidr0ksi- 2,2-di(tiofen-2-il)asetat disakkarinat 1H-NMR spektrumu. i 4-)` " ii 'fl J' Sakkarin sinyalleri (~ BH) /17 il)etilamin0)-metil)-5-met0ksifenilkarbam0il0ksi)etiI)-(metil)amino)sikl0heksil 2- hidroksi-2,2-di(tiofen-2-il)asetat disakkarinat DSC analizi 11/17 il)etilamin0)-metiI)-5-metoksifeniIkarbamoiloksi)etiI)-(metil)amino)sikl0heksil 2- hidroksi-2,2-di(tiofen-2-il)asetat disakkarinat TG analizi. 12/17 metiI)-5-metoksifenilkarbamoiloksi)etil)-(metiI)amin0)sikloheksil 2-hidr0ksi-2,2-di(ti0fen-2- Gepirim [%1 il)asetat disakkarinat FTIR spektrumu. Wave number cm-1 Lin (count) ii)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2- X-ray diffraction (PXRD) pattern of di(thiOphen-2-yl)acetate disaccharinate. 2-Theta Scale yl)ethylamino)-methyl)-5-methoxyphenylcarbamoyloxy)ethyl-(methyl)amino)cyclohexyl 2-hydroxy- 1H-NMR spectrum of 2,2-di(thiophen-2-yl)acetate disaccharinate. i 4-)` " ii 'fl J' Saccharin signals (~BH) /17 yl)ethylamino)-methyl)-5-methoxyphenylcarbam0yloxy)ethyl)-(methyl)amino)cyclohexyl 2- DSC analysis of hydroxy-2,2-di(thiophen-2-yl)acetate disaccharinate 11/17 yl)ethylamino)-methyl-5-methoxyphenylcarbamoyloxy)ethyl-(methyl)amino)cyclohexyl 2- TG analysis of hydroxy-2,2-di(thiophen-2-yl)acetate disaccharinate. 12/17 methyl-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophene-2- I get [1%] il) FTIR spectrum of acetate disaccharinate.

Dalga sayisi ::m-1 13/17 iI)etiIamino)metiI)-5- metoksifenilkarbamoiIoksi)etil)(metiI)amino)sikl0heksil 2-hidroksi-2,2- Lin (sayim) di(tiofen-2- il)asetat L-tartrat X isini kirinim (PXRD) deseni. i\ J I _ti lâ '1 J If!. 2-Teta Olçegi 14/17 iI)etiIamino)-metil)-5-met0ksifenilkarbamoiloksi)etiI)-(metil)amino)sikloheksil 2-hidr0ksi- 2,2-di(ti0fen-2-iI)asetat L-tartrat 1H-NMR spektrumu. sinyal (- 1i-i) i ' L-Tartarik protonlar (~ 2H) /17 metiI)-5-metoksifenilkarbamoiloksi)etiI)-(metiI)amin0)sikl0heksil 2-hidr0ksi-2,2-di(ti0fen-2- il)asetat L-tartrat DSC analizi 4r-'u 16/17 il)etilamino)-metiI)-5-metoksifenilkarbamoiloksi)etiI)-(metil)amin0)sikloheksil 2- hidroksi-2,2-di(tiofen-2-il)asetat L-tartrat TG analizi. 9-' i'l'ü'i, ' .'4 .ni V '5 'Ç ›, 17/17 metil)-5-met0ksifeniIkarbamoiloksi)etil)-(metiI)amin0)sikloheksil 2-hidr0ksi-2,2-di(ti0fen-2- Geçirim [%1 il)asetat L-tartrat FTIR spektrumu. Number of waves ::m-1 13/17 ii)ethylamino)methyl)-5-methoxyphenylcarbamoyloxy)ethyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2- Lin (count) Di(thiophen-2-yl)acetate L-tartrate X-ray diffraction (PXRD) pattern. i\ J I _ti la '1 J If!. 2-Theta Scale 14/17 ii)ethylamino)-methyl)-5-methoxyphenylcarbamoyloxy)ethyl-(methyl)amino)cyclohexyl 2-hydroxy- 1H-NMR spectrum of 2,2-di(thiOphene-2-yl)acetate L-tartrate. signal (- 1i-i) i ' L-Tartaric protons (~ 2H) /17 methyl-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophene-2- il) acetate L-tartrate DSC analysis 4r- 16/17 yl)ethylamino)-methyl-5-methoxyphenylcarbamoyloxy)ethyl-(methyl)amino)cyclohexyl 2- TG analysis of hydroxy-2,2-di(thiophen-2-yl)acetate L-tartrate. 9-' i'l'ü'i, ' .'4 .ni V '5 'Ç ›, 17/17 methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophene-2- Permeability [%1 il) acetate L-tartrate FTIR spectrum.

Dalga sayisi cm-1 Wave number cm-1

Claims (7)

ISTEMLERREQUESTS 1. Asagidakilerden birine karsilik gelen, farmasötik olarak kabul edilebilir bir kristalin katilma il)etilamino)metil)-5-metoksifenilamin0)-3-0ksopropil)(metil)amino)-sikloheksil hidroksi(di-2-tienil)asetat etandisülfonat, il)etilamin0)-metil)-5-metoksifenilkarbamoiloksi)etil)-(metiI)amino)-sikloheksil 2- hidroksi-2,2-di(tiofen-2-il)asetat disakkarinat ve il)etilamin0)-metil)-5-met0ksifenilkarbamoiloksi)etil)-(metiI)amino)sikloheksil 2- hidroksi-2,2-di(tiofen-2-il)asetat L-tartrat, ya da bunlarin farmasötik olarak kabul edilebilir bir solvati.1. A pharmaceutically acceptable crystalline adduct corresponding to one of the following: ethylamino)methyl-5-methoxyphenylamino)-3-Oxopropyl)(methyl)amino)-cyclohexyl hydroxy(di-2-thienyl)acetate ethanedisulfonate, il) ethylamino)-methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)-cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetate disaccharinate and yl)ethylamino-methyl)-5-methoxyphenylcarbamoyloxy )ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetate L-tartrate, or a pharmaceutically acceptable solvate thereof. 2. 1. Istemde tanimlanan bir tuzun terapötik olarak etkili bir miktarini ve farmasötik olarak kabul edilebilir bir tasiyici içeren bir farmasötik bilesim.2. A pharmaceutical composition comprising a therapeutically effective amount of a salt as defined in claim 1 and a pharmaceutically acceptable carrier. 3. 2. Istemde tanimlanan farmasötik bilesim olup, inhalasyon yoluyla bir kuru toz olarak uygulanacak sekilde formüle edilir.3. The pharmaceutical composition as defined in claim 2, formulated for administration as a dry powder by inhalation. 4. 2 veya 3. Istemde tanimlanan farmasötik bilesim olup, bir veya daha fazla baska terapötik maddenin terapötik olarak etkili bir miktarini da içerir.4. The pharmaceutical composition as defined in claim 2 or 3 further comprising a therapeutically effective amount of one or more other therapeutic agents. 5. 4, Istemde tanimlanan farmasötik bilesim olup, burada baska terapötik madde, asagida belirtilenlerin arasindan seçilir: (a) kortikosteroitler, ya da glukokortikoitler, (b) antihistaminler, (C) kemokin reseptör antagonistleri, mesela maravirok veya enfuvirtid, (e) CRth2 antagonistleri, (f) lökotrien reseptör antagonistleri, (g) JAK inhibitörleri, mesela tofasitinib veya INCBOl 8424, (h) Syk inhibitörleri, mesela R-343, (i) fosdiesteraz IV inhibitörleri, (j) p38 inhibitörleri, mesela ARRY-797, (k) PKC inhibitörleri, mesela NVP-AEBO71, (I) 5-Iipoksigenaz aktiflestirici protein inhibitörleri, mesela veliflapon, (m) 5-Iip0ksigenaz inhibitörleri, (n) CYSLTR1antagonistleri, (o) CYSLTR2 antagonistleri, (p) BLT1antagonistleri, (q) BLT2 antagonistleri, (r) tromboksan A2 antagonistleri, mesela ramatroban, (s) DP1 reseptör antagonistleri, mesela Iaropiprant, (t) DP1 reseptör agonistleri, mesela BW-24SC, (u) IP reseptör agonistleri, mesela RO-1138452, (v) Anti-IgE, mesela omalizumab, (w) IL5 antikor, mesela mepolizumab, (x) Iökotrien olusum inhibitörleri, (y) dekongestanlar, mesela efedrin, Ievo-metamfetamin, nafazolin, oksimetazolin, fenilefrin, fenilpropanolamin, propilheksedrin, psödoefedrin, sinefrin veya tetrahidrozolin; (z) mukolitikler, mesela asetilsistein, ambroksol, bromheksin, karbosistein, domiodol, eprazinon, erdostein, Ietostein, nelteneksin, sobrerol, stepronin veya tiopronin; (aa) antitussifler, mesela dekstrometorfan, (bb) anajezikler, mesela aspirin, parasetamol, rofekoksib, selekoksib, morfin, kodein, oksikodon, hidrokodon, dihidromorfin veya flupirtin; ve (C0) ekspektoranlar, mesela antimon pentasülf'L'ir, guaiacolsülfonat, guaifenesin, potasyum iyodur ortiloksapol.5. The pharmaceutical composition as defined in claim 4, wherein the further therapeutic agent is selected from: (a) corticosteroids, or glucocorticoids, (b) antihistamines, (C) chemokine receptor antagonists such as maraviroc or enfuvirtide, (e) CRth2 antagonists, (f) leukotriene receptor antagonists, (g) JAK inhibitors, such as tofacitinib or INCBOl 8424, (h) Syk inhibitors, such as R-343, (i) fosdiesterase IV inhibitors, (j) p38 inhibitors, such as ARRY-797, (k) PKC inhibitors, eg NVP-AEBO71, (I) 5-Lipoxygenase activating protein inhibitors, eg veliflapon, (m) 5-Lipoxygenase inhibitors, (n) CYSLTR1 antagonists, (o) CYSLTR2 antagonists, (p) BLT1 antagonists, (q) ) BLT2 antagonists, (r) thromboxane A2 antagonists such as ramatroban, (s) DP1 receptor antagonists such as Iaropiprant, (t) DP1 receptor agonists such as BW-24SC, (u) IP receptor agonists such as RO-1138452, (v) ) Anti-IgE, eg omalizumab, (w) IL5 ant ikor, such as mepolizumab, (x) Iukotriene formation inhibitors, (y) decongestants such as ephedrine, Ievo-methamphetamine, naphazoline, oxymetazoline, phenylephrine, phenylpropanolamine, propylhexedrine, pseudoephedrine, synephrine or tetrahydrozoline; (z) mucolytics such as acetylcysteine, ambroxol, bromhexine, carbocysteine, domiodol, eprazinone, erdostein, Ietostein, neltenexin, sobrerol, stepronin or tiopronin; (aa) antitussives such as dextromethorphan, (bb) anagesics such as aspirin, paracetamol, rofecoxib, celecoxib, morphine, codeine, oxycodone, hydrocodone, dihydromorphine or flupirtine; and (C0) expectorants such as antimony pentasulfonate, guaiacolsulfonate, guaifenesin, potassium iodide orthilloxapol. 1. Istemde tanimlanan bir tuzu ve 5. Istemde tanimlanan bir veya daha fazla baska terapötik maddeyi içeren bir kombinasyon. Hem B2 adrenerjik reseptör agonist hem de M3 muskarinik aktivite ile iliskili bir patolojik durum veya hastaligin tedavisinde kullanilmaya yönelik olarak, 1. Istemde tanimlanan bir tuz, 2 ila 5. Istemlerin herhangi birinde tanimlanan bir farmasötik bilesim, ya da 6. Istemde tanimlanan bir kombinasyon olup, burada bahsedilen patolojik durum veya hastalik; astim, akut veya kronik bronsit, amfizem, ya da kronik obstruktif akciger hastaligi (KOAH) olmaktadir.A combination comprising a salt as defined in claim 1 and one or more other therapeutic agents as defined in claim 5. A salt as defined in claim 1, a pharmaceutical composition defined in any one of claims 2 to 5, or a combination defined in claim 6 for use in the treatment of a pathological condition or disease associated with both B2 adrenergic receptor agonist and M3 muscarinic activity. , the pathological condition or disease referred to herein; asthma, acute or chronic bronchitis, emphysema, or chronic obstructive pulmonary disease (COPD). 7. Istemde tanimlanan kullanima yönelik bir tuz, bir farmasötik bilesim veya bir kombinasyon olup, burada bahsedilen patolojik durum veya hastalik; astim veya kronik obstruktif akciger hastaligi olmaktadir.7. A salt for use as defined in claim, a pharmaceutical composition or a combination, wherein said pathological condition or disease; asthma or chronic obstructive pulmonary disease.
TR2018/06945T 2013-03-22 2014-02-27 2-amino-1-hydroxyethyl-8-hydroxyquinoline-2 (1H) -one derivatives having both SS2 adrenergic receptor agonist and m3 muscarinic receptor antagonist activities. TR201806945T4 (en)

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