WO2023234891A2 - Novel acetylcholinesterase inhibitors - Google Patents

Novel acetylcholinesterase inhibitors Download PDF

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Publication number
WO2023234891A2
WO2023234891A2 PCT/TR2023/050100 TR2023050100W WO2023234891A2 WO 2023234891 A2 WO2023234891 A2 WO 2023234891A2 TR 2023050100 W TR2023050100 W TR 2023050100W WO 2023234891 A2 WO2023234891 A2 WO 2023234891A2
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Prior art keywords
formula
och3
piperazine
och
molecules
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PCT/TR2023/050100
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French (fr)
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WO2023234891A3 (en
Inventor
Şeref DEMIRAYAK
Barkin BERK
Sevde Nur BILTEKIN KALELI
Zafer ŞAHIN
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Istanbul Medipol Universitesi
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Priority claimed from TR2022/001550 external-priority patent/TR2022001550A2/en
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Publication of WO2023234891A2 publication Critical patent/WO2023234891A2/en
Publication of WO2023234891A3 publication Critical patent/WO2023234891A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to novel acetylcholinesterase inhibitors, methods of preparing acetylcholinesterase inhibitors of the invention, and pharmaceutical compositions comprising the said acetylcholinesterase inhibitors.
  • Alzheimer's disease is a neurodegenerative disorder that causes cognitive symptoms such as forgetfulness and behavioral disorders as a result of impaired neuronal function in the brain.
  • the disease has not yet been fully resolved and therefore treatment is palliative.
  • theories such as 0- amyloid plaques, senile plaques, lysosomal dysfunction, and impaired cholinergic transmission explain the basis and symptoms of the disease. All these theories have been clearly shown to have a causal or consequential role in the disease. Therefore, drug development efforts in this area are mainly focused on targeting these pathways to develop effective small molecules.
  • Physostigmine a natural alkaloid isolated in the late 19th century, was the main drug used to treat Alzheimer's disease.
  • tacrine was previously developed for respiratory diseases, it was later used to treat Alzheimer's disease. Rivastigmine, galantamine, and donepezil were subsequently approved. Today, donepezil, memantine, galantamine, and rivastigmine are the main drugs prescribed in the treatment of mild to moderate AD. All these drugs are reported favorably in terms of efficacy and side effects. Among them, donepezil shows the highest affinity at low micromolar levels but also has significant side effects such as extrapyramidal effects, low blood pressure, severe vomiting, bradycardia, and arrhythmia.
  • An object of the invention is to develop new acetylcholinesterase inhibitor molecules suitable for use in the treatment of Alzheimer's disease.
  • Another object of the invention is to develop new molecules that have the potential to be used in the treatment of Alzheimer's disease and preferably have an acetylcholinesterase inhibitor effect.
  • the inventors have determined that the new molecules shown in Formula I below exhibit high acetylcholinesterase inhibitor activity.
  • the present invention relates to novel acetylcholinesterase derivatives molecules with potential for use in the treatment of Alzheimer's disease, and the inventive molecules are shown in Formula I below, wherein; X: -H, -OCH 3
  • Y -H, -Cl, OCH 3 or X and Y can be -O-CH2-O- forming a combined ring and selected from
  • T -H, -OCH 3 R: -H, 2-CH 3 , 3-CH 3 , 4-CH 3 , 2-OCH 3 , 3-OCH 3 , 4-OCH 3 , 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO 2 , 3-NO2, 4-NO2, n: 0 or 1.
  • the molecules according to the invention are shown in Formula 1.1-1.95 in a preferred embodiment of the invention, and the variables X, Y, Z, T, R, and n of the said molecules are given in the table below (Table 1).
  • a preferred embodiment of the invention relates to pharmaceutically acceptable derivatives of molecules represented by Formula I and/or Formula 1.1 - Formula 1.95.
  • the pharmaceutically acceptable derivatives mentioned herein may be salts, solvates, esters, hydrates of the molecules indicated by Formula I or Formula 1.1 - Formula 1.95.
  • the phrase "pharmaceutically acceptable derivatives" in this application refers to chemical or physical modifications to increase the solubility or facilitate the formulation or increase the bioavailability of molecules shown in Formula I and/or Formula 1.1 - Formula 1.95 that do not result in a change in the therapeutic activity of the molecule.
  • An embodiment of the invention relates to novel acetylcholinesterase inhibitor derivative molecules suitable for use in the treatment of Alzheimer's disease, and the molecules of the invention are denoted by Formula 1.1, Formula 1.2, Formula 1.3, Formula 1.4, Formula 1.5, Formula 1.6, Formula 1.7, Formula 1.8, Formula 1.9, Formula 1.10, Formula 1.11, Formula 1.12, Formula 1.13, Formula 1.14, Formula 1.15, Formula 1.16, Formula 1.17, Formula 1.18, Formula 1.19, Formula 1.20.
  • An embodiment of the invention relates to novel acetylcholinesterase inhibitor derivative molecules suitable for use in the treatment of Alzheimer's disease, and the molecules of the invention are denoted by Formula 1.1, Formula 1.2, Formula 1.3, Formula 1.4, Formula 1.5, Formula 1.7, Formula 1.8, Formula 1.9, Formula 1.10, Formula 1.11, Formula 1.12, Formula 1.13, Formula 1.14, Formula 1.15, Formula 1.19, Formula 1.20.
  • An embodiment of the invention relates to novel acetylcholinesterase inhibitor-derived molecules suitable for use in the treatment of Alzheimer's disease, and the molecules of the invention are denoted by Formula 1.1, Formula 1.2, Formula 1.3, Formula 1.4, Formula 1.5, Formula 1.7, Formula 1.8, Formula 1.9, Formula 1.10, Formula 1.11, Formula 1.12, Formula 1.13, Formula 1.14, Formula 1.15, Formula 1.19, Formula 1.20, Formula 1.21, Formula 1.22, Formula 1.23, Formula 1.24, Formula 1.25, Formula 1.26, Formula 1.27, Formula 1.28, Formula 1.29, Formula 1.30, Formula 1.31, Formula 1.32, Formula 1.32, Formula 1.33, Formula 1.34, Formula 1.35, Formula 1.36, Formula 1.37, Formula 1.38, Formula 1.39, Formula 1.40, Formula 1.41, Formula 1.42, Formula 1.43, Formula 1.44, Formula 1.45, Formula 1.46, Formula 1.47, Formula 1.48, Formula 1.49, Formula 1.50, Formula 1.51, Formula 1.52, Formula 1.53, Formula 1.54, Formula 1.55, Formula 1.56, Formula 1.57,
  • a further embodiment of the invention relates to pharmaceutical compositions comprising molecules indicated by Formula I and/or Formula 1.1 - Formula 1.95.
  • compositions according to the invention may be formulated in oral dosage forms.
  • pharmaceutically acceptable excipients may be used in addition to the molecules shown in Formula I and/or Formula 1.1 - Formula 1.95 used as drug substances.
  • excipient refers to substances that are used to formulate drug substances according to the invention and have no therapeutic efficacy.
  • the said excipients can be selected from agents known to be used in pharmaceutical technology.
  • the invention relates to a method (Method 1) for the synthesis of the molecules indicated by formula I, preferably formula 1.1, formula 1.2, formula 1.3, formula 1.4, formula 1.5, formula 1.6, formula 1.7, formula 1.8, formula 1.9, formula 1.10, formula 1.11, formula 1.12, formula 1.13, formula 1.14, formula 1.15, formula 1.16, the said method comprising the following steps: a) The molecules denoted by Formula II and Formula III, Formula II
  • Formula IV b) comprising the steps of reacting Formula IV in the presence of aryl piperazine or benzyl piperazine derivative, solvent 1, and K2CO3 to obtain Formula I or preferably Formula 1.1-Formula 1.95, particularly preferably Formula 1.1-Formula 1.16, wherein
  • Y -H, -OCH3, Cl or X and Y can be -O-CH2-O- forming a combined ring and selected from
  • the invention relates to a method (Method 2) for the synthesis of molecules shown in formula I, preferably molecules shown in formula 1.17 to formula 1.95, the said method comprising the following steps: 1.
  • Method 2 for the synthesis of molecules shown in formula I, preferably molecules shown in formula 1.17 to formula 1.95, the said method comprising the following steps: 1.
  • Formula I preferably Formula 1.1-Formula 1.95, particularly preferably Formula I.17-formula 1.95, wherein;
  • Y -H, -Cl, OCH 3 or X and Y can be -O-CH2-O- forming a combined ring and selected from
  • R -H, 2-CH 3 , 3-CH 3 , 4-CH 3 , 2-OCH 3 , 3-OCH 3 , 4-OCH 3 , 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO2, 3-NO2, 4-NO2, and n: 0 or 1.
  • Solvent 1 and solvent 2 of Method 1 and Method 2 may be independently selected from the group consisting of DMF, DMSO, ethanol, and methanol.
  • the benzyl halide or substituted benzyl halide agents in the above method can be benzyl chloride or benzyl bromide or benzyl iodide, or substituted benzyl chloride, substituted benzyl bromide, or substituted benzyl iodide.
  • the invention relates, in a further aspect, to a molecule of Formula V which is used as an intermediate to obtain the molecules of Formula I and/or Formula 1.1-Formula 1.95 according to the invention.
  • Y -H, Cl, OCH 3 or X and Y can be -O-CH2-O- forming a combined ring and selected from
  • R -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO 2 , 3-NO2, 4-NO2.
  • a preferred embodiment of the invention relates to the molecule of Formula V.1 used as an intermediate in obtaining the molecules of Formula I and/or Formula 1.1 -Formula 1.95 according to the invention.
  • Formula V.l A preferred embodiment of the invention relates to the molecule of Formula V.2 used as an intermediate in obtaining the molecules of Formula I and/or Formula 1.1 -Formula 1.95 according to the invention.
  • the invention relates to molecules of formula I and/or molecules of formula 1.1- Formula 1.95 according to the invention for use in the treatment of Alzheimer's disease.
  • the invention relates to molecules of Formula I and/or Formula 1.1 -Formula 1.95 for use as acetylcholinesterase inhibitors.
  • Example 6 Results of Molecular Modeling Studies of Formula 1.19 and Formula 1.20
  • protein data bank data coded 4EY7 was used. This file was opened and processed in the Maestr Schrodinger program, its active region was defined, and the donepezil was docked and validated with a rmsd value of 0.45. It has been observed that there are similar and compatible interactions with donepezil-active site interactions described in the introduction.
  • active site interactions of Formula 1.19 are examined, it is seen that the benzyl ring attached to piperazine is in aromatic interaction with Trp86.
  • the carbonyl group attached to the benzofuran ring is in a hydrogen bond interaction with Phe295, similar to the carbonyl in donepezil.
  • the methoxy group has an H bond interaction with the NH group of Trp286 via a double water bridge.
  • the piperazine nitrogen group appears to be located in the region flanked by Tyr337, Tyr341, and Phe338, similar to piperidine in donepezil. It is also seen that the benzofuran ring has an aromatic interaction with Trp286, similar to the indenone ring in donepezil.

Abstract

The present invention relates to novel acetylcholinesterase inhibitors, methods of preparing acetylcholinesterase inhibitors according to the invention, and pharmaceutical compositions comprising the said acetylcholinesterase inhibitors.

Description

DESCRIPTION
NOVEL ACETYLCHOLINESTERASE INHIBITORS
Technical Field
The present invention relates to novel acetylcholinesterase inhibitors, methods of preparing acetylcholinesterase inhibitors of the invention, and pharmaceutical compositions comprising the said acetylcholinesterase inhibitors.
State of the Art
Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive symptoms such as forgetfulness and behavioral disorders as a result of impaired neuronal function in the brain. The disease has not yet been fully resolved and therefore treatment is palliative. Theories such as 0- amyloid plaques, senile plaques, lysosomal dysfunction, and impaired cholinergic transmission explain the basis and symptoms of the disease. All these theories have been clearly shown to have a causal or consequential role in the disease. Therefore, drug development efforts in this area are mainly focused on targeting these pathways to develop effective small molecules. Physostigmine, a natural alkaloid isolated in the late 19th century, was the main drug used to treat Alzheimer's disease. Although tacrine was previously developed for respiratory diseases, it was later used to treat Alzheimer's disease. Rivastigmine, galantamine, and donepezil were subsequently approved. Today, donepezil, memantine, galantamine, and rivastigmine are the main drugs prescribed in the treatment of mild to moderate AD. All these drugs are reported favorably in terms of efficacy and side effects. Among them, donepezil shows the highest affinity at low micromolar levels but also has significant side effects such as extrapyramidal effects, low blood pressure, severe vomiting, bradycardia, and arrhythmia.
There is a need for alternative molecules with acetylcholinesterase inhibitor activity for the treatment of Alzheimer's disease, which is becoming more common with the prolongation of human life. The Objects and Brief Description of the Invention
An object of the invention is to develop new acetylcholinesterase inhibitor molecules suitable for use in the treatment of Alzheimer's disease.
Another object of the invention is to develop new molecules that have the potential to be used in the treatment of Alzheimer's disease and preferably have an acetylcholinesterase inhibitor effect. In the studies carried out for this purpose, the inventors have determined that the new molecules shown in Formula I below exhibit high acetylcholinesterase inhibitor activity.
Figure imgf000003_0001
Formula I
Detailed Description of the Invention
The present invention relates to novel acetylcholinesterase derivatives molecules with potential for use in the treatment of Alzheimer's disease, and the inventive molecules are shown in Formula I below,
Figure imgf000004_0001
wherein; X: -H, -OCH3
Y: -H, -Cl, OCH3 or X and Y can be -O-CH2-O- forming a combined ring and selected from
Z: -H, -OCH3
T: -H, -OCH3 R: -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO2, 3-NO2, 4-NO2, n: 0 or 1.
The molecules according to the invention are shown in Formula 1.1-1.95 in a preferred embodiment of the invention, and the variables X, Y, Z, T, R, and n of the said molecules are given in the table below (Table 1).
Figure imgf000004_0002
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0002
The molecules in Table 1 are provided only to illustrate the invention and the invention is not strictly limited to these examples. The chemical structure of the molecule according to the invention shown in Formula 1.83 is provided for a better understanding of the invention.
Figure imgf000007_0001
Formula 1.83
A preferred embodiment of the invention relates to pharmaceutically acceptable derivatives of molecules represented by Formula I and/or Formula 1.1 - Formula 1.95. The pharmaceutically acceptable derivatives mentioned herein may be salts, solvates, esters, hydrates of the molecules indicated by Formula I or Formula 1.1 - Formula 1.95. The phrase "pharmaceutically acceptable derivatives" in this application refers to chemical or physical modifications to increase the solubility or facilitate the formulation or increase the bioavailability of molecules shown in Formula I and/or Formula 1.1 - Formula 1.95 that do not result in a change in the therapeutic activity of the molecule.
An embodiment of the invention relates to novel acetylcholinesterase inhibitor derivative molecules suitable for use in the treatment of Alzheimer's disease, and the molecules of the invention are denoted by Formula 1.1, Formula 1.2, Formula 1.3, Formula 1.4, Formula 1.5, Formula 1.6, Formula 1.7, Formula 1.8, Formula 1.9, Formula 1.10, Formula 1.11, Formula 1.12, Formula 1.13, Formula 1.14, Formula 1.15, Formula 1.16, Formula 1.17, Formula 1.18, Formula 1.19, Formula 1.20.
An embodiment of the invention relates to novel acetylcholinesterase inhibitor derivative molecules suitable for use in the treatment of Alzheimer's disease, and the molecules of the invention are denoted by Formula 1.1, Formula 1.2, Formula 1.3, Formula 1.4, Formula 1.5, Formula 1.7, Formula 1.8, Formula 1.9, Formula 1.10, Formula 1.11, Formula 1.12, Formula 1.13, Formula 1.14, Formula 1.15, Formula 1.19, Formula 1.20.
An embodiment of the invention relates to novel acetylcholinesterase inhibitor-derived molecules suitable for use in the treatment of Alzheimer's disease, and the molecules of the invention are denoted by Formula 1.1, Formula 1.2, Formula 1.3, Formula 1.4, Formula 1.5, Formula 1.7, Formula 1.8, Formula 1.9, Formula 1.10, Formula 1.11, Formula 1.12, Formula 1.13, Formula 1.14, Formula 1.15, Formula 1.19, Formula 1.20, Formula 1.21, Formula 1.22, Formula 1.23, Formula 1.24, Formula 1.25, Formula 1.26, Formula 1.27, Formula 1.28, Formula 1.29, Formula 1.30, Formula 1.31, Formula 1.32, Formula 1.32, Formula 1.33, Formula 1.34, Formula 1.35, Formula 1.36, Formula 1.37, Formula 1.38, Formula 1.39, Formula 1.40, Formula 1.41, Formula 1.42, Formula 1.43, Formula 1.44, Formula 1.45, Formula 1.46, Formula 1.47, Formula 1.48, Formula 1.49, Formula 1.50, Formula 1.51, Formula 1.52, Formula 1.53, Formula 1.54, Formula 1.55, Formula 1.56, Formula 1.57, Formula 1.58, Formula 1.59, Formula 1.60, Formula 1.61, Formula 1.62, Formula 1.63, Formula 1.64, Formula 1.65, Formula 1.66, Formula 1.67, Formula 1.68, Formula 1.69, Formula 1.70, Formula 1.71, Formula 1.72, Formula 1.73, Formula 1.74, Formula 1.75, Formula 1.76, Formula 1.77, Formula 1.78, Formula 1.79, Formula 1.80, Formula 1.81, Formula 1.82, Formula 1.82, Formula 1.83 Formula 1.84, Formula 1.85, Formula 1.86, Formula 1.87, Formula 1.88, Formula 1.89, Formula 1.90, Formula 1.91, Formula 1.92, Formula 1.93, Formula 1.94, Formula 1.95.
A further embodiment of the invention relates to pharmaceutical compositions comprising molecules indicated by Formula I and/or Formula 1.1 - Formula 1.95.
The pharmaceutical compositions according to the invention may be formulated in oral dosage forms. In pharmaceutical compositions according to the invention, pharmaceutically acceptable excipients may be used in addition to the molecules shown in Formula I and/or Formula 1.1 - Formula 1.95 used as drug substances.
The term excipient refers to substances that are used to formulate drug substances according to the invention and have no therapeutic efficacy. The said excipients can be selected from agents known to be used in pharmaceutical technology.
In another aspect, the invention relates to a method (Method 1) for the synthesis of the molecules indicated by formula I, preferably formula 1.1, formula 1.2, formula 1.3, formula 1.4, formula 1.5, formula 1.6, formula 1.7, formula 1.8, formula 1.9, formula 1.10, formula 1.11, formula 1.12, formula 1.13, formula 1.14, formula 1.15, formula 1.16, the said method comprising the following steps: a) The molecules denoted by Formula II and Formula III,
Figure imgf000009_0001
Formula II
Figure imgf000010_0001
Formula III reacting in the presence of K2CO3 to obtain the molecule indicated by Formula IV; and
Figure imgf000010_0002
Formula IV b) comprising the steps of reacting Formula IV in the presence of aryl piperazine or benzyl piperazine derivative, solvent 1, and K2CO3 to obtain Formula I or preferably Formula 1.1-Formula 1.95, particularly preferably Formula 1.1-Formula 1.16, wherein
X: -H, -OCH3
Y: -H, -OCH3, Cl or X and Y can be -O-CH2-O- forming a combined ring and selected from
Z: -H, -OCH3
T: -H, -OCH3
R: -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO2, 3-NO2, 4-NO2, and n: 0 or 1. In another aspect, the invention relates to a method (Method 2) for the synthesis of molecules shown in formula I, preferably molecules shown in formula 1.17 to formula 1.95, the said method comprising the following steps: 1. The molecules denoted by Formula II and Formula III,
Figure imgf000011_0002
Formula III reacting in the presence of K2CO3 to obtain the molecule indicated by Formula IV; and
Figure imgf000011_0001
Formula IV 2. obtaining Formula V by reacting Formula IV in the presence of piperazine, solvent 1, and
K2CO3; and
Figure imgf000012_0001
Formula V
3. reacting Formula V with benzyl halide or substituted benzyl halide in the presence of solvent 2 and K2CO3 to give Formula I, preferably Formula 1.1-Formula 1.95, particularly preferably Formula I.17-formula 1.95, wherein;
X: -H, -OCH3
Y: -H, -Cl, OCH3 or X and Y can be -O-CH2-O- forming a combined ring and selected from
Z: -H, -OCH3
T: -H, -OCH3
R: -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO2, 3-NO2, 4-NO2, and n: 0 or 1.
Solvent 1 and solvent 2 of Method 1 and Method 2 may be independently selected from the group consisting of DMF, DMSO, ethanol, and methanol.
The benzyl halide or substituted benzyl halide agents in the above method can be benzyl chloride or benzyl bromide or benzyl iodide, or substituted benzyl chloride, substituted benzyl bromide, or substituted benzyl iodide. The invention relates, in a further aspect, to a molecule of Formula V which is used as an intermediate to obtain the molecules of Formula I and/or Formula 1.1-Formula 1.95 according to the invention.
Figure imgf000013_0001
wherein;
X: -H, -OCH3
Y: -H, Cl, OCH3 or X and Y can be -O-CH2-O- forming a combined ring and selected from
Z: -H, -OCH3
T: -H, -OCH3
R: -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO2, 3-NO2, 4-NO2.
A preferred embodiment of the invention relates to the molecule of Formula V.1 used as an intermediate in obtaining the molecules of Formula I and/or Formula 1.1 -Formula 1.95 according to the invention.
Figure imgf000013_0002
Formula V.l A preferred embodiment of the invention relates to the molecule of Formula V.2 used as an intermediate in obtaining the molecules of Formula I and/or Formula 1.1 -Formula 1.95 according to the invention.
Figure imgf000014_0001
In another aspect, the invention relates to molecules of formula I and/or molecules of formula 1.1- Formula 1.95 according to the invention for use in the treatment of Alzheimer's disease.
In another aspect, the invention relates to molecules of Formula I and/or Formula 1.1 -Formula 1.95 for use as acetylcholinesterase inhibitors.
All of the inventive features contained herein may be combined if necessary. The invention will now be illustrated by way of example only for the purpose of a better understanding of the invention, without limiting the scope of the invention to the examples given herein.
EXAMPLES:
Example 1: General synthesis method of molecules indicated by Formula IV
2-hydroxy benzaldehyde derivatives (Formula II, 1 equivalence) were reacted with 4-fluoro phenacyl bromide (Formula III) and potassium carbonate (1 equivalence) in a microwave synthesizer at 850W and for 1 minute without solvent. The crude product was washed with water and then recrystallized from ethanol. This is a microwave application of the Rap-Stoermer reaction. Benzofuran-2-yl(4-fluorophenyl)methanone
Yield: 85% e.n.: 125-127°C. Lit: 133-135°C [26, 27], FT-IR vmax (cm 1): 3127.03 (C-H), 1648.79 (C=O)
(6-Methoxybenzofuran-2-yl)(4-fluorophenyl)methanone
Yield: 80% e.n.: 163-166°C (ethanol). Lit: 156-158°C (ethyl acetate)[28], FT-IR vmax (cm 1):
3116.81-2839.36 (C-H), 1617.94 (C=O)
(5-Chlorobenzofuran-2-yl)(4-fluorophenyl)methanone
Yield: 78% e.n.: 159 - 162°C. FT-IR vmax (cm 1): 3115.32 (C-H), 1642.07 (C=O)
Example 2: General synthesis method of Formula v.l and Formula V.2 molecules
4-fluorophenyl benzofuran methanone derivatives (1 equivalence) were reacted with piperazine (2 equivalence) and K2CO3 (1 equivalence) in N, N-DMF under reflux for 8 hours until the reaction was complete. The mixture was cooled, water was added, and the resulting precipitate was filtered. It was washed with water, dried, and recrystallized from ethanol.
Figure imgf000015_0001
Figure imgf000016_0001
Benzofuran-2-yl(4-piperazine-l-yl)phenyl)methanone (Formula V.l)
Yield: 74% e.n: 263-265°C.FT-IR vmax (cm 1): 2925.18 (N-H), 2674.29-2471.31 (C-H), 1600.87 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.23 (4H, brs, pip-CH2), 3.65 (4H, brs, pip-CH2), 7.14 (2H, d, J: 8.90 Hz, Ar), 7.39 (1H, t, J: 7.66 Hz, Ar), 7.55 (1H, t, J: 7.66 Hz, Ar), 7.71-7.80 (2H, m, Ar), 7.85 (1H, d, J: 8.07 Hz, Ar), 8.01 (2H, d, J: 8.47 Hz, Ar), 9.37 (1H, s, NH). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 42.70 (piperazine CH2), 44.25 (piperazine CH2), 112.65, 114.37, 115.58, 115.63, 124.00, 124.47, 125.41, 127.06, 127.34, 128.55, 131.95, 152.65, 153.61, 155.44, 181.64 (C=O). MS (M+H): For C19H18N2O2 calculated: 307, found: 307.
(6-methoxybenzofuran-2-yl)(4-(piperazine-l-yl)phenyl)methanone (Formula V.2)
Yield: 68% e.n.: 109-114°C. FT-IR vmax (cm 1): 3263.86 (N-H), 2934.18-2753.27 (C-H), 1610.05 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 2.85 (1H, s, NH), 3.30 (4H, brs, pip- CH2), 3.62 (4H, brs, pip-CH2), 6.97-7.05 (3H, m, Ar), 7.33 (1H, d, J: 1.74 Hz, Ar), 7.62 (1H, d, J: 0.67 Hz, Ar), 7.69 (1H, d, J: 8.69 Hz, Ar), 7.94 (1H, d, J: 8.95 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 45.62 (piperazine CH2), 47.83 (piperazine CH2), 56.26 (O-CH3), 96.23, 113.50, 114.49, 115.82, 115.86, 120.54, 124.24, 126.04, 131.77, 152.40, 154.65, 157.01, 160.87, 180.88 (C=O). HRMS (M+H): For C2oH2oN203 calculated: 337.1547, found: 337.1551.
Example 3; Formula 1.1 - General synthesis method of Formula 1.16
4-fluorophenyl benzofuran methanone (1 equivalence) was reacted with 50 mmol suitable arylpiperazine derivative (1 equivalence) and K2CO3 (1 equivalence) in DMSO for 8 hours until the reaction was complete (under reflux). The mixture was cooled, water was added, and the precipitate was filtered. It was washed with water, dried, and recrystallized from the appropriate solvent given in the characterization.
Benzofuran-2-yl(4-(4-phenylpiperazine-l-yl)phenyl)methanone (Formula LI)
Yield: 70%, e.n.: 165-167°C (EtOH). FT-IR vmax (cm 1): 3054.08-2825.09 (C-H), 1628.45 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.30 (4H, brs, piperazine), 3.57 (4H, t, J: 4.5 Hz, piperazine), 6.82 (1H, t, J: 7.25 Hz, Ar), 7.00 (2H, d, J: 7.97 Hz, Ar), 7.13 (2H, d, J: 8.81 Hz, Ar), 7.25 (2H, dd, J: 8.98 Hz, j: 7.37 Hz, Ar), 7.38 (1H, t, J: 7.20 Hz, Ar), 7.54 (1H, td, J: 7.88 Hz, j: 1.31 Hz, Ar), 7.72 (1H, s, benzofuran), 7.76 (1H, d, J: 8.90 Hz, Ar), 7.85 (1H, d, J: 7.70 Hz, Ar), 8.01 (2H, d, J: 8.99 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 46.87 (piperazine CH2), 48.43 (piperazine CH2), 112.61, 113.74, 115.24, 116.09, 119.67, 123.92, 124.41, 126.08, 127.37, 128.40, 129.48, 132.02, 151.20, 152.86, 154.33, 155.40, 181.42 (C=O). HRMS (M+H): For C25H22N2O2 calculated: 383.1754, found: 383.1741.
Benzofuran-2-yl(4-(4-(o-tolyl)piperazine-l-yl)phenyl)methanone (Formula 1.2)
Yield: 65%, e.n.: 131-133°C (DMSO). FT-IR vmax (cm 1): 3124.31-2827.27 (C-H), 1629.44 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 2.31 (3H, s, CH3), 2.99 (4H, brs, piperazine), 3.54 (4H, brs, piperazine), 6.96-7.21 (6H, m, Ar), 7.35-7.42 (1H, m, Ar), 7.54 (1H, tq, J: 7.68 Hz, j: 1.31 Hz, Ar), 7.71 (2H, m, Ar), 7.84 (1H, d, J: 6.94 Hz, Ar), 8.01 (2H, dd, J: 8.96 Hz,j: 2.57 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 18.08 (CH3), 47.52 (piperazine CH2), 51.62 (piperazine CH2), 112.62, 113.74, 115.25, 119.31, 123.64, 123.92, 124.41, 126.09, 127.09, 127.37, 128.39, 131.36, 132.02, 132.33, 151.38, 152.87, 154.56, 155.40, 181.40 (C=O). HRMS (M+H): For C26H24N2O2 calculated: 397.1911, found: 397.1904.
Benzofuran-2-yl(4-(4-(m-tolyl)piperazine-l-yl)phenyl)methanone (Formula 1.3)
Yield: 66%, e.n.: 146-149°C (DMSO). FT-IR vmax (cm 1): 3105.75-2834.64 (C-H), 1625.69 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 2.27 (3H, s, CH3), 3.28 (4H, t, J: 4.83 Hz, piperazine), 3.55 (4H, t, J: 5.05 Hz, piperazine), 6.64 (1H, d, J: 7.36 Hz, Ar), 6.77-6.83 (2H, m, Ar), 7.10-7.16 (3H, m, Ar), 7.38 (1H, t, J: 7.53 Hz, Ar), 7.54 (1H, td, J: 7.72 Hz,j: 1.26 Hz, Ar), 7.71 (1H, s, benzofuran), 7.75 (1H, d, J: 8.43 Hz, Ar), 7.85 (1H, d, J: 7.60 Hz, Ar), 8.01 (2H, d, J: 8.99 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 21.89 (CH3), 46.88 (piperazine CH2), 48.55 (piperazine CH2), 112.61, 113.36, 113.74, 115.23, 115.26, 116.79, 120.57, 123.92, 124.41, 126.08, 127.37, 128.40, 129.31, 132.02, 138.57, 151.20, 152.86, 154.34, 155.40, 181.41 (C=O). HRMS (M+H): For C26H24N2O2, calculated: 397.1911, found: 397.1906.
Benzofuran-2-yl(4-(4-(p-tolyl)piperazine-l-yl)phenyl)methanone (Formula 1.4)
Yield: 53%, e.n.: 194-196°C (DMSO). FT-IR Umax (cm 1): 3059-2827.83 (C-H), 1626.90 (C=O). 1H NMR (300 MHz) DMSO-d6) 6 (ppm): 2.22 (3H, s, CH3), 3.24 (4H, t, J: 4.83 Hz, piperazine), 3.56 (4H, t, J: 5.05 Hz, piperazine), 6.91 (2H, d, J: 8.73 Hz, Ar), 7.06 (2H, d, J: 8.50 Hz, Ar), 7.14 (2H, d, J: 9.07 Hz, Ar), 7.39 (1H, t, J: 7.17 Hz, Ar), 7.55 (1H, td, J: 7.77 Hz, 1.19 Hz, Ar), 7.72 (1H, s, Ar), 7.77 (1H, d, J: 8.48 Hz, Ar), 7.85 (1H, d, J: 7.68 Hz, Ar), 8.01 (2H, d, J: 8.96 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 20.55 (CH3), 46.94 (piperazine CH2), 49.02 (piperazine CH2), 112.62, 113.78, 115.27, 116.46, 123.92, 124.42, 126.07, 127.37, 128.40, 128.60, 129.92, 132.02, 149.17, 152.85, 154.37, 155.40, 181.42 (C=O). HRMS (M+H): C26H24N2O2 calculated: 397.1911, found: 397.1916.
Benzofuran-2-yl(4-(4-(2-methoxyphenyl)piperazine-l-yl)phenyl)methanone (Formula 1.5)
Yield: 78%, e.n.: 100-101°C (DMSO). FT-IR vmax (cm 1): 3109.64-2766.46 (C-H), 1629.09 (C=O). 1H NMR (300 MHz) DMSO-d6) δ (ppm): 3.17 (4H, t, J: 4.63 Hz, piperazine), 3.60 (4H, t, J: 4.66 Hz, piperazine-CH2), 3.87 (3H, s, CH3), 6.91-7.07 (4H, m, Ar), 7.19 (2H, d, J: 9.02 Hz, Ar), 7.44 (1H, d, J: 7.51 Hz, Ar), 7.60 (2H, td, J: 7.72 Hz, 1.05 Hz, Ar), 7.78 (1H, s, Ar), 7.82 (1H, d, J: 8.35 Hz, Ar), 8.06 (2H, d, J: 8.94 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 47.26 (piperazine-CH2), 50.33 (piperazine- CH2), 55.87 (OCH3), 112.38, 112.62, 113.69, 115.21, 118.56, 121.33, 123.29, 123.92, 124.41, 126.00, 127.38, 128.39, 132.02, 141.26, 152.48, 152.87, 154.53, 155.39, 181.39 (C=O). HRMS (M+H): For C26H24N2O3 calculated: 413.1860, found: 413.1839. Benzofuran-2-yl(4-(4-(3-methoxyphenyl)piperazine-l-yl)phenyl)methanone (Formula 1.6)
Yield: 81%, e.n.: 139-141°C (EtOH). FT-IR vmax (cm 1): 3114.97-2834.27 (C-H), 1635.89 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.31 (4H, m, piperazine), 3.56 (4H, t, J: 5.17 Hz, piperazine-CH2), 3.74 (3H, s, CH3), 6.41 (1H, dd, J: 8.02 Hz, 1.98 Hz, Ar), 6.52 (1H, t, J: 2.29 Hz, Ar), 6.59 (1H, dd, J: 8.13 Hz, 1.82 Hz, Ar), 7.11-7.18 (3H, m, Ar), 7.39 (1H, dd, J: 7.55 Hz, 0.88 Hz, Ar), 7.55 (1H, td, J: 7.58 Hz, 1.30 Hz, Ar), 7.72 (2H, d, J: 0.82 Hz, Ar), 7.74 (1H, d, J: 8.40 Hz, 0.82 Hz, Ar), 7.85 (1H, d, J: 7.57 Hz, Ar), 8.01 (2H, d, J: 8.95 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 46.82 (piperazine-CH2), 48.37(piperazine-CH2), 55.39 (OCH3), 102.15, 105.01, 108.65, 112.62, 113.73, 115.25, 123.92, 124.42, 126.06, 127.37, 128.41, 130.19, 132.03, 152.56, 152.85, 154.31, 155.40, 160.71, 181.42 (C=O). HRMS (M+H): For C26H24N2O3 calculated: 413.1860, found: 413.1841.
Benzofuran-2-yl(4-(4-(4-methoxyphenyl)piperazine-l-yl)phenyl)methanone (Formula 1.7) Yield: 74%, e.n.: 184.5-186°C (DMSO). FT-IR vmax (cm 1): 3114.72-2768.64 (C-H), 1621.43 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.17 (4H, t, J: 4.94 Hz, piperazine), 3.57 (4H, t, J: 4.94 Hz, piperazine- CH2), 3.70 (3H, s, CH3), 6.85 (2H, d, J: 9.10 Hz, Ar), 6.97 (2H, d, J: 9.10 Hz, Ar), 7,14 (2H, d, J: 9.10 Hz, Ar), 7.39 (1H, td, J: 7.53 Hz, 0.87 Hz, Ar), 7.55 (1H, td, J: 7.79 Hz, 1.30 Hz, Ar), 7.72 (1H, d, J: 1.03 Hz, Ar), 7.76 (1H, dd, J: 8.41 Hz, 0.77 Hz, Ar), 7.85 (2H, d, J: 7.61 Hz, Ar), 8.01 (2H, d, J: 9.00 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 47.06 (piperazine-CH2), 50.02 (piperazine- CH2), 55.67 (OCH3), 112.62, 113.80, 114.79, 115.26, 118.29, 123.93, 124.42, 126.07, 127.37, 128.41, 132.02, 145.59, 152.84, 153.73, 154.41, 155.39, 181.42 (C=O). HRMS (M+H): For C26H24N2O3 calculated: 413.1860, found: 413.1840.
Benzofuran-2-yl(4-(4-(2-chlorophenyl)piperazine-l-yl)phenyl)methanone (Formula 1.8)
Yield: 66%, e.n.: 153.4-156°C (DMSO)F.T-IR vmax (cm 1): 3075.73-2764.49 (C-H), 1625.19 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.14 (4H, t, J: 4.75 Hz, piperazine), 3.57 (4H, t, J: 4.91 Hz, piperazine-CH2), 7.08 (1H, td, J: 7.58 Hz, 1.57 Hz, Ar), 7.14 (2H, d, J: 9.18 Hz, Ar), 7.21 (1H, dd, J: 8.12 Hz, 1.55 Hz, Ar), 7.30-7.39 (2H, m, Ar), 7.44 (1H, td, J: 8.37 Hz, 1.52 Hz, Ar), 7.54 (1H, td, J: 7.8 Hz, 1.28 Hz, Ar), 7.73 (1H, d, J: 0.92 Hz, Ar), 7.74 (1H, dd, J: 8.40 Hz, 0.80 Hz, Ar), 7.85 (1H, d, J: 7.63 Hz, Ar), 8.01 (2H, d, J: 9.01 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 5 (ppm): 47.27 (piperazine-CH2), 51.07 (piperazine-CH2), 112.62, 113.80, 115.28, 121.44, 123.93, 124.41, 124.70, 126.17, 127.37, 128.13, 128.41, 128.64, 130.86, 132.01, 149.11, 152.83, 154.47, 155.40, 181.43 (C=O). HRMS (M+H): For C25H21C1N2O2 calculated: 417.1364, found: 417.1376.
Benzofuran-2-yl(4-(4-(3-chlorophenyl)piperazine-l-yl)phenyl)methanone (Formula L9)
Yield: 80%, e.n.: 167-170°C (DMSO). FT-IR vmax (cm 1): 3144.85-2819.94 (C-H), 1602.76 (C=O). NMR (300 MHz) DMSO-d6 5 (ppm): 3.37 (4H, m, piperazine), 3.56 (4H, t, J: 4.97 Hz, piperazine-CH2), 6.82 (1H, td, J: 7.88 Hz, 1.35 Hz, Ar), 6.96 (1H, dd, J: 8.38 Hz, 1.85 Hz, Ar), 7.01 (1H, t, J: 2.04 Hz, Ar), 7.12 (1H, d, J: 9.12 Hz, Ar), 7.25 (1H, t, J: 8.15 Hz, Ar), 7.38 (1H, td, J: 7.48 Hz, 0.85 Hz, Ar), 7.54 (1H, td, J: 7.81 Hz, 1.28 Hz, Ar), 7.72 (1H, d, J: 0.86 Hz, Ar), 7.76 (1H, dd, J: 8.40 Hz, 0.74 Hz, Ar), 7.85 (1H, d, J: 7.65 Hz, Ar), 8.01 (2H, d, J: 8.98 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 5 (ppm): 46.62 (piperazine-CH2), 47.71 (piperazine-CH2), 112.62, 113.71, 114.22, 115.12, 115.26, 118.77, 123.92, 124.42, 126.09, 127.36, 128.41, 130.97, 132.03, 134.34, 152.37, 152.84, 154.21, 155.40, 181.42 (C=O). HRMS (M+H): For C25H2IC1N2O2 calculated: 417.1364 found: 417.1353.
Benzofuran-2-yl(4-(4-(4-chlorophenyl)piperazine-l-yl)phenyl)methanone (Formula LIO)
Yield: 76%, e.n.: 200-202°C (DMSO). FT-IR vmax (cm -1): 3069.82-2837.21 (C-H), 1623.42 (C=O). 1H NMR (300 MHz) DMSO-d6 5 (ppm): 3.29 (4H, m, piperazine CH2), 3.57 (4H, t, J: 5.07 Hz, piperazine CH2), 7.02 (2H, d, J: 9.11 Hz, Ar), 7.13 (2H, d, J: 9.11 Hz, Ar), 7.27 (2H, d, J: 7.28 Hz, Ar), 7.39 (1H, td, J: 8.00 Hz, 0.77 Hz, Ar), 7.55 (1H, td, J: 7.81 Hz, 1.22 Hz, Ar), 7.72 (1H, d, J: 0.88 Hz, Ar), 7.76 (1H, dd, J: 8.37 Hz, 0.68 Hz, Ar), 7.85 (1H, d, J: 7.72 Hz, Ar), 8.01 (2H, d, J: 9.04 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 5 (ppm): 46.71 (piperazine-CH2), 48.17 (piperazine-CH2), 112.62, 113.76, 115.29, 117.49, 123.12, 123.93, 124.42, 126.10, 127.36, 128.41, 129.17, 132.02, 149.99, 152.83, 154.25, 155.39, 181.43 (C=O). HRMS (M+H): For C25H2IC1N2O2 calculated: 417.1364 found: 417.1380. (6-Methoxybenzofuran-2-yl) (4-(4-phenylpiperazine-l-yl)phenyl)methanone (Formula Lil)
Yield: 77%, e.n.: 184.5-186°C (DMSO). FT-IR vmax (cm 1): 3124.61-2830.25 (C-H), 1590.05 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.30 (4H, m, piperazine CH2), 3.55 (4H, t, J: 4.99 Hz, piperazine CH2), 3.86 (3H, s, CH3), 6.82 (1H, d, J: 7.23 Hz, Ar), 7.01 (3H, dd, J: 8.69 Hz, 2.08 Hz, Ar), 7.12 (2H, d, J: 9.05 Hz, Ar), 7.25 (2H, t, J: 7.97 Hz, Ar), 7.35 (1H, d, J: 1.57 Hz, Ar), 7.66 (1H, d, J: 0.79 Hz, Ar), 7.71 (1H, d, J: 8.67 Hz, Ar), 7.98 (2H, d, J: 8.92 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 46.95 (piperazine-CH2), 48.46 (piperazine-CH2), 56.24 (OCH3), 96.26, 113.80, 114.54, 115.99, 116.10, 119.68, 120.55, 124.29, 126.43, 129.49, 131.80, 151.21, 152.36, 154.19, 157.05, 160.92, 180.98 (C=O). HRMS (M+H): For C26H24N2O3 calculated: 413.1860, found: 413.1843.
(6-Methoxybenzofuran-2-yl) (4-(4-(4-methoxyphenyl)piperazine-l-yl)phenyl)methanone (Formula 1.12)
Yield: 68%, e.n.: 202-204°C (DMSO). FT-IR vmax (cm 1): 2959.30-2831.36 (C-H), 1614.84 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.17 (4H, brs, piperazine CH2), 3.54 (4H, brs, piperazine CH2), 3.70 (3H, s, CH3), 3.87 (3H, s, CH3), 6.86 (2H, d, J: 9.26 Hz, Ar), 6.92-7.06 (3H, m, Ar), 7.13 (2H, d, J: 8.63 Hz, Ar), 7.35 (1H, s, Ar), 7.66 (1H, s, Ar), 7.71 (1H, d, J: 8.63 Hz, Ar), 7.97 (2H, d, J: 8.88 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 47.14 (piperazine- CH2), 50.03 (piperazine-CH2), 55.75 (OCH3), 96.25, 113.85, 114.54, 114.78, 118.28, 124.29, 126.42, 131.78, 145.60, 154.26, 160.92, 180.97 (C=O). HRMS (M+H): C27H26N2O4 calculated: 443.1965, found: 443.1971.
(4-(4-(4-Chlorophenyl)piperazine-l-yl)phenyl) (6-methoxybenzofuran-2-yl)methanone (Formula 1.13)
Yield: 80%, e.n.: 205-207°C (DMSO). FT-IR vmax (cm 1): 3120.72-2830.72 (C-H), 1613.78 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.30 (4H, m, piperazine CH2), 3.55 (4H, t, J: 5.08 Hz, piperazine CH2), 3.86 (3H, s, OCH3), 6.96-7.06 (3H, m, Ar), 7.12 (2H, d, J: 9.04 Hz, Ar), 7.27 (2H, d, J: 9.04 Hz, Ar), 7.35 (1H, d, J: 1.57 Hz, Ar), 7.66 (1H, d, J: 0.83 Hz, Ar), 7.71 (1H, d, J: 8.64 Hz, Ar), 7.97 (2H, d, J: 8.89 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 46.80 (piperazine-CH2), 48.19 (piperazine-CH2), 58.85 (OCH3), 96.26, 113.82, 114.55, 117.51, 124.29, 129.17, 131.80, 147.83, 150.11, 154.11, 160.98, 182.81 (C=O). HRMS (M+H): For C26H23C1N2O3 calculated: 447.1470, found: 447.1488.
(5-Chlorobenzofuran-2-yl) (4-(4-phenylpiperazine-l-yl)phenyl)methanone (Formula 1.14)
Yield: 65%, e.n.: 201.5-203°C (DMSOF).T-IR vmax (cm 1): 3109.92-2839 (C-H), 1626.47 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.57 (4H, m, piperazine CH2), 3.74 (4H, m, piperazine CH2), 6.82 (1H, t, J: 7.18 Hz, Ar), 7.01 (1H, d, J: 7.20 Hz, Ar), 7.14 (2H, dd, J: 9.10 Hz, 1.75 Hz, Ar), 7.25 (2H, td, J: 8.07 Hz, 1.93 Hz, Ar), 7.57 (1H, td, J: 8.83 Hz, 2.12 Hz, Ar), 7.68 (1H, m, Ar), 7.81 (1H, d, J: 9.37 Hz, Ar), 7.92 (1H, t, J: 1.95 Hz, Ar), 8.00 (2H, dd, J: 8.99 Hz, 1.86 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 46.8 (piperazine-CH2), 48.42 (piperazine- CH2), 113.71, 114.41, 114.52, 116.09, 119.68, 123.14, 125.71, 128.29, 128.68, 128.94, 129.49, 132.11, 151.18, 154.44, 180.97 (C=O). HRMS (M+H): For C25H2iCl2N2O2 calculated: 417.1364, found: 417.1359.
(5-Chlorobenzofuran-2-yl) (4-(4-(4-methoxyphenyl)piperazine-l-yl)phenyl)methanone (Formula 1.15)
Yield: 80%, e.n.: 198-200°C (DMSO). FT-IR vmax (cm 1): 3000-2835.73 (C-H), 1626.21 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.16 (4H, brs, piperazine CH2), 3.57 (4H, brs, piperazine CH2), 3.70 (3H, s, OCH3), 6.85 (2H, d, J: 8.67 Hz, Ar), 6.97 (2H, d, J: 8.67 Hz, Ar), 7.14 (2H, d, J: 8.86 Hz, Ar), 7.57 (1H, d, J: 8.65 Hz, Ar), 7.68 (1H, s, Ar), 7.81 (1H, d, J: 8.88 Hz, Ar), 7.93 (1H, s, Ar), 8.00 (2H, d, J: 8.65 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 47.00 (piperazine-CH2), 50.01 (piperazine-CH2), 113.77, 114.77, 118.29, 121.81, 122.38, 123.23, 125.92, 128.30, 132.11, 134.13, 136.54, 138.67, 145.75, 154.67, 181.30 (C=O). HRMS (M+H): For C26H23C1N2O3 calculated: 447.1470, found: 447.1471. (5-Chlorobenzofuran-2-yl) (4-(4-(4-chlorophenyl)piperazine-l-yl)phenyl)methanone
(Formula 1.16)
Yield: 74%, e.n.: 210-212°C (DMSO). FT-IR vmax (cm 1): 3107.79-2826.69 (C-H), 1626.39 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.30 (4H, m, piperazine CH2), 3.58 (4H, brs, piperazine CH2), 7.02 (2H, d, J: 9.08 Hz, Ar), 7.14 (2H, d, J: 8.48 Hz, Ar), 7.27 (2H, d, J: 8.96 Hz, Ar), 7.56 (1H, d, J: 8.72 Hz, 2.18 Hz, Ar), 7.67 (1H, s, Ar), 7.81 (1H, d, J: 8.72 Hz, Ar), 7.93 (1H, d, J: 2.08 Hz, Ar), 8.00 (2H, d, J: 8.92 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 46.65 (piperazine-CH2), 48.15 (piperazine-CH2), 88.05, 113.72, 114.40, 114.55, 117.48, 123.12, 128.29, 129.17, 132.11, 149.11, 152.21, 153.98, 167.70, 184.51 (C=O). HRMS (M+H): For C25H20Cl2N2O2 calculated: 451.0975, found: 451.0981.
Example 4: General Synthesis Method of Formula L17-Formula 1.95
The molecules indicated by formula V (1 equivalence) are reacted in DMSO using benzyl chloride or 4-chlorobenzyl (1 equivalence) under reflux for 6 hours in the presence of FGCO-, (1 equivalence). After the reaction is completed, water is added, and the resulting precipitate is collected. The collected precipitate is washed twice with water and recrystallized from ethanol.
Benzofuran-2-yl(4-(4-benzylpiperazine-l-yl)phenyl)methanone (Formula 1.17)
Yield: 68% e.n.: 164-167°C. FT-IR vmax (cm 1): 3124.17 - 2776.43 (C-H), 1591.07 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 2.52 (4H, m, piperazine CH2), 3.40 (4H, t, J: 4.60 Hz, piperazine CH2), 3.53 ;(2H, s, CH2), 7.23-7.44 (6H, m, Ar), 7.53 (1H, d, J: 7.81 Hz, Ar), 7.71 (1H, s, Ar), 7.75 (1H, d, J: 8.44 Hz, Ar), 7.84 (1H, d, J: 7.81 Hz, Ar), 7.97 (2H, d, J: 8.86 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 46.95 (piperazine-CH2), 52.69 (piperazine-CH2), 62.41 (benzyl-CH2), 112.61, 113.60, 115.20, 115.24, 123.91, 124.40, 125.84, 127.36, 127.51, 128.38, 128.70, 129.41, 131.99, 138.36, 152.84, 154.47, 155.37, 181.36 (C=O). HRMS (M+H): For C26H24N2O2 calculated: 397.1911, found: 397.1921.
Benzofuran-2-yl(4-(4-chlorobenzyl)piperazine- l-yl)phenyl)methanone (F ormula 1.18) Yield: 70% e.n.: 177-179°C. FT-IR vmax (cm 1): 3104.42-2828.01 (C-H), 1602.01 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 3.30-3.71 (10H, m, piperazine CH2, benzyl CH2), 6.89- 8.18 (12H, m, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 46.94 (piperazine-CH2), 52.62 (piperazine- CH2), 61.42 (benzyl-CH2), 112.62, 113.63, 115.22, 123.92, 124.41, 125.87, 127.36, 128.39, 128.68, 131.17, 132.00, 137.50, 152.82, 154.45, 155.37, 181.37 (C=O). HRMS (M+H): For C26H23C1N2O2 calculated: 431.1521, found: 431.1541.
(4-(4-benzylpiperazine-l-yl)phenyl) (6-methoxybenzofuran-2-yl)methanone (Formula 1.19);
Yield: 70% e.n.: 158-161°C. FT-IR vmax (cm 1): 3107.96-2773.77 (C-H), 1602.95 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 2.52 (4H, m, piperazine CH2), 3.38 (4H, t, J: 4.60 Hz, piperazine CH2), 3.53 ;(2H, s, CH2), 3.85 (3H, s, Ar), 6.94-7.10 (3H, m, Ar), 7.22-7.41 (6H, m, Ar), 7.64 (1H, s, Ar), 7.70 (1H, d, J: 8.37 Hz, Ar), 7.94 (2H, d, J: 8.86 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 47.01 (piperazine-CH2), 52.70 (piperazine-CH2), 56.26 (OCH3), 62.42 (benzyl-CH2), 96.24, 113.64, 114.52, 115.92, 120.54, 124.26, 126.19, 127.50, 128.70, 129.41, 131.76, 138.37, 152.37, 154.32, 157.02, 160.89, 180.92 (C=O). HRMS (M+H): For C27H26N2O3 calculated: 427.2016, found: 427.2016.
(4-(4-(4-chlorobenzyl)piperazine-l-yl)phenyl) (6-methoxybenzofuran-2-yl)methanone (Formula 1.20)
Yield: 75% e.n.: 218-220°C. FT-IR vmax (cm 1): 3108.20-2835.19 (C-H), 1602.28 (C=O). 1H NMR (300 MHz) DMSO-d6 δ (ppm): 2.54 (4H, m, piperazine CH2), 3.341 (4H, m, piperazine CH2), 3.53 ;(2H, s, CH2), 3.86 (3H, s, Ar), 6.97-7.09 (3H, m, Ar), 7.32-7.47 (5H, m, Ar), 7.65 (1H, s, Ar), 7.70 (1H, d, J: 8.65 Hz, Ar), 7.94 (2H, d, J: 9.14 Hz, Ar). 13C NMR (75 MHz) DMSO-d6 δ (ppm): 52.64 (OCH3), 60.31 (piperazine CH2), 94.88, 113.67, 128.68, 131.17, 131.77, 142.13, 148.28, 151.35, 154.04, 156.35, 175.17, 187.85 (C=O). HRMS (M+H): For C27H25C1N2O3 calculated: 461.1626, found: 461.1632. Example 5: Analysis of Acetylcholinesterase (AchE) and Butyl cholinesterase (BuChE)
Enzyme Inhibition of Formula 1.1 - Formula 1.22
Figure imgf000025_0001
When the enzyme activities of the compounds were analyzed, it was observed that they did not affect butyrylcholinesterase, while they were effective on acetylcholinesterase. The main reason for this is believed to be a binding mode similar to donepezil, which is the binding mode specific to acetylcholinesterase. According to these results, the structure-activity evaluation obtained from the compounds is quite parallel to donepezil structure-activity relationships.
Example 6: Results of Molecular Modeling Studies of Formula 1.19 and Formula 1.20 In molecular modeling studies, protein data bank data coded 4EY7 was used. This file was opened and processed in the Maestr Schrodinger program, its active region was defined, and the donepezil was docked and validated with a rmsd value of 0.45. It has been observed that there are similar and compatible interactions with donepezil-active site interactions described in the introduction. When the active site interactions of Formula 1.19 are examined, it is seen that the benzyl ring attached to piperazine is in aromatic interaction with Trp86. The carbonyl group attached to the benzofuran ring is in a hydrogen bond interaction with Phe295, similar to the carbonyl in donepezil. The methoxy group has an H bond interaction with the NH group of Trp286 via a double water bridge. The piperazine nitrogen group appears to be located in the region flanked by Tyr337, Tyr341, and Phe338, similar to piperidine in donepezil. It is also seen that the benzofuran ring has an aromatic interaction with Trp286, similar to the indenone ring in donepezil.
When the active site interactions of Formula 1.20 are examined, it is seen that the benzyl ring attached to piperazine is in aromatic interaction with Trp86. The nitrogen group of piperazine is in 7t- cation interaction with Tyr 337 and is also located in the region surrounded by Tyr337, Tyr341, and Phe338, similar to piperidine in donepezil. It is also seen that the benzofuran ring is in aromatic interaction with Trp286, similar to the indenone ring in donepezil. The methoxy group attached to the benzofuran ring appears to be positioned to hydrogen bond with the water molecules HOH793 and HOH953.
All these results demonstrate the potential of the compounds of Formula I according to the invention to be acetylcholinesterase inhibitors.

Claims

CLAIMS A molecule suitable for use in the treatment of Alzheimer's disease and characterized in that it is shown by following Formula I,
Figure imgf000027_0001
Formula I wherein,
X: -H, -OCH3
Y: -H, -OCH3, Cl or X and Y can be -O-CH2-O- forming a combined ring and selected from
Z: -H, -OCH3
T: -H, -OCH3
R: -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2- NO2, 3-NO2, 4-NO2, n: 0 or 1. Pharmaceutical compositions comprising as drug substance the molecule indicated by Formula I according to Claim 1. A pharmaceutical composition according to Claim 2, characterized in that it comprises a pharmaceutically acceptable excipient. A method (Method 1) to be used in the preparation of molecules indicated by Formula I according to Claim 1, characterized in that it comprises the following: a) The molecules denoted by Formula II and Formula III,
F
Figure imgf000028_0001
F
Formula III b) reacting in the presence of K2CO3 to obtain the molecule indicated by Formula IV; and
Figure imgf000028_0002
Formula IV c) comprising the steps of reacting Formula IV in the presence of aryl piperidine or benzyl piperazine derivative, solvent 1, and K2CO3 to obtain Formula I or preferably Formula I.l-Formula 1.95 or particularly preferably Formula I.l-Formula 1.16, wherein;
X: -H, -OCH3
Y: -H, -OCH3, Cl or X and Y can be -O-CH2-O- forming a combined ring and selected from Z: -H, -OCH3
T: -H, -OCH3
R: -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO2, 3-NO2, 4-NO2, and n: 0 or 1. A method (Method 2) to be used in the preparation of molecules indicated by Formula I according to Claim 1, characterized in that it comprises the following: a) The molecules denoted by Formula II and Formula III,
Figure imgf000029_0001
b) reacting in the presence of K2CO3 to obtain the molecule indicated by Formula IV; and
Figure imgf000029_0002
c) obtaining Formula V by reacting Formula IV in the presence of piperazine, solvent 1, and
K2CO3; and
Figure imgf000030_0001
Formula V d) the reaction of Formula V with benzyl halide or substituted benzyl halide in the presence of solvent 2 and K2CO3 to give Formula I, preferably Formula I.l-Formula 1.95, wherein;
X: -H, -OCH3
Y: -H, -OCH3, Cl or X and Y can be -O-CH2-O- forming a combined ring and selected from
Z: -H, -OCH3
T: -H, -OCH3
R: -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-NO2, 3-NO2, 4-NO2, and n: 0 or 1. 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. A molecule of Formula V for use as an intermediate in the preparation of molecules according to Claim 1 ;
Figure imgf000031_0001
wherein;
X: -H, -OCH3
Y: -H, -OCH3, Cl or X and Y can be -O-CH2-O- forming a combined ring and selected from
Z: -H, -OCH3
T: -H, -OCH3
R: -H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-C1, 3-C1, 4-C1, 2-F, 3-F, 4-F, 2-
NO2, 3-NO2, 4-NO2.
8. A molecule according to Claim 7, characterized in that it is represented by Formula V.l and/or Formula V.2.
Figure imgf000031_0002
Formula V.2
9. Molecules indicated by Formula I according to Claim 1 for use as an acetylcholinesterase inhibitor.
10. Molecules indicated by Formula I according to Claim 1 for use in the treatment of Alzheimer's disease.
PCT/TR2023/050100 2022-02-07 2023-02-07 Novel acetylcholinesterase inhibitors WO2023234891A2 (en)

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TR2022/001550 TR2022001550A2 (en) 2022-02-07 NEW ACETYLCHOLINESTERASE INHIBITORS

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