TR2022001550A2

TR2022001550A2 - NEW ACETYLCHOLINESTERASE INHIBITORS

Info

Publication number: TR2022001550A2
Application number: TR2022/001550
Authority: TR
Inventors: Demi̇rayak Eref; Ahi̇n Zafer; Nur Bi̇lteki̇n Kaleli̇ Sevde; Berk Barkin
Original assignee: İstanbul Medi̇pol Üni̇versi̇tesi̇
Filing date: 2022-02-07
Publication date: 2023-08-21

Abstract

Mevcut buluş yeni asetilkolinesteraz inhibitörlerine, buluşa uygun asetilkolinesteraz inhibitörlerinin hazırlanmasında kullanılan yöntemlere ve söz konusu asetilkolinesteraz inbhibitörlerini içeren farmasötik bileşimlere ilişkindir.The present invention relates to novel acetylcholinesterase inhibitors, methods used in the preparation of acetylcholinesterase inhibitors according to the invention, and pharmaceutical compositions containing said acetylcholinesterase inhibitors.

Description

TARIFNAME YENI ASETILKOLINESTERAZ INHIBITÖRLERI Teknik Alan Mevcut bulus yeni asetilkolinesteraz inhibitörlerine, bulus konusu asetilkolinesteraz inhibitörlerinin hazirlanmasinda kullanilan yöntemlere ve söz konusu asetilkolinesteraz inhibitörlerini içeren farmasötik bilesimlere iliskindir. DESCRIPTION NEW ACETYLCHOLINESTERASE INHIBITORS Technical Field The present invention relates to novel acetylcholinesterase inhibitors, the acetylcholinesterase inhibitors of the invention. methods used in the preparation of inhibitors and the acetylcholinesterase It relates to pharmaceutical compositions containing inhibitors.

Teknigin Bilinen Durumu Alzheimer hastaligi (AH), beyindeki nöron fonksiyonunun bozulmasi sonucu unutkanlik ve davranis bozukluklari gibi bilissel belirtilere neden olan nörodejeneratif bir hastaliktir. Hastalik henüz tam olarak çözülememis ve bu nedenle tedavi palyatif hale getirilmistir. ß-amiloid plaklar, senil plaklar, lizozomal disfonksiyon ve kolinerjik iletimin bozulmasi gibi hastaligin temelini ve semptomlarini açiklayan teoriler vardir. Tüm bu teorilerin hastalikta nedense] ya da sonuçsal rolü oldugu açikça gösterilmistir. Bu nedenle, bu alandaki ilaç gelistirme çabalari esas olarak etkili küçük moleküller gelistirmek için bu yollari hedeflemeye odaklanmistir. Alzheimer hastaliginin tedavisinde kullanilan fizostigmin, 19. yüzyilin sonlarinda izole edilen dogal bir alkaloid olan ana ilaçti. Takrin ise daha önce solunum yolu hastaliklari için gelistirilmis olmasina ragmen, sonrasinda Alzheimer hastaliginin tedavisinde kullanildi. Daha sonra rivastigmin, galantamin ve donepezil takip eden süreçte onaylandi. Günümüzde donepezil, memantin, galantamin ve rivastigmin, hafif ila orta dereceli AH'nin tedavisinde reçete edilen baslica ilaçlardir. Tüm bu ilaçlar, etkinlikleri ve yan etkileri açisindan olumlu rapor edilmektedir. Bunlarin arasinda donepezil, düsük mikromolar düzeyde en yüksek afiniteyi göstermekle birlikte ekstrapiramidal etkiler, düsük tansiyon, siddetli kusma, bradikardi ve aritmi gibi önemli yan etkileri de vardir. Known Status of the Technique Alzheimer's disease (AD) is a disorder of neuron function in the brain resulting in forgetfulness and It is a neurodegenerative disease that causes cognitive symptoms such as behavioral disorders. Illness It has not yet been fully resolved and therefore the treatment has been made palliative. ß-amyloid plaques, the basis of the disease, such as senile plaques, lysosomal dysfunction and disruption of cholinergic transmission, and There are theories explaining its symptoms. The causal or consequential role of all these theories in the disease It has been clearly shown that . Therefore, drug development efforts in this field are mainly focused on effective has focused on targeting these pathways to develop small molecules. Alzheimer's disease Physostigmine, used in the treatment of anaphylaxis, is a natural alkaloid isolated in the late 19th century. It was medicine. Although tacrine was previously developed for respiratory diseases, it was later It was used in the treatment of Alzheimer's disease. Then rivastigmine, galantamine and donepezil It was approved in the following process. Today, donepezil, memantine, galantamine and rivastigmine are mild These are the main drugs prescribed for the treatment of to moderate AD. All these drugs, their effectiveness and It is reported positively in terms of side effects. Among these, donepezil, low micromolar Although it shows the highest affinity at the highest level, extrapyramidal effects, low blood pressure, severe It also has important side effects such as vomiting, bradycardia and arrhythmia.

Insan ömrünün uzamasiyla beraber daha siklikla görülmeye baslanan Alzheimer hastaliginin tedavisinde kullanim için asetilkolinesteraz inhibitörü etkinlik gösteren, alternatif moleküllere ihtiyaç bulunmaktadir. Alzheimer's disease, which is becoming more common as human life increases, Alternative molecules that show acetylcholinesterase inhibitor activity for use in the treatment of There is a need.

Bulusun amaci ve kisa özeti Bulusun amaçlarindan biri Alzheimer hastaliginin tedavisinde kullanima uygun yeni asetilkolinesteraz inhibitörü moleküller gelistirmektir. Purpose and brief summary of the invention One of the aims of the invention is to develop new products suitable for use in the treatment of Alzheimer's disease. To develop acetylcholinesterase inhibitor molecules.

Bulusun bir diger amaci ise Alzheimer hastaliginin tedavisinde kullanima uygun potansiyele sahip ve tercihen asetilkolinesteraz inhibitörü etkisi gösteren yeni moleküller gelistirmektir. Another aim of the invention is to develop a drug that has the potential to be used in the treatment of Alzheimer's disease. and preferably to develop new molecules that have an acetylcholinesterase inhibitor effect.

Bulus sahipleri bu amaçla yaptiklari çalismalarda, asagida yer alan Formül 1 ile gösterilen yeni moleküllerin yüksek asetilkolinesteraz inhibitörü aktivitesi gösterdigini tespit etmislerdir. In the studies they carried out for this purpose, the inventors developed new solutions shown in Formula 1 below. They found that the molecules showed high acetylcholinesterase inhibitor activity.

Formül 1 Bulusun Detayli Anlatimi Mevcut bulus, Alzheimer hastaliginin tedavisinde kullanim potansiyeli tasiyan yeni asetilkolinesteraz türevleri moleküllere iliskin olup, bulus konusu moleküller asagida verilen veya X ve Y bir birlesik halka olusturacak sekilde -O-CHz-O- olabilir ve, 3-N02, 4-N02, içerisinden seçilir. Formula 1 Detailed Explanation of the Invention The present invention is a new invention that has potential for use in the treatment of Alzheimer's disease. Acetylcholinesterase derivatives are related to molecules, and the molecules of the invention are given below. or X and Y may be -O-CH2-O- to form a combined ring and, 3-N02, 4-N02, is selected from.

Bulusun tercih edilen bir uygulamasinda, bulusa uygun moleküller Formül 1.1-l.95 ile gösterilmekte olup, bahsi geçen moleküllerin X, Y, Z, T, R ve n degiskenleri asagida yer alan tabloda (Tablo 1) yer almaktadir. In a preferred embodiment of the invention, the molecules according to the invention are defined as Formula 1.1-1.95. are shown, and the X, Y, Z, T, R and n variables of the molecules in question are given below. It is included in the table (Table 1).

Molekül X Y Z T R 11 Numarasi Formül 1.1 -H -H -H -H -H 0 Formül 1.8 -H -H -H -H 2-C1 Formül 1.9 -H -H -H -H 3-C1 Formül 1.10 -H -H -H -H 4-C1 Formül 1.11 -OCH3 -H -H -H -H Formül 1.14 -H -Cl -H -H -H Formül 1.16 -H -Cl -H -H 4-Cl Formül 1.17 -H -H -H -H -H Formül 1.18 -H -H -H -H 4-C1 Formül 1.19 -OCH3 -H -H -H -H Formül 1.28 -OCH3 -H -H -H 2-NO2 Formül 1.29 -OCH3 -H -H -H 3-N02 Formül 1.30 -OCH3 -H -H -H 4-N02 Formül 1.32 -OCH3 -OCHs -H -H 2-OCH3 Formül 1.34 -OCHg -OCH3 -H -H 4-OCH3 Formül 1.38 -OCH3 -OCHs -H -H 2-F Formül 1.41 -OCH3 -OCH3 -H -H 2-N02 Formül 1.42 -OCH3 -OCH3 -H -H 3- N02 Formül 1.43 -OCH3 -OCH3 -H -H 4- N02 Formül 1.54 -OCH3 -H -OCH3 -H 2-N02 Formül 1.55 -OCH3 -H -OCH3 -H 3- N02 Formül 1.56 -OCH3 -H -OCH3 -H 4- N02 Formül 1.69 -OCH3 -H -H -0CH3 4- N02 Formül 1.76 -H -OCHs -H -0CH3 4-C1 Formül 1.80 -H -0CH3 -H -OCH3 2-N02 Formül 1.81 -H -OCH3 -H -OCH3 3- N02 Formül 1.82 -H -OCH3 -H -0CH3 4- N02 Formül 1.84 -O-CHz-O- -H -H 2-OCH3 Formül 1.85 -O-CHz-O- -H -H 3-OCH3 Formül 1.86 -O-CHz-O- -H -H 4-OCH3 Formül 1.87 -O-CHz-O- -H -H 2-Cl Formül 1.88 -O-CHz-O- -H -H 3-Cl Formül 1.89 -O-CHz-O- -H -H 4-C1 Formül 1.90 -O-CHz-O- -H -H 2-F Formül 1.91 -O-CHz-O- -H -H 3-F Formül 1.92 -O-CHz-O- -H -H 4-F Formül 1.93 -O-CHz-O- -H -H 2-N02 Formül 1.94 -O-CHz-O- -H -H 3- N02 Formül 1.95 -O-CHz-O- -H -H 4- N02 Tablo l°de verilen moleküller yalnizca bulusu örneklendirmek amaciyla verilmis olup herhangi bir sekilde bulus bu örneklerle sinirlandirilmamaktadir. Molecule X Y Z T R 11 Its number Formula 1.1 -H -H -H -H -H 0 Formula 1.8 -H -H -H -H 2-C1 Formula 1.9 -H -H -H -H 3-C1 Formula 1.10 -H -H -H -H 4-C1 Formula 1.11 -OCH3 -H -H -H -H Formula 1.14 -H -Cl -H -H -H Formula 1.16 -H -Cl -H -H 4-Cl Formula 1.17 -H -H -H -H -H Formula 1.18 -H -H -H -H 4-C1 Formula 1.19 -OCH3 -H -H -H -H Formula 1.28 -OCH3 -H -H -H 2-NO2 Formula 1.29 -OCH3 -H -H -H 3-NO2 Formula 1.30 -OCH3 -H -H -H 4-NO2 Formula 1.32 -OCH3 -OCHs -H -H 2-OCH3 Formula 1.34 -OCHg -OCH3 -H -H 4-OCH3 Formula 1.38 -OCH3 -OCHs -H -H 2-F Formula 1.41 -OCH3 -OCH3 -H -H 2-NO2 Formula 1.42 -OCH3 -OCH3 -H -H 3- N02 Formula 1.43 -OCH3 -OCH3 -H -H 4- N02 Formula 1.54 -OCH3 -H -OCH3 -H 2-NO2 Formula 1.55 -OCH3 -H -OCH3 -H 3- N02 Formula 1.56 -OCH3 -H -OCH3 -H 4- N02 Formula 1.69 -OCH3 -H -H -OCH3 4- N02 Formula 1.76 -H -OCHs -H -OCH3 4-C1 Formula 1.80 -H -0CH3 -H -OCH3 2-NO2 Formula 1.81 -H -OCH3 -H -OCH3 3- N02 Formula 1.82 -H -OCH3 -H -OCH3 4- N02 Formula 1.84 -O-CHz-O- -H -H 2-OCH3 Formula 1.85 -O-CHz-O- -H -H 3-OCH3 Formula 1.86 -O-CHz-O- -H -H 4-OCH3 Formula 1.87 -O-CHz-O- -H -H 2-Cl Formula 1.88 -O-CHz-O- -H -H 3-Cl Formula 1.89 -O-CHz-O- -H -H 4-C1 Formula 1.90 -O-CHz-O- -H -H 2-F Formula 1.91 -O-CHz-O- -H -H 3-F Formula 1.92 -O-CHz-O- -H -H 4-F Formula 1.93 -O-CHz-O- -H -H 2-NO2 Formula 1.94 -O-CHz-O- -H -H 3- N02 Formula 1.95 -O-CHz-O- -H -H 4- N02 The molecules given in Table 1 are given only to exemplify the invention and do not represent any In this way, the invention is not limited to these examples.

Bulusa uygun Formül 1.83 ile gösterilen molekülün kimyasal yapisi bulusun daha iyi anlasilmasi için verilmistir. The chemical structure of the molecule shown in Formula 1.83 in accordance with the invention can be used to better understand the invention. given for.

Bulusun tercih edilen bir uygulamasi, Formül 1 ve/veya Formül 1.1 - Formül 1.95 ile gösterilen moleküllerin farmasötik olarak kabul edilebilir türevlerine iliskindir. Burada bahsi geçen farrnasötik olarak kabul edilebilir türevler Formül 1 veya Formül 1.1 - Formül 1.95 ile gösterilen moleküllerin tuzlari, solvatlari, esterleri, hidratlari olabilir. Bu basvuru kapsaminda bahsedilen gösterilen moleküllerin çözünürlügünü arttirmak veya formülasyonunu kolaylastirmak veya biyOyararlanimini arttirmak için molekülün terapötik aktivitesinde bir degisiklige yol açmayan kimyasal veya fiziksel modifikasyonlari ifade etmektedir. A preferred embodiment of the invention is represented by Formula 1 and/or Formula 1.1 - Formula 1.95. It relates to pharmaceutically acceptable derivatives of molecules. mentioned here pharmaceutically acceptable derivatives represented by Formula 1 or Formula 1.1 - Formula 1.95 Molecules can have salts, solvates, esters and hydrates. Mentioned within the scope of this application to increase the solubility or facilitate the formulation of the molecules shown, or does not cause a change in the therapeutic activity of the molecule to increase its bioavailability It refers to chemical or physical modifications.

Bulusun uygulamasi; Alzheimer hastaliginin tedavisinde kullanima uygun yeni asetilkolinesteraz inhibitörü türevi moleküllere iliskin olup, bulus konusu moleküller Formül 1.1, Formül 1.2, Formül Formül 1.19, Formül 1.20 ile gösterilir. Application of the invention; New acetylcholinesterase suitable for use in the treatment of Alzheimer's disease It relates to inhibitor derivative molecules and the molecules of the invention are Formula 1.1, Formula 1.2, Formula Formula 1.19 is represented by Formula 1.20.

Bulusun bir uygulamasi Alzheimer hastaliginin tedavisinde kullanima uygun yeni asetilkolinesteraz inhibitörü türevi moleküllere iliskin olup, bulus konusu moleküller Formül 1.1, gösterilir. One embodiment of the invention is a new drug suitable for use in the treatment of Alzheimer's disease. It relates to acetylcholinesterase inhibitor derivative molecules and the molecules in question are Formula 1.1, is shown.

Bulusun bir uygulamasi Alzheimer hastaliginin tedavisinde kullanima uygun yeni asetilkolinesteraz inhibitörü türevi moleküllere iliskin olup, bulus konusu moleküller Formül 1.1, 1.94, Formül 1.95 ile gösterilir. One embodiment of the invention is a new drug suitable for use in the treatment of Alzheimer's disease. It relates to acetylcholinesterase inhibitor derivative molecules and the molecules in question are Formula 1.1, 1.94 is represented by Formula 1.95.

Bulusun bir baska uygulamasi Formül 1 ve/veya Formül 1.1 - Formül 1.95 ile gösterilen molekülleri içeren farrnasötik bilesimlere iliskindir. Another application of the invention is the molecules shown with Formula 1 and/or Formula 1.1 - Formula 1.95. Relates to pharmaceutical compositions containing

Bulusa uygun farmasötik bilesimler oral dozaj formlarinda formüle edilebilir. Bulusa uygun farrnasötik bilesimler içerisinde etken madde olarak kullanilan Formül 1 ve/veya Formül 1.1 - Formül 1.95 ile gösterilen moleküllerinin yani sira farmasötik olarak kabul edilebilir yardimci maddeler kullanilabilir. Pharmaceutical compositions according to the invention can be formulated in oral dosage forms. inventive Formula 1 and/or Formula 1.1 used as active ingredients in pharmaceutical compositions - In addition to the molecules shown in formula 1.95, pharmaceutically acceptable excipients substances can be used.

Burada bahsi geçen yardimci madde ifadesi bulusa uygun etken maddeleri formüle etmek için kullanilan ve herhangi bir terapötik etkinligi olmayan maddeleri ifade etmektedir. Bahsi geçen yardimci maddeler farrnasötik teknolojide kullanimi bilinen ajanlar içerisinden seçilebilir. The term auxiliary substance mentioned herein is used to formulate active substances according to the invention. It refers to substances that are used and do not have any therapeutic activity. Aforementioned Excipients may be selected from agents known for use in pharmaceutical technology.

Bulus bir diger açidan formül 1 ile gösterilen moleküllerin, tercihen formül 1.1, formül 1.2, formül (Yöntem 1) iliskin olup söz konusu yöntem; a) Formül 11 ve Formül 111 ile gösterilen moleküllerin Formül 11 Formül HI K2C03 varliginda reaksiyona girmesi ile Formül IV ile gösterilen molekülün elde edilmesi Formül IV b) Formül lVjün aril piperizin veya benzil piperazin türevi, çözücü 1 ve K2C03 varliginda reaksiyona girmesi ile Formül Pin veya tercihen Formül l.l-F0rrnül I.95”in, özellikle tercihen formül l.1-f0rmül 1.16”nin elde edilmesi adimlarini içerir, ki burada; veya X ve Y bir birlesik halka olusturacak sekilde -O-CHz-O- olabilir ve, 2-N02, 3-N02, 4-N02, ve n: 0 veya 1 içerisinden seçilir. In another aspect, the invention is based on the molecules shown with formula 1, preferably formula 1.1, formula 1.2, formula It is related to (Method 1) and the method in question is; a) Molecules shown with Formula 11 and Formula 111 Formula 11 Formula HI Obtaining the molecule shown in Formula IV by reacting in the presence of K2CO3 Formula IV b) Aryl piperizine or benzyl piperazine derivative of formula 1V in the presence of solvent 1 and K2CO3 Formula Pin or preferably Formula I.1-Formula I.95, especially preferably includes the steps of obtaining formula 1.1-formula 1.16, where; or X and Y may be -O-CH2-O- to form a combined ring and, 2-N02, 3-N02, 4-N02, and n: Selected from 0 or 1.

Bulus bir diger açidan formül I ile gösterilen moleküllerin, tercihen formül 1.17 ila forinül 1.95 ile gösterilen moleküllerin sentezinde kullanilacak bir yönteme (Yöntem 2) iliskin olup söz konusu yöntem; 1. Formül 11 ve Formül III ile gösterilen moleküllerin Formül 11 Formül HI K2C03 varliginda reaksiyona girmesi ile Formül IV ile gösterilen molekülün elde edilmesi Formül IV 2. Formül IV'ün piperazin, çözücü 1 ve K2C03 varliginda reaksiyona girmesi ile Formül V,in elde edilmesi ve FormülV Formül V7in benzil halojenür veya sübstitüe benzil halojenür, çözücü 2 ve K2CO3 varliginda reaksiyona girmesi ile Formül Fin, tercihen Formül l.l-Formül 1.95'in, özellikle tercihen formül 1.17-formül I.95°in elde edilmesi adimlarini içerir ki burada; Y: -H, -Cl, OCHs veya X ve Y bir birlesik halka olusturacak sekilde -O-CHz-O- olabilir ve, 2-N02, 3-N02, 4-N02, ve içerisinden seçilir. In another aspect, the invention relates to molecules represented by formula I, preferably with formula 1.17 to formula 1.95. It is about a method (Method 2) to be used in the synthesis of the molecules shown. method; 1. Molecules represented by Formula 11 and Formula III Formula 11 Formula HI Obtaining the molecule shown in Formula IV by reacting in the presence of K2CO3 Formula IV 2. Formula V is obtained by reacting Formula IV in the presence of piperazine, solvent 1 and K2CO3. to obtain and FormulaV Formula V7 contains benzyl halide or substituted benzyl halide, solvent 2 and K2CO3 Formula I, preferably Formula 1.1-Formula 1.95, especially Formula I, reacts in the presence of preferably includes the steps of obtaining formula 1.17-formula I.95, wherein; Y: -H, -Cl, OCHs or X and Y may be -O-CH2-O- to form a combined ring and, 2-N02, 3-N02, 4-N02, and is selected from.

Yöntem 1 ve Yöntem 2”de bahsi geçen çözücü 1 ve çözücü 2, birbirinden bagimsiz olarak DMF, DMSO, etanol, metanolden olusan bir grubun içerisinden seçilebilir. Solvent 1 and solvent 2 mentioned in Method 1 and Method 2 are used independently of each other as DMF, It can be selected from the group consisting of DMSO, ethanol, and methanol.

Yukaridaki yöntemde yer alan benzil halojenür veya sübstitüe benzil halojenür maddeleri benzil klorür veya benzil bromür veya benzil iyodür, veya sübstitüe benzil klorür, sübstitüe benzil bromür veya sübstitüe benzil iyodür olabilir. The benzyl halide or substituted benzyl halide substances in the above method are benzyl halides. chloride or benzyl bromide or benzyl iodide, or substituted benzyl chloride, substituted benzyl bromide or substituted benzyl iodide.

Bulus bir diger açidan, bulusa uygun Formül 1 ve/Veya Formül 1.] -Formül 1.95 moleküllerinin elde edilmesinde ara ürün olarak kullanilan Formül V molekülüne iliskindir Formül V veya X ve Y bir birlesik halka olusturacak sekilde -O-CHz-Ü- olabilir ve, Bulusun tercih edilen bir uygulamasi, bulusa uygun Formül 1 ve/Veya Formül 1.1-F0nnül 1.95 moleküllerinin elde edilmesinde ara ürün olarak kullanilan Formül V.1 molekülüne iliskindir. From another aspect of the invention, the molecules of Formula 1 and/or Formula 1.]-Formula 1.95 in accordance with the invention are obtained. It is related to the Formula V molecule used as an intermediate in the production of Formula V or X and Y can be -O-CH2-Ü- to form a combined ring and, A preferred embodiment of the invention is Formula 1 and/or Formula 1.1-Formula 1.95 in accordance with the invention. It is related to the Formula V.1 molecule, which is used as an intermediate product in obtaining the molecules.

Formül V.1 Bulusun tercih edilen bir uygulamasi, bulusa uygun Formül 1 ve/veya Formül 1.1-F0rmül I.95 moleküllerinin elde edilmesinde ara ürün olarak kullanilan Formül V.2 molekülüne iliskindir. Formula V.1 A preferred embodiment of the invention is Formula 1 and/or Formula 1.1-Formula I.95 according to the invention. It is related to the Formula V.2 molecule, which is used as an intermediate product in obtaining the molecules.

Formül V.2 Bulus bir diger açidan Alzheimer hastaliginin tedavisinde kullanim için bulusa uygun formül I ve/veya Formül 1.1-F0rmül 1.95 numarali moleküllere iliskindir. Formula V.2 In another aspect, the invention is based on the formula I according to the invention for use in the treatment of Alzheimer's disease. and/or relates to molecules numbered Formula 1.1-Formula 1.95.

Bulus bir diger açidan asetilkolinesteraz inhibitörü olarak kullanim için Formül 1 ve/veya Formül 1.1-F0rmül 1.95 numarali moleküllere iliskindir. In another aspect, the invention includes Formula 1 and/or Formula 1 for use as an acetylcholinesterase inhibitor. Formula 1.1 is related to molecules numbered 1.95.

Bu tarifname içerisinde yer alan tüm bulus özellikleri gerekli olmasi durumunda birbiri ile birlestirilebilir. Simdi sadece bulusun daha iyi anlasilmasi amaciyla, bulus örneklendirilecektir, bulus kapsami burada verilen örneklerle sinirlandirilmamaktadir. ÖRNEKLER: Örnek 1: Formül IV ile gösterilen moleküllerin genel sentez yöntemi 2-hidroksi benzaldehit türevleri (Formül [1, l ekivalans) solventsiz olarak 4-florofenasil bromür (Formül III) ve potasyum karbonat (1 ekivalans) ile mikrodalga sentezleyicide 850W ve 1 dakikada reaksiyona sokuldu. Ham ürün suyla yikandi ve ardindan etanolden yeniden kristallestirildi. Bu, Rap-Stoermer reaksiyonunun bir mikrodalga uygulamasidir. All invention features included in this specification can be combined with each other if necessary. can be combined. Now, just for the purpose of better understanding the invention, the invention will be exemplified, The scope of the invention is not limited to the examples given here. EXAMPLES: Example 1: General synthesis method of molecules represented by Formula IV 2-hydroxy benzaldehyde derivatives (Formula [1, l equivalence) 4-fluorophenacyl bromide without solvent (Formula III) and potassium carbonate (1 equivalence) in a microwave synthesizer at 850W and 1 minute. reacted. The crude product was washed with water and then recrystallized from ethanol. This, It is a microwave application of the Rap-Stoermer reaction.

Benzofuran-Z-il(4-Iluor0fenil)metanon Verim: 85% e.n.: , (6-Met0ksibenzofuran-2-il)(4-ilu0r0fenil)metanon (S-Klorobenzofuran-Z-il)(4-Ilu0r0fenil)metanon Verim: 78% e.n.: 159 - Örnek 2: Formül V.1 ve Formül V.2 moleküllerinin genel sentez vöntemi 4-Ilorofenil benzofuran metanon türevleri (1 ekivalans), N,N-DMF içinde piperazin (2 ekivalans) ve K2CO3 (1 ekivalans) ile reaksiyon tamamlanana kadar 8 saat boyunca reHux altinda reaksiyona sokuldu. Karisim sogutuldu, su eklendi ve olusan çökelti süzüldü. Su ile yikandi, kurutuldu ve etanolden yeniden kristallendirildi. Benzofuran-Z-yl(4-Iluorophenyl)methanone Yield: 85% e.n.: , (6-Methoxybenzofuran-2-yl)(4-methylphenyl)methanone (S-Chlorobenzofuran-Z-yl)(4-Ilu0r0phenyl)methanone Yield: 78% e.n.: 159 - Example 2: General synthesis method of Formula V.1 and Formula V.2 molecules 4-Ilorophenyl benzofuran methanone derivatives (1 equivalence), piperazine in N,N-DMF (2 equivalence) and react with K2CO3 (1 equivalence) under reHux for 8 hours until the reaction is completed. stung. The mixture was cooled, water was added and the resulting precipitate was filtered. Washed with water, dried and recrystallized from ethanol.

Formül V.l10 Formül V.2 Benzofuran-Z-il(4-piperazin-l-il)fenil)metanon (Formül V.1) Verim: 74% e.n: , (6-metoksibenzofuran-Z-il)(4-(piperazin-1-il)fenil)metan0n (Formül V.2) Verim: 68% cm.: , Örnek 3: Formül 1.] - Formül 1.16,nm genel sentez vöntemi 4-f10r0feni1 benzofuran metanonlar (1 ekivalans), 50 mmol uygun arilpiperazin türevi (1 ekivalans) ve K2C03 (1 ekivalans) ile DMSO içinde reaksiyon tamamlanana kadar 8 saat geri akitilarak (ref1ux altinda) reaksiyona sokuldu. Karisim sogutuldu, su eklendi ve çökelti süzüldü. Su ile yikandi, kurutuldu ve karakterizasyonda verilen uygun çözücüden yeniden kristallestirildi. Formula V.l10 Formula V.2 Benzofuran-Z-yl(4-piperazin-1-yl)phenyl)methanone (Formula V.1) Yield: 74% e.n: , (6-methoxybenzofuran-Z-yl)(4-(piperazin-1-yl)phenyl)methane (Formula V.2) Yield: 68% cm.: , Example 3: Formula 1.] - Formula 1.16,nm general synthesis method 4-f10r0phenyl1 benzofuran methanones (1 equivalent), 50 mmol of the appropriate arylpiperazine derivative (1 equivalent) and K2CO3 (1 equivalent) in DMSO by refluxing for 8 hours until the reaction is complete (ref1ux below) was reacted. The mixture was cooled, water was added and the precipitate was filtered. washed with water, It was dried and recrystallized from the appropriate solvent given in the characterization.

Benzofuran-Z-il(4-(4-fenilpiperazin-l-il)fenil)metan0n (Formül 1.1) Verim: 70%, e.n.: , , 3.57 (4H, t, J: 4.5 Hz, Benzofuran-2-il(4-(4-(0-tolil)piperazin-1-il)fenil)metan0n (Formül 1.2) Verim: 65%, e.n.: , , 3.54 Benzofuran-Z-il(4-(4-(m-t01il)piperazin-1-il)fenil)metan0n (Formül 1.3) Verim: 66%, e.n.: , , 3.28 (4H, t, J.' 4.83 Hz, HZ, Ar). 13C NMR (75 MHZ) DMSO-dis ö (ppm): . 48.55 Benzofuran-2-il(4-(4-(p-t01il)piperazin-l-il)fenil)metan0n (Formül 1.4) Verim: 53%, e.n.: . 13C NMR (75 MHz) DMSO-da ö (ppm): , 49.02 (piperazin Benzofuran-2-il(4-(4-(2-metoksifeniDpiperazin-1-il)fenil)metan0n (Formül 1.5) 413.1839. Benzofuran-Z-yl(4-(4-phenylpiperazin-1-yl)phenyl)methane (Formula 1.1) Efficiency: 70%, e.n.: , , 3.57 (4H, t, J: 4.5 Hz, Benzofuran-2-yl(4-(4-(0-tolyl)piperazin-1-yl)phenyl)methane (Formula 1.2) Yield: 65%, e.n.: , , 3.54 Benzofuran-Z-yl(4-(4-(m-to1yl)piperazin-1-yl)phenyl)methane (Formula 1.3) Yield: 66%, e.p.: , , 3.28 (4H, t, J.' 4.83 Hz, HZ, Ar). 13C NMR (75 MHZ) DMSO-disc (ppm): . 48.55 Benzofuran-2-yl(4-(4-(p-to1yl)piperazin-1-yl)phenyl)methane (Formula 1.4) Yield: 53%, e.n.: . 13C NMR (75 MHz) DMSO (ppm): , 49.02 (piperazine Benzofuran-2-yl(4-(4-(2-methoxyphenylDpiperazin-1-yl)phenyl)methane (Formula 1.5) 413.1839.

Benzofuran-Z-il(4-(4-(3-met0ksifenil)piperazin-1-il)fenil)metan0n (Formül 1.6) Verim: 81%, am.: , , 3.56 (4H, t, J: 5.17 HZ, Benzofuran-2-il(4-(4-(4-metoksifenil)piperazin-1-il)fenil)metan0n (Formül 1.7) Benzofuran-Z-il(4-(4-(2-klorofenil)piperazin-1-il)fenil)metan0n (Formül 1.8) Benzofuran-Z-il(4-(4-(3-klorofeniDpiperazin-1-il)fenil)metaii0n (Formül 1.9) Verim: 80%, e.n.: , , 3.56 (4H, t, J: 4.97 Hz, J.' , 48.17 (piperazin- (6-Met0ksibenzofuran-Z-il)(4-(4-fenilpiperazin-1-il)fenil)metan0n (Formül 1.11) (6-Metoksibenzofuran-2-il)(4-(4-(4-metoksifenil)piperazin-1-il)fenil)metan0n (Formül I.12) (4-(4-(4-Klorofenil)piperazin-1-il)fenil)(6-met0ksibenzofuran-Z-il)metanon (Formül 1.13) Hz, piperazin CHz), , 7.27 (S-Klorobenzofuran-2-il)(4-(4-fenilpiperazin-1-il)fenil)metan0n (Formül 1.14) (S-Klorobenzofuran-2-il)(4-(4-(4-met0ksifenil)piperazin-l-il)fenil)metan0n (Formül 1.15) Verim: 80%, e.n.: . iH NMR (, 3.57 (4H, brs, piperazin (1H, s, Ar), : 47.00 Örnek 4: Formül I.17-F0rmül I.95,in Genel Sentez Yöntemi Formül V ile gösterilen moleküller (1 ekivalans) benzil klorür veya 4-klorobenzil (1 ekivalans) kullanilarak DMSO içerisinde, K2C03 (1 ekivalans) varliginda 6 saat boyunca reflux altinda reaksiyona sokulur. Reaksiyon tamamlandiktan sonra su eklenir ve olusan çökelti toplanir. Benzofuran-Z-yl(4-(4-(3-methoxyphenyl)piperazin-1-yl)phenyl)methane (Formula 1.6) Efficiency: 81%, am.: , , 3.56 (4H, t, J: 5.17 HZ, Benzofuran-2-yl(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)methane (Formula 1.7) Benzofuran-Z-yl(4-(4-(2-chlorophenyl)piperazin-1-yl)phenyl)methane (Formula 1.8) Benzofuran-Z-yl(4-(4-(3-chlorophenylDpiperazin-1-yl)phenyl)metai0n (Formula 1.9) Efficiency: 80%, e.n.: , , 3.56 (4H, t, J: 4.97 Hz, J.' , 48.17 (piperazine- (6-Methoxybenzofuran-Z-yl)(4-(4-phenylpiperazin-1-yl)phenyl)methane (Formula 1.11) (6-Methoxybenzofuran-2-yl)(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)methane (Formula I.12) (4-(4-(4-Chlorophenyl)piperazin-1-yl)phenyl)(6-methoxybenzofuran-Z-yl)methanone (Formula 1.13) Hz, piperazine CHz), , 7.27 (S-Chlorobenzofuran-2-yl)(4-(4-phenylpiperazin-1-yl)phenyl)methane (Formula 1.14) (S-Chlorobenzofuran-2-yl)(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)methane (Formula 1.15) Yield: 80%, e.n.: . 1H NMR (, 3.57 (4H, brs, piperazine (1H, s, Ar), : 47.00 Example 4: General Synthesis Method of Formula I.17-Formula I.95 Molecules represented by formula V (1 equivalence) benzyl chloride or 4-chlorobenzyl (1 equivalence) using DMSO under reflux for 6 hours in the presence of K2CO3 (1 equivalence). is put into reaction. After the reaction is completed, water is added and the resulting precipitate is collected.

Toplanan çökelti iki kez su ile yikanir ve etanolden rekristalize edilir. The collected precipitate is washed twice with water and recrystallized from ethanol.

Verim: 68% e.n.: . lH Verim: 70% e.n.: . iH Verim: 70% e.n.: . iH DMSO-dg ö (ppm): , 62.42 (benzil- Verim: 75% e.n.: . lH Örnek 5: Formül 1.1 - Formül 1.22”nin Asetilkolinesteraz (AChE) ve Bütilkolinesteraz (BuChE) Enzim Inhibisyonu Analizi Molekül Formül 1.2 1.08 ± 0.21 ND Formül 1.4 31.65 ± 1.20 ND Formül 1.7 17.37 ± 0.98 ND Formül 1.8 19.11 ± 0.56 ND Formül 1.9 16.22 ± 0.67 ND Formül 1.13 3.07 ± 1.09 ND Formül 1.14 2.32 ± 0.95 ND Formül 1.15 2.99 ± 1.13 ND Formül 1.20 1.98 ± 0.45 ND Formül 1.21 1.07 ± 0.18 ND Formül 1.22 0.98 ± 0.12 ND Donepezil 0.12 ± 0.01 ND Bilesiklerin enzim aktiviteleri incelendiginde, bütirilkolinesteraz üzerine etkilerinin olmadigi, asetilkolinesteraz üzerine ise etkili olduklari görülmüstür. Bu durumun baslica nedeninin, asetilkolinesteraza özgü baglanma modu olan donepezile benzer bir baglanma biçimi oldugu düsünülmektedir. Bu sonuçlara göre, bilesiklerden elde edilen yapi-aktivite degerlendirilmesi donepezil yapi-etki iliskilerine oldukça paralellik göstermektedir. Örnek 6: Formül 1.19 ve Formül 1.20,nin Moleküler Modelleme Çalismalari Sonuçlari Moleküler modelleme çalismalarinda, 4EY7 kodlu protein data bank verisi kullanilmistir. Bu dosya, Maestr Schrödinger programinda açilip islenerek aktif yöresi tanimlanmis, donepezil dock edilerek 0.45 nnsd degeriyle validasyonu yapilmistir. Giris kisminda açiklanan donepezil-aktif yöre etkilesimlerine benzer ve uyumlu etkilesimler oldugu gözlenmistir. Formül 1.19”un aktif yöre etkilesimleri incelendiginde, piperazine bagli benzil halkasinin Trp86 ile aromatik etkilesmede oldugu görülmektedir. Benzofuran halkasina bagli karbonil grubu, donepezildeki karbonile benzer sekilde Phe295 ile hirojen bagi etkilesimi içindedir.Metoksi grubunun çift su köprüsüyle Trp286 NH grubuyla H bagi etkilesimi vardir. Piperazin azot grubunun da donepezildeki piperidine benzer sekilde Tyr337, Tyr341 ve Phe338 ile çevrelenen bölgeye yerlestigi görülmektedir. Ayrica benzofuran halkasinin, donepezildeki indenon halkasina benzer sekilde Trp286 ile aromatik etkilesimde oldugu görülmektedir. Yield: 68% e.n.: . lH Yield: 70% e.n.: . iH Yield: 70% e.n.: . iH DMSO-dg o (ppm): , 62.42 (benzyl- Yield: 75% e.n.: . lH Example 5: Acetylcholinesterase (AChE) and Butylcholinesterase of Formula 1.1 - Formula 1.22 (BuChE) Enzyme Inhibition Analysis Molecule Formula 1.2 1.08 ± 0.21 ND Formula 1.4 31.65 ± 1.20 ND Formula 1.7 17.37 ± 0.98 ND Formula 1.8 19.11 ± 0.56 ND Formula 1.9 16.22 ± 0.67 ND Formula 1.13 3.07 ± 1.09 ND Formula 1.14 2.32 ± 0.95 ND Formula 1.15 2.99 ± 1.13 ND Formula 1.20 1.98 ± 0.45 ND Formula 1.21 1.07 ± 0.18 ND Formula 1.22 0.98 ± 0.12 ND Donepezil 0.12 ± 0.01 ND When the enzyme activities of the compounds were examined, it was seen that they had no effect on butyrylcholinesterase. It has been observed that they are effective on acetylcholinesterase. The main reason for this situation is It has a similar binding mode to donepezil, which has a binding mode specific to acetylcholinesterase. It is considered. According to these results, the structure-activity evaluation of the compounds It is very similar to the structure-effect relationships of donepezil. Example 6: Results of Molecular Modeling Studies of Formula 1.19 and Formula 1.20 In molecular modeling studies, protein data bank coded 4EY7 was used. This The file was opened and processed in the Maestr Schrödinger program, its active region was defined, donepezil dock It was validated with an nnsd value of 0.45. donepezil-active as explained in the introduction It has been observed that there are similar and compatible interactions with the local interactions. Active region of Formula 1.19 When the interactions were examined, it was seen that the benzyl ring attached to piperazine was involved in the aromatic interaction with Trp86. It appears to be. The carbonyl group attached to the benzofuran ring is similar to the carbonyl in donepezil. It interacts with Phe295 by hydrogen bonding in the following way. Trp286 is formed by the double water bridge of the methoxy group. There is an H bond interaction with the NH group. The nitrogen group of piperazine is similar to the piperidine in donepezil. It can be seen that it is located in the region surrounded by Tyr337, Tyr341 and Phe338. Moreover The benzofuran ring is aromatized with Trp286, similar to the indenone ring in donepezil. It appears that there is an interaction.

Formül I.20”nin aktif yöre etkilesimleri incelendiginde, piperazine bagli benzil halkasinin Trp86 ile aromatik etkilesmede oldugu görülmektedir. Piperazin azot grubunun Tyr 337 ile n-katyon etkilesiminde oldugu, ayrica donepeZildeki piperidine benzer sekilde Tyr337, Tyr34l ve Phe338 ile çevrelenen bölgeye yerlestigi görülmektedir. Ayrica benzofuran halkasinin, donepezildeki indenon halkasina benzer sekilde Trp286 ile aromatik etkilesimde oldugu görülmektedir. When the active site interactions of Formula I.20 are examined, it is seen that the benzyl ring attached to piperazine is Trp86 It is seen that there is an aromatic interaction with . n-cation of the piperazine nitrogen group with Tyr 337 Tyr337, Tyr34l and Phe338, similar to the piperidine in donepeZil. It is seen that it settled in the region surrounded by . Additionally, the benzofuran ring in donepezil It appears to have an aromatic interaction with Trp286, similar to the indenone ring.

Benzofuran halkasina bagli metoksi grubunun HOH793 ve HOH953 su molekülleriyle hidrojen bagi yapacak sekilde konumlandigi görülmektedir. HOH793 and HOH953 of the methoxy group attached to the benzofuran ring form hydrogen bonds with water molecules. It appears to be positioned to make the connection.

Tüm bu sonuçlar bulusa uygun Formül I bilesiklerinin asetilkolinesteraz inhibitörü olma potansiyelini ortaya koymaktadir. All these results indicate that the compounds of Formula I according to the invention are acetylcholinesterase inhibitors. demonstrates its potential.

Claims

STEMLER is a molecule suitable for use in the treatment of Alzheimer's disease and its feature is shown by Formula 1, where Y: -H, -OCHa, Cl or X and Y can be -O-CH2-O- to form a combined ring and, n: 0. or selected from 1. Pharmaceutical compositions containing the molecule represented by Formula 1 according to claim 1 as an active ingredient. A pharmaceutical composition according to claim 2, characterized in that it contains a pharmaceutically acceptable excipient. It is a method (Method 1) to be used in the preparation of molecules shown with Formula I according to Claim 1, and its feature is; 5 a) By reacting the molecules shown with Formula H and Formula 111 in the presence of Formula 11, Formula III 10 b) K2CO3, the molecule shown with Formula IV is obtained. Formula IV 0) aryl piperizine or benzyl piperazine derivative of Formula 1V by reacting 15 in the presence of solvent 1 and K 2 CO 3 to form Formula Pin or preferably Formula I.1 - Formula 1.95 or particularly preferably Formula 1.1 - Formula I.16 It includes the steps of obtaining the 5 or where 5. It is a method (Method 2) to be used in the preparation of molecules shown with Formula 1 according to Claim 1 and its feature is; a) The molecules shown with Formula 11 and Formula 111 are reacted in the presence of 15 Formula 11 Formula 111 b) K2CO3 to obtain the molecule shown with Formula IV. c) Formula IV is reacted with Formula V in the presence of piperazine, solvent 1 and K2CO3. It includes the steps of obtaining 10 Formula V d) Reacting Formula V in the presence of benzyl halide or substituted benzyl halide, solvent 2 and K2CO3 to obtain Formula I, preferably Formula L1-Formula I.95, where; 15 Y: -H, -OCH3, Cl or -O-CH2-O- such that X and Y form a combined ring and, n: is selected from 0 or 1.10 . It is a method according to claim 5, characterized in that the benzyl halide is selected from benzyl chloride, benzyl bromide, benzyl iodide or substituted benzyl chloride or substituted benzyl bromide or substituted benzyl iodide. . Formula V molecule for use as an intermediate in the preparation of molecules according to claim 1; Formula V where; or X and Y can be -O-CH2-O- to form a combined ring, and it is a molecule according to Claim 7 and its feature is shown with Formula V.] and/or Formula V.2. Formula V.1 Formula V.2 9. Molecules represented by Formula 1 according to claim 1 for use as acetylcholinesterase inhibitors. 10. Molecules of Formula 1 according to claim 1 for use in the treatment of Alzheimer's disease.