ES2288406B1 - ACETILCOLINESTERASE INHIBITING COMPOUNDS FOR THE TREATMENT OF ALZHEIMER'S DISEASE. - Google Patents

Abstract

Acetylcholinesterase inhibitor compounds for the treatment of Alzheimer's disease. Compounds of formula (I) and their pharmaceutically acceptable salts or solvates, including any stereoisomer or mixture of stereoisomers, wherein R {sub, 1}, R {sub, 2}, R {sub, 3} and R {sub, 4} are radicals independently selected from the group consisting of H, Cl, F, Br, CF {sub, 3}, (C {sub, 1} -C {sub, 4}) -alkyl, (C {sub, 1} - C {sub, 4}) -alkoxy and nitro; R {sub, 5}, R {sub, 6}, R {sub, 7} and R {sub, 8} are radicals independently selected from the group consisting of H and (C {sub, 1} -C {sub, 6}) -alkoxy, n is an integer from 3 to 5; r is an integer from 2 to 5; s is an integer from 1 to 5 and X is a birradical selected from CO and CH {sub, 2}, they behave as dual-binding acetylcholinesterase inhibitors and are useful as active ingredients against Alzheimer's disease.

Description

Acetylcholinesterase inhibitor compounds for the treatment of Alzheimer's disease.

The invention relates to inhibitor compounds of acetylcholinesterase and a process for its preparation. Too refers to pharmaceutical compositions comprising said compounds and their use for the treatment of disease Alzheimer's

State of the art

Alzheimer's disease, the form of dementia most common in the elderly, it is one of the largest health problems in developed countries along with disorders cardiovascular and cancer. Be slow, progressive and finally fatal neurodegenerative disorder is characterized clinically by a notable cognitive decline defined by a loss of memory and learning ability, along with a reduced ability to develop basic activities of daily life, and a varied range of neuropsychiatric symptoms such as apathy, agitation verbal and physical, irritability, anxiety, depression, delusions and hallucinations Alzheimer's disease currently affects approximately 20 million people worldwide, and this amount will increase substantially in the future as increase the number of elderly in the population, taking into account that the prevalence of Alzheimer's disease doubles every 5 years from 65, with 47% affected among those over 85 years As a result of the increasing incidence and effects devastating this disease, there is an urgent and growing Need for effective pharmacotherapy. The multifaceted character of Alzheimer's disease has led to the development of a variety of approaches for pharmacological correction. Though enormous progress has been made in the identification of molecular origins of Alzheimer's disease, currently not There is a cure for this disease.

Alzheimer's disease is characterized by two main pathological aspects: amyloid plaques and neurofibrillar clews, in addition to the loss of neuronal cells in specific regions of the brain. An increase in the production of β-amyloid peptide (Aβ) and its subsequent deposition as insoluble amyloid plaques, forming the extraneuronal senile plaques, it seems to constitute the key pathological fact that triggers the neurodegenerative process in Alzheimer's disease. They have developed different strategies aimed at reducing, preventing or even reversing the generation and deposition of A? with the idea of reducing the speed of disease progression and prevent further losses of neuronal cells

The development of the most advanced of these approaches, which involved immunization with A?, were recently discontinued due to the observation of effects unwanted sides, such as inflammation of the nervous system central (CNS), during Phase II clinical trials. Other approaches such as the use of β-inhibitors and γ-secretase or β-leaf cutters they are promising for the treatment and prevention of the disease of Alzheimer, although they are still in their infancy and at the moment there is no clinical experience available.

In contrast to these approaches, the symptomatic treatment of Alzheimer's disease, in Particular treatment of cognitive deficits has been successfully addressed through the replenishment of deficient neurotransmitters, especially acetylcholine, in the CNS of patients with Alzheimer's disease. So the efforts of research have addressed, among others, the potential Acetylcholinesterase (AChE) inhibitor therapy to slow the progression of the disorder. The approach most established therapeutic for Alzheimer's disease involves the use of a group of indirect cholinomimetic agents with the Pharmacological profile of AChE inhibitors (tacrine, donepezil, rivastigmine and galantamine), which increase the central cholinergic neurotransmission inhibiting the degradation of Acetylcholine

AChE inhibitors have proven to be a class of effective medications to improve cognitive function and activities of daily living, and generally have profiles of favorable tolerability and safety. Recent tests suggest that the AChE enzyme also has secondary functions not cholinergic Thus, while AChE has an activity non-cholinergic neurotrophic, can also play a key role in the development of senile plates, by acceleration of the Aβ deposition.

The design and synthesis of new inhibitors of AChE capable of interacting simultaneously with the active site and with the peripheral site of the AChE enzyme (AChE inhibitors of dual binding site) as drug candidates anti-Alzheimer's with potential to modify the disease currently constitute a very research area intense

Donepezil, the second FDA-approved anti-Alzheimer's drug, is the only dual-binding AChE inhibitor currently marketed, although it was not specifically designed as such. The character of the dual-binding site inhibitor of donepezil may explain its excellent pharmacological profile. On the one hand, donepezil (IC 50 = 5.7 nM, using rat brain AChE) is the AChE inhibitor, licensed for the treatment of mild to moderate cases of Alzheimer's disease, more widely used. On the other hand, in a recent study on the ability of several AChE inhibitors to prevent aggregation of Aβ induced by human recombinant AChE, a significant anti-aggregating effect for donepezil (22% inhibition) was observed, while Specific peripheral site ligands such as propidium showed a greater antiaggregant effect (82% inhibition of aggregation). The superior pharmacological profile of donepezil has stimulated the development of other N- benzylpiperidine derivatives as potential candidates for drugs for the treatment of Alzheimer's disease.

In recent years, several groups of research have described the design, synthesis and evaluation pharmacological of a series of homo- and hetero-dimers  containing two identical or different structural units of known AChE inhibitors linked through a chain oligomethylene The first known AChE inhibitor that was used as a lead in this strategy was the Tacrine, the first drug approved (in 1993) for treatment of Alzheimer's disease, currently largely displaced of the market due to hepatotoxicity induction. A great number of dual binding site AChE inhibitors based on Tacrine have been developed by different groups, some of the which exhibit a very potent Aβ antiaggregant effect. Similarly, tacrine has been used for the design of dual binding site AChE inhibitors in combination with a Donepezil fragment. For example, WO 2004/032929 describes a family of heterodimers, containing the indanone unit of donepezil and a tacrine residue, which behave as inhibitors AChE dual binding site and that can be used for the Alzheimer's disease treatment.

Thus, despite all the efforts of Research carried out in the past, treatment and / or Alzheimer's disease prevention is far from being satisfactory. Therefore, the development of compounds for Alzheimer's disease treatment in humans is still of The most important.

Explanation of the invention.

The inventors have found new compounds that behave as site acetylcholinesterase inhibitors of dual union showing a high potency of inhibition of ACHE Thus, these compounds are very promising agents for Alzheimer's disease treatment.

Thus, according to one aspect of the present invention, a compound of formula (I), or a salt is provided pharmaceutically acceptable thereof, or a solvate thereof, including any stereoisomer or mixture of stereoisomers, where R 1, R 2, R 3 and R 4 are radicals independently selected from the group consisting of H, F, Cl, Br, CF 3, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy and nitro; R 5, R 6, R 7 and R 8 are radicals selected from independent of the group consisting of H and (C 1 -C 6) -alkoxy; n is a integer from 3 to 5; r is an integer from 2 to 5; s is an integer from 1 to 5 and X is a biradical selected from CO and CH2.

one

Preferred compounds of formula (I) are those in which R_ {1}, R_ {2}, R_ {3} and R_ {4} are radicals independently selected from the group that it consists of H, F, Cl and Br; R 5, R 6, R 7 and R 3 are radicals independently selected from the group that It consists of H and methoxy, and s is 1.

More preferred compounds of formula (I) are those in which R2 is selected from H and Cl; R_ {1}, R 3, R 4, R 5 and R 8 are H; R 6 and R 7 are methoxy; n is an integer from 3 to 4; and r is an integer from 2 to 3. Sales Preferred pharmaceutically acceptable compounds of Formula (I) are hydrochloride or dihydrochloride.

The most preferred compounds are those following:

9 - [(2- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine;

6-chloro-9 - [(2- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine;

9 - [(3- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine;

6-chloro-9 - [(3- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine;

9 - [(2- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine;

6-chloro-9 - [(2- (4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl) ethyl) amino] -1,2,3,4- tetrahydroacridine;

9 - [(3- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine; Y

6-chloro-9 - [(3- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4- tetrahydroacridine

Another aspect of the present invention relates to to a process for the preparation of compounds of formula (I), according to Scheme I, which comprises reacting a intermediate of formula (II) with an intermediate of formula (III), where radicals and variables are as defined before to the corresponding compounds, and R 9 is a radical selected from the group consisting of CF_ {3}, (C 1 -C 4) - alkyl, phenyl, and mono- or disubstituted phenyl by a radical selected from (C 1 -C 4) - alkyl, halogen and nitro; n is an integer from 3 to 5; and r is an integer from 2 to 5. When a pharmaceutically acceptable salt is desired, this is obtained by treatment with the corresponding acid. A preferred acid is HCl

Preferably, the sulfonate -OSO 2 R 9 is selected from mesylate (R 9 = -CH 3), tosylate (R 9 = -C 6 H 4 - p -CH_ {3}), besylate (R 9 = -C 6 H 5) and triflate (R 9 = -CF 3), with mesylate being the most preferred.

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Scheme I

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The intermediates of formula (III) can be prepared by reacting an acridine derivative of the formula (V) with an alkanolamine of formula (VI), followed by reaction of the hydroxyl group of the compound obtained with a sulfonyl chloride to give the corresponding sulfonate, according to the Scheme II, where radicals and variables have defined values before.

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Scheme II

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The intermediates of formula (V) are either known in the art or easily prepared by analogy with those known in the art. Intermediates (II) can be obtained by debenzylation of donepezil (R 6 = R 7 = OMe; R 5 = R 8 = H; X = CO; s = 1) or of the analogues Donepezil corresponding.

The compounds of formula (I) can be also obtained through the procedure indicated in the Scheme (III), which comprises reacting an intermediate of formula (VII) with an intermediate of formula (V).

The intermediates of formula (VII) may be prepared by conventional methods from intermediates of formula (II).

Scheme III

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Another aspect of the present invention relates to to a pharmaceutical composition that contains an amount therapeutically effective of a compound of formula (I), or a salt pharmaceutically acceptable thereof, or a solvate thereof, including any stereoisomer or mixture of stereoisomers, together with appropriate amounts of excipients or carriers Pharmacists

Example 17 illustrates that the compounds of the present invention are potent AChE inhibitors (of bovine or human erythrocytes), showing inhibitory concentrations, expressed as IC 50 (nM), which are in the range of 0.09-5 nM, evaluated by the method described by Ellman et al . The IC 50 inhibitory concentrations (nM) of these compounds are considerably lower than those of chlorotacrine or donepezil. Compared with the results of the heterodimers described in WO 2004/032929, also evaluated by the same method of Ellman et al ., The IC 50 (nM) inhibitory concentrations of the compounds of the present invention are also considerably lower. Consequently, these compounds are useful for the treatment of Alzheimer's disease with advantages over those known in the art.

In addition to the AChE inhibitory activity, the inventors have found that the compounds of the present invention also inhibit butyrylcholinesterase (BChE), which may represent an advantage over other anti-Alzheimer's agents known in the art. Recent evidence has shown that, in patients with advanced Alzheimer's disease, AChE activity is greatly reduced in specific regions of the brain, while BChE activity increases (cf. Giacobini, E., Neurochem. Res 2003, vol. 28, pp. 515-522). The increasing importance of BChE in the hydrolysis of the neurotransmitter acetylcholine, as the AChE / BChE ratio gradually decreases in these patients, makes BChE inhibition an important target in the search for new anti-Alzheimer's agents. Compared with chlorotacrine or donepezil, as well as with the heterodimers described in WO 2004/032929, the compounds of the present invention show considerably lower IC 50 (nM) inhibitory concentrations against BChE (from human serum).

Thus, an additional aspect of the present invention refers to the use of the compounds of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate of the themselves, including any stereoisomer or mixture of stereoisomers, for the preparation of a medicament for prophylactic and / or therapeutic treatment of the disease of Alzheimer's in mammals, including humans. The invention it is also related to a method for treatment or prophylaxis of a mammal, including a human being, who suffers or He is susceptible to Alzheimer's disease. Said method comprises administering to said patient a quantity therapeutically effective of a compound of formula (I) defined before, or a pharmaceutically acceptable salt thereof, or a solvate thereof, including any stereoisomer or mixture of stereoisomers, together with excipients or carriers Pharmacists

For those skilled in the art, other objects, advantages and features of the invention will be partly detached of the description and in part of the practice of the invention. At throughout the description and claims the word "understand" and its variants are not intended to exclude other technical characteristics, additives, components or steps. The summary of this application is incorporated here by reference. The following Examples are provided by way of illustration, and are not intended that are limiting of the present invention.

Examples General procedure for the reaction of 9-Chloro-1,2,3,4-tetrahydroacridine or 6,9-dichloro-1,2,3,4-tetrahydroacridine with ome-amino-1-alcohols

A mix of 9-Chloro-1,2,3,4-tetrahydroacridine or 6,9-dichloro-1,2,3,4-tetrahydroacridine  (1 mmol) and excess amino alcohol (3 mmol) in pentanol (1 mL / mmol tetrahydroacridine) was heated to reflux under magnetic stirring for 18 h. The resulting mixture was cooled to room temperature, diluted with CH2Cl2 (3.5 mL / mmol) and washed with aqueous NaOH solution (10%, 3.5 mL) and water (2 x 3 mL / mmol). The Organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo giving an oily residue. Excess of amino alcohol and solvent was removed from the residue by distillation in a rotary microdistiller at 85ºC / 0.8 Torr giving the product replacement as a slightly brown solid residue. The Analytical samples of the hydrochlorides were prepared as follows: The 9 - (? -Hydroxyalkylamino) tetrahydroacridine (1 mmol) was dissolved in methanol (10 mL), the solution was filtered to through a 0.45 µm PTFE filter, and treated with an excess of methanolic HCl solution (3 mmol / mmol) and the solution resulting was concentrated to dryness in vacuo. The solid is recrystallized from a methanol / ethyl acetate mixture in the ratio 1: 4 (5 mL / mmol). The solid was isolated by filtration and dried at 80 ° C / 30 Torr for 48 h, giving the hydrochloride of the 9 - (? -Hydroxyalkylamino) tetrahydroacridine like a slightly brown solid.

The structure of the intermediates and the Compounds of the following Examples have been assigned by 1 H-NMR (500 MHz, CD 3 OD or CDCl 3) and 13 C-NMR (100.6 MHz, CD 3 OD or CDCl 3).

Example 1 9 - [(2-hydroxyethyl) amino] -1,2,3,4-tetrahydroacridine hydrochloride

5

This compound was obtained by the general method described above: from 9-Chloro-1,2,3,4-tetrahydroacridine (3.00 g, 13.8 mmol) and 2-aminoethanol (2.49 mL, 40.6 mmol) was obtained 9 - [(2-hydroxyethyl) amino] -1,2,3,4-tetrahydroacridine (3.07 g, 92% base yield): CCF (silica gel plate), R f = 0.38 (25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the 9: 1 ratio: 0.1). From this compound (239 mg, 0.99 mmol), the corresponding hydrochloride analytical sample was obtained (215 mg, 78% yield): mp 184-185 ° C (MeOH / AcOEt); IR (KBr), nu (cm -1): 3700-2400 (max. To 3358, 3142, 3058, 3016, 2938, 2872; OH, + N-H and C-H st), 1633, 1592, 1577, 1524, 1477, 1447, 1412, 1375, 1352, 1324, 1296, 1253, 1181, 1160, 1057, 986, 946, 869, 831, 779, 758, 706, 680.

Example 2 6-chloro-9 - [(2-hydroxyethyl) amino] -1,2,3,4-tetrahydroacridine hydrochloride

6

This compound was obtained by the general method described above: from 6,9-dichloro-1,2,3,4-tetrahydroacridine (3.00 g, 11.9 mmol) and 2-aminoethanol (2.16 mL, 35.9 mmol) was obtained 6-chloro-9 - [(2-hydroxyethyl) amino] -1,2,3,4-tetrahydroacridine  (3.16 g, 98% base yield): TLC (silica gel plate), R f = 0.42 (25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the 9: 1 ratio: 0.1). From the above compound (150 mg, 0.54 mmol) the analytical sample of the hydrochloride was obtained corresponding (149 mg, 88% yield): mp 221-222 ° C (MeOH / AcOEt); IR (KBr), nu (cm -1): 3600-2400 (max. to 3372, 3291, 3136, 3052, 3009, 2939, 2872, 2784; OH + N-H and C-H st), 1632, 1588, 1573, 1518, 1455, 1365, 1351, 1317, 1291, 1254, 1180, 1084, 1072, 1055, 952, 918, 886, 818, 759, 680, 616.

Example 3 9 - [(3-hydroxypropyl) amino] -1,2,3,4-tetrahydroacridine hydrochloride

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This compound was obtained by the general method described above: from 9-Chloro-1,2,3,4-tetrahydroacridine (1.12 g, 5.14 mmol) and 3-amino-1-propanol (1.16 mL, 15.2 mmol) was obtained 9 - [(3-hydroxypropyl) amino] -1,2,3,4-tetrahydroacridine  (1.25 g, 95% base yield): CCF (silica gel plate), R f = 0.27 (25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the 9: 1 ratio: 0.1). From the above compound (371 mg, 1.45 mmol) the analytical sample of the hydrochloride was obtained corresponding (340 mg, 83% yield): mp 125-126 ° C (MeOH / AcOEt); IR (KBr), nu (cm -1): 3700-2400 (max. at 3283, 3145, 3052, 3020, 2938, 2868, 2806, 2773; OH N + H and C-H st), 1632, 1582, 1528, 1477, 1461, 1448, 1414, 1348, 1323, 1278, 1260, 1180, 1167, 1085, 1071, 1038, 993, 979, 917, 883, 864, 828, 798, 781, 755, 706, 682, 607.

Example 4 6-chloro-9 - [(3-hydroxypropyl) amino] -1,2,3,4-tetrahydroacridine hydrochloride

8

This compound was obtained by the general method described above: from 6,9-dichloro-1,2,3,4-tetrahydroacridine (3.00 g, 11.9 mmol) and 3-amino-1-propanol (2.16 mL, 28.2 mmol) 6-chloro-9 - [(3-hydroxypropyl) amino] -1,2,3,4-tetrahydroacridine (1.25 g, 36% base yield) was obtained: TLC (plate silica gel), R f = 0.32 (CH 2 Cl 2 / MeOH /
25% aqueous NH 4 OH in the ratio 9: 1: 0.1). From the above compound (334 mg, 1.15 mmol) the corresponding hydrochloride analytical sample (270 mg, 72% yield) was obtained: mp 164-165 ° C (MeOH / AcOEt); IR (KBr), ν (cm -1): 3500-2400 (max. To 3353, 3314, 3263, 3131, 3051, 3014, 2936, 2907, 2875, 2845, 2803; OH, + NH and CH st), 1630, 1572, 1526, 1467, 1436, 1421, 1356, 1341, 1322, 1253, 1245, 1184, 1102, 1068, 1056, 948, 881, 818, 760, 726, 709.

General procedure for the mesylation of 9 - (? -Hydroxyalkylamino) -1,2,3,4- tetrahydroacridines

At a cold solution (-10ºC, bath of ice-salt) of the 9 - (? -Hydroxyalkylamino) -1,2,3,4-tetrahydroacridine (1 mmol) and triethylamine (1.7 mmol) in anhydrous CH2Cl2 (6 mL / mmol) methanesulfonyl chloride (1.5) was added dropwise mmol) and the mixture was stirred for 30 min at that temperature. The mixture was concentrated in vacuo, the residue was dissolved in CH 2 Cl 2 (3 mL / mmol) and the organic solution was washed with aqueous NaOH solution (10%, 2 x 3 mL / mmol) until the phase aqueous remained basic (pH> 10), dried with Na2SO4 anhydrous and concentrated in vacuo giving the corresponding mesylate as a brown oily residue. The analytical samples of the mesylates were obtained by treatment of the oily product with ethyl acetate.

Example 5 9 - [(2-methanesulfonyloxyethyl) amino] -1,2,3,4-tetrahydroacridine

9

This compound was obtained by the general method described above: from 9- (2-hydroxyethylamino) -1,2,3,4-tetrahydroacridine (2.15 g, 8.87 mmol), was obtained 9 - [(2-methanesulfonyloxyethyl) amino] -1,2,3,4-tetrahydroacridine (3.13 g, quantitative yield): TLC (silica gel plate), R f = 0.67 (25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the 9: 1 ratio: 0.1). IR (NaCl), ν (cm -1): 3391, 3339 (N-H st), 3092, 3069, 2936, 2866 (C-H st), 1638, 1586, 1524, 1493, 1440, 1413, 1352, 1331, 1194, 1178, 1051, 771.

Example 6 6-chloro-9 - [(2-methanesulfonyloxyethyl) amino] -1,2,3,4-tetrahydroacridine hydrochloride

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This compound was obtained by the general method described above: from 6-Chloro-9- (2-hydroxyethylamino) -1,2,3,4-tetrahydroacridine (2.95 g, 10.7 mmol), was obtained 6-chloro-9 - [(2-methanesulfonyloxyethyl) amino] -1,2,3,4-tetrahydroacridine  (3.72 g, 98% yield): TLC (silica gel plate), R f = 0.63 (25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 9: 1: 0.1). In this case, an analytical sample of the hydrochloride as follows: the above compound (2.59 g, 7.3 mmol) dissolved in methanol (20 mL), the solution was filtered through a 0.45 µm PTFE filter was treated with excess solution methanolic HCl (1.7 M, 14 mL) and the solution was concentrated to vacuum dryness. The solid (2.65 g) was recrystallized from methanol (10 mL). After filtering, the solid was dried at 80 ° C / 30 Torr for 48 h, giving the corresponding hydrochloride as a solid white (2.30 g, 81% yield), mp: 149-150 ° C (MeOH); IR (KBr), \ nu (cm -1): 3700-2500 (max. 3426, 3234, 3114, 3012, 2925, 2798; + N-H and C-H st), 1630, 1606, 1582, 1572, 1487, 1463, 1452, 1409, 1374, 1354, 1161, 1094, 1030, 1002, 983, 933, 916, 874, 804, 762, 733, 671.

Example 7 9 - [(3-methanesulfonyloxypropyl) amino] -1,2,3,4-tetrahydroacridine

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This compound was obtained by the general method described above: from 9- (3-hydroxypropylamino) -1,2,3,4-tetrahydroacridine (433 mg, 1.68 mmol), was obtained 9 - [(3-methanesulfonyloxypropyl) amino] -1,2,3,4-tetrahydroacridine (565 mg, quantitative yield): CCF (silica gel plate), R f = 0.95 (25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the 9: 1 ratio: 0.1). IR (NaCl), ν (cm -1): 3282 (N-H st), 3100, 3065, 2935, 2864 (C-H st), 1639, 1586, 1524, 1501, 1448, 1418, 1352, 1332, 1194, 1174, 1041, 964, 931, 767, 733.

Example 8 6-Chloro-9 - [(3-methanesulfonyloxypropyl) amino] -1,2,3,4-tetrahydroacridine

12

This compound was obtained by the general method described above from 6-Chloro-9- (3-hydroxypropylamino) -1,2,3,4-tetrahydroacridine. The crude product was used in the next stage without further purification (see examples 12 and 16).

General procedure for coupling 9 - (? -Methanesulfonyloxyalkylamino) -1,2,3,4-tetrahydroacridines Y 5,6-dimethoxy-2 - [(4-piperidyl) methyl] indane or 5,6-dimethoxy-2 - [(4-piperidyl) methyl] indan-1-one

A solution of the mesylate (1 mmol), the piperidine derivative (1 mmol) and anhydrous triethylamine (2.5 mmol) in DMSO (8 mL) was heated at 85 ° C for 48 h. The solution was left temper and concentrated in vacuo. The brown oily residue is treated with aqueous NaOH (2 N, 25 mL) and extracted with CH 2 Cl 2 (3 x 35 mL). The combined organic extracts are washed with water (5 x 40 mL) and brine (2 x 30 mL), dried with Anhydrous Na 2 SO 4 and concentrated in vacuo giving a oily residue that was subjected to column chromatography (gel 35-70 µm silica, mixtures CH 2 Cl 2 / methanol / 25% aqueous NH 4 OH as eluent). He product was transformed into the corresponding dihydrochloride as continue: A solution of the base (1 mmol) in methanol (40 mL) is filtered through a 0.45 µm PTFE PTFE filter and treated with excess methanolic HCl solution (5 mmol). Dissolution it was concentrated to dryness in vacuo and the solid residue was recrystallized  of methanol (20 mL). The solid was filtered off and dried at 80ºC / 30 Torr for 48 h.

Example 9 9 - [(2- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} ethyl) -amino] -1,2,3,4-tetrahydroacridine dihydrochloride

13

This compound was obtained by the general method described above from 9- (2-methanesulfonyloxyethylamino) -1,2,3,4-tetrahydroacridine (365 mg, 1.14 mmol) and 4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidine (306 mg, 1.11 mmol). By eluting with a mixture of 25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 99: 1: 0.1, was obtained 9 - [(2- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine (191 mg, 34% yield) as a slightly brown solid: CCF (silica gel plate), R f = 0.68 (25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 90: 10: 0.1). The analytical sample of dihydrochloride was obtained in the form described in the general method: from the base (114 mg, 0.23 mmol) the corresponding dihydrochloride monohydrate was obtained as a pale yellow solid (48 mg, 35% yield), mp 254-255 ° C (methanol). IR (KBr), nu (cm -1): 3700-2400 (max. to 3399, 3245, 2928, 2834; + N-H and C-H st), 1635, 1613, 1584, 1524, 1504, 1452, 1440, 1310, 1226, 1181, 1095, 989, 953, 850, 758, 677.

Example 10 6-Chloro-9 - [(2- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine dihydrochloride

14

This compound was obtained by the general method described above from 6-chloro-9- (2-methanesulfonyloxyethylamino) -1,2,3,4-tetrahydroacridine (386 mg, 1.20 mmol) and 4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidine (300 mg, 1.09 mmol). By eluting with a mixture of 25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 99: 1: 0.1, was obtained 6-Chloro-9 - [(2- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine (165 mg, 28% yield) as a slightly brown solid: CCF (silica gel plate), R f = 0.68 (25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 90: 10: 0.1). The analytical sample of dihydrochloride was obtained as It was described in the general method: from the base (165 mg, 0.31 mmol), the corresponding hydrated dihydrochloride was obtained as a slightly yellow solid (80 mg, 40% yield), mp 159-160 ° C (methanol). IR (KBr), nu (cm -1): 3700-2400 (max at 3414, 3259, 3047, 2932, 2835; + N-H and C-H st), 1631, 1585, 1504, 1451, 1362, 1315, 1252, 1223, 1181, 1094, 949, 886, 839, 760.

Example 11 9 - [(3- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine dihydrochloride

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This compound was obtained by the general method described above from 9- (3-methanesulfonyloxypropylamino) -1,2,3,4-tetrahydroacridine (294 mg, 0.88 mmol) and 4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidine (242 mg, 0.88 mmol). By eluting with a mixture of 25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 99: 1: 0.2, was obtained 9 - [(3- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine (81 mg, 18% yield) as a pale yellow solid: TLC (plate silica gel), R f = 0.66 (CH 2 Cl 2 / MeOH / NH 4 OH 25% aqueous in the ratio 90: 10: 0.1). The analytical sample of dihydrochloride was obtained as described in the general method: a from the base (81 mg, 0.16 mmol), dihydrochloride was obtained corresponding hydrated as a pale yellow solid (95 mg, 93% yield), mp 184-185 ° C (methanol). IR (KBr), nu (cm -1): 3660-2200 (max. to 3370, 2924, 2854, 2706; + N-H and C-H st), 1634, 1588, 1522, 1503, 1455, 1363, 1308, 1249, 1117, 1182, 1093, 1033, 987, 947, 844, 759, 678.

Example 12 6-Chloro-9 - [(3- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine dihydrochloride

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16

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At a cold solution (-10ºC, bath of ice-salt) of 6-Chloro-9- (3-hydroxypropylamino) -1,2,3,4-tetrahydroacridine (1.50 g, 5.16 mmol) and triethylamine (1.20 mL, 8.6 mmol) in CH 2 Cl 2 anhydrous (35 mL), was added dropwise methanesulfonyl (0.65 mL, 8.40 mmol) and the mixture was stirred at that temperature for 30 min. The mixture was concentrated in vacuo, the residue was dissolved in CH2Cl2 (50 mL) and the solution Organic was washed with saturated aqueous NaHCO3 solution (3 x 50 mL) until the aqueous phase remained basic (pH = 10), it dried with anhydrous Na 2 SO 4, and concentrated in vacuo giving a brown oily residue (1.90 g), which contained the mesylate corresponding, which was used as such in the next stage. Part of this product (368 mg, 1.0 mmol) was reacted with 4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidine (271 mg, 0.98 mmol) following the general method described above. To the elute with a mixture of aqueous CH2Cl2 / MeOH / NH4OH at 25% in the 97: 3: 0.2 ratio, was obtained 6-Chloro-9 - [(3- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine (210 mg, 39% yield) as a pale brown solid: TLC (plate silica gel), R f = 0.49 (CH 2 Cl 2 / MeOH / NH 4 OH 25% aqueous in the ratio 90: 10: 0.1). The analytical sample of dihydrochloride was obtained as described in the general method: a from the base (81 mg, 0.15 mmol), the corresponding one was obtained hydrated dihydrochloride as a pale yellow solid (52 mg, 52% yield), mp 173-174 ° C (methanol). IR (KBr), nu (cm -1): 3700-2450 (max at 3401, 2928; N + H and C-H st), 1630, 1581, 1503, 1463, 1451, 1358, 1309, 1250, 1217, 1182, 1093, 988, 949, 880, 759.

Example 13 9 - [(2- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine dihydrochloride

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This compound was obtained by the general method described above from 9- (2-methanesulfonyloxyethylamino) -1,2,3,4-tetrahydroacridine (276 mg, 0.86 mmol) and 4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidine (249 mg, 0.86 mmol). By eluting with a mixture of 25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 99.5: 0.5: 0.4, was obtained 9 - [(2- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine (87 mg, 19% yield) as a pale brown solid: TLC (gel plate silica), R f = 0.91 (CH 2 Cl 2 / MeOH / NH 4 OH aqueous 25% in the ratio 90: 10: 0.1). The analytical sample of dihydrochloride was obtained as described in the procedure general: from the base (54 mg, 0.10 mmol), the corresponding hydrated dihydrochloride as a yellow solid pale (62 mg, 98% yield), mp 190-191 ° C (methanol). IR (KBr), nu (cm -1): 3700-2400 (max. At 3401, 2928, 2871, 2718; N + H and C-H st), 1685, 1672 (C = O st), 1636, 1588, 1523, 1500, 1458, 1363, 1317, 1266, 1220, 1120, 1037, 949, 863, 760.

Example 14 6-chloro-9 - [(2- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4- tetrahydroacridine dihydrochloride

18

This compound was obtained by the general method described above, from 6-chloro-9- (2-methanesulfonyloxyethylamino) -1,2,3,4-tetrahydroacridine (305 mg, 0.86 mmol) and 4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidine (248 mg, 0.86 mmol). By eluting with a mixture of 25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 99.2: 0.8: 0.4, was obtained 6-chloro-9 - [(2- {4 - [(5,6-dimethoxy-1-oxoindan-2-i) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4- tetrahydroacridine (178 mg, 38% yield) as a pale brown solid: TLC (plate silica gel), R f = 0.94 (CH 2 Cl 2 / MeOH / NH 4 OH 25% aqueous in the ratio of 90: 10: 0.1). The analytical sample of the dihydrochloride was obtained as described in the method general: from the base (168 mg, 0.31 mmol), the corresponding hydrated dihydrochloride as a beige solid (65 mg, 33% yield), mp 222-223 ° C (methanol). GO (KBr) \ nu (cm -1): 3700-2400 (max. A 3375, 3259, 3125, 3051, 2927, 2854, 2792; + N-H and C-H st), 1687 (C = O st), 1633, 1588, 1501, 1456, 1363, 1316, 1266, 1220, 1179, 1121, 1091, 1036, 949, 917, 884, 759

Example 15 9 - [(3- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine dihydrochloride

19

This compound was obtained by the general method described above, from 9- (3-methanesulfonyloxypropylamino) -1,2,3,4-tetrahydroacridine (80 mg, 0.24 mmol) and 4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidine (82 mg, 0.28 mmol). By eluting with a mixture of 25% aqueous CH 2 Cl 2 / MeOH / NH 4 OH in the ratio 98: 2: 0.5, was obtained 9 - [(3- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine (87 mg, 68% yield) as a pale brown solid: TLC (plaque silica gel), R f = 0.46 (CH 2 Cl 2 / MeOH / NH 4 OH 25% aqueous in the 9: 1 ratio: 0.1). The analytical sample of dihydrochloride was obtained according to the general method: from the base (50 mg, 0.095 mmol), hydrated dihydrochloride was obtained corresponding as a pale yellow solid (37 mg, 60% yield), mp 198-199 ° C (methanol). IR (KBr), nu (cm -1): 3700-2400 (max at 3435, 2930, 2706; <+> N-H and C-H st), 1690 (C = O st), 1636, 1590, 1522, 1500, 1458, 1364, 1316, 1265, 1121, 1036, 759.

Example 16 6-chloro-9 - [(3- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4- tetrahydroacridine dihydrochloride

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At a cold solution (-10ºC, bath of ice-salt) of 6-Chloro-9- (3-hydroxypropylamino) -1,2,3,4-tetrahydroacridine (1.50 g, 5.16 mmol) and triethylamine (1.20 mL, 8.6 mmol) in CH 2 Cl 2 anhydrous (35 mL), was added dropwise methanesulfonyl (0.65 mL, 8.40 mmol) and the mixture was stirred at that temperature for 30 min. The mixture was concentrated in vacuo, the residue was dissolved in CH2Cl2 (50 mL) and the solution Organic was washed with saturated aqueous NaHCO3 solution (3 x 50 mL) until the aqueous phase remained basic (pH = 10), it dried with anhydrous Na 2 SO 4, and concentrated in vacuo giving a brown oily residue (1.90 g), containing the mesylate corresponding, which was used as such in the next stage. Part of this product (506 mg, 1.37 mmol) was reacted with 4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidine (470 mg, 1.62 mmol) following the general method described above: elution with a mixture of aqueous CH2Cl2 / MeOH / NH4OH at 25% in the ratio 98: 2: 0.2, was obtained 6-chloro-9 - [(3- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4- tetrahydroacridine (254 mg, 33% yield) as a pale brown solid: TLC (plate silica gel), R f = 0.52 (CH 2 Cl 2 / MeOH / NH 4 OH 25% aqueous in the 9: 1 ratio: 0.1). The analytical sample of dihydrochloride was obtained as described in the general method: a from the base (254 mg, 0.45 mmol), dihydrochloride was obtained corresponding hydrated as a pale yellow solid (212 mg, 68% yield), mp 185-186 ° C (methanol). IR (KBr), nu (cm -1): 3700-2400 (max. to 3402, 3263, 3071, 3039, 2925, 2842; + N-H and C-H st), 1695 (C = O st), 1631, 1608, 1590, 1556, 1501, 1462, 1357, 1313, 1264, 1218, 1124, 1036, 971, 948, 882, 803, 758

Example 17 Biochemical studies

AChE inhibitory activity was evaluated spectrophotometrically at 25 ° C by the method of Ellman (see Ellman et al ., Biochem. Pharmacol . 1961, vol. 7, p. 88), using AChE substrate of bovine or human erythrocytes and acetylthiocholine iodide (0.53 mM or 0.27 mM for bovine and human AChE, respectively). The reaction took place in a final volume of 3 mL of 0.1 M phosphate buffer solution pH 8.0, containing 0.025 units of AChE and a 333 µM solution of 5,5'-dithiobis (2-nitrobenzoic acid) was used ( DTNB) to produce the yellow anion of 5-thio-2-nitrobenzoic acid The inhibition curves were carried out in triplicate by incubating with at least 12 inhibitor concentrations for 15 min A triplicate sample without inhibitor was always present to know 100% AChE activity The reaction was stopped by the addition of 100 µL of 1 mM serine, and the color production was determined at 414 nm. BChE inhibitory activity determinations were performed similarly, using 0.035 units of human serum BChE and 0.56 mM butyrylthiocholine, instead of AChE and acetylthiocholine, in a final volume of 1 mL.

The data from the experiments inhibitor concentration-inhibition were calculated by non-linear regression analysis, using the GraphPad Prism program package (GraphPad Software; San Diego, USA), which gives estimates of IC50 (concentration of drug that produces 50% inhibition of enzyme activity). The results are expressed as mean ± S.E.M. of at least 4 experiments carried out in triplicate. DTNB, acetylthiocholine, butyrylthiocholine, and the enzymes were purchased from Sigma and the eserine at Fluka

TABLE 1 Pharmacological data of the new heterodimers donepezil-tacrine, and tacrine, 6-chlorotacrine and donepezil as compounds of reference. Values are expressed as mean ± standard error from the average of at least four experiments. Concentration IC 50 inhibitor (nM) of AChe (erythrocyte) activity bovine or human) or BChE (serum human)

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Claims (16)

1. Compound of formula (I), or a salt pharmaceutically acceptable thereof, or a solvate thereof, including any stereoisomer or mixture of stereoisomers, where:

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R 1, R 2, R 3, and R 4 are radicals independently selected from the group consisting of H, F, Cl, Br, CF 3,
(C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, and nitro; R 5, R 6, R 7, and R 8 are radicals independently selected from the group consisting in H and (C 1 -C 6) -alkoxy; n is an integer from 3 to 5; r is an integer from 2 to 5; s is an integer from 1 to 5; Y X is a birradical selected from CO and CH_ {2}. 2. Compound according to claim 1, where: R 1, R 2, R 3, and R 4 are radicals independently selected from the group consisting in H, F, Cl and Br; R 5, R 6, R 7 and R 8 are radicals independently selected from the group consisting in H and methoxy; Y s is 1. 3. Compound according to claim 2, wherein R2 is selected from H and Cl; R1, R3, R4, R5 and R8 are H; R 6 and R 7 are methoxy; n is an integer from 3 to 4; Y r is an integer from 2 to 3. 4. Compound according to claim 3, which is 9 - [(2- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine. 5. Compound according to claim 3, which is 6-chloro-9 - [(2- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine. 6. Compound according to claim 3, which is 9 - [(3- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4-tetrahydroacridine. 7. Compound according to claim 3, which is 6-chloro-9 - [(3- {4 - [(5,6-dimethoxyindan-2-yl) methyl] piperidin-1-yl} pro
pil) amino] -1,2,3,4-tetrahydroacridine. 8. Compound according to claim 3, which is 9 - [(2- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4-tetrahydroacridine. 9. Compound according to claim 3, which is 6-chloro-9 - [(2- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} ethyl) amino] -1,2,3,4- tetrahydroacridine 10. Compound according to claim 3, which is 9 - [(3- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} pro
pil) amino] -1,2,3,4-tetrahydroacridine. 11. Compound according to claim 3, which is 6-chloro-9 - [(3- {4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidin-1-yl} propyl) amino] -1,2,3,4- tetrahydroacridine 12. Compound according to any of the claims 1-11, wherein the salt Pharmaceutically acceptable is hydrochloride or dihydrochloride. 13. Procedure for the preparation of a compound as defined in any of the claims 1-12, which comprises reacting an intermediate of formula (II)

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2. 3

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with an intermediate of formula (III),

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and optionally deal with the acid pharmaceutically acceptable to form the salt correspondent;

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where R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, n, r, s and X have the values that have been defined in the compound claim correspondent; and R_ {9} is a radical selected from the group that consists of CF 3, (C 1 -C 4) - alkyl, phenyl, and mono- or disubstituted phenyl by a radical selected from (C 1 -C 4) - alkyl, halogen and nitro.

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14. Procedure for the preparation of a compound as defined in any of the claims 1-12, which comprises reacting an intermediate of formula (VII), 25 with an intermediate of formula (V), 26 and optionally deal with an acid pharmaceutically acceptable to form the salt correspondent; where R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, n, r, s and X have the values defined in the corresponding compound claim. 15. Use of the compounds defined in any of claims 1-12, for the preparation of a medicine for the treatment and / or prevention of Alzheimer's disease in a mammal, including a being human. 16. Pharmaceutical composition comprising a therapeutically effective amount of a compound defined in any of claims 1-12, together with the appropriate amounts of excipients or carriers pharmaceutically acceptable.