OF ALZHEIMER'S DISEASE

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.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a progressive neurological disorder characterized by deterioration of cognitive function, dementia, memory loss, and altered behavior.

Despite massive investments by the pharmaceutical industry, there are few, if any, effective treatments for AD.

Although AD was once thought to result from a cholinergic deficit alone, it has been shown that other neurotransmitters, including dopamine, noradrenalin, serotonin, and glutamate are reduced or dysregulated in AD. Currently, the neurotransmitter systems most studied in the pathogenesis of AD are the cholinergic and the glutamatergic (Palmer, A. M.; Gershon, S. Is the neuronal basis of Alzheimer's disease cholinergic or glutamatergic? FASEB J 1990, 4, 2745-52), and approved drugs for the treatment of AD are four acetylcholinesterase (AChE) inhibitors - Donepezil, Galantamine, Rivastigmine, and Tacrine (almost no longer used in the clinical practice) - and one noncompetitive N- methyl-D-aspartate (NMDA) receptor antagonist, Memantine.

According to the cholinergic hypothesis of AD, the loss of cholinergic functions in the central nervous system (CNS) contributes significantly to the cognitive decline associated with AD (Bartus, R. T.; Dean, R. L., 3rd; Beer, B.; Lippa, A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982, 217, 408-14).

Moreover, although the relationship between cholinergic depletion, amyloidogenesis, and T-phosphorylation is complex, it appears that cholinergic reduction may increase the production of β-amyloid and may induce τ-phosphorylation. On the other hand, the glutamatergic hypothesis of AD states that glutamate-related excitoxic mechanisms involving the NMDA receptor lead to neurodegeneration and cell death (Bleich, S.;

Romer, K.; Wiltfang, J.; Kornhuber, J . Glutamate and the glutamate receptor system: a target for drug action. Int J Geriatr Psychiatry 2003, 18, S33-40). Synaptic stimulation

l through NMDA receptors is important for learning and memory functions, but excess glutamate can cause excitotoxicity and neurodegeneration (Michaels, R. L; Rothman, S. M. Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J Neurosci 1990, 10, 283-92).

In this scenario, 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. However, this combination therapy, presents some drawbacks. Other than facing the cumbersome administration of two separate drugs, which is an additional problem for elder patients affected by Alzheimer and for people caring them, different pharmacokinetics of the respective drugs can impact on different pharmacodynamic. In practice, the clinician should face and manage a combination therapy with two different ADME curves (Absorption Distribution Metabolism Excretion).

An innovative alternative to cumbersome drug combinations are drugs that can hit multiple targets - the so-called multitarget drugs (MTD).

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.; Bolognesi, 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. Drug Discov Today 2007, 12, 156-60; Hopkins, A. L. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008, 4, 682-90). This can be explained by the number of potential benefits offered by the use of MTDs over cocktails or multicomponent drugs. The advantages of 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.

Another important advantage is a simplified therapeutic regimen and improved compliance, which is particularly important for elderly AD patients and their caregivers (Small, G.; Dubois, B. A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch. Curr Med Res Opin 2007, 23, 2705-13). With this regard, a key issue is that 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. Thus, 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. Two drugs that themselves are safe cannot be assumed to be safe in combination, particularly in elderly patients. It follows that the number of drugs administered simultaneously should be reduced as much as possible, since advanced age is an unpredictable risk factor for drug treatment (Turnheim, K. (2003). When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp. Geront. 38, 843-853). As such, 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). CNS Targets for multi-functional drugs in the treatment of Alzheimer's and Parkinson's diseases. J Neural Transm 1 12, 519-537). Compliance with prescribed medication regimens is essential for effective treatment. Noncompliance represents a general problem, but is especially challenging for forgetful AD patients and their caregivers (Small, G., and Dubois, B. (2007). A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch. Curr. Med. Res. Opin. 23, 2705-2713). Consequently, a simplified MTD regimen may increase treatment adherence. All the above mentioned advantages are not available with drug cocktails.

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.; Bolognesi, 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. Indeed, 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.

One problem connected to multitarget compounds is that many of them 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. Mol Pharmacol 2002, 61 , 1222-34; Moriguchi, S.; Marszalec, W.; Zhao, X.; Yeh, J. Z.; Narahashi, T. Mechanism of action of Galantamine on N-methyl-D-aspartate receptors in rat cortical neurons. J Pharmacol Exp Ther 2004, 310, 933-42). Many reports have shown that activation of a7 nicotinic receptors located on presynaptic glutamatergic neurons stimulates glutamate release and increases the NMDA receptor activity on postsynaptic neurons (McGehee, D. S.; Heath, M. J.; Gelber, S.; Devay, P.; Role, L. W. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 1995, 269, 1692-6). Since glutamate has a positive action on memory function (mainly through NMDA receptors), this indirect action further increases the efficacy of Galantamine on memory loss.

Abundant patent literature exists on Galantamine. For example, US 5777108 discloses Galantamine derivatives as acetylcholinesterase inhibitors for the treatment of neurodegenerative disorders, such as Alzheimer's disease and 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 . Of note, WO 2008/022365 relates to the use of Galantamine and its derivatives for controlling the effect of toxic organic phosphorous compounds.

Methods of preparation of Galantamine and derivatives are disclosed in WO 1996012692, US 6797819, and US 6043359.

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.

Although at a first glance the two drugs appear to have some opposing mechanisms, a closer examination reveals that working together 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.

Particularly relevant in the context of the present invention is the role of the NMDA receptors in neurodegeneration, and in particular of the NR2B subunit of said receptors. 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. 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.

Ifenprodil

This compound, together with its congener Eliprodil, is recognized as the template for the development of new generations of selective antagonists of the NR2B-containing receptors (Chazot P.L. "The NMDA receptor NR2B Subunit: a valid therapeutic target for multiple CNS pathology" Current Medicinal Chemistry, 2004, 1 1 , 399-396).

Compounds selectively targeting the NR2B subunit containing receptors are generally known. For example, US2003229096 (A1 ) discloses a broad variety of substituted imidazol-pyridazine derivatives that are NMDA receptor subtype selective blockers, which are said to be useful in the therapy of CNS disorders. Combinations of Memantine and Galantamine are already known in the art, as discussed in "Rationale for combination therapy with Galantamine and Memantine in Alzheimer's disease" (Grossberg G. T.; Edwards, K. R.; Zhao, Q. J Clin Pharmacol 2006, 46, 17S-26S).

US2010227852A1 discloses a drug combination therapy comprising 1- amminocyclohexane derivative such as Memantine and an acetylcholinesterase inhibitor (AChEI) such as Galantamine.

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. In particular 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. Also, only the 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. In a specific embodiment, the 1-amminocyclohexane derivative is Memantine and the AChEI is Galantamine. Compared to the combination disclosed in this document, 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.

Although the concept of MTDs is well-known in the art, and a combination therapy of Galantamine and Memantine is currently in clinical practice, a combination of the two drugs in one single MTD compound is still unknown. WO2005030332A2 discloses Galantamine and derivatives thereof, however, none of the disclosed compounds presents the adamantane moiety.

There is still the need of a drug 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.

SUMMARY OF THE INVENTION

It has now been found that multitarget compounds obtained by the combination of Galantamine and Memantine achieve the pharmacological profile of a drug combination in a single new chemical entity.

In particular, it has been found that said compounds have an unexpected activity on the 2B subunit of the NMDA receptor, which has been shown to be the actual modulator of neuroprotection and its selective antagonism in the family of NMDA receptor subunits is a desirable pharmacological target (Chazot P.L. "The NMDA receptor NR2B Subunit: a valid therapeutic target for multiple CNS pathology" Current Medicinal Chemistry, 2004, 1 1 , 389-396).

Therefore, 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):

(I)

wherein:

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.

Z is selected from the group consisting of (CH2) _n , wherein n is comprised between 2 and 12, C=0 and CH ₂ 0(CH ₂ )2, or Z 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, the same or different, are Ci-C ₄ alkyl, preferably methyl.

The present invention comprises also the pharmaceutically acceptable salts of the compounds of formula (I).

Other than the sterical configuration of the Galantamine residue, which remains set in the present invention, 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).

It is also an object of the present invention the use of said compounds of general formula (I) in the preparation of a medicament useful in the treatment of 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. It is also an object of the present invention a method for the treatment of 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, by administering the compounds of general formula (I) to a patient in need thereof.

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.

It is also an object of the present invention the use of the compounds of general formula (I) for the neuroprotection from NMDA toxicity as well as a method for the treatment of said toxicity by administering said compounds to a patient in need thereof.

Another object of the present invention are pharmaceutical 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 above objects of the present invention will be described in the detail also through some preferred embodiments and by means of examples.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The compounds of the present invention can be also defined as MultiTarget Drugs (MTD), in that they combine in their molecule two different drugs. Basically, the compounds of formula (I) can be schematized as

G-L-M

wherein, G is the part of the Galantamine molecule, L is a linker and M is the part of the Memantine molecule.

In the context of the present invention and if not differently explicitly specified, the following terms have the following meaning.

"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, In this context, 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.

The term "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. Examples of said acids are 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. The term "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. Examples of 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. The compounds of the present invention, have to be considered, if not differently specified, as comprising their pharmaceutically acceptable salts. Examples of this kind of salts are: formate, acetate, propionate, butiyric, pentanoate, hexanoate, heptanoate, decanoate, oxalate, succinate, malonate, glutarate, adipate, pimelate, methansulfonate, salicylate, succinate, citrate, tartrate; chloride, bromide, sulfate, phosphate. For a general reference, see also P. Heinrich Stahl, Camille G. Wermuth (Eds.) Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley-VCH, 2008.

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 fourth 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 absent, Z is C=0 and R is H.

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 following compounds are preferred:

a) ferf-butyl ((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(2-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)ethyl)carbamate;

b) ferf-butyl ((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(3-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)propyl)carbamate;

c) ferf-butyl ((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(4-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)butyl)carbamate; d) ferf-butyl ((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(5-((4aS,6R,8aS)-6 hydroxy-3-methoxy-5, 6,9,10-tetrahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin- 1 1 (12H)-yl)pentyl)carbamate;

e) ferf-butyl ((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(6-((4aS,6R,8aS)-6 hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)hexyl)carbamate;

f) ferf-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(7-((4aS,6R,8aS)-6 hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)heptyl)carbamate;

g) ferf-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(8-((4aS,6R,8aS)-6 hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)octyl)carbamate;

h) ferf-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(9-((4aS,6R,8aS)-6 hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)nonyl)carbamate;

i) (4aS,6R,8aS)-1 1 -(2-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)amino)ethyl)-3- methoxy-5,6,9,10,1 1 ,12-hexahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; j) (4aS,6R,8aS)-1 1 -(3-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)amino)propyl)- 3-methoxy-5, 6,9, 10,1 1 ,12-hexahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin-6- ol;

k) (4aS,6R,8aS)-1 1 -(4-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)amino)butyl)-3- methoxy-5,6,9,10,1 1 ,12-hexahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin-6-ol;

I) (4aS,6R,8aS)-1 1 -(5-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)amino)pentyl)- 3-methoxy-5, 6,9, 10,11 ,12-hexahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin-6- ol

m) (4aS,6R,8aS)-1 1 -(6-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)amino)hexyl)- 3-methoxy-5, 6,9, 10,1 1 ,12-hexahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin-6- ol;

n) (4aS,6R,8aS)-1 1 -(7-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)amino)heptyl)- 3-methoxy-5, 6,9, 10,1 1 ,12-hexahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin-6- ol;

o) (4aS,6R,8aS)-1 1 -(8-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)amino)octyl)-3- methoxy-5,6,9,10,1 1 ,12-hexahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; p) (4aS,6R,8aS)-1 1 -(9-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)amino)nonyl)- 3-methoxy-5, 6,9, 10,1 1 ,12-hexahydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin-6- ol;

q) (4aS,6R,8aS)-1 1 -(3-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)propyl)-3-methoxy-5,6,9,10,1 1 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; r) (4aS,6R,8aS)-1 1 -(4-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)butyl)-3-nnethoxy-5,6,9,10,11 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; s) (4aS,6R,8aS)-1 1 -(5-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)pentyl)-3-nnethoxy-5,6,9,10,1 1 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; t) (4aS,6R,8aS)-1 1 -(6-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)hexyl)-3-methoxy-5,6,9,10,1 1 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; u) (4aS,6R,8aS)-1 1 -(7-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)heptyl)-3-nnethoxy-5,6,9,10,1 1 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; v) (4aS,6R,8aS)-1 1 -(8-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)octyl)-3-nnethoxy-5,6,9,10,1 1 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; w) (4aS,6R,8aS)-1 1 -(10-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)decyl)-3-methoxy-5,6,9,10,1 1 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; x) 3-((4aS,6R,8aS)-3,6-dimethoxy-5,6,9,10-tetrahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-1 1 (12H)-yl)-N-((1 R^R^SJS)^- dimethyladamantan-1-yl)propanamide; y) 4-((4aS,6R,8aS)-3,6-dimethoxy-5,6,9,10-tetrahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-1 1 (12H)-yl)-N-((1 R,3R,5S,7S)-3,5- dimethyladannantari-1-yl)butanannide; z) N-((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)-5-((4aS,6R,8aS)-6-hydroxy-3- methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofuro[4,3-cd]a zepin-1 1 (12H)- yl)pentanamide aa)N-((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)-6-((4aS,6R,8aS)-6-hydroxy-3- methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofuro[4,3-cd]a zepin-1 1 (12H)- yl)hexanamide; bb)tert-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]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)ethoxy)ethoxy)ethyl)carbamate; cc)terf-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]benzofur o[4,3-cd]azepin- 1 1 (12H)-yl)ethoxy)ethyl)carbamate; dd) (4aS,6R,8aS)-1 1 -(2-(2-(2-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 - yl)amino)ethoxy)ethoxy)ethyl)-3-methoxy-5,6,9,10,1 1 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol; ee) (4aS,6R,8aS)-1 1 -(2-(2-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)amino)ethoxy)ethyl)-3-methoxy-5,6,9,10,1 1 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol.

The invention furthermore provides processes for the preparation of compounds of general formula (I).

In a general perspective, the compounds of formula (I) can be prepared starting from a Memantine derivative M

wherein R ₄ and R5 are as defined above for formula (I).

A linker L of formula D-X-Y-Z-NR-E, wherein X, Y, Z and R are as defined above for formula (I), D and E are a leaving group is reacted with M to give an intermediate M-X-

Y-Z-NR-E. The intermediate M-X-Y-Z-NR-E is then reacted with a des-methyl-galanthamine derivative G

wherein 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.

For the preparation of the compounds of formula (I), according to the present invention, wherein X is (CH2) _m as defined above, Y and Z are absent, the general synthesis can be described by the following reaction :

II wherein R, R2, R3, R ₄ and R5, are as defined above for formula (I), 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.

In case R is H, 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 .

Within the scopes of the present invention, 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. Examples of activating groups are tosyl, mesyl. To provide a good leaving group the alcohol function can also be converted into halogenous groups (Br, CI, I) according to the general procedures. Finally, 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.

Alternatively, the alcohol can be converted into aldehyde directly via Swern oxidation or after esterification following reduction with DIBAL Then, the M-L-aldehyde can be connected to the Galantamine scaffold through reductive amination, this latter synthetic route is applicable only to obtain compounds of formula (I) wherein R=H and R= C1-C4 alkyl.

For the preparation of the compounds of formula (I), according to the present invention, wherein X is (CH2)m as defined above, Y and Z are absent and R is C1-C4, the synthetic route is the same as above, wherein R is H, except, in the starting building block M-L-A, wherein M is N-Ci-C-rMemantine, most preferably N-methyl-Memantine. In this synthetic route, there is no need to protect the nitrogen atom on the Memantine moiety.

Generally, a salt of Memantine, for example chloride, is dissolved in a suitable solvent, such as dimethyl formamide, tetrahydrofuran or dioxane. Then the appropriate halo- alcohol is added to the vigorously stirred solution of Memantine. Suitable 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. 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 compounds present in the reaction mixture. After completion of reaction, the solvent is removed, for example by vacuum-evaporation. 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.

As a second step, 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 preferred example of protecting group is di-fe/f-butyl dicarbonate (BOC). General methods used to protect the nitrogen as carbamate:: Methyl and Ethyl carbamate, 9-Fluorenylmethyl Carbamate (Fmoc group), 9-(2-Sulfo)fluorenylmethyl Carbamate, 9-(2,7-Dibromo)fluorenylmethyl Carbamate, Tetrabenzofluorenyl methyl carbamate (Tbfmoc group), 2-Chloro-3-indenylmethyl Carbamate (Climoc group), Benzinden3-ylmethyl Carbamate (Bimoc group), 2,7-Di-t-butyl[9-(10,10-dioxo- 10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc Group), 1 ,1 Dioxobenzothiophene-2-ylmethylcarbamate(Bsmoc Group), 2-Furanylmethyl carbamate, 2,2,2-Trichloethyl carbamate (Troc Group), 2-Trimethylsilylethyl carbamate (Teoc group), 2-Phenylethyl carbamate (hZ group), 1 -(1 -Adamantyl)-1 -methylethyl carbamate (Adpoc group), 2-Haloethyl Carbamate,1 ,1 -Dimethyl carbamate-2,2- dibromoethyl carbamate (DB-i-BOC group), 1 ,1 -Dimethyl-2,2,2-trichloroethyl carbamate (TCBOC group),1 -methyl-1 -(4-biphenylyl)ethyl carbamate (Bpoc group), 1 -(3,5-Di-f- butylphenyl)-1 -methylethyl carbamate (i-Bumeoc group), 2-(2'-and 4'-Pyridyl)ethyl carbamate (Pyoc group), 2,2-Bis(4'-nitrophenyl)ethyl carbamate (Bnpeoc group), N-(2- Pivaloylamino)-1 ,1 -dimethylethyl carbamate, 2-[(2-Nitrophenyl)dithio]-1 -phenylethyl carbamate (NpSSPeoc group), 2-(N,N-Dicyclohexylcarboxamido)ethyl carbamate, 1 - Adamantyl carbamate (1 -Adoc group), 2-Adamantyl carbamate (2-Adoc group),Vinyl carbamate (Voc group), Allyl carbamate (Aloe or Alloc group), 1 -lsopropylallyl carbamate (Ipaoc group), cinnamyl carbamate (Coc group), 4-Nitrocinnamyl carbamate (Noc group), 3-(3'-Pyridyl)prop-2-enyl carbamate (Paloc group), 8-Quinolyl carbamate, N-Hydroxypiperdinyl carbamate, Alkyldithio carbamate, benzyl carbamate (Cbz group) and miscelloneus benzyl carbamates such as p-Methoxybenzyl carbamate (Moz group), p-Nitrobenzyl carbamate (PNZ group), p-halobenzyl carbamate, 4-Methylsulfinylbenzyl carbamate (Msz group), 9-Anthrylmethyl carbamate, Diphenylmethyl carbamate, 2- methylthioethyl carbamate, 2-Methylsulfonylethyl carbamate, [2-(1 ,3-Dithianyl)methyl carbamate (Dmoc group). (Protective groups in organic synthesis, T.W. Greene, P.G.M. Wuts, Third Edition (1999), Wiley Interscience). The resultant mixture is allowed to stir at room temperature for a time sufficient to completion of the reaction, for example overnight. The solvent is removed, preferably in vacuo, yielding a residue which is subsequently dissolved in water and extracted with an organic solvent, such as AcOEt, for a sufficient number of times. The extracts are gathered, washed, for example with brine, dried over Na ₂ S0 ₄ or other desiccant agents, concentrated, and purified. Flash chromatography is a suitable purification technique.

As a third step, 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. For example, p-TsCI (p-tosyl chloride) is added to a mixture of the appropriate alcohol, a base, such as Et ₃ N (triethylamine) and DMAP (dimethylaminopyridine) in catalytical amounts in 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. Then, the 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. The tosylate derivative is then purified by ordinary means, such as flash chromatography.

Finally, 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.

If desired, the protecting groups on nitrogen are removed by well-known methods. For example, 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.

According to the present invention, the amido compounds, corresponding to the compounds of formula (I) wherein X is (CHk)™ and m is comprised between 2 and 12, Y is absent, Z is C=0 can be prepared following the general synthesis

wherein 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.

As starting step, 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.

To a solution of 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, the appropriate acylating agent is added. The reaction is left, preferably under stirring, until completion of the reaction, which is checked by ordinary means. After removing the solvent, for example by vacuum evaporation, 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. 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. At the end, the solvent is removed as usual and the residue is purified by conventional technique, for example flash chromatography.

According to the present invention, 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:

(iv) wherein 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.

Starting from the suitable di-alcohol and transforming one end hydroxy I group into an activated hydroxyl group, as explained above and with conventional procedures, for example by reacting with tosyl chloride. The reaction is carried out in the presence of 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. The 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. The 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.

In a closed vessel the appropriate activated alcohol is added to a solution of a Memantine salt, preferably hydrochloride, and a base (K2CO3 for example) in 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. 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.

Finally, the reaction with des-methyl-Galantamine is carried out as above described. If desired, the N-protecting group is removed. In view of the complementary pharmacology of Galantamine and Memantine, the two activities combined into a single dual-target molecule produce a significant synergy against the main AD hallmarks, i.e. memory loss, cognition loss, and neuronal death.

A further object of the present invention is 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. By way of example, 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. According to the administration route chosen, the 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.

The following examples illustrate the invention without limiting it.

PREPARATIONS AND EXAMPLES In the following section, exemplary preparations of intermediate compounds are given. It is intended that the skilled reader can adapt or modify the synthetic routes in order to obtain the compounds of the present invention.

Chemical reagents were purchased from Sigma Aldrich, Fluka (Italy) and TCI-Europe. N-desmethyl galantamine was purchased from Synfine research.

Solvents were RP grade. Dichloromethane was distilled from calcium chloride. Dry dimethylformamide and triethylamine were used as supplied.

The structures of the unknown compounds were unambiguously assessed by MS(EI), H NMR and ¹³ C NMR.

Nuclear magnetic resonance spectra (NMR) 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 1.7μιη) 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 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.

Preparation I

General synthesis of Compounds of Formula (I) wherein X is (CH2) _m , as defined above, Y and Z are absent, R is H. Step 1

(Ha)

In a pressure tube (Sigma Aldrich, ACE pressure tube) the appropriate bromo-alcohol was added to a vigorously stirred solution of Memantine hydrochloride (0.500 g, 2.32 mmol) and K ₂ C0 ₃ (0.8 g, 5.75 mmol) in DMF (10 mL). The reaction mixture was stirred at 80°C for 48 hours. After evaporating the solvent, the residue was taken up with water and extracted with CH2CI2 (3 x 10 mL). The collected organic layers were concentrated to yield crude /V-alkylated Memantine derivative which was further purified by flash chromatography.

m=2(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%). H-NMR (CDCI3, 400 MHz) δ 0.80 (s, 6H), 1.04-1.12 (AB m, 2H), 1.22- 1.30 (m, 8H), 1.46-1.47 (m, 2H), 1.54-1.66 (m, 4H), 2.09-2.11 (m, 1 H), 2.59 (t, J=4.8 Hz, 2H), 3.52, (t, J=5.2 Hz, 2H), 3.85 (br s exchangeable with D ₂ 0, 1 H). ³ C-NMR (CDCI ₃ , 100 MHz) δ 29.95, 30.12, 30.15, 32.34, 32.80, 40.15, 40.72, 42.84, 48.39, 50.79, 52.59, 62.41.

m=3(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 %). ¹ H-NMR (CDCI3, 400 MHz) δ 0.83 (s, 6H), 1.11-1.12 (AB m, 2H), 1.25-1.34 (m, 8H), 1.40-1.44 (m, 2H), 1.50-1.60 (m, 6H), 2.13-2.14 (m, 1 H), 2.47 (br s exchangeable with D ₂ 0, 1 H ), 2.61 (t, J=6.8 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H). ³ C-NMR (CDCI ₃ , 100 MHz) δ 23.49, 29.97, 30.19, 30.25, 32.29, 32.35, 40.36, 40.79, 42.91 , 48.44, 50.85, 52.83, 62.15.

m=4(ES92) 6-(((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)amino)hexan-1-o l. 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%). H-NMR (CDCI _3l 400 MHz) δ 0.84 (s, 6H), 1.1 1-1.12 (AB m, 2H), 1.22-1.39 (m, 12H), 1.49-1.58 (m, 6H), 2.13-2.14 (m, 1 H), 2.51 (br s exchangeable with D ₂ 0, 1H), 2.59 (t, J=7.6 Hz, 2H), 3.61 (t, J=6.4 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 25.64, 27.21 , 29.66, 30.17, 30.26, 30.44, 32.35, 32.65, 40.46, 40.70, 42.88, 48.34, 50.82, 52.93, 62.40.

m=5(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) δ 0.84 (s, 6H), 1.09-1. 21 (AB m, 2H), 1.19-1.36 (m, 14H), 1.42-1.47 (m, 4H), 1.52-1.56 (m, 2H), 2.11-2.13 (m, 1 H), 2.51 (br s exchangeable with D ₂ 0, 1 H), 2.55 (t, J=7.6 Hz, 2H), 3.6 (t, J=6.4 Hz, 2H). ¹³ C-NMR (CDC , 100 MHz) δ 25.77, 27.43, 29.31 , 30.16, 30.78, 32.26, 32.71 , 40.51 , 41.03, 42.49, 48.71 , 50.89, 52.22, 61.93.

m=6(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1.1 1-1.12 (AB m, 2H), 1.21 -1.36 (m, 16H), 1.43-1.57 (m, 6 H), 2.12-2.14 (m, 1 H), 2.51 (br s exchangeable with D ₂ 0, 1 H), 2.53-2.57 (m, 2H), 3.59 (t, J=6.8 Hz, 2H). ¹³ C-NMR (CDCI3, 100 MHz) δ 25.68, 27.38, 29.31 , 29.42, 30.17, 30.24, 30.63, 32.30, 32.70, 40.54, 40.85, 42.91 , 48.53, 50.86, 52.53, 57.81 , 62.42.

m=7(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%). ¹ H-NMR (CDCb, 400 MHz) δ 0.84 (s, 6H), 1.10-1.1 1 (AB m, 2H), 1.21-1.29 (m, 14H), 1.45-1.49 (m, 4H), 1.53-1.57 (m, 6H), 2.12-2.14 (m, 1 H), 2.51 (br s, H), 2.55 (t, J=7.6 Hz, 2H), 3.60 (t, J=6.8 Hz, 2H). ¹³ C-NMR (CDCI3, 100 MHz) δ 25.75, 25.79, 27.47, 29.34, 29.41 , 29.44, 29.52, 30.28, 30.82, 32.32, 32.77, 40.59, 40.99, 42.97, 48.68, 50.91 , 52.42, 62.53.

In this Preparation I, all intermediates (I la) are novel, except the ones wherein m is 0, 1 or 2, which are commercially available. Therefore, these intermediates are a further object of the present invention.

Step 2

(lib)

The appropriate secondary amine (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 (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 (3x15 ml_). The extracts were combined, washed with brine, dried over Na ₂ S0 ₄ , concentrated, and purified by flash chromatography.

m=2(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.81 (s, 6H), 1.10-1.13 (AB m, 2H), 1.22-1.33 (m, 4H), 1.43 (s, 9H) 1.46-1.54 (m, 4H), 1.68-1.71 (AB m, 4H), 1.89-1.90 (m, 2H), 2.10-2.12 (m, 1 H), 3.24 (t, J=8.4 Hz, 2H), 3.63(t, J=6.0 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 27.99, 28.58, 29.97, 30.47, 30.67, 32.78, 39.43, 42.63, 43.19, 46.96, 50.48, 57.98, 62.39, 79.10, 155.36.

m=3(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.85 (s, 6H), 1.12-1.14 (AB m, 2H), 1.24-1.37 (m, 6H), 1.45 (s, 9H) 1.48-1.60 (m, 4H), 1.70-1.73 (AB m, 4H+1 H exchangeable with D ₂ 0), 1.92-1.93 (m, 2H), 2.13-2.15 (m, 1 H), 3.21 (t, J=8.0 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H). ¹³ C- NMR (CDCI3, 100 MHz) δ 23.27, 28.59, 30.47, 30.67, 31.43, 32.35, 32.76. 39.37, 42.65, 43.58, 46.89, 50.49, 57.97, 62.71 , 78.89, 155.21.

m=4(ES94) ferf-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)(6- hydroxyhexyl)carbamate. It was synthesized from ES92 (0.400 g, 1.43 mmol). Elution with petroleum ether/ AcOEt (6:4) afforded ES94 as a foam solid: 0.410 g (75%). H-

NMR (CDCI ₃ , 400 MHz) δ 0.85 (s, 6H), 1.09-1.17 (AB m, 2H), 1.22-1.29 (m, 4H), 1.34-

1.41 (m, 4H), 1.42-1.52 (m, 11 H), 1.58-1.61 (m, 4H), 1.70-1.77 (AB m, 4H), 2.13-2.15 (m, 1H), 3.21 (t, J=8.0 Hz, 2H), 3.64 (t, J=6.8 Hz, 2H). ³ C-NMR (CDCI ₃ , 100 MHz) δ 25.46, 26.90, 28.59, 30.47, 30.67, 31.72, 32.73, 32.76, 39.35, 42.67, 43.58, 46.87, 50.51 , 57.95, 62.78, 78.79, 155.19.

m=5(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%). ¹ H-NMR (CDCIs, 400 MHz) δ 0.85 (s, 6H), 1.09-1.14 (AB m, 2H), 1.22-1.37 (m, 10H), 1.43-1.49 (m, 10H), 1.53-1.58 (m, 2H), 1.70-1.73 (AB m, 4H), 1.92-1 .93 (m, 2H), 2.13- 2.15 (m, 1 H), 2.29-2.31 (m, 1 H), 3.21 (t, J=8.0 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H). ¹³ C-NMR (CDCI _3l 100 MHz) δ 25.69, 27.05, 28.55, 29.07, 30.46, 30.62, 31.59, 32.60, 32.71 , 39.28, 42.63, 43.63, 46.80, 50.47, 57.89, 62.61 , 78.73, 155.10.

m=6(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.81 (s, 6H), 1.05-1.14 (AB m, 2H), 1 .17-1.34 (m, 12H), 1.39-1.57 (m, 13H) 1.67-1.74 (AB m, 4H), 1.89-1.90 (2H), 2.09-2.12 (m, 1 H), 3.17 (t, J=7.6 Hz, 2H), 3.60 (t, J=6.4 Hz, 2H). ³ C-NMR (CDCI ₃ , 100 MHz) δ 25.64, 27.06, 28.59, 29.29, 29.39, 30.47, 30.68, 31.69, 32.72, 32.76, 39.32, 42.67, 43.71 , 46.84, 50.51 , 57.92, 62.93, 78.72, 155. 3.

m=7(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.80 (s, 6H), 1.05-1.14 (AB m, 2H), 1.17-1.34 (m, 14H), 1.39-1.57 (m, 13H) 1.67-1.74 (AB m, 4H), 1.89-1.90 (2H), 2.09-2.12 (m, 1 H), 3.17 (t, J=7.6 Hz, 2H), 3.60 (t, J=6.4 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 25.69, 27.10, 28.57, 29.25, 29.30, 29.55, 30.46, 30.67, 31.71 , 32.73, 32.74, 39.30, 42.67, 43.71 , 46.82, 50.51 , 57.91 , 62.90, 78.68, 155.10.

In this Preparation I, all intermediates (lib) are novel. Therefore, these intermediates are a further object of the present invention.

Step 3

(lie) p-TsCI (1 eq.) was added to a mixture of the appropriate alcohol (1 eq.), Et ₃ N (2 eq.), and D AP (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. After completion, the reaction was quenched with saturated NH ₄ CI aqueous solution and extracted with AcOEt ( 3 x 10 mL). Combined extracts were washed with brine, dried over Na ₂ S0 ₄ , and evaporated. The tosylate derivative was then purified by flash chromatography.

m=2(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.81 (s, 6H), 1.08-1.13 (AB m, 2H), 1.18-1.33 (m, 4H), 1.40 (s, 9H), 1.43-1.49 (m, 4H), 1.67-1.71 (m, 4H), 1.85-1.86 (m, 2H), 2.10-2.1 1 (m, 1H), 2.42 (s, 3H), 3. 8 (t, J=8.0 Hz, 2H), 4.00 (t, J=6.4 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H). ¹³ C-NMR (CDCI3, 100 MHz) δ 21.60, 26.55, 27.69, 28.54, 28.56, 30.44, 30.64, 32.77, 39.37, 42.60, 42.63, 42.91 , 46.88, 50.44, 58.06, 70.29, 79.06, 127.83, 129.79, 133.17, 144.67, 155.05.

m=3(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1.11-1.14 (AB m, 2H), 1.24-1.29 (m, 4H), 1.33-1.46 (m,4H), 1.44 (s, 9H), 1.64-1.71 (m, 6H), 1.90-1.91 (m, 2H), 2.13-2.14 (m, 1 H), 2.45 (s, 3H), 3.18 (t, J=7.6 Hz, 2H), 4.02 (t, J=6.4 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 21.58, 22.97, 28.56, 30.45, 30.64, 31.01, 32.75, 39.35, 42.62, 43.30, 46.86, 50.46, 57.97, 70.45, 78.87, 127.80, 129.79, 133.15, 144.63, 155.05.

m=4(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.80 (s, 6H), 1.07-1.36 ( m, 12H), 1.40 (s, 9H), 1.58-1.68 (m, 6H), 1.86-1.87 (m, 2H), 2.08-2.10 (m, 1 H), 2.40 (s, 3H), 3.13 (t, J=8.0 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 7.30 (d, J=7.6 Hz, 2H), 7.74 (d, J=7.6 Hz, 2H). ¹³ C-NMR (CDCI3, 100 MHz) δ 21.59, 25.16, 26.51 , 28.57, 28.85, 30.46, 30.65, 31.50, 32.74, 39.34, 42.64, 43.48, 46.84, 50.46, 57.93, 70.50, 127.80, 129.78, 133.16, 144.61 , 155.06.

m=5(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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.81 (s, 6H), 1.07-1.39 ( m, 14H), 1 .41 (s, 9H), 1 .58-1.62 (m, 2H), 1.65-1.72 (m, 4H), 1.88-1.89 (m, 2H), 2.10-2.11 (m, 1 H), 2.41 (s, 3H), 3.14 (t, J=8.0 Hz, 2H), 3.98 (t, J=6.0 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.75 (d, J=7.9 Hz, 2H). ¹³ C-NMR (CDCI _3l 100 MHz) δ 21.60, 25.38, 26.91 , 28.59, 28.71 , 28.75, 30.47, 30.67, 31.62, 32.76, 39.34, 42.67, 43.60, 46.85, 50.50, 57.92, 70.56, 78.73, 127.82, 129.76, 133.19, 144.60, 155.10.

m=6(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%). H-NMR (CDCI _3l 400 MHz) δ 0.84 (s, 6H), 1.08-1.37 ( m, 16H), 1 .45 (s, 9H), 1.60-1.67 (m, 2H), 1.70-1.77 (m, 4H), 1.92-1.93 (m, 2H), 2.12-2.15 (m, 1 H), 2.45 (s, 3H), 3.19 (t, J=7.6 Hz, 2H), 4.01 (t, J=6.8 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 21.58, 25.25, 26.99, 28.60, 28.79, 28.96, 29.1 1 , 30.48, 30.67, 31.69, 32.76, 39.34, 42.67, 43.66, 46.85, 50.51 , 57.92, 70.60, 78.69, 127.82, 129.76, 133.23, 144.57, 155.10.

m=7(ES155) S-Wteff-butoxycarbonylJiil R.SR.SSJRJ-a.S-dimethyladamantan-l - yl)amino)nonyl 4-methylbenzenesulfonate. It was synthesized from ES153 (0.370 g, 0.877 mmol). Elution with petroleum ether/AcOEt (9.5:0.5) afforded ES155 as an oil: 0.490 g (97%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.82 (s, 6H), 1.06-1.40 ( m, 18H), 1.42 (s, 9H), 1.56-1.63 (m, 2H), 1.68-1.74 (m, 4H), 1.90-1 .91 (m, 2H), 2.11 -2.12 (m, 1 H), 2.43 (s, 3H), 3.17 (t, J=8.0 Hz, 2H), 4.00 (t, J=6.4 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.75 (d, J=8.0 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 21.61 , 25.30, 27.10, 28.60, 28.80, 28.86, 29.22, 29.40, 30.49, 30.69, 31 .74, 32.77, 39.34, 42.69, 43.71 , 46.86, 50.52, 57.93, 70.63, 76.67, 76.98, 77.30, 78.71 , 127.85, 129.76, 133.24, 144.57,· 155.13.

In this Preparation I, all intermediates (lie) are novel. Therefore, these intermediates are a further object of the present invention.

Examples 1 -6

In a pressure tube (Sigma Aldrich, ACE pressure tube) a mixture of the appropriate activated alcohol (1.2 eq), N-desmethyl galantamine (1 eq) and Et3 (2 eq) in CH3CN (0.1 M) was stirred at 80°C for 48 hours. After evaporating the solvent, the residue was purified by flash chromatography.

Example 1

m=2; fe/f-butyl ((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(4-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 11(12H)-yl)butyl)carbamate. It was synthesized from ES137 (0.80 g, 0.158 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH (9:1 ) afforded the compound of interest as a waxy solid: 0.066 g (83%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.81 (s, 6H), 1.05-1.12 ( m, 2H), 1.20-1.32 (AB m, 4H), 1.41 -1.50 (m+s, 14H), 1.65-1.72 (AB m, 4H), 1 .88 (m, 2H), 1.95-2.04 (m, 2H), 2.08-2.10 (m, 1 H), 2.42-2.49 (m, 2H), 2.64-2.67 (m, 1 H), 3.12-3.21 (m, 3H), 3.29- 3.36 (m, 1 H), 3.75-3.82 (s+d, =16.0 Hz, 4H), 4.08 12 (m+d, J=16.0 Hz, 2H), 4.57 (br m, 1 H), 5.97 (dd, J,=10.2 Hz, J ₂ =4.3 Hz 1 H), 6.06 (d, J=10.4 Hz, 1 H), 6.57 (d, J=8.4, 1 H), 6.62 (d, =8.0, 1H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 24.98, 28.60, 29.52, 29.95, 30.47, 30.67, 32.76, 32.95, 39.33, 42.65, 43.56, 46.85, 48.41, 50.49, 51.49, 53.39, 55.87, 57.67, 57.97, 62.06, 78.79, 88.72, 1 11.12, 121.94, 126.92, 127.57, 129.45, 133.12, 144.05, 145.79, 155.08. UPLC/MS: Purity 100%, r.t = 2.72 min.MS (ESI+):m/z 607.46 [M+H] ⁺ .

Example 2

m=3; ferf-butyl ((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(5-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 11(12H)-yl)pentyl)carbamate. It was synthesized from ES97 (0.180 g, 0.34 mmol). Elution with CH2CI ₂ /CH3OH (9: 1 ) afforded compound of interest as a waxy solid: 0.170 g (96%). ¹ H-NMR (CDCI3, 400 MHz) δ 0.84 (s, 6H), 1.12-1 .13 (AB m, 2H), 1.19-1.27 (m, 4H), 1.33-1.36 (m, 2H), 1.44-1.54 (m+s, 14H), 1.69-1.76 (AB m, 4H), 1 .92-1.93 (m, 2H), 1.98-2.05 (m, 2H), 2.13-2.14 (m, H), 2.35 (br s, exchangeable with D ₂ 0, 1 H), 2.45-2.51 (m, 2H), 2.66-2.71 (m, 1 H), 3.17-3.22 (m, 3H), 3.29-3.36 (m, 1 H), 3.78-3.83 (s+d, J=16.0 Hz, 4H), 4.1 1 -4.14 (m+d, J=16.0 Hz, 2H), 4.61 (br m, 1 H), 5.98 (dd, 4=10.4 Hz, J ₂ =4.2 Hz, 1 H), 6.09 (d, J=9.2 Hz, 1 H), 6.61 (d, J=8 Hz, 1 H), 6.66 (d, J=8.4 Hz, 1 H). ¹³ C-NMR (CDC , 100 MHz) δ 24.92, 27.17, 28.59, 29.94, 30.48, 30.67, 31.65, 32.76, 32.98, 39.35, 42.66, 43.63, 46.87, 48.38, 50.50, 51.52, 53.21 , 55.85, 57.75, 57.93, 62.03, 78.75, 88.68, 111.12, 121.94, 126.91 , 127.56, 129.38, 133.12, 144.04, 145.78, 155.10. UPLC/MS: Purity 100%. MS (ESI+):m/z 621.62 [M+H] ⁺ .

Example 3

m=4; terf-butyl ((1R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)(6-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetra ydro-4aH-benzo[2,3]benzofuro[4,3-cd]azepin- 11(12H)-yl)hexyl)carbamate. It was synthesized from ES104 (0.280 g, 0.524 mmol). Elution with CH2CI2/CH3OH (9:1 ) afforded the compound of interest as a waxy solid: 0.190 g (68%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.82 (s, 6H), 1.06-1.14 (AB m, 2H), 1.18- 1.35 (m, 9H), 1.43-1.52 (m+s, 13H), 1.67-1.74 (AB m, 4H), 1.90 (m, 2H), 1.96-2.07 (m, 2H), 2.1 1-2.12 (m, 1 H), 2.33 (br s, exchangeable with D ₂ 0, 1 H), 2.40-2.50 (m, 2H), 2.65-2.69 (m, 1 H), 3.13-3.20 (m, 3H), 3.30-3.37 (m, 1 H), 3.77-3.82 (s+d, J=15.6 Hz, 4H), 4.10-4.13 (m+d, J=15.6 Hz, 2H), 4.59 (br m, 1 H), 5.98 (dd, J,= 15.2, Hz, J ₂ = 4.8 Hz 1 H), 6.07 (d, J=10.04 Hz, 1 H), 6.59 (d, J=8.4, 1 H), 6.64 (d, J=8.4, 1 H). ¹³ C-NMR (CDCI3, 100 MHz) 627.39, 27.44, 27.77, 28.84, 29.91 , 30.18, 30.73, 30.92, 32.03, 33.01 , 33.19, 39.61 , 42.91 , 43.91 , 47.12, 48.64, 50.75, 51.77, 56.11 , 58.03, 58.16, 62.30, 78.99, 11 1.34, 122.21 , 127.18, 127.80, 129.68, 133.39, 144.28, 144.02, 155.39. UPLC/MS: Purity 100%. MS (ESI+):m/z 635.64 [M+H] ⁺ .

Example 4

m=5; terf-butyl ((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 -yl)(7-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 11(12H)-yl)heptyl)carbamate It was synthesized from ES102 (0.290 g, 0.53 mmol). Elution with CH2CI2/CH3OH (9:1 ) afforded the compound of interest as a waxy solid: 0.230 g, (81 %). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1.1 1 -1.13 (AB m, 2H), 1.19- 1.35 (m, 11 H), 1.43-1.53 (m+s, 13H), 1.69-1.76 (AB m, 4H), 1.92-1.93 (m, 2H), 1.98- 2.05 (m, 2H), 2.13-2.14 (m, 1H), 2.44-2.51 (m, 2H), 2.66-2.71 (m, 1 H), 3.15-3.21 (m+t, J=8.0, 3H), 3.30-3.37 (m, 1 H), 3.80-3.83 (s+d, J=15.2 Hz, 4H), 4.11 -4.15 (m+d, J=15.2

Hz, 2H), 4.61 (br m, 1 H), 6.00 (dd, 4.4 Hz, 1 H), 6.09 (d, J=9.2 Hz, 1 H),

6.61 (d, J=8.4, 1 H), 6.66 (d, J=8.4, 1 H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 27.14, 27.42,

28.60, 29.34, 29.66, 29.94, 30.48, 30.68, 31 .71 , 32.76, 32.90, 39.33, 42.67 , 43.69,

46.85, 48.38, 50.51 , 51.46, 55.85, 57.75, 57.92, 62.04, 78.69, 88.71 , 111.12, 121.98, 126.91 , 127.57, 129.35, 133.13, 144.05, 145.77, 155.1 1. UPLC/MS: Purity 100%. MS (ESI+):m/z 649.66 [M+H] ⁺ .

Example 5

m=6; terf-butyl ((1 R,3R,5S _l 7R)-3,5-dimethyladamantan-1-yl)(8-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 11(12H)-yl)octyl)carbamate. It was synthesized from ES110 (0.210 g, 0.374 mmol). Elution with CH2CI ₂ /CH ₃ OH (9.25:0.75) afforded the compound of interest as a waxy solid: 0.190 g (92%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1.08-1.17 (AB m, 2H), 1.21-1.37 (m, 13 H), 1.41 -1.53 (m+s, 13H), 1.70-1.77 (AB m, 4H), 1.92-1.93 (m, 2H), 1.98-2.09 (m, 2H), 2.13-2.15 (m, 1 H), 2.41-2.54 (m, 2H), 2.65-2.70 (m, 1 H), 3.15-3.23 (m, 3H), 3.32-3.38 (m, 1 H), 3.79-3.84 (s+AB d, J=14.8 Hz, 4H), 4.1 1-4.15 (m+AB d, - =15.2 Hz, 2H), 4.60 (br m, 1 H), 6.00 (dd, 4= 10, Hz, J ₂ = 4.4 Hz, 1 H), 6.09 (d, J=9.0 Hz, 1 H), 6.61 (d, J=8A, 1 H), 6.66 (d, J=8.4, 1 H). ¹³ C-NMR (CDCI3, 100 MHz) δ 27.07, 27.37, 28.60, 28.94, 29.28, 29.96, 30.48, 30.67, 31.71 , 32.75, 32.91 , 39.33, 42.68, 43.70, 46.85, 48.38, 50.52, 51.57, 55.78, 55.83, 55.88, 57.91, 62.03, 78.66, 88.64, 88.71 , 111.12, 121.96, 126.94, 127.55, 129.38, 133.14, 144.03, 145.78, 155.10. UPLC/MS: Purity 100%. MS (ESI+):m/z 663.70[M+1] ⁺ .

Example 6

m=7; terf-butyl ((1 R.SR.SSJRJ-a.S-dimethyladamantan-l -yl)(9-((4aS,6R,8aS)-6- hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofur o[4,3-cd]azepin- 11(12H)-yl)nonyl)carbamate. It was synthesized from ES155 (0.200 mg, 0.347 mmol). Elution with CH2CI ₂ /CH3OH (9:1 ) afforded the compound of interest as a waxy solid: 0.160 g (83%). H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1.08-1.17 (AB m, 2H), 1.20- 1.37 (m, 15 H), 1.41-1.55 (m+s, 13H), 1.70-1.77 (AB m, 4H), 1.92-1.93 (m, 2H), 1.98- 2.05 (m, 2H), 2.13-2.15 (m, 1 H), 2.44-2.51 (m, 2H), 2.66-2.71 (m, 1 H), 3.16-3.22 (m+t, J=8.0, 3H), 3.32-3.39 (m, 1H), 3.81-3.84 (s+AB d, J=15.2 Hz, 4H), 4.12^.16 (m+AB d, J=15.2 Hz, 2H), 4.61 (br m, 1 H), 6.00 (dd, J\= 10.4, Hz, J ₂ = 4.8 Hz, 1 H), 6.08 (d, J=10.0 Hz, 1 H), 6.61 (d, J=8.4, 1 H), 6.66 (d, J=8.4, 1 H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 27.13, 27.33, 27.35, 28.60, 29.31 , 29.48, 29.58, 29.66, 29.93, 30.49, 30.68, 31.75, 32.76, 32.83, 39.33, 42.68, 43.73, 46.84, 48.36, 50.52, 51.43, 55.86, 57.92, 62.03, 78.68, 88.69, 111.14, 122.04, 126.86, 127.61 , 129.80, 133.12, 144.09, 145.78, 155.12. UPLC/MS: purity 99%. MS (ESI+): m/z 677.7[M+1] ⁺ .

Examples 7-12

Deprotection of nitrogen

HCI 4M in dioxane (1 mL) was carefully added to the appropriate Boc derivative (1 eq.) at 0 °C and the solution was allowed to stir at room temperature for 2 hours. After removing the solvent the obtained residue was purified by flash chromatography.

Example 7

m=2; (4aS,6R,8aS)-11 -(4-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)amino)butyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzo [2,3]benzofuro[4,3- cd]azepin-6-ol. It was synthesized from the compound of Example 1 (0.066 g, 0.109 mmol). Elution with CH ₂ Cl2/CH ₃ OH/33% aqueous ammonia (9:1 :0.1 ) afforded the compound of interest as a waxy solid: 0.050 g (91 %). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1.08-1.16 (AB m, 2H), 1.25-1.37 (m, 9 H), 1.52-1.61 (m, 6H), 1 .98-2.09 (m, 2H), 2.13-2.14 (m, 1 H), 2.48-2.58 (m, 2H), 2.61 -2.71 (m, 3H), 3.19-3.33 (2H), 3.82 (AB d, J=15.2, 1 H), 3.83 (s, 3H), 4.10-4.13 (m+AB d, J=15.2 Hz, 2H), 4.60 (br m, H), 6.00 (dd, 4=10.4, Hz, 4=4.8 Hz, 1 H), 6.07 (d, 4=10.4 Hz, 1 H), 6.63 (d, 4=8.0, 1 H), 6.66 (d, J=8.0, 1H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 25.27, 27.91, 29.67, 29.92, 30.06, 30.16, 32.37, 33.01 , 40.28, 42.70, 47.69, 48.32, 50.65, 51.46, 51.81, 55.85, 57.62, 62.02, 88.71 , 1 11.19, 122.14, 126.75, 127.70, 128.80, 133.13, 144.17, 145.83. UPLC/MS: Purity 97%, r.t = 3.00 min.MS (ESI+):m/z 507.35 [M+H] ⁺ .

Example 8

m=3; (4aS,6R,8aS)-11 -(5-((( R,3R,5S,7S)-3,5-dimethyladamantan-1- yl)amino)pentyl)-3-methoxy -5,6,9,10,11,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol It was synthesized from compound of Example 2 (0.170 g, 0.274 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH/33% aqueous ammonia (9:1 :0.1 ) afforded the compound of interest as a waxy solid: 0.095 g (66%). ¹ H-NMR (CDCIs, 400 MHz) δ 0.84 (s, 6H), 1.11 -1.21 (AB m, 2H), 1.26-1.35 (m, 1 1 H), 1.46-1.52 (m, 6H), 1.98-2.03 (m, 2H), 2.13-2.14 (m, 1 H), 2.42-2.50 (m, 2H), 2.59 (t, J=7.6, 2H), 2.66-2.71 (m, 1 H), 3.16-3.17 (1 H), 3.33-3.34 (m, 1 H), 3.79 (AB d, J=15.2, 1 H), 3.83 (s, 3H), 4.10-4.13 (m+AB d, J=15.2 Hz, 2H), 4.60 (br m, 1 H), 6.00 (dd, 4=10.4, Hz, 4=4.8 Hz, 1 H), 6.08 (d, 4=10.0 Hz, 1H), 6.60 (d, J=8.4, 1 H), 6.65 (d, J=8.4, 1 H). ¹³ C-NMR (CDCIs, 100 MHz) δ 25.14, 27.25, 29.94, 30.17, 30.23, 32.37, 32.94, 40.43, 42.85, 48.41 , 50.79, 51.52, 55.88, 57.76, 62.07, 88.71 , 111.13, 121.97, 126.96, 127.53, 129.52, 133.14, 144.03, 144.77. UPLC/MS: Purity 97%, MS (ESI+):m/z 521.58 [M+H] ⁺ .

Example 9

m=4; (4aS,6R,8aS)-11 -(6-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - y aminoihex -S-methoxy-S.e.S.IO.H.IZ-hexahydro^aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol. It was synthesized from the comound of Example 3 (0.160 g, 0.252 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH/33% aqueous ammonia (9:1 :0.1 ) afforded the compound of interest as a waxy solid: 0.075 g (56%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1.09-1 15 (AB m, 2H), 1.18-1.37 (m, 11 H), 1.42-1.54 (m, 8H), 1.98-2.04 (m, 2H), 2.13-2.14 (m, 1 H), 2.42-2.51 (m, 2H), 2.60 (t, J=7.6, 2H), 2.66-2.71 (m, 1H), 3.16-3.17 (1 H), 3.31-3.33 (m, 1 H), 3.79 (AB d, J=16.0, 1 H), 3.83 (s, 3H), 4.10-4.13 (m+AB d, J=16.0 Hz, 2H), 4.60 (br m, 1 H), 6.00 (dd, Ji=10.4, Hz, J ₂ =4.8 Hz, 1 H), 6.08 (d, J=10.0 Hz, 1 H), 6.60 (d, J=8.4, 1 H), 6.65 (d, J=8.4, 1 H). ¹³ C-NMR (CDCI3, 100 MHz) δ 22.66, 26.67, 27.21 , 27.38, 29.67, 29.94, 30.14, 30.21 , 31.89, 32.38, 32,95, 33.66, 40.45, 42.80, 47.95, 48.41 , 50.74, 51.50, 53.66, 55.85, 55.88, 57.77, 62.07, 88.70, 11 1.11 , 121.97, 126.97, 127.51 , 129.56, 133.15, 144.00. 145.76. UPLC/MS: Purity 100%. MS (ESI+):m/z 535.59 [M+H] ⁺ .

Example 10

m=5; (4aS,6R,8aS)-11 -(7-(((1 R,3R,5S JRJ-S.S-dimethyladamantan-l - ylJamlnoJhe tylJ-S-methoxy-S.e.g.lO.l

benzo[2,3]benzofuro[4,3-cd]azepin-6-ol. It was synthesized from the compound of Example 4 (0.130 g, 0.200 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH (9:1 ) afforded the compound of interest as a waxy solid: 0.070 g (64%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1.08-1.15 (AB m, 2H), 1.23-1.34 ( m, 15H), 1 .44-1.51 (m, 6H), 1.94-2.07 (m, 2H), 2.13 ( br m, 1 H), 2.40-2.52 (m, 2H), 2.57 (t, J=7.2 Hz, 2H), 2.66-2.69 (m, 1 H), 3.14- 3.18 (1 H), 3.31 -3.37 (m, 1 H), 3.79 (AB d, J=15.2, 1 H), 3.83 (s, 3H), 4.09-4.15 (m+AB d, J=15.2 Hz, 2H), 4.60 (br m, 1 H), 5.99 (dd, ^=10.4, Hz, J ₂ =4.Q Hz, 1 H), 6.08 (d, J=10.0 Hz, 1 H), 6.61 (d, =8.4, 1 H), 6.65 (d, J=8.4, 1 H). ³ C-NMR (CDCI ₃ , 100 MHz) δ 27.35, 27.50, 27.55, 27.72, 29.40, 29.91 , 30.05, 30.16, 32.14, 32.72, 33.19, 38.29, 40.36, 42.46, 45.58, 48.64, 50.41 , 51.74, 56.1 1 , 57.25, 58.02, 62.31 , 88.94, 1 11.37, 122.21 , 127.21 , 127.77, 129.74, 133.39, 144.25, 146.01. UPLC/MS: Purity 100%. MS (ESI+):m/z 549.6[M+H] ⁺ .

Example 11 m=6; (4aS,6R,8aS)-11 -(8-(((1R,3R,5S,7R)-3,5-dimethyladamantan-1- ylJaminoJocty -S-methoxy-S.e.g.lO.I I.^-hexahydro^aH-benzop.aibenzofurot^S- cd]azepin-6-ol. It was synthesized from the compound of Example 5 (0.160 g, 0.241 mmol). Elution with CH2CI2/CH3OH (9:1 ) afforded the compound of interest as a waxy solid: 0.093 g (68%). ¹ H-N R (CDCI ₃ , 400 MHz) δ 0.86 (s, 6H), 1.14-1.15 (AB m, 2H), 1.22-1.37 (m, 13H), 1.43-1.53 (m, 7H), 1.64-1.68 (m, 4H), 1.98-2.05 (m, 2H), 2.16-2.17 ( m, 1 H), 2.43-2.49 (m, 2H), 2.66-2.70 (m, 2H), 3.16-3.17 (m, 1 H), 3.29-3.35 (m, 1 H), 3.79 (AB d, J=15.2, 1 H), 3.83 (s, 3H), 4.10-4.15 (m+AB d, J=15.2 Hz, 2H), 4.61 (br m, 1 H), 6.00 (dd, ^=10.4, Hz, J _z = 4.8 Hz, 1 H), 6.08 (d, J=10.0 Hz, 1 H), 6.61 (d, =8.4, 1 H), 6.66 (d, J=8.4, 1 H). ¹³ C-NMR(CDCI ₃ , 100 MHz) δ 27.27, 27.30, 27.40, 29.25, 29.51 , 29.66, 29.94, 30.06, 32.42, 32.97, 40.18, 42.48, 46.21, 50.43, 51.46, 55.84, 55.90, 58.60, 62.07, 88.74, 111.12, 121.97, 126.97, 127.53, 129.51 , 133.15, 144.01 , 145.77, 177.21. UPLC/MS: Purity 100%. MS (ESI+):m/z 563.43 [M+H] ⁺ .

Example 12

m=7; (4aS,6R,8aS)-11 -(9-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 - yl)amino)nonyl)-3-methoxy-5,6,9, 10,11,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol. It was synthesized from the compound of Example 6 (0.095 g, 0.138 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH (9:1 ) afforded the compound of interest as a waxy solid: 0.060 (75% ). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.85 (s, 6H), 1.1 1-1.14 ( AB m, 2H), 1.26-1.59 (m, 25 H), 1.98-2.09 (m, 2H), 2.16-2.17 (m, 1 H), 2.40-2.53 (m, 2H), 2.60-2.71 (m, 3H), 3.15-3.18 (m, 1 H), 3.21 -3.37 (m, 1 H), 3.79 (AB d, J=15.2, 1 H), 3.83 (s, 3H), 4.10-4.14 (m+AB d, J=15.2 Hz, 2H), 4.61 (br m, 1 H), 6.00 (dd, J,= 10.4 Hz, J ₂ = 4.8 Hz, 1 H), 6.10 (d, J=10.0 Hz, 1 H), 6.61 (d, J=8.4, 1 H), 6.65 (d, J=8.4, 1 H). ¹³ C-NMR (CDCI3, 100 MHz) δ 27.35, 27.45, 29.40, 29.48, 29.52, 29.95, 30.12, 30.19, 32.40, 32.98, 40.56, 42.76, 48.41 , 50.70, 51.50, 55.87, 57.82, 62.07, 88.71 , 111.10, 121.95, 126.98, 127.51 , 129.62, 133.15, 143.10, 145.77. UPLC/MS: purity 99%. MS (ESI+): m/z 577.6[M+1] ⁺ .

Preparation II

General synthesis of Compounds of Formula (I) wherein X is (CH ₂ )m, as defined above, Y and Z are absent, R is C1-C4 alkyl, preferably methyl.

Step 1

(IR.SR.SS RJ-NAS-trimethyladamantan-l -amine. To a solution of Memantine hydrochloride (0.720 g, 3.33 mmol) in dioxane/H ₂ 0 (1 :1 ) was sequentially added glacial acetic acid (0.382 ml, 6.66 mmol), Zn duster (0.436 g, 6.66 mmol), and 35% aqueous formaldehyde (0.833 ml, 16.65 mmol). The mixture was allowed to stir at 30 °C for 2 days. Then, saturated NH ₄ CI aqueous solution was added (5 mL), the resulting mixture was extracted with CH ₂ CI2 (3 x 10 mL), and the combined organic layers were washed with brine and dried over Na ₂ S04. The crude product was purified by flash chromatography (CH ₂ CI ₂ /MeOH/ 33% aqueous NH3 9:1 :1.8) to achieve the desired compound as a white solid (0.480 g, 75%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.76 (s, 6H), 1.04-1.05 (AB m, 2H), 1.15-1.23 (m, 8H), 1.40-1.41 (m, 2H), 2.05-2.07 (m, 1 H), 2.26 (s, 3H), 2.75 (br s, exchangeable with D ₂ 0, 1 H).

In a pressure tube (Sigma Aldrich, ACE pressure tube) the appropriate Bromo-alcohol (1.2 eq.) was added to a vigorously stirred solution of N,3,5-trimethyladamantan-1- amine (0.270 g, 1.40 mmol) and K ₂ C0 ₃ (0.484 g, 3.50 mmol) in DMF (4 ml). The reaction mixture was stirred at 80°C for 48 hours. After evaporating the solvent, the residue was taken up with water and extracted with CH ₂ CI ₂ (3 ^χ 10 mL). The crude was purified by flash chromatography.

m=2 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%). ¹ H-NMR (CDCI3, 400 MHz) δ 0.80 (s, 6H), 1.00-1.10 (AB m, 2H), 1.21- 1.38 (M, 12H), 1.43-1.56 (m, 6H), 2.09-2.12 (m, 1 H), 2.21 (s, 3H), 2.30-2.38 (m, 2H), 3.57 (t, J =6.8 Hz, 2H). ). ¹³ C-NMR(CDCI ₃ , 100 MHz) δ 25.54, 27.38, 29.05, 30.16, 30.53, 32.30, 32.65, 33.76, 36.71 , 42.91 , 44.36, 49.58, 50.82, 57.32, 62.59.

m=3 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:

0.375 g (87%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.75 (s, 6H), 0.95-1.03 (AB m, 2H), 1.18- 1.47 (m, 19H), 2.03-2.05 (m, 1 H), 2.11 (s, 3H), 2.25-2.29 (m, 2H), 3.16 (br s, exchangeable with D ₂ 0, 1H), 3.49 (t, J =6.8 Hz,3H). ¹³ C-NMR (CDCI3, 100 MHz) δ 25.94, 27.86, 29.16, 30.36, 30.79, 32.23, 32.55, 33.99, 36.73, 43.32, 44.81 , 49.99, 51.28, 56.80, 62.60.

m=4 ES132; 8-(((1R,3R _J 5S,7R)-3,5-dimethyladamantan-1-yl)(methyl)amino)octan- 1-

01. It was synthesized from 8-bromo-1-octanol (0.288 mL, 1.68 mmol). Elution with CH2CI2/CH3OH/ 33% aqueous ammonia (9:1 :1.5) afforded ES132 as a waxy solid : 0.410 g (91%). ¹ H-NMR (CDCI3, 400 MHz) δ 0.77 (s, 6H), 0.98-1.06 (AB m, 2H), 1.20- 1.26 (m, 14H), 1.33-1.39 (m, 2H), 1.46-1.49 (m, 6H), 2.06-2.07 (m, 1 H), 2.14 (s, 3H), 2.28-2.32 (m, 2H), 2.75 (br s, exchangeable with D ₂ 0, 1 H), 3.52 (t, J =6.8 Hz, 2H). ¹³ C- NMR (CDCI3, 100 MHz) δ 25.94, 27.86, 29.16, 30.36, 30.79, 32.23, 32.55, 33.99, 36.73, 43.32, 44.81 , 49.99, 51.28, 56.80, 62.60.

In this Preparation II, all intermediates (Ilia) are novel. Therefore, these intermediates are a further object of the present invention.

Examples 13-15

a) Tsci, DMAP, Et ₃ N, CH ₂ CI ₂ , it b) des-methyl-galantamine, Et ₃ N, CH ₃ CN, 80°C p-TsCI (1 eq.) was added to a mixture of the appropriate alcohol (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 Na ₂ S0 ₄ , and solvent evaporation. The crude was then transferred into a pressure tube (Sigma Aldrich, ACE pressure tube) and added with des-methyl-Galantamine (0.5 eq.), and Et ₃ N (2 eq.) in CH ₃ CN, with stirring at 80°C for 48 hours. After evaporating the solvent, the residue was purified by flash chromatography. Example 13 m=2; (4aS,6R,8aS)-11 -(6-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)hexyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4 aH- enzo[2,3]benzofuro[4,3-cd]azepin-6-ol. It was synthesized from ES122 (0.210 g, 0.716 mmol). Elution with CH2CI2/CH3OH/ 33% aqueous ammonia (9:1 :0.15) afforded the compound of interest as a waxy solid: 0.085 g (43%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.87 (s, 6H), 1.08-1.17 (AB m, 2H), 1.24-1 .33 (m, 9H), .38-1.52 (m, 7H), 1.60-1.65 (m, 3H), 1.98-2.07 (m, 2H), 2.19 (br m, 1 H), 2.35 (s, 3H), 2.41-2.53 (m, 4H), 2.67-2.71 (m, 1 H), 3.11-3.18 (m, 1 H), 3.31 -3.38 (m, 1 H), 3.80 (AB d, J =16 Hz, 1 H) 3.83 (s, 3H), 4.10- 4.14 (m+AB d, J =16 Hz, 2H), 4.61 (br m, 1 H), 6.00 (dd, ^= 10.0 Hz, J ₂ = 4.8 Hz, 1 H), 6.09 (d, J=10.0 Hz, 1 H), 6.61 (d, J=8.4 Hz, 1 H), 6.66 (d, J=8.4 Hz, 1 H). ¹³ C-NMR (CDCI _3> 100 MHz) δ 24.36, 27.20, 27.38, 27.51 , 28.63, 29.94, 30.14, 30.38, 32.48, 32.91 , 33.64, 36.45, 41.26, 42.07, 42.67, 44.02, 47.15, 48.41 , 49.69, 50.60, 51.48, 55.88, 55.94, 57.78, 62.07, 88.71 , 111.13, 121.99, 126.98, 127.52, 129.52, 133.14, 144.01 , 145.76. UPLC/MS: Purity 92%, r.t = 1.91 min.MS (ESI+):m/z 549.45[M+HV\

Example 14 m=3; (4aS,6R,8aS)-11 -(6-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)(methyl)amino)heptyl)-3-methoxy-5,6 _> 9,10 _l 11,12-hexariydro-4aH- enzo[2,3]benzofuro[4,3-cd]azepin-6-ol. It was synthesized from ES128 (0.190 g, 0.618 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH/ 33% aqueous ammonia (9:1 :0.15) afforded the compound of interest as a waxy solid: 0.084 g (49%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.82 (s, 6H), 1.03-1.08 (AB m, 2H), 1.22-1.36 (m, 14H), 1.40-1.49 (m, 5H), 1.52-1.55 (m, 2H), 1.95-2.00 (m, 2H), 2.12-2.18 (m, 1 H), 2.25 (s, 3H), 2.37-2.48 (m, 4H), 2.67- 2.67 (m, 1 H), 3.11 -3.15 (m, 1 H), 3.28-3.31 (m, 1 H), 3.78 (AB d, J =16 Hz, 1 H) 3.83 (s, 3H), 4.07-4.1 1 (m+AB d, J 4.8 Hz 1 H), 6.09 (d, J=9.6 Hz, 1H), 6.61 (d, J=8.4 Hz, 1 H), 6.66 (d, J=8.4 Hz, 1 H). ¹³ C-NMR (CDCIa, 100 MHz) δ 27.32, 27.54, 29.49, 29.65, 29.94, 30.18, 30.50, 32.33, 32.93, 33.73, 36.69, 42.88, 44.33, 48.40, 49.64, 50.79, 51.48, 55.86, 57.76, 62.07, 88.71 , 111.11 , 121.97, 126.99, 127.51 , 129.53, 133.15, 144.00, 145.75. UPLC/MS: Purity 98%, r.t = 2.09 min.MS (ESI+):m/z 563.48[M+H] ⁺ .

Example 15 m=4; (4aS,6R,8aS)-11 -(6-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - ylHmethylJaminoJoctylj-S-methoxy-S.e.S.IO.H.ia-hexahydro^aH- enzo[2,3]benzofuro[4,3-cd]azepin-6-ol. It was synthesized from ES132 (0.160 g, 0.499 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH/ 33% aqueous ammonia (9:1 :0.15) afforded the compound of interest as a waxy solid: 0.075 g (52%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.81 (s, 6H), 1.01-1.13 (AB m, 2H), 1.25-1.31 (m, 16H), 1.38-1.46 (m, 5H), 1.47-1.50 (m, 2H), 1.94-2.02 (m, 2H), 2.10-2.1 1 ( m, 1 H), 2.19 (s, 3H), 2.31-2.38 (m, 4H), 2.40- 2.77 (m, 1 H), 3.1 1-3.15 (m, 1 H), 3.28-3.32 (m, 1 H), 3.78 (AB d, J =16 Hz, 1 H) 3.83 (s, 3H), 4.07-4.1 (m+AB d, J =16 Hz, 2H), 4.58 (br m, 1 H), 5.97 (dd, 4= 10.0 Hz, J ₂ = 5.2 Hz 1 H), 6.07 (d, J=10.0 Hz, 1 H), 6.58 (d, J=8.4 Hz, 1 H), 6.63 (d, J=8.4 Hz, H). ¹³ C- NMR(CDCI ₃ , 100 MHz) δ 27.45, 29.54, 29.95, 30.24, 30.62, 32.23, 32.98, 33.90, 37.02, 43.08, 44.74, 48.41 , 49.70, 50.99, 51.51, 55.87, 57.81 , 62.08. UPLC/MS: Purity 94%, r.t = 2.09 min.MS (ESI+):m/z 577.5 [M+H] ⁺ .

Preparation III

General synthesis of Compounds of Formula (I) wherein X is (CH ₂ ) _m and m is

comprised between 2 and 12, Y is absent, Z is C=0 and R is H, Step 1

(lllb)

To a vigorously stirred solution of Memantine hydrochloride (0.300 g, 1.40 mmol) and K ₂ C0 ₃ (0.480 g, 3.5 mmol) in CH ₃ CN the appropriate acylating agent was added dropwise. The reaction was stirred at room temperature for 4 hours. After evaporating the solvent the crude was purified by flash chromatography. m=1; ES113; ^chloro-N-iil R^R.SSJRJ-S.S-dimethyladamantan-l-y butanamide.

It was synthesized from 4-chlorobutanoyl chloride (0.16 mL, 1.40 mmol). Elution with petroleum ether/ AcOEt (8.5:1.5) afforded ES113 as a oil: 0.340 g (86%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.79 (s, 6H), 1.06-1.14 (AB m, 2H), 1.20-1.25 (m, 2H), 1.30-1.34 (m, 2H), 1.55- .59 (AB m, 4H), 1.77-1.78 (m, 2H), 1.98-2.05 (m, 2H), 2.07-2.10 (m, 1 H), 2.22 (t, J=7.2 Hz, 2H), 3.54 (t, J=6.4 Hz, 2H), 5.28 (br s, 1 H). ¹³ C-NMR (CDCI3, 100 MHz) δ 28.17, 30.01 , 32.32, 34.07, 40.15, 42.60, 44.54, 47.56, 50.53, 53.54, 170.78. m=2; ES82; 5-chloro-N-((1R,3R,5S,7R)-3 _p 5-dimethyladamantan-1-yl)pentanamide.

It was synthesized from 5-chloropentanoyl chloride (0. 8 mL, 1.40 mmol). Elution with petroleum ether/ AcOEt (8.5:1.5) afforded ES82 as a oil: 0.380 g (91%). ¹ H-NMR (CDCI3, 400 MHz) δ 0.81 (s, 6H), 1.07-1.16 (AB m, 2H), 1.23-1.26 (m, 2H), 1.32-1.35 (m, 2H), 1.56-1.63 (AB m, 4H), 1.68-1.80 (m, 6H), 2.07-2.11 (m, 3H), 3.50 (t, J=6.4 Hz, 2H), 5.18 (br s, 1 H). ³ C-NMR (CDCI ₃ , 100 MHz) δ 22.97, 30.10, 31.91 , 32.33, 35.56, 40.19, 42.63, 44.66, 47.61 , 50.55, 53.44, 171.46. m=3; ES114; G-chloro-N-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)esanami de. It was synthesized from 6-chloroesanoyl chloride (0.21 mL, 1.40 mmol). Elution with petroleum ether/ AcOEt (8.5:1.5) afforded ES114 as a oil: 0.370 g (85%). ¹ H-NMR (CDCI3, 400 MHz) δ 0.79 (s, 6H), 1.06-1.14 (AB m, 2H), 1.21-1.34 (AB m, 4H), 1 .37- 1.44 (m, 2H), 1.53-1.62 ( m, 6H), 1.70-1.77 (m, 4H), 1.98-2.08 (m, 3H), 3.46-3.49 (m, 2H), 5.31 (br s, H). ¹³ C-NMR (CDCI3, 100 MHz) δ 24.88, 26.35, 30.07, 32.29, 37.26, 40.14, 42.62, 44.79, 47.56, 50.55, 53.33, 171.87.

In this Preparation III, all intermediates (Ilia) are novel. Therefore, these intermediates are a further object of the present invention.

Examples 16-18

A mixture of the chloride derivative (1.2 eq.), des-methyl-Galantamine (1 eq.), Et ₃ N (2 eq.) and Kl (cat.) in CH ₃ CN (0.1 ) was stirred at 80°C for 48 hours in a pressure tube (Sigma Aldrich, ACE pressure tube). After evaporating the solvent, the residue was purified by flash chromatography. Example 16 m=1 ; 4-((4aS,6R,8aS)-3,6-dimethoxy-5,6,9, 0-tetrahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-11 (12H)-yl)-N-((1 R,3R,5S,7S)-3,5- dimethyladamantan-1-yl)butanamide. It was synthesized from ES113 (0.070 g, 0.247 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH/ 33% aqueous ammonia (9:1 :0.02) afforded the compound of interest as a waxy solid: 0.070 g (65%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.83 (s, 6H), 1.13-1.15 (AB m, 2H), 126-1.38 ( AB m, 4H), 1.61 (br m, 4H), 1.72-1.79 (m, 4H), 1.98-2.04 (m, 2H), 2.1 1-2.14 (m, 3H), 2.47-2.55 (m, 3H), 2.65-2.70 (m, 1 H), 3.11- 3.18 (m, 1 H), 3.31 -3.38 (m, 1H), 3.77 (AB d, J =16 Hz, 1H) 3.83 (s, 3H), 4.09-4.14 (m+AB d, J =16 Hz, 2H), 4.60 (br m, 1 H), 5.57 (br s,1 H), 6.00 (dd, J,= 10.0 Hz, J ₂ = 4.8 Hz, 1H), 6.09 (d, J=10.0 Hz, 1H), 6.61 (d, J=8.4 Hz, 1 H), 6.66 (d, J=8.4 Hz, 1 H). ¹³ C- NMR (CDCI3, 100 MHz) δ 22.92, 30.05, 32.30, 33.04, 35.24, 40.17, 42.63, 47.60, 48.33, 50.56, 51.52, 53.25, 58.81 , 55.89, 55.96, 57.60, 61.98, 88.68, 111 .24, 122.04, 126.82, 127.65, 129.01 , 133.10, 144.11 , 145.82, 172.01. UPLC/MS. Purity 96%. MS (ESI+):m/z 521.38 [M+H] ⁺ .

Example 17 m=2; N-((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 -yl)-5-((4aS,6R,8aS)-6-hydroxy-3- methoxy-5,6,9,10-tetrahydro-4aH-benzo[2,3]benzofuro[4,3-cd]a zepin-11(12H)- yl)pentanamjde It was synthesized from ES82 (0.070 g, 0.235 mmol). Elution with CH2CI2/CH3OH/ 33% aqueous ammonia (9:1:0.02) afforded the compound of interest as a waxy solid: 0.070 g (67%). ¹ H-NMR (CDCI3, 400 MHz) δ 0.83 (s, 6H), 1.11 -1.19 (AB m, 2H), 1.24-1.47 (AB m, 4H), (m, 4H), 1.49-1.60 (m, 5H), 1.62-1.80 (br m, 2H), 1.98- 2.09 (m, 2H), 2.11-2.14 (m, 3H), 2.44-2.54 (m, 2H), 2.65-2.70 (m, 1 H), 3.13-3.17 (m, 1 H), 3.31 -3.37 (m, 1 H), (AB d, J =15.6 Hz, 1 H) 3.83 (s, 3H), 4.09-4.14 (m+AB d, J =15.6 Hz, 2H), 4.60 (br m, 1 H), 5.12 (br s, 1 H), 6.00 (dd, ^= 9.6 Hz, J ₂ = 5.2 Hz, 1 H), 6.08 (d, j=10.0 Hz, 1 H), 6.60 (d, J=8.0 Hz, 1 H), 6.65 (d, j=8.4 Hz, 1 H). ³ C-NMR (CDCI3, 00 MHz) δ 23.51 , 26.87, 30.12, 32.34, 32.99, 37.50, 40.21 , 42.63, 47.65, 48.38, 50.57, 51.60, 53.34, 55.92, 57.67, 62.05, 88.72, 11 1.18, 121.96, 126.94, 127.57, 129.38, 133.15, 144.07, 145.81, 171.97. UPLC/MS: Purity 100%. MS (ESI+):m/z 535.42 [M+H] ⁺ .

Example 18 m=3; N-(( R,3R,5S,7S)-3,5-dirnethyladamantan-1-yl)-6-((4aS,6R,8aS)-6-h ydroxy-3- methoxy-5,6,9,10-tetrahydro-4aH-benzo[2 _p 3]benzofuro[4 _l 3-cd]azepin-11(12H)- yl)hexanamide. It was synthesized from ES114 (0.070 g, 0.224 mmol). Elution with CH2CI2/CH3OH/ 33% aqueous ammonia (9:1:0.02) afforded the compound of interest as a waxy solid: 0.080 g (78%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.83 (s, 6H), 1.07-1.14 (AB m, 2H), 1.18-1.38 (AB m, 4H), 1.48-1.66 (m, 10H), 1.81 (br m, 2H), 1.96-2.06 (m, 4H), 2.12 br (m, 1 H), 2.41 -2.54 (m, 3H), 2.41-2.54 (m, 1 H), 3.14-3.18 (m, 1 H), 3.27-3.37 (m, 1 H), 3.77 (AB d, J =16 Hz, 1H) 3.83 (s, 3H), 4.09^.14 (m+AB d, J =16 Hz, 2H), 4.60 (br m, 1 H), 5.23 (br s, 1 H), 6.00 (dd, J,= 10.0 Hz, J ₂ = 4.8 Hz, 1 H), 6.09 (d, J=10.0 Hz, 1 H), 6.61 (d, J=8.4 Hz, 1 H), 6.66 (d, J=8.4 Hz, 1 H). ¹³ C-NMR (CDCI3, 100 MHz) δ 25.54, 26.84, 27.08, 29.63, 30.04, 32.30, 32.85, 37.52, 40.15, 42.62, 47.58, 48.35, 50.55, 51.43, 53.30, 55.81 , 55.87, 57.65, 62.01 , 61.99, 88.67, 1 11.18, 121.98, 126.91 , 127.53, 129.25, 133.09, 144.01 , 145.74, 172.17. UPLC/MS: Purity 100%. MS (ESI+):m/z 549.45 [M+H] ⁺ .

Preparation IV

General synthesis of compounds of formula (I), wherein X is (CH2) _m and m is comprised between 2 and 12; Y is O or 0(CH ₂ ) O, wherein p is comprised between 1 and 6; Z is selected from the group consisting of (CH ₂ ) _n , wherein n is comprised between 1 and 12; R is H, C ₁ -C4 alky I or a protective group, such as Boc, Fmoc, Cbz.

Step 1

ES154

.OH o. OTs

TSCI, DMAP, Et ₃ N

CH ₂ CI _2l rt

HO. OH HO. OTs

ES117

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%). ¹ H-NMR (CDCI _3> 400 MHz) δ 2.30 (s, 3H), 2.99 (br s, exchangeable with D ₂ 0, 1 H), 3.40-3.63 (m, 10H), 4.02 (t, J=4.8 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 21 .48, 42.73, 61 .39, 68.47, 69.24, 70.06, 70.42, 71 .12, 72.46, 127.79, 129.81 , 132.71 , 144.87. ES117; 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate. It was synthesized from diethylene glycol (1 .000 g, 9.42 mmol). Elution with petroleum ether/ AcOEt (5:5) afforded ES117 as a waxy solid: 0.850 g (35%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 2.26 (br s, exchangeable with D ₂ 0, 1 H), 2.30 (s, 3H), 3.54 (t, J=5.6 Hz, 2H), 3.65-3.70 (m, 4H), 4.20 (t, J=4.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) 5 21.58, 61 .56, 68.51 , 69.20, 72.47, 127.91 , 129.83, 132.90, 144.95.

Step 2

Synthesis of compounds ES157, ES1 19

In a pressure tube (Sigma Aldrich, ACE pressure tube) the appropriate activated alcohol (1 .2 eq.) was added to a vigorously stirred solution of Memantine hydrochloride (1 eq) and K ₂ CO ₃ (2.5 eq) in DMF (0.1 M). The reaction mixture was stirred at 80°C for 48 hours. After evaporating the solvent, the residue was taken up with water and extracted with CH ₂ CI ₂ (3 x 10 ml_). The crude was purified by flash chromatography. ES157; 2-(2-(2-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1- yl)amino)ethoxy)ethoxy)ethanol. It was synthesized from ES154 (0.450 g, 1 .48 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH/ 33% aqueous ammonia (9:1 :0.13) afforded ES157 as a waxy solid: 0.230 g (60%). ¹ H-NMR (CDCI _3> 400 MHz) δ 0.73 (s, 6H), 0.97-1 .07 (AB m, 2H), 1 .10-1 .20 (m, 8H), 1 .31 -1 .38 (m, 2H), 2.02-2.03 ( br m, 1 H), 2.60-2.70 (m, 2H), 3.48-3.67 (m, 10H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 30.05, 32.26, 40.00, 40.90, 42.50, 42.91 , 48.59, 50.85, 51 .94, 52.28, 61 .18, 69.87, 70.56, 71 .23.

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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.77 (s, 6H), 1.04-1 .08 (AB m, 2H), 1 .17-1 .26 (m, 8H), 1 .42-1 .43 ( m, 2H), 2.04-2.08 ( br m, 1 H), 2.72 (t, J=5.2 Hz, 2H), 3.08 (br m, exchangeable with D ₂ 0, 1 H), 3.50-3.57 (m, 4H).3.62-3.64 (m, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 30.06, 30.21 , 32.31 , 40.28, 40.76, 42.85, 48.46, 50.81 , 52.39, 61 .57, 71.06, 72.59. In this Preparation IV, all intermediates (IVa) and (IVb) are novel. Therefore, these intermediates are a further object of the present invention.

Step 3

Synthesis of compounds ES158, ES185.

The appropriate secondary amine (1 eq.) was dissolved in THF/H ₂ O (1 :1 ) and treated with Na ₂ C03 (2.5 eq.) and di-ieri-butyl dicarbonate (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_). The extracts were combined, washed with brine, dried over Na ₂ S0 ₄ , concentrated by evaporation, and purified by flash chromatography.

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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.78 (s, 6H), 1 .01 -1 .05 (AB m, 2H), 1 .16-1 .28 (AB m, 4H), 1 .38 (s, 9H), 1 .65-1 .68 (AB m, 4H), 1 .85 ( br m, 2H), 2.06- 2.07 (m, 1 H), 3.40-3.52 (m, 4H), 3.53-3.59 (m, 6H), 3.66 (t, J=4.4 Hz, 2H). ¹³ C-NMR (CDCIs, 100 MHz) δ 28.52, 30.43, 30.62, 32.77, 39.23, 42.51 , 42.57, 46.79, 50.44, 58.03, 61.62, 70.36, 70.43, 70.91 , 72.52, 79.23, 154.99.

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%). ¹ H-NMR (CDCI _3> 400 MHz) δ 0.82 (s, 6H), 1 .09-1 .1 1 (AB m, 2H), 1 .21 -1 .33 (AB m, 4H), 1 .43 (s, 9H), 1 .70-1 .78 (AB m, 4H), 1 .90 ( br m, 2H), 2.1 1 -2.14 (m, 1 H), 3.46- 3.52 (m, 4H), 3.53-3.55 (m, 2H), 3.70 (t, J=4.4 Hz, 2H). ¹³ C-NMR (CDCI _3> 100 MHz) δ 28.55, 30.47, 30.67, 32.81 , 39.40, 42.62, 46.92, 50.48, 58.08, 61 .86, 70.99, 72.10, 79.36, 155.15.

In this Preparation IV, all intermediates (IVc) and (IVd) are novel. Therefore, these intermediates are a further object of the present invention.

Step 4

Synthesis of compounds ES159, ES188.

(I f) p-TsCI (1 eq.) was added to a mixture of the appropriate alcohol (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 the whole was extracted with AcOEt. The extract was washed with brine prior to drying over Na ₂ S0 ₄ , and solvent evaporation. The tosylate activated derivative was then purified by flash chromatography.

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%). ¹ H-NMR (CDCI _3> 400 MHz) δ 0.79 (s, 6H), 1 .06-1 .07 (AB m, 2H), 1 .18-1 .30 (AB m, 4H), 1 .40 (s, 9H), 1 .70-1 .78 (AB m, 4H), 1 .87 (br m, 2H), 2.06-

2.09 (m, 1 H), 2.40 (s, 3H), 3.40 (br m, 4H), 3.47-3.54 (m, 4H), 3.64 (t, J=4.8 Hz, 2H), 4.1 1 (t, =5.2 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 21.60, 28.54, 30.47, 30.65, 32.79, 39.22, 42.57, 42.59, 46.77, 50.47, 58.04, 68.70, 69.14, 70.29, 70.72, 71 .00, 79.16, 127.92, 129.78, 132.96, 144.75, 154.94.

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 %). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.82 (s, 6H), 1 .07-1 .08 (AB m, 2H), 1 .18-1 .31 (AB m, 4H), 1 .41 (s, 9H), 1 .70-1 .78 (AB m, 4H), 1 .87 (br m, 2H), 2.01 -

2.10 (m, 1 H), 2.42 (s, 3H), 3.37 3.39 (m, 4H), 3.60 (t, J=4.8 Hz, 2H), 4.12 (t, J=4.8 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.75 (d, =8.4 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 21 .61 , 28.54, 30.44, 30.67, 32.81 , 39.27, 42.50, 42.60, 46.79, 50.45, 58.07, 68.42, 69.12, 71 .10, 79.26, 127.92, 129.79, 133.02, 144.76, 154.96. In this Preparation IV, all intermediates (IVe) and (IVf) are novel. Therefore, these intermediates are a further object of the present invention.

Examples 19-20

In a pressure tube (Sigma Aldrich, ACE pressure tube) a mixture of the appropriate activated alcohol (1 eq), des-methyl-Galantamine (1 eq) and Et ₃ N (2 eq) in CH ₃ CN (0.1 M) was stirred at 80°C for 48 hours. After evaporating the solvent, the residue was purified by flash chromatography.

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]benzofur o[4,3-cd]azepin- 11(12H)-yl)ethoxy)ethoxy)ethyl)carbamate. It was synthesized from ES159 (0.120 g, 0.212 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH (9:1 ) afforded the compound of interest as a waxy solid: 0.080 g (57%). ¹ H-NMR (CDCI3, 400 MHz) δ 0.80 (s, 6H), 1 .03-1 .01 (AB m, 2H), 1 .18-1 .31 (AB m, 4H), 1 .42 (s, 9H), 1.46-1 .49 (m, 1 H), 1.69 (AB m, 4H), 1 .89 (br m, 2H), 1 .94-2.09 (m, 3H), 2.61 -2.67 (m, 1 H), 2.71 (t, J=4.8 Hz, 2H), 3.15-3.19 (m, 1 H), 3.35-3.39 (m, 1 H), 3.40-3.43 (m, 4H), 3.53-3.59 (m, 6H), 3.79 (s, 3H), 3.83 (d, 15.2 Hz, 1 H), 4.09-4.1 1 (m, 1 H), 4.15 (d, J=15.6 Hz, 1 H), 4.60 (br m, 1 H), 5.96 (dd, =10.0, J ₂ =4.4 Hz, 1 H), 6.00 (d, J=10.0 Hz, 1 H), 6.57 (d, J=8.4 Hz, 1 H), 6.62 (d, J=8.4 Hz, 1 H). ¹³ C-NMR (CDCI3, 100 MHz) δ 28.56, 29.93, 30.47, 30.67, 32.81 , 32.95, 39.23, 42.61 , 46.78, 48.41 , 50.48, 51 .91 , 55.87, 57.98, 58.06, 62.03, 69.34, 70.44, 70.98, 79.14, 88.69, 1 11 .14, 122.12, 126.84, 127.60, 128.65, 129.36, 133.12, 144.11 , 145.83, 154.94. 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]benzofur o[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%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.82 (s, 6H), 1 .09-1 .10 (AB m, 2H), 1 .20-1 .33 (AB m, 4H), 1 .42 (s, 9H), 1 .47-1 .51 (m, 1 H), 1 .69 (AB m, 4H), 1 .90-1 .91 (br m, 2H), 1 .95-2.1 1 (m, 3H), 2.63-2.64 (m, 1 H), 2.67-2.71 (m, 2H), 3.15-3.19 (m, 1 H), 3.36-3.40 (m, 1 H), 3.42-3.45 (m, 4H), 3.48-3.56 (m, 2H), 3.80 (s, 3H), 3.83 (d, J=15.2 Hz, 1 H), 4.10-4.1 1 (m, 1 H), 4.16 (d,

j ₂ =4.4 Hz, 1 H), 6.00 (d, J=10.0 Hz, 1 H), 6.57 (d, J=8.4 Hz, 1 H), 6.62 (d, J=8.4 Hz, 1 H). 1 ³ C-NMR (CDCIs, 100 MHz) δ 28.57, 29.93, 30.47, 30.68, 32.81 , 33.00, 39.28, 42.61 , 46.81 , 48.41 , 50.48, 50.72, 51 .91 , 53.39, 55.88, 58.02, 58.08, 62.04, 69.01 , 70.90, 79.17, 88.71 , 11 1 .14, 122.06, 126.85, 127.61 , 129.40, 133.12, 144.12, 145.80, 154.98.

Examples 21 -22

Compound of

Example 19 or 20

HCI 4M in dioxane (1 ml.) was carefully added to the appropr derivative (1 eq.) at 0 °C and the solution was allowed to stir at room temperature for 2 hours. After removing the solvent the obtained residue was purified by flash chromatography.

Example 21

(4aS,6R,8aS)-11 -(2-(2-(2-(((1 R,3R,5S,7R)-3,5-dimethyladamantan-1 - yl)amino)ethoxy)ethoxy)ethyl)-3-methoxy-5,6,9,10,11,12-hexah ydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol. It was synthesized from the compound of Example 19 (0.080 g, 0.120 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH/ 33% aqueous ammonia (9:1 :0.05) afforded THE COMPOUND OF INTEREST as a waxy solid: 0.060 g (88%). ¹ H-NMR (CDCIs, 400 MHz) δ 0.84 (s, 6H), 1 .08-1 .16 (AB m, 2H), 1 .26-1 .37 ( m, 8H), 1 .51-1 .54 (m, 3H), 1 .98-2.09 (m, 2H), 2.15 (br m, 1 H), 2.66-2.70 (m, 1 H), 2.74 (t, J=5.8 Hz, 2H), 2.83 (t, J=4.8 Hz, 2H), 3.21 -3.25 (m, 1 H), 3.38-3.44 (m, 1 H), 3.54-3.67 (m, 8H), 3.83 (s, 3H), 3.88 (d, J=15.2 Hz, 1 H), 4.13-4.15 (m, 1 H), 4.18 (d, J=15.2 Hz, 1 H), 4.60 (br m, 1 H), 6.00 (dd, Hz, 1 H), 6.61 (d, J=8.0 Hz, 1 H), 6.65 (d, J=8.4 Hz, 1 H). ¹³ C-NMR(CDCI ₃ , 100 MHz) δ 29.92, 30.12, 30.18, 32.38, 32.91 , 40.05, 40.29, 42.77, 47.95, 48.40, 50.72, 51 .83, 55.87, 57.89, 62.03, 68.99, 70.04, 70.16, 70.27, 88.68, 1 1 1 .17, 122.21 , 126.80, 127.63, 129.22, 133.14, 144.12, 145.82. UPLC/MS: purity 99%. MS (ESI+): m/z 567.5 [M+1 ] ⁺ .

Example 22

(4aS,6R,8aS)-11 -(2-(2-(((1 R,3R,5S,7S)-3,5-dimethyladamantan-1 - yl)amino)ethoxy)ethyl)-3-methoxy-5,6,9,10,11 ,12-hexahydro-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol It was synthesized from compound of Example 20 (0.1 15 g, 0.184 mmol). Elution with CH ₂ CI ₂ /CH ₃ OH/ 33% aqueous ammonia (9:1 :0.05) afforded THE COMPOUND OF INTEREST as a waxy solid: 0.085 g (88%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.87 (s, 6H), 1 .1 1 -1 .01 (AB m, 2H), 1 .24-1 .33 (m, 4H), 1 .36-1 .45 (AB m, 4H), 1 .54-1 .62 (m, 3H), 1 .98-2.1 1 (m, 2H), 2.20 (br m, 1 H), 2.66- 2.71 (m, 1 H), 2.76 (t, J=5.2 Hz, 2H), 2.90 (t, J=4.8 Hz, 2H), 3.34-3.39 (m, 2H), 3.53-3.62 (m, 2H), 3.71 -3.72 (m, 2H), 3.83 (s, 3H), 3.95 (d, J=15.2 Hz, 1 H), 4.14-4.17 (m+d, J=15.2 Hz, 2H), 4.61 (br m, 1 H), 6.00-6.08 (m, 2H), 6.65-6.67 (m, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 30.06, 32.58, 40.34, 42.55, 48.35, 50.50, 51 .54, 55.87, 57.30, 62.00, 88.70, 1 1 1 .27, 122.38, 126.52, 127.86, 133.10, 144.28, 145.83. UPLC/MS: Purity 95%, r.t = 2.24 min.MS (ESI+):m/z 523.35 [M+H] ⁺ .

Synthesis of compound ES194

a) TsCI, DMAP, Et ₃ N, CH ₂ CI ₂ , rt. b) memantine hydrochloride, K ₂ C0 ₃ , DMF, 80°C.

ES194. 2-((2-(((1s,3s,5R7S)-3-methyladamantan-1 -yl)amino)ethyl)thio)ethanol. p- TsCI (1 eq.) was added to a mixture of tiodietilenglicole (0.500 mg, 1 eq.), Et ₃ N (1 .140 mL, 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. The crude was then transferred into a pressure tube (Sigma Aldrich, ACE pressure tube) and added with Memantine hydrochloride (0.441 g, 0.5 eq.), and K2CO3 (2 eq.) in DMF, with stirring at 80°C for 36 hours. After evaporating the solvent, the residue was purified by flash chromatography. Elution with CH2CI2/CH ₃ OH/ 33% aqueous ammonia (9:1 :0.14) afforded ES194 as a waxy solid: 0.250 g (435%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.76 (s, 6H), 1 .03-1 .04 (AB m, 2H), 1 .15-1 .24 (m, 8H); 1 .41 (br m, 2H), 2.05-2.06 (m, 1 H), 2.60-2.72 (m, 4H), 3.29 (br s, exchangeable with D ₂ 0, 1 H), 3.64-3.70 (m, 4H). Synthesis of compounds ES195.

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_). The extracts were combined, washed with brine, dried over Na2S0 ₄ , concentrated by evaporation, and purified by flash chromatography. Eluting with petroleum ether/ AcOEt (8:2) afforded ES195 as a waxy solid: 0.220 g (65%). ¹ H-NMR (CDCI3, 400 MHz) δ 0.81 (s, 6H), 1 .08-1 .1 1 (AB m, 2H), 1 .22-1 .32 (AB m, 4H), 1 .43 (s, 9H), 1 .67 (AB m, 4H), 1.88 ( br m, 2H), 2.10-2.12 (m, 1 H), 2.54 (t, J=8.0 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H), 3.40 (t, J=8.0 Hz, 2H), 3.71 (t, J=5.6 Hz, 2H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 28.57, 30.40, 30.62, 31 .82, 32.81 , 34.92, 39.52, 42.54, 43.92, 47.04, 50.39, 58.26, 60.84, 79.60, 154.98.

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.

tert-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]benzofur o[4,3-cd]azepin- 11 (12H)-yl)ethyl)thio)ethyl)carbamate. 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. The crude was then transferred into a pressure tube (Sigma Aldrich, ACE pressure tube) and added with des-methyl-Galantamine (0.5 eq.), and Et ₃ N (2 eq.) in CH ₃ CN, with stirring at 80°C for 48 hours. After evaporating the solvent, the residue was purified by flash chromatography. Elution with CH ₂ CI ₂ /CH ₃ OH (9.5:0.5) afforded the compound of interest as a waxy solid: 0.075 g (90%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.84 (s, 6H), 1 .12 (AB m, 2H), 1 .25-1 .36 (AB m, 4H), 1 .46 (s, 9H), 1 .51 -1 .55 (m, 1 H), 1 .71 (AB m, 4H), 1 .90-1 .91 (br m, 2H), 1 .98-2.04 (m, 2H), 2.14- 2.15(m, 1 H), 2.54-2.58 (m, 2H), 2.66-2.77 (m, 5H), 3.15-3.19 (m, 1 H), 3.38-3.43 (m, 3H), 3.82 (s, 3H), 3.83 (d, J=15.2 Hz, 1 H), 4.14 ( m, 1 H), 4.18 (d, J=15.6 Hz, 1 H), 4.61 (br m, 1 H), 6.01 (dd, Hz, 1 H), 6.61 (d, J=8.4 Hz, 1 H), 6.65 (d, =8.4 Hz, 1 H). ¹³ C-NMR (CDCI ₃ , 100 MHz) δ 28.60, 29.66, 29.92, 30.10, 30.43, 30.65, 32.55, 32.82, 33.05, 39.54, 42.58, 44.02, 47.04, 48.41 , 50.41 , 51 .59, 55.89, 57.47, 58.23, 62.03, 79.37, 88.68, 1 1 1 .16, 121 .95, 126.77, 127.68, 129.25, 133.07, 144.17, 145.90, 154.83.

Example 24 HCI 4M in dioxane

Compound of

Example 23 0°C-rt

(4aS,6R,8aS)-11 -(2-((2-(((1r,3R,5S,7S)-3,5-dimethyladamantan-1- yl)amino)ethyl)thio)ethyl)-3-methoxy-5,6,9,10,11,12-hexahydr o-4aH- benzo[2,3]benzofuro[4,3-cd]azepin-6-ol. HCI 4M in dioxane (1 mL) was carefully added to COMPOUND OF EXAMPLE 23 (0.075 g, 1 eq.) at 0 °C and the solution was allowed to stir at room temperature for 2 hours. After removing the solvent the obtained residue was purified by flash chromatography. Elution with CH ₂ CI ₂ /CH3OH/ 33% aqueous ammonia (9:1 :0.05) afforded the compound of interest as a waxy solid: 0.055 g (88%). ¹ H-NMR (CDCI ₃ , 400 MHz) δ 0.82 (s, 6H), 1 .04-1 .13 (AB m, 2H), 1 .19-1 .27 (m, 8H), 1 .43 (br s, 2H), 1 .48-1 .51 (m, 1 H), 1 .98-2.04 (m, 2H), 2.09-2-1 1 ( m, 1 H), 2.59-2.75 (m, 8H), 3.15 (m, 1 H), 3.18 (m, 1 H), 3.36-3.42 (m, 1 H), 3.60-3.64 (m, 1 H), 3.72-3.76 (m, 1 H), 3.81 (s, 3H), 3.82 (d, J=15.2 Hz, 1 H), 4.10- 4.17 (m+d, J=15.2 Hz, 2H), 4.58 (br m, 1 H), 5.99 (dd, Ji = 10.0, J ₂ =4.4 Hz, 1 H), 6.05 (d, J=10.0 Hz, 1 H), 6.58 (d, J=8.4 Hz, 1 H), 6.63 (d, J=8.4 Hz, 1 H). ¹³ C-NMR (CDCI3, 100 MHz) δ 29.67, 29.86, 29.93, 30.25, 30.30, 32.37, 33.00, 33.68, 39.65, 41.27, 42.85, 42.97, 48.41 , 49.00, 49.04, 50.91 , 51 .70, 52.25, 55.89, 57.38, 62.03, 71 .11 , 72.29, 88.69, 1 11 .17, 121 .94, 126.74, 127.69, 129.15, 133.07, 144.20, 145.90. UPLC/MS: purity 95%. MS (ESI+): m/z 539.32 [M+1 ] ⁺ .

Biological results 1) Evaluation of compound binding affinity at NMDA Glutamate receptors

In order to evaluate [ ³ H] MK-801 binding parameters, saturation binding studies were performed. Aliquots of rat brain cortex (40 pg) were incubated in the presence of increasing radioligand concentrations ranging from 0.3 to 68 nM. Scatchard analysis of saturation binding data demonstrated the radioligand labelled an homogenous population of binding sites with an affinity constant value of 4.0 nM and a maximum density of binding sites of 955 fmol/mg of proteins. The activity of the new compounds towards NMDA glutamate receptors were evaluated by competition binding assays. Aliquots of rat brain cortex membranes (40 pg proteins) were incubated with 3 nM [ ³ H] MK-801 and two different concentrations of each compounds (100 nM and 10 μΜ). In parallel, Memantine, Ifenprodil and dextromethorphan 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. They were transformed into Ki values according to Cheng-Prussof (Cheng -Prusoff 1973): Ki = IC5o/(1 +L/Kd), where L is the radioligand concentration, and Kd is the dissociation constant. The % of binding inhibition at 10 μΜ or the Ki values of the compounds are reported in Table 1 .

TABLE 1

% of [ ^J H] MK-801 binding

Compound Ki (μΜ)

inhibition at 10 μΜ

EXAMPLE 17 21.65 ± 2.95

EXAMPLE 16 30.46 ± 3.25

EXAMPLE 13 22.2 ± 3.9

EXAMPLE 14 31 .6 ± 2.8

EXAMPLE 15 39.3 ± 3.2

EXAMPLE 1 43.7 ± 6.6

EXAMPLE 6

32.3 ± 0.3

EXAMPLE 12 4.63 ± 1 .54

EXAMPLE 21 13.1 ± 2.9

Memantine 1 .16 ± 0.07

Galantamine 8.60 ± 0.40

Ifenprodil 3.08 ± 0.76

Dextromethorphan 0.207 ± 0.021

2) Determination of compound inhibitory effect on rat acetylcholinesterase (AChE)

In order to evaluate AChE kinetic parameters in rat brain, Km and Vmax for the enzyme was calculated by Michaelis-Menten equation.

Aliquots of enzyme preparation (10 pg) were incubated in the presence of different acetylthiocholine iodide (ACTHI) substrate concentrations ranging from 0.025 to 2.5 mM and 0.25 mM dithiobisnitrobenzoate (DTNB). The enzyme activity was measured quantifying the increase of absorbance at 412 nm due to the yellow colour produced from the reaction of ACTHI with the DTNB ion.

Screening of the new compounds as AChE inhibitors was performed evaluating the ability of two selected concentrations of each compounds (100 nM and 10 μΜ) to inhibit the enzyme activity at a specific substrate concentration, corresponding to Km. Activities of the synthetized compounds were compared with the inhibitory activity shown by the known standard inhibitor Galantamine. Based on the data obtained from the screening, the IC ₅ o value of the compounds, showing the higher % of enzyme activity inhibition, was evaluated. Aliquots of brain homogenates (containing 10 μg of proteins) were incubated with five different compound concentrations and the AChE activity was quantified as above described. The IC ₅ o values of the compounds towards AChE activity are reported in Table 2.

TABLE 2

Determination of IC ₅₀ value of the compounds towards AChE activity.

Compound ICso

(nM ± SEM)

EXAMPLE 14 1 .33 ± 0.12

EXAMPLE 15 0.52 ± 0.05

EXAMPLE 1 1380 ± 120

EXAMPLE 6 368.3 ± 89.3

EXAMPLE 12 2.32 ± 0.50

EXAMPLE 21 80.9 ± 12.8

Galantamine 2550 ± 690

Memantine 8.50% ± 1.30

at 10 μΜ

3) [ ³ H] ifenprodil binding assay on rat cortex

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).

In order to evaluate [ ³ H] ifenprodil binding parameters, saturation binding studies were performed. Aliquots of rat brain cortex (100 pg) were incubated in the presence of increasing radioligand concentrations ranging from 0.5 to 100 nM. Scatchard analysis of saturation binding data demonstrated the radioligand labelled an homogenous population of binding sites with an affinity constant value of 28.0 ± 1 .8 nM and a maximum density of binding sites of 1508 ± 321 fmol/mg of proteins.

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 μΜ). 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. They were transformed into Ki values according to Cheng-Prussof (Cheng-Prusoff 1973): Ki = IC ₅₀ /(1 +L/Kd), where L is the radioligand concentration, and K _d is the dissociation constant. The % of binding inhibition at 100 μΜ or the Ki values of the compounds are reported in Table 3.

TABLE 3

Compound Ki (μΜ) % of [ ^J H] ifenprodil

inhibition at 100 μΜ

EXAMPLE 8 40.9 ± 5.6

EXAMPLE 2 33 ± 9

EXAMPLE 4 70 ± 9

EXAMPLE 10 10.95 ± 3.44

EXAMPLE 9 4.6 ± 0.7

EXAMPLE 3 1.93 ± 0.36

EXAMPLE 11 2.9 ± 1 .0

EXAMPLE 5 38 ± 4

EXAMPLE 18 9.76 ± 4.48

EXAMPLE 17 27 ± 4

EXAMPLE 16 46 ± 10

EXAMPLE 13 5.25 ± 1.6

EXAMPLE 14 46 ± 17

EXAMPLE 15 43 ± 15

EXAMPLE 1 36 ± 6

EXAMPLE 6 16.4 ± 2.5

EXAMPLE 12 21 .3 ± 4.8

EXAMPLE 21 8.15 ± 1.87

Eliprodil 0. 54 ± 0.07

Ifenprodil 0.029 ± 0.003

Galantamine 21 .8 ± 4.8

Memantine 23.3 ± 5.6 4) Evaluation of NMDA toxicity in SHSY-5Y cells

Cell culture, pharmacological treatments and MTS assay.

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.

Cells were seeded in 96-well microplates (5.000 cells/well); the day after, cells were incubated with NMDA, in the absence or in the presence of different compound concentrations. The 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. In parallel classical NMDA receptor antagonist (Eliprodil and Ifenprodil) and AChE inhibitor (Galantamine) were used as standard compounds.

Following incubation times, cell viability was determined using the MTS assay according to manufacturer's instruction. The dehydrogenase activity in active mitochondria reduces 3-(4, 5-dimethylthiazol-2-yl)-5- (3-carboxy methoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium (MTS) to the soluble formazan product. The absorbance of formazan at 490 nM was measured in a colorimetric assay with an automated plate reader.

Within an experiment, 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).

Student's i-test was used to evaluate whether differences between the experimental groups and the control were statistically significant.

Preliminary experiments were carried out to characterize the effects of NMDA on cell viability; SHSY-5Y cells were incubated with different NMDA concentrations (ranging from 50 μΜ to 5 mM) for 1 , 3, 6 or 24 hours in non complete medium. After 1 hour of treatment NMDA was able to significantly decrease cell viability only at the highest concentration. On the contrary, when cells were exposed to NMDA for 3, 6, or 24 hours, a significant decrease of cells viability was observed at 500 μΜ, 1 mM and 5 mM. Based on these data, all the other experiments were carried out exposing cells to 500 μΜ NMDA for 6 hours.

The IC ₅ o values of the compounds toward NMDA-induced toxicity in SHSY-5Y cells are reported in Table 4.

TABLE 4

In light of the above reported results, 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. In fact, while 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. Therefore, the ability of the Galantamine fragment to interact with other receptor systems involved in neurodegeneration (likely nicotinic receptors) could be responsible for the remarkable pharmacological profile of the present series of compounds. We can therefore summarize that the present series of dual 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.