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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/63—Esters of sulfonic acids
  • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic 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
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
  • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
  • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
  • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
  • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C233/06—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/06—Peri-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/56—Ring systems containing bridged rings
  • C07C2603/58—Ring systems containing bridged rings containing three rings
  • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
  • C07C2603/74—Adamantanes

Definitions

• the present invention refers to the field of medicinal chemistry, in particular compounds for the treatment of neurological disorders, in particular of Alzheimer's disease. More in particular, it refers to multi-target compounds obtained by the combination of Galantamine and Memantine, as well as to their preparation, their use as medicaments and compositions containing them.
• AD Alzheimer's disease
• AD Alzheimer's disease
• AD Alzheimer's disease cholinergic or glutamatergic?
• AD Alzheimer's disease 2019
• AChE acetylcholinesterase
• Donepezil Galantamine
• Rivastigmine Rivastigmine
• Tacrine almost no longer used in the clinical practice
• NMDA noncompetitive N- methyl-D-aspartate
• treatment strategies may address impairments in both systems by combining an inhibitor of the AChE enzyme, able to improve the cholinergic tone, with an NMDA receptor antagonist, able to contrast the glutamate-induced neurodegeneration.
• AChE enzyme able to improve the cholinergic tone
• NMDA receptor antagonist able to contrast the glutamate-induced neurodegeneration.
• this combination therapy presents some drawbacks.
• different pharmacokinetics of the respective drugs can impact on different pharmacodynamic.
• the clinician should face and manage a combination therapy with two different ADME curves (Absorption Distribution Metabolism Excretion).
• MTD multitarget drugs
• the strategy of targeting two or more proteins at the same time with a single compound can provide therapeutic effects superior to those of a selective drug (Cavalli, A.; B perfumesi, M. L; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008, 51 , 347-72; Zimmermann, G. R.; Lehar, J.; Keith, C. T. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today 2007, 12, 34-42; Morphy, R.; Rankovic, Z. Fragments, network biology and designing multiple ligands.
• MTDs can be summarized as follows: 1 ) reduced uncertainty in clinical development since predicting the pharmacokinetics of a single compound is much easier than with a drug cocktail, overcoming the problem of different bioavailability, pharmacokinetics and metabolism; 2) certainty on the pharmacodynamics; 3) improved efficacy due to the synergistic effect of simultaneously inhibiting multiple targets; 4) improved safety by decreasing the side effects related to the load of a drug cocktail (reduced risk of drug-drug interactions); this is particularly relevant for drug metabolism, where the competition of different drugs for the same metabolic enzyme affect their toxicity. All these considerations are of particular relevance as one of the major contributions to attrition rate in drug development continues to be the drug candidate's pharmacokinetic profiling.
• AD patients are susceptible to a wide range of concomitant medical conditions (co-morbidity), including hypertension, vascular diseases, and diabetes, which can often be associated.
• co-morbidity concomitant medical conditions
• problems associated with polypharmacy in the geriatric population have been recognized as critical in recent years. These problems primarily consist of drug interactions which occur more frequently in this population because of the co-existence of chronic disease and impaired organ functions.
• MTDs are strongly favored over combination therapy with respect to the complexity of interactions between polypharmacy, comorbidity, altered pharmacodynamic sensitivity, and changes in pharmacokinetics in the elderly.
• the clinical use of MTDs can also simplify the therapeutic regimen (Youdim, M.B., and Buccafusco, J.J. (2005).
• the multitarget ligand strategy is an innovative approach to the development of novel drug candidates for the treatment of complex neurological disorders, especially in view of the fact that the major basic processes involved in neurodegenerative diseases are multifactorial in nature (Cavalli, A.; B perfumesi, M. L; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008, 51 , 347-72).
• Such a strategy is thus based on the concept that a single multifunctional compound can be deployed to hit multiple targets that cooperate in the neurodegenerative process underlying AD and other neurodegenerative diseases, and therefore would prevent unwanted compensation among interacting pathogenic pathways.
• the multitarget compounds could represent a practical alternative to the use of drug combinations. Since most of the neurodegenerative mechanisms are shared by many neuronal disorders, such multitarget compounds may also be used as medications for other illnesses.
• multitarget compounds are inefficient in terms of their binding energy per unit of molecular weight. This is because they contain groups that are only important for one of the targets, being merely tolerated by the others. This results in an unbalanced profile (Morphy, R., and Rankovic, Z. (2007). Fragments, network biology and designing multiple ligands. Drug Discov. Today 12, 156-160; Morphy, R. (2006). The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds. J Med Chem 49, 2969-2978). The consequent optimization of activities is not an easy task. In fact, a multitarget compound is to be considered as a new chemical entity, with its own pharmacological profile, therefore it's efficacy on the targets of the parent compounds is not predictable a priori, and the complete process of drug development must be faced.
• Galantamine is a reversible cholinesterase inhibitor. Unlike other inhibitors, it also enhances acetylcholine transmission by sensitizing postsynaptic nicotinic receptors (possibly via a7) (Samochocki, M.; Hoffle, A.; Fehrenbacher, A.; Jostock, R.; Ludwig, J.; Christner, C; Radina, M.; Zerlin, M.; Ullmer, C; Pereira, E. F.; Lubbert, H.; Albuquerque, E. X.; Maelicke, A.
• Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 2003, 305, 1024-36). This dual action increases Galantamine's effect on cholinergic input with respect to classical AChE inhibitors, leading to increased efficacy against memory loss. Moreover, Galantamine has also been shown to augment central glutamatergic transmission via indirect action on the nicotinic receptor pathway (Santos, M. D.; Alkondon, M.; Pereira, E. F.; Aracava, Y.; Eisenberg, H. M.; Maelicke, A.; Albuquerque, E. X.
• the nicotinic allosteric potentiating ligand Galantamine facilitates synaptic transmission in the mammalian central nervous system.
• Galantamine Abundant patent literature exists on Galantamine.
• US 5777108 discloses Galantamine derivatives as acetylcholinesterase inhibitors for the treatment of neurodegenerative disorders, such as Alzheimer's disease
• WO 0174339 refers to the use of Galantamine for the treatment of neuropsychiatric behavior associated with Alzheimer's disease.
• Other derivatives of Galantamine for the treatment of neurodegenerative diseases, in particular Alzheimer, are disclosed in US 2004023984 and WO 9740049A1 .
• WO 2008/022365 relates to the use of Galantamine and its derivatives for controlling the effect of toxic organic phosphorous compounds.
• Memantine is an NMDA receptor antagonist that, unlike other antagonists, has a beneficial effect on Alzheimer's patients without significant side effects (Lipton, S. A. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 2007, 8, 803-8).
• a process for the manufacture of Memantine and intermediate products is disclosed in WO 20091 15334A2.
• Galantamine and Memantine provide a more normal neurophysiologic response in patients with AD (Geerts, H.; Grossberg, G. T. Pharmacology of acetylcholinesterase inhibitors and N-methyl-D-aspartate receptors for combination therapy in the treatment of Alzheimer's disease. J Clin Pharmacol 2006, 46, 8S-16S).
• Multiple neurotransmitters are involved in AD and the most studied systems are the cholinergic and glutamatergic. Due to the complexity of the interaction between the two systems, it is difficult to predict the pharmacological profile of a drug acting on both of them.
• NMDA receptors play a pivotal role in synaptic transmission and neural plasticity.
• These receptors are hetero-oligomeric channels comprising two major types of subunits, termed NR1 and NR2 (A-D) subunits.
• NR1 and NR2 (A-D) subunits are hetero-oligomeric channels comprising two major types of subunits, termed NR1 and NR2 (A-D) subunits.
• NR1 and NR2 (A-D) subunits The pharmacological and functional properties of NMDA receptors are highly dependent on the NR2 isoform(s) present in the receptor.
• NR2B subunit containing receptors have been implicated in modulating functions, such as learning, memory processing, attention, emotion, mood, and pain perception, as well as been involved in a number of human disorders.
• Such disorders include, for example, cognitive impairment, neurodegenerative disorders, such as AD and Parkinson's disease, pain, depression, attention deficit hyperactivity disorder, and addiction.
• Ifenprodil is the prototype for NMDA receptor antagonists which display a high degree of selectivity for NR2B-containing receptors.
• US2010227852A1 discloses a drug combination therapy comprising 1- amminocyclohexane derivative such as Memantine and an acetylcholinesterase inhibitor (AChEI) such as Galantamine.
• AhEI acetylcholinesterase inhibitor
• EP1397138B1 discloses combinations of Galantamine with Memantine for treating a dependence on addictive substances or narcotics.
• the only disclosed compound which contains both the Galantamine and the adamantine moiety is (-)-(6-0-demethyl)-6-0- [(adamantan-1-yl)carbonyl]galantamine (P1 1149).
• US20030199493 discloses derivatives and analogues of Galantamine.
• the compound of example 192 (SPH-1517) is structurally similar to the compounds of the present invention, which, however, differ from it in the presence of two methyl groups on the adamantane residue, providing therefore a Memantine residue.
• SPH-1517 compound anticholinergic activity as Galantamine analogue is disclosed and no mention is made to the NMDA receptor as a possible pharmacological target of the same compound.
• the person of ordinary skill in the art would not recognize any contribution for targeting the NMDA receptor in the adamantane residue of the compound SPH-1517. As a matter of fact, this residue is an aliphatic scaffold with no specific pharmacological target.
• WO2004037234 discloses a combination therapy of 1 -amminocyclohexane derivatives and acetylcholinesterase inhibitors (AChEI) for the treatment of dementia associated with disorders of the central nervous system, e.g. Alzheimer's disease.
• the 1-amminocyclohexane derivative is Memantine and the AChEI is Galantamine.
• the compounds of the present invention provide the advantages above mentioned for being multitarget drugs and the further effect of being specifically active on the NMDA receptor containing the NR2B subunit. None of these issues is addressed in the mentioned document.
• WO2005030332A2 discloses Galantamine and derivatives thereof, however, none of the disclosed compounds presents the adamantane moiety.
• AChEI drugs for Alzheimer's disease which is effective in combining the stimulation of the cholinergic system with the suppression of the glutamate neurotoxicity, providing molecules which are endowed with neuroprotective profile.
• Particular interest is on the attempt of broadening the window of efficacy of the AChEI drugs, by contrasting the progressive neurodegeneration responsible of their decline in efficacy.
• the neuroprotective profile achieved through the activity on the NR2B subunit containing NMDA receptors can broaden the temporal window in which AChEI drugs can provide beneficial effects on memory and cognition.
• the claimed compounds achieve neuroprotection from NMDA toxicity mainly thanks to their activity on said subunit.
• the compounds of the present invention have the general formula (I):
• X is (CH 2 )m and m is comprised between 2 and 12;
• Y is selected from the group consisting of NRi , where Ri is H, a protecting group, preferably Boc, Fmoc, Cbz, or C1-C4 alkyl ; O, S, SO, S0 2 , S-S, 0(CH 2 ) P 0, wherein p is comprised between 1 and 6; a cyclic hydrocarbon having from 3 to 8 carbon atoms, an aromatic hydrocarbon having from 6 to 10 carbon atoms; a heterocyclic ring having from 3 to 7 members; or Y is absent.
• R is H, Ci-C 4 alkyl or a protective group, such as Boc, Fmoc, Cbz.
• R 2 is H, Ci-C alkyl, the residue of a pharmaceutically acceptable acid.
• R 3 is Ci-C 4 alkyl, preferably methyl
• R and R5 are Ci-C 4 alkyl, preferably methyl.
• the present invention comprises also the pharmaceutically acceptable salts of the compounds of formula (I).
• the compounds of formula (I) may have additional chiral carbon atoms, therefore, enantiomers, racemates, diastereoisomers and mixtures thereof are comprised in the present invention.
• a further object of the present invention are methods for the preparation of the compounds of formula (I).
• a further object of the present invention are compounds useful as intermediates in the synthesis of the compounds of formula (I).
• a disease selected from the group consisting of: cognitive impairment, memory dysfunction, neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, and related dementia, neuropsychiatric behavior associated with Alzheimer's disease, pain, depression, attention deficit hyperactivity disorder, and for pharmacological addictive substance or intoxicant therapy, in particular the therapy of alcoholism, and the same compounds for the treatment of said diseases.
• a disease selected from the group consisting of: cognitive impairment, memory dysfunction, neurodegenerative disorders, such as Alzheimer disease and Parkinson's disease, and related dementia, neuropsychiatric behavior associated with Alzheimer's disease, pain, depression, attention deficit hyperactivity disorder and for pharmacological addictive substance or intoxicant therapy, in particular the therapy of alcoholism
• a preferred embodiment is a method for the treatment of Alzheimer's disease by administering the compounds of general formula (I) to a patient in need thereof.
• Another preferred embodiment is a method for the treatment of alcoholism by administering the compounds of general formula (I) to a patient in need thereof.
• compositions comprising an effective dose of at least one compound of formula (I).
• the compounds of the present invention provide the advantages of 1 ) reduced uncertainty in clinical development since predicting the pharmacokinetics of a single compound is much easier than with a drug cocktail, overcoming the problem of different bioavailability, pharmacokinetics and metabolism; 2) certainty on the pharmacodynamics; 3) improved efficacy due to the synergistic effect of simultaneously inhibiting multiple targets; 4) improved safety by decreasing the side effects related to the load of a selective drug or drug cocktail (reduced risk of drug-drug interactions). They also provide the advantage of achieving neuroprotection by specifically targeting the 2B subunit of the NMDA receptor.
• the compounds of the present invention can be also defined as MultiTarget Drugs (MTD), in that they combine in their molecule two different drugs.
• MTD MultiTarget Drugs
• the compounds of formula (I) can be schematized as
• G is the part of the Galantamine molecule
• L is a linker
• M is the part of the Memantine molecule.
• Protective group is as normally acknowledged by the person of ordinary skill in the art of organic synthesis. Here, it protects NH function through a temporarily link to a position of a molecule during the course of a synthetic path.
• the protective group does not take part to the reaction and can be easily released from the molecule.
• Boc is tert-butyl carbamate
• Fmoc is 9-fluorenylmethyl carbamate
• Cbz is benzyl carbamate
• "Ci-C 4 alkyl” is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, ter- butyl. See for example Protective groups in organic synthesis, T.W. Greene, P.G.M. Wuts, Third Edition (1999), Wiley Interscience.
• Leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. See for example Smith, March. Advanced Organic Chemistry 6th ed. (501 -502).
• Cyclic hydrocarbon having from 3 to 8 carbon atoms is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a polycyclic ring, such as bicyclo[2.1 .1 ]hexane, bicyclo[2.2.1 ]heptane, bicyclo[3.1 .1 ]heptane, bicyclo[3.2.1 ]octane, bicyclo[4.1 .1 ]octane, bicyclo[3.3.0]octane, which can optionally contain one or more carbon-carbon unsaturated bonds, except aromatic rings, and can optionally be substituted by a Ci-C 4 alkyl or a C 2 -C 4 alkenyl or a C2-C 4 alkyinyl.
• Aromatic hydrocarbon having from 6 to 10 carbon atoms is phenyl or naphthtyl, which can optionally be substituted by a Ci-C 4 alkyl or a C2-C 4 alkenyl or a C 2 -C 4 alkyinyl.
• Heterocyclic ring having from 3 to 7 members means a carbocyclic ring wherein at least one ring member is one or more heteroatom selected from the group consisting of N, O, S.
• Said heterocyclic ring can contain one or more unsaturated bonds between each of carbon atom or heteroatom.
• Said heterocyclic ring can optionally be substituted by a Ci-C 4 alkyl or a C 2 -C 4 alkenyl or a C 2 -C 4 alkyinyl. Examples of said rings are oxazine, aziridine, piperidine, piperazine, pyridine, pyrimidine, furane, thiopene, imidazole, oxazole, pyrane.
• pharmaceutically acceptable acid means an acid that forms an ester with the hydroxy group on the Galantamine hydroxy group. This ester maintains or improves the biological properties of the starting compound. Examples of improvement are enhances solubility, enhanced bioavailability, taste masking, or complementary pharmacological activity. Methods for the preparation of said esters are well-known in the art and are part of the common general knowledge of the person skilled in organic chemistry.
• acids examples include organic acids, such as formic acid, acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, heptanoic acid, decanoic acid, oxalic acid, succinic acid, malonic acid, glutaric acid, adipic acid, pimelic acid methansulfonic acid, salicylic acid, succinic acid, citric acid; inorganic acids, such as chloridric acid, bromidric acid, sulfuric acid, phosphoric acid.
• pharmaceutically acceptable salt means a salt that maintains or improves the biological properties of the starting compound.
• Examples of improvement are enhances solubility, enhanced bioavailability, taste masking, or complementary pharmacological activity.
• methods for the preparation of said salts include the following: addition of inorganic acids (e.g., chloridric acid, bromidric acid, sulfuric acid, phosphoric acid, and similar) or organic (e.g., acetic acid, ossalic acid, maleic acid, methansulfonic acid, salicylic acid, succinic acid, citric acid, and similar), and the free base of the starting compound.
• inorganic acids e.g., chloridric acid, bromidric acid, sulfuric acid, phosphoric acid, and similar
• organic e.g., acetic acid, ossalic acid, maleic acid, methansulfonic acid, salicylic acid, succinic acid, citric acid, and similar
• the compounds of the present invention have to be considered, if not differently specified, as comprising their pharmaceutically acceptable salts.
• salts examples include: formate, acetate, propionate, butiyric, pentanoate, hexanoate, heptanoate, decanoate, oxalate, succinate, malonate, glutarate, adipate, pimelate, methansulfonate, salicylate, succinate, citrate, tartrate; chloride, bromide, sulfate, phosphate.
• the compounds of the present invention contain at least one chiral carbon, therefore, if not differently specified, they will be considered as comprising the individual isomer(s) or mixtures thereof, which may be racemic or of other kind.
• Methods for the stereochemistry determination and stereoisomer separation are known in the art (see for instance, Chapter 4 in "Advanced Organic Chemistry” IV Edition L. March, John Wiley and Sons, New York, 1992).
• a first group of preferred compound of formula (I) are those wherein X is (CH 2 ) m and m is comprised between 2 and 12, Y and Z are absent.
• a second group of preferred compound of formula (I) are those wherein X is (CH 2 ) m and m is comprised between 2 and 12, Y and Z are absent and R is H.
• a third group of preferred compound of formula (I) are those wherein X is (CH 2 ) m and m is comprised between 2 and 12, Y and Z are absent and R is CH 3 .
• a fifth group of preferred compound of formula (I) are those wherein X is (CH2) m and m is comprised between 2 and 12, Y is 0(CH 2 ) p O, wherein p is comprised between 1 and 6, Z is (CH 2 ) n , wherein n is comprised between 1 and 12.
• a sixth group of preferred compound of formula (I) are those wherein X is (CH 2 ) m and m is comprised between 2 and 12, Y is S, Z is (CH 2 ) n , wherein n is comprised between 1 and 12.
• a seventh group of preferred compound of formula (I) are those wherein X is (CH 2 )m and m is comprised between 2 and 12, Y is O, Z is (CH 2 ) n , wherein n is comprised between 1 and 12.
• An eigth group of preferred compound of formula (I) are those wherein X is (CH 2 ) m and m is comprised between 2 and 12, Y is NH, Z is (CH2) n , wherein n is comprised between 1 and 12.
• the invention furthermore provides processes for the preparation of compounds of general formula (I).
• the compounds of formula (I) can be prepared starting from a Memantine derivative M
• R 4 and R5 are as defined above for formula (I).
• R 2 and R3 are as defined above for formula (I), to give the compounds of formula (I).
• the intermediate M-X-Y-Z-NR-E is novel, hence is a further object of the present invention.
• n is an integer comprised between 0 and 10 and A is an activated alcohol group.
• the compound of formula (I I) is novel, hence is a further object of the present invention.
• a first building block M-L-A wherein M is Memantine, L is an alkylene chain (namely X as defined above) and A is an activated alcohol group, is obtained by reacting Memantine with a halo-alcohol of the desired length, followed by protection of the nitrogen atom on the Memantine moiety and, finally, activating the alcoholic function .
• activated alcohol group is well understood by the person of ordinary skill in the art and means an alcohol function (OH), wherein the hydrogen atom is substituted by another functional group so to provide a good leaving group.
• activating groups are tosyl, mesyl.
• the alcohol function can also be converted into halogenous groups (Br, CI, I) according to the general procedures.
• the M-L-A building block is reacted with N-desmethyl Galantamine to provide the desired compound.
• the N-protecting group on the Memantine moiety can be released.
• a salt of Memantine for example chloride
• a suitable solvent such as dimethyl formamide, tetrahydrofuran or dioxane.
• halo-alcohols are for example bromo-, chloro or iodo-alcohol.
• the reaction is carried out at the presence of a base, for example a base derived from an alkaline metal, such as K2CO 3 ., NaOH, KOH, Na 2 C0 3 ; inorganic base in general can be used, under adequate stirring conditions and at a temperature above room temperature, for example ranging from 60°C to 110°C, for example 80°C, and for a time spanning from 12 h to 48 h.
• a base for example a base derived from an alkaline metal, such as K2CO 3 ., NaOH, KOH, Na 2 C0 3 ; inorganic base in general can be used, under adequate stirring conditions and at a temperature above room temperature, for example ranging from 60°C to 110°C, for example 80°C, and for a time spanning from 12 h to 48 h.
• the stoichiometry of the reaction is according to the type of reaction, however the molar ratios can be varied depending on other conditions, such as the solvent, the temperature, reaction time and other
• Completion of reaction is checked by ordinary means, such as chromatography, for example thin layer chromatography, gaschromatography; spectroscopy, for example IR or NMR.
• the residue is re-dissolved in a suitable medium, such as water and extracted with a suitable amount of an organic solvent immiscible with water, such as CH2CI2, for a sufficient number of times.
• the collected organic layers are concentrated to yield the crude /v-alkylated Memantine derivative which, if desired, is further purified by flash chromatography.
• the N-alkylated Memantine is dissolved into a suitable solvent, for example a mixture of an organic solvent and water, for example THF/H 2 O (1 :1 or other convenient ratios) and treated with a base, preferably an alkaline carbonate, for example Na2C0 3 and a protecting group is introduced on the nitrogen of the Memantine moiety.
• a suitable solvent for example a mixture of an organic solvent and water, for example THF/H 2 O (1 :1 or other convenient ratios
• a base preferably an alkaline carbonate, for example Na2C0 3
• a preferred example of protecting group is di-fe/f-butyl dicarbonate (BOC).
• the OH group at the end of the alkyl chain is activated for the final step, when the Galantamine moiety is added.
• This activation is conventional and well known to the person of ordinary skill in the art.
• p-TsCI p-tosyl chloride
• a base such as Et 3 N (triethylamine) and DMAP (dimethylaminopyridine)
• a dry organic solvent such as CH2CI2 under inert atmosphere (for example 2) with stirring at low temperature, such as 0°C.
• the stirring is then continued at room temperature after 30 minutes for until completion of the reaction.
• reaction is quenched, for example with saturated NH 4 CI aqueous solution and extracted with an organic solvent, such as AcOEt. Combined extracts are washed, for example with brine, dried over Na 2 S04,or other desiccant, and evaporated.
• organic solvent such as AcOEt.
• the building block M-L-A is treated with N-desmethyl galantamine and a suitable base, for example E ⁇ in a reaction solvent, such as CH3CN for example is stirred at a temperature ranging from 60 °C to 90 °C, for a time sufficient to completion of the reaction. After elimination of the solvent, the residue is purified by conventional means, for example flash chromatography.
• a reaction solvent such as CH3CN for example
• the protecting groups on nitrogen are removed by well-known methods.
• HCI 4M in dioxane is added to the Boc derivative at low temperature, for example 0 °C, and the solution is allowed to stir at room temperature for a sufficient time. After removing the solvent the obtained residue is purified as usual, for example by flash chromatography.
• All the reactions are preferably carried out in a closed vessel, such as a pressure tube or a sealed reactor.
• R, R 2 , R 3 , R and R 5 are as defined above for formula (I), m is an integer comprised between 0 and 10, Hal is an halogen atom.
• the compound of formula (III) is novel, hence is a further object of the present invention.
• Memantine is treated with a halo-acyl chloride of the desired length.
• the reduction of the amido functionality with LiAIH 4 represents a further synthetic route.
• Memantine salt preferably a hydrochloride and a base, for example a carbonate of alkali metal, such as K2CO3 in a suitable solvent, for example acetonitrile
• a suitable solvent for example acetonitrile
• the appropriate acylating agent is added.
• the reaction is left, preferably under stirring, until completion of the reaction, which is checked by ordinary means.
• the crude is purified by ordinary techniques, such as flash chromatography.
• the intermediate of the preceding step is reacted with des-methyl-Galantamine at the presence of an organic base, such as a trialkyl amine, preferably triethylamine, and a suitable catalyst, for example Kl, in an appropriate solvent, such as CH3CN.
• an organic base such as a trialkyl amine, preferably triethylamine
• a suitable catalyst for example Kl
• the reaction mixture is kept at high temperature, the boiling point of the solvent is convenient, or lower temperature, for example 80°C until completion of the reaction,
• the reaction is conveniently carried out in a closed vessel.
• the solvent is removed as usual and the residue is purified by conventional technique, for example flash chromatography.
• compounds of formula (I), wherein X is (CH 2 )m and m is comprised between 2 and 12; Y is O or 0(CH 2 ) p O, wherein p is comprised between 1 and 6; Z is (CH2) n , wherein n is comprised between 1 and 12 can be prepared following the general synthesis:
• R, R 2 , R3, R4 and R5, are as defined above, A is an activated alcohol group.
• the compound of formula (IV) is novel, hence is a further object of the present invention.
• a base for example an organic base, for example a trialkyl amine, preferably triethyl amine, and a catalyst used in such a kind of reactions, for example DMAP (dimethylaminopyridine) in dry organic solvent, such as CH2CI 2 and in a inert atmosphere (argon or nitrogen) with stirring at low temperature, conveniently 0°C, then raising the temperature to about room temperature until completion of the reaction.
• a base for example an organic base, for example a trialkyl amine, preferably triethyl amine
• a catalyst used in such a kind of reactions for example DMAP (dimethylaminopyridine) in dry organic solvent, such as CH2CI 2 and in a inert atmosphere (argon or nitrogen) with stirring at low temperature, conveniently 0°C, then raising the temperature to about room temperature until completion of the reaction.
• DMAP dimethylaminopyridine
• reaction is then quenched, for example with saturated NH 4 CI aqueous solution and the whole mixture is extracted with an immiscible or partially miscible organic solvent, for example ethyl acetate.
• organic extract is washed with brine, dried with conventional means, for example over Na 2 SC>4, and, following solvent removal, the crude is purified by conventional means, such as flash chromatography.
• a Memantine salt preferably hydrochloride, and a base (K2CO3 for example) in a suitable solvent, for example dimethylformamide (DMF).
• a suitable solvent for example dimethylformamide (DMF).
• the reaction mixture is warmed (for example about 80°C) for a suitable time (typically 48 hours), until completion.
• the solvent is removed and the residue is worked properly, for example is taken up with water and extracted with an organic solvent (such as CH 2 CI 2 ).
• the crude is finally purified by usual means, for example flash chromatography.
• the intermediate compound obtained in the previous step is dissolved in a reaction medium (for example THF/H 2 0) and treated with an alkali carbonate, for example sodium, and a suitable protecting group for the nitrogen, di-fert-butyl dicarbonate is preferred.
• a reaction medium for example THF/H 2 0
• an alkali carbonate for example sodium
• a suitable protecting group for the nitrogen, di-fert-butyl dicarbonate is preferred.
• the resultant suspension is allowed to stir at room temperature, for example overnight.
• the solvent is then removed yielding a residue which is dissolved in water and extracted with an organic solvent, such as AcOEt.
• the gathered extracts are combined, washed with brine, dried, for example over Na 2 S0 4 , concentrated by evaporation, and purified as usual, for example by flash chromatography.
• the primary alcohol is activated according to conventional methods, for example with tosyl chloride, as described above.
• a further object of the present invention is a pharmaceutical composition
• a pharmaceutical composition comprising at least one compound of Formula (I) as an active ingredient, in an amount such as to produce a significant therapeutic effect.
• the amount of active ingredient can be determined by the skilled person resorting to methods of dose finding conventionally adopted in the pharmaceutical industry.
• the dosage can range from 0.01 pg/kg to 1 mg/kg.
• Unitary dosages can provide a dose of active ingredient varying from 1 to 50 mg.
• the compositions covered by the present invention are entirely conventional and are obtained with methods which are common practice in the pharmaceutical industry, such as, for example, those illustrated in Remington's Pharmaceutical Science Handbook, Mack Pub. N. Y. - last edition.
• compositions will be in solid or liquid form, suitable for oral, parenteral or intravenous administration.
• the compositions according to the present invention contain, along with the active ingredient, at least one pharmaceutically acceptable vehicle or excipient.
• These may be particularly useful formulation coadjuvants, e.g. solubilising agents, dispersing agents, suspension agents, and emulsifying agents.
• Solvents were RP grade. Dichloromethane was distilled from calcium chloride. Dry dimethylformamide and triethylamine were used as supplied.
• Nuclear magnetic resonance spectra were recorded at 400 MHz on Varian VXR 400 spectrometers and reported in parts per million.
• UPLC-MS analyses were run on a Waters ACQUITY UPLC-MS instrument consisting of a SQD Single Quadropole Mass Spectrometer equipped with an electrospray ionization interface and a photodiode array detector. The analyses were performed on an ACQUITY UPLC BEH C18 column (50x2.1mm ID, particle size 1.7 ⁇ ) with a VanGuard BEH C18 pre-column (5x2.1 mmlD, particle size 1.7pm). The mobile phases were 10mM NH 4 OAc at pH 5 adjusted with AcOH (A) and 10mM NH 4 OAc in MeCN-H20 (95:5) at pH 5 (B). Electrospray ionization in positive and negative mode was used in the mass scan range 100-500Da. Column chromatography purifications were performed under "flash conditions" using Sigma Aldrich silica gel grade 9385, 230-400 mesh.
• TLC TLC were performed on 0.20 mm silica gel 60 F254 plates (Merck, Germany), which were visualized by exposure to ultraviolet light and potassium permanganate stain. Reactions involving generation or consumption of amine were visualized by using bromocresol green spray (0.04% in EtOH made blue by NaOH) following heating of the plate.
• ES129 4-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)amino)butan-1-ol. It was synthesized from 4-bromo-1-butanol (0.251 mL, 2.78 mmol). Elution with CH 2 CI 2 /MeOH/33% aqueous ammonia (9:1 :0.16) afforded ES129 as a waxy solid: 0.501 g (86%).
• ES91 5-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)amino)pentan-1 -ol. It was synthesized from 5-bromo-1-pentanol (0.464 g, 2.78 mmol). Elution with CH 2 CI 2 /MeOH/33% aqueous ammonia (9:1 :0.15) afforded ES91 as foam solid: 0.560 g (91 %).
• ES92 6-(((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)amino)hexan-1-ol. It was synthesized from 6-bromo-1-esanol (0.37 mL, 2.78 mmol). Elution with CH 2 CI 2 /MeOH/33% aqueous ammonia (9:1 :0.15) afforded ES92 as a foam solid: 0.577 (89%).
• ES93 7-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)amino)heptan-1-ol. It was synthesized from 7-bromo-1-eptanol (0.427 ml_, 2.78 mmol). Elution with CH 2 CI 2 /MeOH/33% aqueous ammonia (9:1 :0.15) afforded ES93 as a foam solid: 0.626 g (92%). H-NMR (CDCI 3 , 400 MHz) ⁇ 0.84 (s, 6H), 1.09-1.
• ES105 8-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)amino)octan-1 -ol. It was synthesized from 8-bromo-1-octanol (0.477 ml_, 2.78 mmol). Elution with CH 2 CI 2 /MeOH/33% aqueous ammonia (9:1:0.1) afforded ES105 as a foam solid: 0.613 g (86%).
• ES152 9-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)amino)nonan-1-ol. It was synthesized from 9-bromo-1-nonanol (0.620 g, 2.78 mmol). Elution with CH 2 CI 2 /MeOH/33% aqueous ammonia (9:1 :0.1) afforded ES152 as a foam solid: 0.671 g (90%).
• ES134 ferf-butyl ((1 R.3R.5S JR)-3 dimethyladamantan-1 -yl)(4- hydroxybutyl)carbamate. It was synthesized from ES129 (0.250 g, 0.99 mmol). Elution with petroleum ether/AcOEt (6:4) afforded ES134 as a foam solid: 0. 280 g (80%).
• ES96 ferf-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)(5- hydroxypentyl)carbamate. It was synthesized from ES91 (0.300 g, 1.13 mmol). Elution with petroleum ether/ AcOEt (7:3) afforded ES96 as a foam solid: 0.360 g (87%).
• ES99 fert-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(7- hydroxyheptyl)carbamate. It was synthesized from ES93 (0.480 g, 1.64 mmol). Elution with petroleum ether/ AcOEt (7:3) afforded ES99 as a foam solid: 0.530 g (83%).
• ES109 fert-butyl ((1R,3R,5SJR)-3,5 iimethyladamantan-1-yl)(8- hydroxyoctyl)carbamate. It was synthesized from ES105 (0.380 g, 1.24 mmol). Elution with petroleum ether/ AcOEt (7.5:2.5) afforded ES109 as a foam solid: 0.430 g (85%).
• ES153 fert-butyl ((IR.SR.SSJR ⁇ S.S-dimethyladamantan-l-ylKS- hydroxynonyl)carbamate. It was synthesized from ES152 (0.600 g, 1.87 mmol). Elution with petroleum ether/ AcOEt (8:2) afforded ES153 as a foam solid: 0.650 g (82%).
• ES137 4- ⁇ (terf-butoxycarbonyl)((1R,3R,5S,7R)-3,5-dimethyladamantan-1- yl)amino)butyl 4-methylbenzenesulfonate. It was synthesized from ES134 (0.090 g, 0.26 mmol). Elution with petroleum ether/ AcOEt (9:1) afforded ES137 as an oil: 0. 10 g (85%).
• ES97 5-((terf-butoxycarbonyl)((1R,3R,5S,7R)-3,5-dimethyladamantan-1- yl)amino)pentyl 4-methylbenzenesulfonate. It was synthesized from ES96 (0.180 g, 0.492 mmol). Elution with petroleum ether/ AcOEt (9:1 ) afforded ES97 as an oil: 0.250 g (98%).
• ES104 6-((fe:t-butoxycarbonyl)((1R,3R l 5S l 7R)-3 l 5-dimethyladamantan-1 - yl)amino)hexyl 4-methylbenzenesulfonate. It was synthesized from ES94 (0.710 g, 1.945 mmol). Elution with petroleum ether/ AcOEt (9: 1 ) afforded ES104 as an oil: 0.900 g (87%).
• ES102 7-((terf-butoxycarbonyl)((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 - yl)amino)heptyl 4-methylbenzenesulfonate. It was synthesized from ES99 (0.530 g, 1.349 mmol). Elution with petroleum ether/ AcOEt (9.2:0.8) afforded ES102 as an oil: 0.720 g (98%).
• ES110 8-((terf-butoxycarbonyl)((1R,3R,5S,7R)-3,5-dimethyladamantan-1 - yl)amino)octyl 4-methylbenzenesulfonate. It was synthesized from ES109 (0.380 g, 0.934 mmol). Elution with petroleum ether/ AcOEt (9: 1 ) afforded ES110 as an oil: 0.460 g (88%).
• ES122 6-(((1 R.aR.SSJRJ-a.S-dimethyladamantan-l-ylJtmethy aminoJhexan- l-ol. It was synthesized from 6-bromo-1 -esanol ( 0.308 mL, 1.68 mmol). Elution with CH2CI2/CH 3 OH/ 33% aqueous ammonia (9:1 :1.5) afforded ES122 as a waxy solid: 0.370 g (90%).
• ES128 7-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(methyl)amino)heptan- 1-ol. It was synthesized from 7-bromo-1 -eptanol ( 0.258 mL, 1.68 mmol). Elution with CH2CI2/CH3OH/ 33% aqueous ammonia (9:1 :1.4) afforded ES128 as a waxy solid:
• p-TsCI (1.2 eq.) was added dropwise to a mixture of the appropriate di-alcohol, Et 3 N (1 eq.), and DMAP (cat.) in dry CH 2 CI 2 (0.01 M) under N 2 atmosphere with stirring at 0°C. The stirring was continued at room temperature for 4 hours. The reaction was quenched with saturated NH 4 CI aqueous solution and the whole was extracted with AcOEt. The extract was washed with brine, dried over Na 2 S0 4 , and, following solvent evaporation, the crude was purified by flash chromatography.
• ES154 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate. It was synthesized from triethylene glycol (1 .000 g, 6.66 mmol). Elution with petroleum ether/ AcOEt (2:8) afforded ES154 as a waxy solid: 0.450 g (22%).
• ES119 2-(2-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)amino)ethoxy)ethanol. It was synthesized from ES117 (0.210 g, 0.81 mmol). Elution with CH 2 CI 2 /CH 3 OH/ 33% aqueous ammonia (9:1 :0.13)afforded ES119 as a waxy solid: 0.160 g (88%).
• ES158 terf-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)carbamateethanol. It was synthesized from ES157 (0.230 g, 0.740 mmol). Elution with petroleum ether/ AcOEt (5:5) afforded ES158 as a waxy solid: 0.160 g (53%).
• ES185 fert-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(2-(2- hydroxyethoxy)ethyl)carbamate. It was synthesized from ES119 (0.160 g, 0.599 mmol). Elution with petroleum ether/ AcOEt (5:5) afforded ES185 as a waxy solid: 0.140 g (64%).
• ES159 5-((1 R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)-2,2-dimethyl-4-oxo-3,8,11 - trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate. It was synthesized from ES158 (0.160 g, 0.390 mmol). Elution with petroleum ether/AcOEt (7:3) afforded ES159 as a waxy solid: 0.120 g (55%).
• ES188 2-(2-((ieri-butoxycarbonyl)((1 R,3R,5S,7R)-3,5-dimethyladamantan-1- yl)amino)ethoxy)ethyl 4-methylbenzenesulfonate. It was synthesized from ES185 (0.140 g, 0.38 mmol). Elution with petroleum ether/AcOEt (8:2) afforded ES188 as a waxy solid: 0.180 g (91 %).
• Example 19 ferf-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(2-(2-(2-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin- 11(12H)-yl)ethoxy)ethoxy)ethyl)carbamate. It was synthesized from ES159 (0.120 g, 0.212 mmol).
• Example 20 ferf-butyl ((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(2-(2-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin- 11(12H)-yl)ethoxy)ethyl)carbamate. It was synthesized from ES188 (0.180 g, 0.345 mmol). Elution with CH 2 CI 2 /CH 3 OH (9.5:0.5) afforded COMPOUND OF INTEREST as a waxy solid: 0.1 15 g (53%).
• ES195 terf-buty I ((1 r,3R,5S,7r)-3,5-d imethy ladamantan-1 -y l)(2-((2- hydroxyethyl)thio)ethyl)carbamate.
• ES194 (0.250 g, 1 eq.) was dissolved in THF/H 2 0 (1 :1 ) and treated with Na 2 C0 3 (2.5 eq.) and di-ferf-butyl dicarbonate (0.140 g, 1 .5 eq). The resultant suspension was allowed to stir at room temperature overnight. The solvent was then removed in vacuo yielding a residue which was dissolved in water and extracted with AcOEt (3 x 15 ml_).
• Example 23 a) TsCI, D AP, Et 3 N, CH 2 CI 2 , rt. b) des-methyl-galantamine, Et 3 N, CH 3 CN, 80°C.
• p-TsCI (1 eq.) was added to a mixture of ES 195 (0.100 g, 1 eq.), Et 3 N (2 eq.), and DMAP (cat.) in dry CH 2 CI 2 (0.1 M) under N 2 atmosphere with stirring at 0°C. The stirring was continued at room temperature for 3.5 hours. The reaction was quenched with saturated NH 4 CI aqueous solution and extracted with AcOEt (3 x 10 ml_). The extract was washed with brine prior to drying over Na2S0 4 , and solvent evaporation.
• Km and Vmax for the enzyme was calculated by Michaelis-Menten equation.
• Ifenprodil a heterocyclic amino alcohol, is an atypical noncompetitive antagonist, which selectively binds to and inhibits NR2B-containing NMDA receptors (Carter et al.,1990; Mott et al., 1998; Williams, 2001 ). Owing to its subunit selectivity [ 3 H]ifenprodil has been extensively used as a ligand in receptor-binding studies on NR2B-containing NMDA receptor complexes (Chenard & Menniti, 1999).
• the activity of the new compounds towards NR2B/NMDA glutamate receptors were evaluated by competition binding assays. Aliquots of rat brain cortex membranes (100 g proteins) were incubated with 10 nM [ 3 H] ifenprodil and two different concentrations of each compounds (100 nM and 100 ⁇ ). In parallel, eliprodil and ifenprodil were tested as standard compounds. Based on the obtained preliminary data, the most promising compounds showing the higher % of binding inhibition were tested at 6 concentrations. Isotherms were analyzed by nonlinear regression using PRISM (GraphPad Software, San Diego, CA) to generate IC 5 o values.
• PRISM GraphPad Software, San Diego, CA
• Ki IC 50 /(1 +L/Kd), where L is the radioligand concentration, and K d is the dissociation constant.
• L the radioligand concentration
• K d the dissociation constant.
• SHSY-5Y cells were maintained in DMEM/F12 medium supplemented with 15% fetal bovine serum, 1 % non-essential amino acids, 2 mM L-glutamine and penicillin/streptomycin in humidified atmosphere (5% C0 2 ) at 37 °C.
• NMDA receptor antagonists/AChE inhibitor were added for 5 min prior to addition of NMDA, in order to determine the inhibition of NMDA-mediated cell toxicity.
• classical NMDA receptor antagonist Edliprodil and Ifenprodil
• AChE inhibitor Galantamine
• each condition was assayed in duplicate or triplicate and each experiment was performed at least three times. The results were calculated by subtracting the mean background from the values obtained from each test condition and were expressed as the percentage of the control (untreated cells).
• the present series of molecules which show a dual AChE/NR2B mechanism, are able to contrast the NMDA-induced neurotoxicity in neuroblastoma cell lines.
• This profile is rather unexpected and not fully justified by the molecular data.
• the molecules were micromolar binders of the 2B subunit of the NMDA receptor, they were able to contrast the NMDA-induced neurodegeneration at a subnanomolar level, concentrations much lower than the concentration at which Memantine is able to revert the neurotoxicity by NMDA.
• the ability of the Galantamine fragment to interact with other receptor systems involved in neurodegeneration could be responsible for the remarkable pharmacological profile of the present series of compounds.
• AChE/NR2B inhibitors show activities against the biological targets for which these compounds were designed (i.e. AChE, NMDAR, NR2B), along with an unexpected and remarkable neuroprotective profile, as assessed by cell-based experiments.

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