WO2014129989A1

WO2014129989A1 - 3-substituted-6h-benzo[c]chromen-6-ones and 3-substituted-7,8,9,10-tetrahydro-6h-benzo[c]chromen-6-ones against senile dementia

Info

Publication number: WO2014129989A1
Application number: PCT/TR2014/000027
Authority: WO
Inventors: Serdar Unlu; Ilker ESIRINGU; Yasemin SAHIN; Tugba ERCETIN; Demet OZ; Fethi SAHIN
Original assignee: Fargem Farmasöti̇k Araştirma Geli̇şti̇rme Merkezi̇ Sanayi̇ Ve Ti̇caret A.Ş.
Priority date: 2013-02-21
Filing date: 2014-02-06
Publication date: 2014-08-28
Also published as: EP2958906A1

Abstract

This invention is related with the conversion of xenobiotics to potent ACHE and BCHE inhibitors that have activity comparable to the current ACHE and BCHE inhibitor drugs (i.e., donepezil, rivastigmine, and galantamine).

Description

3-SUBSTITUTED-6H-BENZO[C]CHROMEN-6-ONES AND 3-SUBSTITUTED- 7,8,9,10-TETRAHYDRO-6H-BENZO[C]CHROMEN-6-ONES AGAINST

SENILE DEMENTIA

This invention relates to novel 3-substituted-6H-benzo[c]chromen-6-one and 3-substituted- 7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one compounds which are useful as pharmaceutical compositions. This invention further relates to pharmaceutical compositions having benefit in the therapy for the senile dementia, such as Alzheimer senile dementia.

Insufficiency in cognition has serious deleterious effects in life quality and expectancy of sufferers, concomitant to negative effects on patient relatives, and caregivers. Indeed, cognition deeply defines the social lives, natural habits, behaviors, and personal characteristics. The mental processes such as interaction (i.e., understanding, speaking, observation) with the environment, attention, problem-solving, remembering, reminding are all parts of cognition and a disability in cognition results in decline of previously-known personal characteristics. Thus, serious loss in cognitive abilities produces dementia.

Although dementia can be seen independent from aging, senile dementia is the most common form in populations. It has variations depending on its etiology, but in particular, the Alzheimer senile dementia is the most common form. Numerous attempts have been examined so far not only to treat the symptoms of the disease but also to figure out the mechanism underlying in the formation of Alzheimer's disease. However, today, there is no single or combination drug that completely treats the Alzheimer's disease and the accompanying dementia. Therefore, there is a need to provide novel medicines in the treatment of the symptoms of Alzheimer's disease, particularly, the accompanying the Alzheimer senile dementia. This is also of particular interest since the aging of population in most developed and undeveloped countries is increasing, and the incidence of Alzheimer's disease arises from 10% to 35% of population for the people aged from 65 to 85 years old. In addition, dementia associated decline in cognitive abilities requires serious patient healthcare which brings together heavy economical and socioeconomic burdens not only to patient relatives but also to national health economics of countries worldwide. Therefore, there is a certain need to new medicines that prevents the continuous decline in cognition of sufferers having dementia, in particular the Alzheimer senile dementia.

Furthermore, quite a few drugs (i.e., donepezil, rivastigmine, galantamine) are currently on the market for the treatment of the cognition symptoms of dementia, and in particular, the Alzheimer's disease accompanying dementia. Although these drugs are prescribed worldwide in the relieving of dementia symptoms of Alzheimer's disease, their clinical efficiency shows great variance among patients. In addition to that, the clinical data also points out that their benefit is limited with time, generally less than 2 years, which means less beneficiary effect is seen with these drugs after sometime following the starting of the treatment. This also indicates the need for new drugs that might possess different characteristics in terms of the prevention of cognitive decline as well as the conservation of the cognitive status from getting worse in a longer period of treatment.

Cholinergic hypothesis has long been known and employed in the treatment of Alzheimer's disease associated dementia. Indeed, besides the NMDA receptor antagonist drug memantine, all currently prescribed drugs (i.e., donepezil, rivastigmine, and galantamine) have been developed to inhibit one of the or both the acetylcholine hydrolyzing enzymes (i.e., Acetylcholinesterase (ACHE), and Butyrylcholinesterase (BCHE)) to increase the levels of acetylcholine, since cholinergic insufficiency is known to associate in cognitive decline. However, these drugs have quite different characteristics in terms of the inhibition of the two enzymes. First of all, galantamine and donepezil are ACHE selective inhibitors, since their selectivity is around 30 and 800 times more for ACHE, respectively. In addition, they have quite distinctive IC50 values, since donepezil has an IC50 for ACHE at a very low nM level in comparison to the IC50 of galantamine for ACHE which is close to 1 μΜ level. Moreover, IC50 of rivastigmine for the both enzymes are above 10 μΜ level, although this drug has selectivity for BCHE. This definitely indicates the need of novel medicines having the potential to inhibit the both enzymes with less selectivity. Furthermore there is also need for new drugs that possess IC50 values for both enzymes at low μΜ levels. Moreover, there is a need for new drugs that have from high n to low μΜ IC₅o values to inhibit BCHE.

Hydroxylated-6H-benzo[c]ch^'romen-6-ones, also referred to as urolithins, are ellagitannin and ellagic acid-derived metabolites produced by human colonic microflora following the digestion of most of the berries, walnut, and pomegranate. The ability of these xenobiotics in neuroprotection and their possible beneficiary effects on cognitive skills have been studied. However, urolithins are not potential inhibitors of ACHE and BCHE enzymes in comparison to the current ACHE and BCHE inhibitor drugs (i.e., donepezil, rivastigmine, and galantamine). Therefore, urolitihins have no use in the treatment of dementia, particularly the Alzheimer senile dementia, via the employment of the cholinergic hypothesis that involves the inhibition of ACHE and BCHE enzymes. Furthermore, urolithins are not drugs used in the treatment of dementia, particularly in Alzheimer senile dementia.

Surprisingly by the present invention, these xenobiotics can be converted to potent ACHE and BCHE inhibitors that have activity comparable to the current ACHE and BCHE inhibitor drugs (i.e., donepezil, rivastigmine, and galantamine).

Thus according to the present invention there is now provided the compounds of general formula I

Formula wherein: A and B together form benzene or cyclohexane; n is the number of carbon atoms. Preferably n is from 2 to 6. Most preferably n is from 2 to 4;

R is selected from:

CH₃

N

\

Ri

wherein Ri is a lower alkyl group, cyclohexyl group, benzyl group, and 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof.

In one embodiment of the present invention there 3-Aminoalkyloxy-Substituted-6H- benzo[c]chromen-6-one compounds having the general formula II or the pharmacologically acceptable salts thereof are provided:

Formula II wherein: n is the number of carbon atoms. Preferably n is from 2 to 6. Most preferably n is from 2 to 4. R is selected from: \

R

Preferable compounds of the invention bearing the formula II structure include: 3- 2-(benzyl(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one

3- 3-(benzyl(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one

3- 4-(benzyl(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one

2-((3-methoxybenzyl)(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one

3-((3-methoxybenzyl)(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one 3- 4-((3-methoxybenzyl)(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one

2-(4-benzylpiperidin-1 -yl)ethoxy)-6H-benzo[c]chromen-6-one

3- 3-(4-benzylpiperidin-1 -yl)propoxy)-6H-benzo[c]chromen-6-one

3- 4-(4-benzylpiperidin-1 -yl)butoxy)-6H-benzo[c]chromen-6-one

3- 2-(4-(3-methoxybenzyl)piperidin-1 -yl)ethoxy)-6H-benzo[c]chromen-6-one 3- 3-(4-(3-methoxybenzyl)piperidin-1 -yl)propoxy)-6H-benzo[c]chromen-6-one

4-(4-(3-methoxybenzyl)piperidin-1-yl)butoxy)-6H-benzo[c]chromen-6-one

2-(4-benzylpiperazin-1 -yl)ethoxy)-6H-benzo[c]chromen-6-one

3-(4-benzylpiperazin-1 -yl)propoxy)-6H-benzo[c]chromen-6-one 3-(4-(4-benzylpiperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one 3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one 3-(3-(4-(3-rnethoxybenzyl)piperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one 3-(4-(4-(3-methoxybenzyl)piperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one

In the other embodiment of the present invention 3-Aminoalkyloxy-Substituted-7,8,9,10- tetrahydro-6H-benzo[c]chromen-6-one compounds having the general formula III or a pharmacologically acceptable salts thereof are provided:

Formula III wherein: n is the number of carbon atoms. Preferably n is from 2 to 6. Most preferably n is from 2 to 4.

R is selected from:

CH₃

N

\

Ri

wherein Ri is a lower alkyl group, cyclohexyl group, benzyl group, and 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof. Preferable compounds of the invention bearing the formula III structure include:

3-(2-(benzyl(methyl)amino)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-(3-(benzyl(methyl)amino)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-(4-(benzyl(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one

3-(3-((3-methoxybenzyl)(methyl)amino)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one

3-(4-((3-methoxybenzyl)(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one

3-(2-(4-benzylpiperidin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one

3-(3-(4-benzylpiperidin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-(4-(4-benzylpiperidin-1-yl)butoxy)-7,8,9_l10-tetrahydro-6H-benzo[c]chromen-6-one

3-(2-(4-(3-methoxybenzyl)piperidin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one

3-(3-(4-(3-methoxybenzyl)piperidin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one

3-(4-(4-(3-methoxybenzyl)piperidin-1-yl)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one

3-(2-(4-benzylpiperazin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one

3-(3-(4-benzylpiperazin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-(4-(4-benzylpiperazin-1 -yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one

3-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one 3-(3-(4-(3-methoxybenzyl)piperazin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen- 6-one

3-(4-(4-(3-methoxybenzyl)piperazin-1-yl)butoxy)-7,8,9 0-tetrahydro-6H-benzo[c]chromen-6- one

In addition, the present invention provides a therapeutically composition which comprises a pharmacologically effective amount of the compound having the formula II or formula III or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier and then a method for preventing and treating a disease due to acetylcholinesterase or butyryicholinesterase activity by administering to a human patient the compound having the formula II or formula III or a pharmacologically acceptable salts thereof.

The compound of the present invention may be prepared by various processes.

A process for the preparation of formula II

wherein: n is the number of carbon atoms. Preferably n is from 2 to 6. Most preferably n is from 2 to 4. R is selected from:

CH₃

N I

\

R

and Ri is a lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof, comprises the steps where resorcinol is reacted with a halo benzoic acid compound to obtain the compound of formula IV;

IV alkylation of the compound IV with appropriate alkyl halide to obtain the compound of formula V,

V

n=2,3,4

X= -CI, -Br, -I and reaction of the compound V with an appropriate amine compound.

The general process for the manufacture of compounds having general formula II is given figure 1 :

IV

n=2,3,4

X= -Ci, -Br, -I

Y= -CI, -Br, -I

6H-benzo(c)-chromen-6-one compounc

-N N-R

lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group

Figure 1

A process for the preparation of formula

wherein: n is the number of carbon atoms. Preferably n is from 2 to 6. Most preferably n is from 2 to 4.

R is selected from:

-N N-R and Ri is a lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof, comprises the steps where resorcinol is reacted with ethyl 2-oxocyclohexanecarboxylate to obtain the compound of formula VI;

VI alkylation of the compound VI with appropriate alkyl halide to obtain the compound of formula

VII

n=2,3,4

X= -CI, -Br, -I and reaction of the compound VII with an appropriate amine compound.

The general process for the manufacture of compounds having general formula III is given in figure 2:

n=2,3,4

X= -CI, -Br, -I

Y= -CI, -Br, -I

7,8,9, 10-tetrahydro-6H-benzo(c)-chromen-6-one compounc

— N N-R«

Ri: a lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group

Figure 2

Representative examples for the preparation of the compound having the formula II, or formula III are described below.

Example 1 :

3-hydroxy-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one A mixture of resorcinol (5.0 gram, 45.45 mmol) and ethyl 2-oxocyclohexanecarboxylate (7.73 gram, 45.45 mmol) is heated at 70°C in the presence of zirconium (IV) chloride (1.06 gram, 10 mol%). After completion of the reaction, the reaction mixture is cooled to room temperature and poured onto crushed ice (200 g). The solid product obtained is filtered off, and washed with ice-cold water. Yield obtained: 91 %, H NMR (DMSO) δ 1.68-1.73 (m, 4H), 2.27-2.40 (m, 2H), 2.62-2.76 (m, 2H), 6.65 (d, 1 H), 6.74 (dd, 1 H), 7.47 (d, 1 H), 10.35 (s, 1 H).

Example 2:

3-hydroxy-6H-benzo[c]chromen-6-one

A mixture of 2-lodobenzoic acid (30 gram, 0.12 mol), resorcinol (40 gram, 0.36 mol), and NaOH (17.4 g, 0.44 mol) in water (150 mL) is heated under reflux for 30 min. After the addition of aqueous CuS0₄ (28%, 25 mL) the mixture is refluxed for additional 10 min, during which time the product (0.62 g) precipitates as a white powder. The precipitate is filtered and washed with cold water. Yield obtained: 80.1 %, ¹H NMR (DMSO) δ 6.71 (d, 1 H), 6.80 (dd, 1H), 7.51 (t, 1 H), 7.83 (t, 1 H), 8.08-8.22 (m, 3H ), 10.32 (s, 1 H). Example 3:

3-(2-chloroethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

Na(s) (1.9 gram, 82.6 mmol) is dissolved in 50 mL dry ethanol to give NaOEt solution. To 3- hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (15 gram, 69.4 mmol) solution in 150 mL Ethanol, previously prepared NaOEt solution is added at ambient temperature. Ethanol is distilled out under reduced vacuum and then 100 mL dry DMF is added onto the residue. 100 mL 1 ,2-dichloroethane is put into the reaction mixture and the content is refluxed for 7 hours. The reaction mixture is cooled to room temperature and it is poured onto 250 mLcold 0.8 N NaOH solution. 100 mL 1 ,2-dichloroethane is added to the medium and organic phase is separated. Then, the aqueous phase is extracted with additional 1 ,2- dichloroethane (2x50 mL). Combined organic extracts are washed with water, dried over MgS0₄ and concentrated under reduced pressure to give the white solid product. Yield obtained: 49.6 %. (300 MHz, CDCI₃, ppm): δ 1.69-1.82 (m, 4H), 2.41-2.54 (m, 2H), 2.62-2.73 (m, 2H ), 3.79 (t, 2H ), 4.21 (t, 2H ), 6.72 (d, 1 H), 6.80 (dd, 1 H), 7.40 (d, 1 H). Example 4:

3-(3-chloropropoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (10 gram, 46.2 mmol) and NaH (2.76 gram, 69 mmol) are mixed in 40 mL DMF. 1-bromo-3-chloropropane (18.17 gram, 115.5 mmol) is added to this mixture and the reaction is mixed at ambient temperature for 6 hours. After completion of the reaction, the reaction mixture is poured onto 200 mL cold 15% NaOH solution. The mixture is mixed for 5 min and then 50 mL of hexane is added. The solid product precipitated is filtered and washed with cold water. Yield obtained: 81.2% (300 MHz, CDCI₃, ppm): δ 1.68-1.82 (m, 4H), 2.20 (p, 2H), 2.47-2.51 (m, 2H ), 2.65-2.70 (m, 2H), 3.70 (t, 2H ), 4.09 (t, 2H ), 6.73-6.79 (m, 2H),7.39 (d, 1H).

Example 5:

3-(4-chlorobutoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-(4-chlorobutoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 4, except the employment of 1-bromo-4-chlorobutane instead of 1-bromo-3-chloropropane. Yield obtained: 82.5 %. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.58-1.72 (m, 4H), 1.73-2.06 (m, 4H), 2.37-2.56 (m, 2H ), 2.57-2.76 (m, 2H), 3.56 (t, 2H ), 3.96 (t, 2H ), 6.61-6.79 (m, 2H), 7.37 (d, 1 H).

Example 6:

3-(2-chloroethoxy)-6H-benzo[c]chromen-6-one 3-(2-chloroethoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 3, except the employment of 3-hydroxy-6H-benzo[c]chromen-6-one instead of 3- hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one. Yield obtained: 46.8 %. ¹H NMR (300 MHz, CDCI3, ppm): δ 3.80 (t, 2H), 4.23 (t, 2H), 6.79 (d, 1 H), 6.87 (dd, 1 H), 7.45 (dt, 1H), 7.72 (dt, 1 H), 7.87- 7.95 (m, 2H), 8.28 (dd, 1 H). Example 7:

3-(3-chloropropoxy)-6H-benzo[c]chromen-6-one 3-(3-chloropropoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 4, except the employment of 3-hydroxy-6H-benzo[c]chromen-6-one instead of 3- hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one. The reaction is completed in 40 min. Yield obtained: 79.3 %. H NMR (300 MHz, CDCI_3> ppm): δ 2.22 (p, 2H), 3.71 (t, 2H), 4.12 (t, 2H), 6.79(d, 1 H), 6.84 (dd, 1 H), 7.44 (t, 1 H), 7.72 (tt, 1 H), 7.86-7.94 (m, 2H) 8.28 (dd, 1 H).

Example 8:

3-(4-chlorobutoxy)-6H-benzo[c]chromen-6-one

3-(4-chlorobutoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 4, except the employment of 3-hydroxy-6H-benzo[c]chromen-6-one instead of 3- hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one. The reaction is completed in 40 min. Yield obtained: 83.6 %. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.89-1.99 (m, 4H), 3.56-3.60 (m, 2H), 3.98-4.01 (m, 2H), 6.77 (d, 1 H), 6.83 (dd, 1 H), 7.43 (dt, H), 7.71 (dt, 1 H), 7.86 (d, 1 H), 7.93 (d, 1 H), 8.28 (dd, 1 H). Example 9: THU-2C-BA

3-(2-(benzyl(methyl)amino)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

A mixture of 0.76 gram 3-(2-chloroethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2.73 mmol), 0.6 gram K₂C0₃ (4.34 mmol), and 0.6 gram Nal (4.00 mmol) in ACN (10 mL) is mixed for 5 minutes. Then, 0.992 gram N-Methylbenzylamine (8,19 mmol) is added and the resulting content is mixed for additional 2 minutes. The reaction is heated to reflux for 12 h. Following that, acetonitrile is distilled out under vacuum and the residue thus obtained is mixed with 20 mL of K₂C0₃ solution (5.0 %) and this mixture is heated at 60^°C for 1 hour. Then the mixture is cooled down to room temperature and the aqueous phase is extracted 3 times with 20 mL of ethylacetate. Combined organic extracts are dried and concentrated under reduced pressure to give the product. Yield obtained: 75.1%, ¹H NMR (300 MHz, CDCI3, ppm): δ 1.71-1.80 (m, 4H), 2.31 (s, 3H), 2.43-2.54 (m, 2H), 2.62-2.73 (m, 2H), 2.80 (t, 2H), 3.58 (s, 2H), 4.06 (t, 2H), 6.71 (d, 1H), 6.76 (dd, 1 H), 7.15-7.31 (m, 5H), 7.37 (d, 1 H). Example 10: THU-2C-BAHCI

3-(2-(benzyl(methyl)amino)ethoxy)-7,8₎9, 10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride

HCI gaseous is passed through 2.72 gram (7,49 mmol) 3-(2-benzyl(methyl)amino)ethoxy)- 7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one solution in dry acetone (10 mL) until salt precipitation takes place. The content is mixed for additional 1 hour and then filtrated. The filtrate is washed with acetone and water, and dried at 40 under vacuum. Yield obtained: 83.3%, HPLC purity: 99.67%, HRMS(EI) C23H26NO3 calcd 364.1913 (M+), found 364.1909, DSC: 196.0Ό. Example 1 1 : THU-2C-MBA

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one is synthesized according to procedure given in Example 9 . Yield obtained: 68.1 %. H NMR (300 MHz, CDCI3, ppm): δ 1.71-1.80 (m, 4H), 2.35 (s, 3H), 2.42-2.55 (m, 2H), 2.63-2.72 (m, 2H), 2.84 (brs, 2H), 3.60 (s, 2H), 3.75 (s, 3H), 4.10 (t, 2H), 6.71-6.79 (m, 3H), 6.83-6.91 (m, 2H), 7.18( t, 1 H), 7.38 (d, 1 H).

Example 12: THU-2C-MBA.HCI

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 90.1 %, HPLC purity: 99.98%, HRMS(ESI) C24H28NO4 calcd 394.2018 [M+H]⁺, found 394.2000, DSC: 176.5'C. Example 13: THU-2C-BPP

3-(2-(4-benzylpiperidin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one 3-(2-(4-benzylpiperidin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 66.3%. ¹H NMR (300 MHz, CDCI3, ppm): δ 1.32-1.45 (m, 2H), 1.46-1.53 (m, 1H), 1.57 (d, 2H), 1.63-1.78 (m, 4H), 2.05 (t, 2H), 2.39-2.54 (m, 4H), 2.62-2.73 (m, 2H), 2.81 (t, 2H), 2.99 (d, 2H), 4.13 (t, 2H),

6.72 (d, 1 H), 6.77 (dd, 1H), 7.06-7.15 (m, 3H), 7.18-7.24 (m, 2H), 7.37 (d, 1H).

Example 14: THU-2C-BPP.HCI

3-(2-(4-benzylpiperidin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride

3-(2-(4-benzylpiperidin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 87.4%, HPLC purity: 99.85 %, HRMS(ESI) C27H32NO3 calcd 418.2382 [M+H]⁺, found 418.2392, DSC: 153.1°C.

Example 15: THU-2C-MBPP

3-(2-(4-(3-methoxybenzyl)piperidin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one

3-(2-(4-(3-methoxybenzyl)piperidin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one is synthesized according to procedure given in Example 9. Yield obtained: 76.1. %,¹H NMR (300 MHz, CDCI3, ppm): 51.28-1.36 (m, 2H), 1.44-1.52 (m, 1 H), 1.60 (d, 2H), 1.71- 1.79 (m, 4H), 2.02 (t, 2H), 2.44-2.50 (m, 4H), 2.62-2.71 (m, 2H), 2.76 (t, 2H), 2.94 (d, 2H),

3.73 (s, 3H), 4.08 (t, 2H), 6.62-6.78 (m, 5H), 7.12 (t, 1H), 7.37 (d, 1H).

Example 6: THU-2C-MBPP. HCI

3-(2-(4-(3-methoxybenzyl)piperidin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride

3-(2-(4-(3-methoxybenzyl)piperidin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride was synthesized according to procedure given in Example 10. Yield obtained: 88.3%, HPLC purity: 99.66%, HRMS(ESI) C28H34 O4 calcd 448.2488 [M+H]⁺, found 448.2496, DSC: 101.9°C. Example 17: THU-2C-BPZ

3-(2-(4-benzylpiperazin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 70.3%. H NMR (300 MHz, CDCI₃, ppm): δ 1.69-1.81 (m, 4H), 2.35-2.62 (m, 10H), 2.63-2.70 (m, 2H), 2.78 (t, 2H), 3.46 (s, 2H), 4.07(t, 2H), 6.71 (d, 1H), 6.76 (dd, 1H), 7.15-7.27 (m, 5H), 7.36 (d, 1 H).

Example 18: THU-2C-BPZ.2HCI

3-(2-(4-benzylpiperazin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one dihydrochloride

3-(2-(4-benzylpiperazin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 88.8%, HPLC purity: 99.70%, HRMS(ESI) C26H31N2O3 calcd 419.2335 [M+H]⁺, found 419.2333, DSC: 129.6°C, and 133.5°C.

Example 19: THU-2C-MBPZ

3-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)ethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one

3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one is synthesized according to procedure given in Example 9. Yield obtained: 66.3%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.71-1.79 (m, 4H), 2.38-2.63 (m, 10H), 2.64-2.73 (m, 2H), 2.78 (t, 2H), 3.44 (s, 2H), 3.74 (s, 3H), 4.07 (t, 2H), 6.69-6.88 (m, 5H), 7.16 (t, 1H), 7.37 (d, 1H).

Example 20: THU-2C-MBPZ.2HCI

3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)ethoxy)-7, 8,9,10-tetrahydro-6H-benzo[c]chromen-6- one dihydrochloride

3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 80.3%, HPLC purity: 100.0%, HRMS(ES!) C27H33N2O4 calcd 449.2440 [M+H]⁺, found 449.2453, DSC: 125.6°C.

Example 21 : THU-3C-BA

3-(3-(benzyl(methyl)amino)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one 3-(3-(benzyl(methyl)amino)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 69.3 %. ¹H NMR (300 MHz, CDCI3, ppm): δ 1.66-1.89 (m, 4H), 1.90-2.08 (m, 2H), 2.22 (s, 3H), 2.40-2.62 (m, 4H), 2.63-2.79 (m, 2H), 3.50 (s, 2H), 4.02 (t, 2H), 6.67-6.82 (m, 2H), 7.12-7.33 (m, 5H), 7.34-7.46 (m, 1 H). Example 22: THU-3C-BA.HCI

3-(3-(benzyl(methyl)amino)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride

3-(3-(benzyl(methyl)amino)propoxy)-7_I8,9,10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 85.2 %, HPLC purity: 99.00%, HRMS(ESI) C24H28NO3 calcd 378.2069 [M+H]⁺, found 378.2070, DSC: 84.8°C.

Example 23: THU-3C-MBA

3-(3-((3-methoxybenzyl)(methyl)amino)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one 3-(3-((3-methoxybenzyl)(methyl)amino)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one is synthesized according to procedure given in Example 9. Yield obtained: 60.2 %. H NMR (300 MHz, CDCI3, ppm): 51.68-1.84 (m, 4H), 1.89-2.01 (m, 2H), 2.19 (s, 3H), 2.45-2.54 (m, 4H), 2.64-2.73 (m, 2H), 3.45 (s, 2H), 3.71 (s, 3H), 3.99 (t, 2H), 6.67-6.76 (m, 3H), 6.82 (dd, 2H), 7.14 (t, 1 H), 7.37 (dd, 1 H).

Example 24: THU-3C-MBA.HCI 3-(3-((3-methoxybenzyl)(methyl)amino^

one hydrochloride

3-(3-((3-methoxybenzyl)(methyl)amino)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 86.4 %, HPLC purity: 99.45%, HRMS(ESI) C25H30NO4 calcd 408.2175 [M+H]⁺, found 408.2 66, DSC: 215.6°C.

Example 25: THU-3C-BPP

3-(3-(4-benzylpiperidin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 66.2 %. ¹H NMR (300 MHz, CDCI3, ppm): δ 1.22-1.42 (m, 2H), 1.43-1.56 (m, 1H), 1.57-1.69 (m, 2H), 1.70- 1.86 (m, 4H), 1.87-2.09 (m, 4H), 2.39-2.61 (m, 6H), 2.63-2.76 (m, 2H), 2.95 (d, 2H), 4.01 (t, 2H), 6.70-6.83 (m, 2H), 7.03-7.28 (m, 5H), 7.39 (d, 1H).

Example 26: THU-3C-BPP.HCI

3-(3-(4-benzylpiperidin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride

3-(3-(4-benzylpiperidin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 82.5 %, HPLC purity: 99.59%, HRMS(ESI) C28H34NO3 calcd 432.2539 [M+H]⁺, found 432.2559, DSC: 121.7°C.

Example 27: THU-3C-MBPP

3-(3-(4-(3-methoxybenzyl)piperidin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one

3-(3-(4-(3-methoxybenzyl)piperidin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one is synthesized according to procedure given in Example 9. Yield obtained: 65.6 %. ¹H NMR (300 MHz, CDCI3, ppm): δ 1.30-1.42 (m, 2H), 1.46-1.57 (m, 1H), 1.58-1.71 (m, 2H), 1.72-1.88 (m, 4H), 1.92-2.02 (m, 4H), 2.42-2.61 (m, 6H), 2.66-2.78 (m, 2H), 2.97 (d, 2H), 3.77 (s, 3H), 4.03 (t, 2H), 6.63-6.83 (m, 5H), 7.17 (t, 1H), 7.42 (d, 1H).

Example 28: THU-3C-MBPP.HCI

3-(3-(4-(3-methoxybenzyl)piperidin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride

3-(3-(4-(3-methoxybenzyl)piperidin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 81.1 %, HPLC purity: 99.00%, HRMS(ESI) C29H36NO4 calcd 462.2644 [M+H]⁺, found 462.2644, DSC: 19.1°C.

Example 29: THU-3C-BPZ

3-(3-(4-benzylpiperazin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 68.2 %. H NMR (300 MHz, DMSO, ppm): 51.57-1.78 (m, 4H), 1.83 (p, 2H), 2.14-2.52 (m, 12H), 2.64-2.78 (m, 2H), 3.40 (s, 2H), 4.04 (t, 2H), 6.83-6.93 (m, 2H), 7.15-7.34 (m, 5H), 7.55 (d, 1 H).

Example 30: THU-3C-BPZ.2HCI

3-(3-(4-benzylpiperazin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one dihydrochloride

3-(3-(4-benzylpiperazin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 90.2 %, HPLC purity: 100.0%, HRMS(ESI) C₂7H₃3N₂03 calcd 433.2491 [M+H]⁺, found 433.2488, DSC: 96.3°C.

Example 31 : THU-3C-MBPZ

3-(3-(4-(3-methoxybenzyl)piperazin-1-yl)propoxy)-7, 8,9,10-tetrahydro-6H-benzo[c]chromen- 6-one 3-(3-(4-(3-methoxybenzyl)piperazin-1-yl)propoxy)-7,8,9 0-tetrahydro-6H-benzo[c]chromen- 6-one is synthesized according to procedure given in Example 9. Yield obtained: 64.3 %. H NMR (300 MHz, CDCI₃, ppm): δ 1.72-1.79 (m, 4H), 1.93-2.10 (m, 2H), 2.39-2.73 (m, 4H), 3.50 (s, 2H), 3.75 (s, 3H), 4.00 (t, 2H), 6.71-6.91 (m, 5H), 7.17 (t, 1 H), 7.38 (d, 1 H).

Example 32: THU-3C-MBPZ.2HCI

3-(3-(4-(3-methoxybenzyl)piperazin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen- 6-one dihydrochloride

3-(3-(4-(3-methoxybenzyl)piperazin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen- 6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 80.3 %, HPLC purity: 98.72%, HRMS(ESI) C28H35N2O4 calcd 463.2597 [M+H]⁺, found 463.2597, DSC: 274.2°C.

Example 33: THU-4C-BA

3-(4-(benzyl(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-(4-(benzyl(methyl)amino)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 61.6%. ¹H NMR (300 MHz, CDCI3, ppm): δ 1.62-1.88 (m, 8H), 2.20 (s, 3H), 2.43 (t, 2H), 2.49-2.58 (m, 2H), 2.68-2.76 (m, 2H), 3.49 (s, 2H), 3.96 (t, 2H), 6.74 (d, 1 H), 6.79 (dd, 1 H), 7.18-7.32 (m, 5H), 7.42 (d, 1H).

Example 34: THU-4C-BA. HCI

3-(4-(benzyl(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

hydrochloride

3-(4-(benzyl(methyl)amino)butoxy)-7, 8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 86.2%, HPLC purity: 99.98 %, HRMS (ESI) C25H30NO3 calcd 392.2226 [M+H]⁺, found 392.2227, DSC: 150.7°C.

Example 35: THU-4C-MBA 3-(4-((3-methoxybenzyl)(methyl)ami

one

3-(4-((3-methoxybenzyl)(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one is synthesized according to procedure given in Example 9. Yield obtained: 59.4%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.59-1.84 (m, 8H), 2.19 (s, 3H), 2.41 (t, 2H), 2.46-2.53 (m, 2H), 2.63-2.72 (m, 2H), 3.46 (s, 2H), 3.73 (s, 3H), 3.92 (t, 2H), 6.67-6.77 (m, 3H), 6.81-6.88 (m, 2H), 7.16 (t, 1 H), 7.37 (d, 1H).

Example 36: THU-4C-MBA.HCI

3-(4-((3-methoxybenzyl)(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride

3-(4-((3-methoxybenzyl)(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 89.2%, HPLC purity: 99.67%, HRMS (ESI) C26H32NO₄ calcd 422.2331 [M+H]⁺, found 422.2345, DSC: 184.8°C.

Example 37: THU-4C-BPP

3-(4-(4-benzylpiperidin-1-yl)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one

3-(4-(4-benzylpiperidin-1-yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 70.4%. H NMR (300 MHz, CDCb, ppm): δ 1.19-1.38 (m, 2H), 1.39-1.53 (m, 1 H), 1.53-1.94 (m, 12H), 2.34 (t, 2H), 2.42-2.56 (m, 4H), 2.62-2.73 (m, 2H), 2.89 (d, 2H), 3.94 (t, 2H), 6.70 (d, 1H), 6.74 (dd, 1H), 7.03-7.25 (m, 5H), 7.36 (d, 1H).

Example 38: THU-4C-BPP. HCI

3-(4-(4-benzylpiperidin-1 -yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride

3-(4-(4-benzylpiperidin-1-yl)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 80.3%, HPLC purity: 99.71 %, HRMS (ESI) CjgHseNOs calcd 446.2695 [M+H]⁺, found 446.2695, DSC: 94.6°C.

Example 39: THU-4C-MBPP

3-(4-(4-(3-methoxybenzyl)piperidin-1 -yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one

3-(4-(4-(3-methoxybenzyl)piperidin-1-yl)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one is synthesized according to procedure given in Example 9. Yield obtained: 59.5%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.20-1.41 (m, 2H), 1.41-1.55 (m, 1 H), 1.55-1.95 (m, 12H), 2.36 (t, 2H), 2.45-2.57 (m, 4H), 2.62-2.76 (m, 2H), 2.91 (d, 2H), 3.75 (s, 3H), 3.96 (t, 2H), 6.62-6.80 (m, 5H), 7.14 (t, 1H), 7.39 (d, 1 H).

Example 40: THU-4C-MBPP. HCI

3-(4-(4-(3-methoxybenzyl)piperidin-1 -yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one hydrochloride

3-(4-(4-(3-methoxybenzyl)piperidin-1 -yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 81.9%, HPLC purity: 96.54 %, HRMS (ESI) C₃oH₃8N0₄ calcd 476.2801 [M+H]⁺, found 476.2816, DSC: 151.9°C.

Example 41: THU-4C-BPZ

3-(4-(4-benzylpiperazin-1 -yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 64.3%. ¹H NMR (300 MHz, CDCI3, ppm): δ 1.58-1.85 (m, 8H), 2.30-2.62 (m, 12H), 2.63-2.74 (m, 2H), 3.46 (s, 2H), 3.95 (t, 2H), 6.68-6.78 (m, 2H), 7.14-7.29 (m, 5H), 7.37 (d, 1H).

Example 42: THU-4C-BPZ.2HCI

3-(4-(4-benzylpiperazin-1 -yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one dihydrochloride 3-(4-(4-benzylpiperazin-1-yl)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 84.7%, HPLC purity: 99.36%, HRMS (ESI) CaHas^Oa calcd 447.2648 [M+H]⁺, found 447.2637, DSC: 270.7°C.

Example 43: THU-4C-MBPZ

3-(4-(4-(3-methoxybenzyl)piperazin-1-yl)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one

3-(3-(4-(3-methoxybenzyl)piperazin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen- 6-one is synthesized according to procedure given in Example 9. Yield obtained: 72.6%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.62-1.88 (m, 8H), 2.35-2.66 (m, 12H), 2.67-2.78 (m, 2H), 3.47 (s, 2H), 3.76 (s, 3H), 3.97 (t, 2H), 6.71-6.79 (m, 3H), 6.82-6.88 (m, 2H), 7.18 (t, 1 H), 7.39 (d, 1 H).

Example 44: THU-4C-MBPZ.2HCI

3-(4-(4-(3-methoxybenzyl)piperazin-1 -yl)butoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6- one dihydrochloride

3-(4-(4-(3-methoxybenzyl)piperazin-1 -yl)butoxy)-7,8,9, 0-tetrahydro-6H-benzo[c]chromen-6- one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 82.2%, HPLC purity: 99.54%, HRMS(ESI) C29H37N2O4 calcd 477.2753 [M+H]⁺, found 477.2762, DSC: 243.4°C.

Example 45: URO-2C-BA

3-(2-(benzyl(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one

3-(2-(benzyl(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 79.2 %. ¹H NMR (300 MHz, CDC , ppm): δ 2.35 (s, 3H), 2.84 (t, 2H), 3.62 (s, 2H), 4.12 (t, 2H), 6.81 (d, 1H), 6.85 (dd, 1H), 7.19-7.32 (m, 5H), 7.47 (t, 1 H), 7.75 (dt, 1H), 7.84-7.98 (m, 2H), 8.32 (d, 1H).

Example 46: URO-2C-BA.HCI 3-(2-(benzyl(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride

3-(2-(benzyl(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 83.2%, HPLC purity: 99.54%, HRMS(ESI) C23H22NO3 calcd 360.1600 [M+H]⁺, found 360.1613, DSC: 221.7°C. Example 47: URO-2C-MBA

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 74.4%. ¹H N R (300 MHz, CD3OD, ppm): δ 2.96 (s, 3H), 3.63 (brs, 2H), 3.78 (s, 3H), 4.34-4.54 (m, 4H), 6.88-7.17 (m, 5H), 7.37 (t, 1 H), 7.53 (t, 1H) 7.81 (t, 1 H), 7.99-8.14 (m, 2H), 8.21 (d, 1H).

Example 48: URO-2C-MBA.HCI

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride

3-(2-((3-methoxybenzyl)(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 85.1 %, HPLC purity: 99.40%, HRMS(ESI) C24H24NO4 calcd 390.1705 [M+H]⁺, found 390.1709, DSC: 205.9°C.

Example 49: URO-2C-BPP

3-(2-(4-benzylpiperidin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one

3-(2-(4-benzylpiperidin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 70.1 %. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.16-1.40 (m, 2H), 1.42-1.56 (m, 1 H), 1.57-1.70 (m, 2H), 2.03 (t, 2H), 2.50 (d, 2H), 2.78 (t, 2H), 2.96 (d, 2H), 4.12 (t, 2H), 6.74-6.91 (m, 2H), 7.03-7.28 (m, 5H), 7.46 (t, 1H), 7.73 (dt, 1 H), 7.82-7.99 (m, 2H), 8.31 (d, 1 H).

Example 50: UR0-2C-BPP.HCI 3-(2-(4-benzylpiperidin-1 -yl)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride 3-(2-(4-benzylpiperidin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 9. Yield obtained: 88.3%, HPLC purity: 99.37%, HRMS(ESI) C27H28NO3 calcd 414.2069 [M+H]⁺, found 414.2075, DSC: 199.6°C.

Example 51 : URO-2C-MBPP 3-(2-(4-(3-methoxybenzyl)piperidin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one

3-(2-(4-(3-methoxybenzyl)piperidin-1 -yl)ethoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 69.3%. ¹H NMR (300 MHz, CDCI3, ppm): δ 1.29-1.95 (m, 7H), 2.53 (d, 2H), 3.13-3.33 (m, 2H), 3.38-3.56 (m, 2H), 3.73 (s, 3H), 4.15 (t, 2H), 6.58-6.72 (m, 3H), 6.78 (d, 1 H), 6.86 (dd, 1 H), 7.14 (t, 1 H), 7.47 (d, 1 H), 7.74 (dt, 1 H), 7.86-7.98 (m, 2H), 8.30 (dd, 1 H).

Example 52: URO-2C-MBPP.HCI

3-(2-(4-(3-methoxybenzyl)piperidin-1 -yl)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride-

3-(2-(4-(3-methoxybenzyl)piperidin-1 -yl)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 84.9%, HPLC purity: 99.49%, HRMS(ESI) C28H30NO4 calcd 444.2175 [M+H]⁺, found 444.2171 , DSC: 174.3°C,and 190.2°C.

Example 53: URO-2C-BPZ

3-(2-(4-benzylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one

3-(2-(4-benzylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 71.8%. ¹H NMR (300 MHz, CDCI3 , ppm): δ 2.35-2.71 (m, 8H), 2.80 (t, 2H), 3.47 (s, 2H), 4.10 (t, 2H), 6.79 (d, 1 H), 6.85 (dd, 1 H), 7.16- 7.29 (m, 5H), 7.44 (dt, 1 H), 7.72 (dt, 1 H), 7.87 (d, 1 H), 7.93 (d, 1 H), 8.29 (dd, 1 H).

Example 54: URO-2C-BPZ.2HCI

3-(2-(4-benzylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one dihydrochloride 3-(2-(4-benzylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 90.1 %, HPLC purity: 99.97%, HRMS(ESI) C26H27N2O3 calcd 415.2022 [M+H]⁺, found 415.2039, DSC: 176.6°C.

Example 55: URO-2C-MBPZ

3-(2-(4-(3-methoxybenzyl)pipera2in-1-yl)ethoxy)-6H-benzo[c]chromen-6-one 3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 65.6%. H NMR (300 MHz, CDCI3, ppm): δ 2.36-2.73 (m, 8H), 2.80 (t, 2H), 3.44 (s, 2H), 3.74 (s, 3H), 4.10 (t, 2H), 6.69- 6.89 (m, 5H), 7.16 (t, 1H), 7.44 (dt, 1H), 7.72 (dt, 1H), 7.87 (d, 1H), 7.93 (d, 1 H), 8.29 (dd, 1H). Example 56: URO-2C-MBPZ.2HCI

3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one dihydrochloride

3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 88.2%, HPLC purity: 99.62%, HRMS(ESI) C₂7H₂9N₂04 calcd 445.2127 [M+H]⁺, found 445.2143, DSC: 282.3°C, and 285.4°C.

Example 57: URO-3C-BA

3-(3-(benzyl(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one

3-(3-(benzyl(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 75.2%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.97 (p, 2H), 2.19 (s, 3H), 2.52 (t, 2H), 3.47 (s, 2H), 4.03 (t, 2H), 6.75-6.85 (m, 2H), 7.17-7.25 (m, 5H), 7.44 (dt, 1H), 7.73 (dt, 1H), 7.87 (d, 1H), 7.95 (d, 1 H), 8.30 (dd,1 H).

Example 58: URO-3C-BA.HCI

3-(3-(benzyl(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one hydrochloride

3-(3-(benzyl(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 80.8%, HPLC purity: 99.92%, HRMS(ESI) C24H24NO3 calcd 374.1756 [M+H]⁺, found 374.1750, DSC: 86.9°C.

Example 59: URO-3C-MBA

3-(3-((3-methoxybenzyl)(methyl)amino)propoxy)-6H-ben2o[c]chromen-6-one

3-(3-((3-methoxybenzyl)(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 75.8%. ¹H NMR (300 MHz, CDC , ppm): δ 1.96 (p, 2H), 2.20 (s, 3H), 2.51 (t, 2H), 3.44 (s, 2H), 3.71 (s, 3H), 4.02 (t,2H), 6.67-6.87 (m, 5H), 7.14 (t, 1 H), 7.43 (dt, 1 H), 7.72 (dt, 1 H), 7.85 (d, 1 H), 7.94 (d, 1H), 8.29 (dd,1 H).

Example 60: URO-3C-MBA.HCI

3-(3-((3-methoxybenzyl)(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one hydrochloride

3-(3-((3-methoxybenzyl)(methyl)amino)propoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 80.3%, HPLC purity: 99.95%, HRMS(ESI) C25H26NO4 calcd 404.1862 [M+H]⁺, found 404.1856, DSC: 215.1 °C.

Example 61 : URO-3C-BPP

3-(3-(4-benzylpiperidin-1-yl)propoxy)-6H-benzo[c]chromen-6-one

3-(3-(4-benzylpiperidin-1-yl)propoxy)-6H-benzo[c]chromen-6-one was synthesized according to procedure given in Example 9. Yield obtained: 60.9%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.30-1.75 (m, 7H), 2.10-2.23 (m, 2H), 2.55 (d, 2H), 2.75-3.06 (m, 2H), 3.19-3.44 (m, 2H), 4.06 (t, 2H), 6.77 (d, 1 H), 6.82 (dd, 1H), 7.12-7.26 (m, 5H), 7.46 (m, 1 H), 7.73 (dt, 1 H), 7.89 (d, 1H), 7.94 (d, 1H), 8.3 (dd, 1H).

Example 62: URO-3C-BPP.HCI

3-(3-(4-benzylpiperidin-1-yl)propoxy)-6H-benzo[c]chromen-6-one hydrochloride

3-(3-(4-benzylpiperidin-1 -yl)propoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 88.8%, HPLC purity: 99.09%, HRMS(ESI) C28H30NO3 calcd 428.2226 [M+H]⁺, found 428.2212, DSC: 232.4°C.

Example 63: URO-3C-MBPP

3-(3-(4-(3-methoxybenzyl)piperidin-1-yl)propoxy)-6H-benzo[c]chromen-6-one

3-(3-(4-(3-methoxybenzyl)piperidin-1-yl)propoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 76.5 %. H NMR (300 MHz, CDC , ppm): δ 1.20-1.35 (m, 2H), 1.41-1.53 (m, 1H), 1.54-1.66 (m, 2H), 1.85 (t, 2H), 1.95 (p, 2H), 2.37-2.53 (m, 4H), 2.88 (d, 2H), 3.74 (s, 3H), 4.01 (t, 2H), 6.59-6.73 (m, 3H), 6.77- 6.88 (m, 2H), 7.14 (t, 1H), 7.44 (dt, 1 H), 7.72 (dt, 1H), 7.87 (d, 1H), 7.94 (d, 1 H), 8.29 (dd, 1 H).

Example 64: URO-3C-MBPP.HCI

3-(3-(4-(3-methoxybenzyl)piperidin-1-yl)propoxy)-6H-benzo[c]chromen-6-one hydrochloride

3-(3-(4-(3-methoxybenzyl)piperidin-1-yl)propoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 80.4%, HPLC purity: 99.19%, HRMS(ESI) C29H32NO4 calcd 458.2331 [M+H]⁺, found 458.2317, DSC: 225.8°C.

Example 65: URO-3C-BPZ

3-(3-(4-benzylpiperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one

3-(3-(4-benzylpiperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 59.8%. H NMR (300 MHz, CDCI₃, ppm): δ 1.95 (p, 2H), 2.43-2.68 (m, 10H), 3.46 (s, 2H), 4.01 (t, 2H), 6.78 (d, 1H), 6.83 (dd, 1H), 7.14- 7.29 (m, 5H), 7.43 (t, 1H), 7.71 (dt, H), 7.89 (d, 1H), 7.93 (d, 1H), 8.28 (dd, 1 H).

Example 66: URO-3C-BPZ.2HCI

3-(3-(4-benzylpiperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one dihydrochloride

3-(3-(4-benzylpiperazin-1 -yl)propoxy)-6H-benzo[c]chromen-6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 80.0%, HPLC purity: 99.74%, HRMS(ESI) C27H29N2O3 calcd 429.2178 [M+H]⁺, found 429.2171 , DSC: 283.8°C.

Example 67: URO-3C-MBPZ

3-(3-(4-(3-methoxybenzyl)piperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one

3-(3-(4-(3-methoxybenzyl)piperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 76.8%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.88-2.03 (m, 2H), 2.22-2.71 (m, 10H), 3.45 (s, 2H), 3.73 (s, 3H), 4.02 (t, 2H), 6.69-6.89 (m, 5H), 7.16 (d, 1H), 7.44 (dt, 1H), 7.72 (dt, 1 H), 7.87 (d, 1H),7.94 (d, 1 H), 8.29 (dd, 1H).

Example 68: URO-3C-MBPZ.2HCI

3-(3-(4-(3-methoxybenzyl)piperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one

di hydrochloride

3-(3-(4-(3-methoxybenzyl)piperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one

dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 81.6%, HPLC purity: 99.52%, HRMS(ESI) C28H31N2O4 calcd 459.2284 [M+H]⁺, found 459.2277, DSC: 265.0°C, 272.4°C.

Example 69: URO-4C-BA

3-(4-(benzyl(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one

3-(4-(benzyl(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 78.3%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.66 (p, 2H), 1.80 (p, 2H), 2.16 (s, 3H), 2.39 (t, 2H), 3.45 (s, 2H), 3.94 (t, 2H), 6.76 (d, 1 H), 6.82 (dd, 1H), 7.13-7.29 (m, 5H), 7.43 (dt, 1H), 7.71 (dt, 1H), 7.86 (d, 1H), 7.93 (d, 1H), 8.29 (dd, 1H).

Example 70: URO-4C-BA.HCI

3-(4-(benzyl(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one hydrochloride 3-(4-(benzyl(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 85.6%, HPLC purity: 99.92%, HRMS(ESI) C25H26NO3 calcd 388.1913 [M+H]⁺, found 388.1911 , DSC: 107.1 °C, 126.5°C, 151.5°C, 169.2°C.

Example 71 : URO-4C-MBA

3-(4-((3-methoxybenzyl)(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one

3-(4-((3-methoxybenzyl)(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 80.3%. ¹H NMR (300 MHz, CDCI3, ppm): δ 1.64 (p, 2H), 1.80 (p, 2H), 2.16 (s, 3H), 2.38 (t, 2H), 3.42 (s, 2H), 3.73 (s, 3H), 3.94 (t, 2H), 6.67-6.87 (m, 5H), 7.15 (t, 1H), 7.42 (dt, 1 H), 7.71 (dt, 1H), 7.85 (d, 1 H), 7.92 (d, 1 H), 8.28 (dd, 1H).

Example 72: URO-4C-MBA. HCI

3-(4-((3-methoxybenzyl)(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one hydrochloride

3-(4-((3-methoxybenzyl)(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 86.1 %, HPLC purity: 99.89%, HRMS(ESI) CaeHasNC calcd 418.2018 [M+H]⁺, found 418.2024, DSC: 209.5°C.

Example 73: URO-4C-BPP

3-(4-(4-benzylpiperidin-1-yl)butoxy)-6H-benzo[c]chromen-6-one

3-(4-(4-benzylpiperidin-1-yl)butoxy)-6H-benzo[c]chromen-6-one was synthesized according to procedure given in Example 9. Yield obtained: 68.9%. ¹H NMR (300 MHz, CDCI₃, ppm): δ 1.21-1.39 (m, 2H), 1.40-1.54 (m, 1H), 1.55-1.86 (m, 8H), 2.35 (t, 2H), 2.48 (d, 2H), 2.90 (d, 2H), 3.98 (t, 2H), 6.79 (d, 1H), 6.84 (dd, 1 H), 7.03-7.26 (m, 5H), 7.44 (dt, 1 H), 7.73 (dt, 1 H), 7.88 (d, 1H), 7.94 (d, H), 8.30 (dd, 1H).

Example 74: URO-4C-BPP.HCI

3-(4-(4-benzylpiperidin-1-yl)butoxy)-6H-benzo[c]chromen-6-one hydrochloride 3-(4-(4-benzylpiperidin-1 -yl)butoxy)-6H-ben2o[c]chromen-6-onehydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 90.8%, HPLC purity: 99.26%, HRMS(ESI) C29H32NO3 calcd 442.2382 [M+H]⁺, found 442.2403, DSC: 85.3°C, 159.2°C.

Example 75: URO-4C-MBPP

3-(4-(4-(3-methoxybenzyl)piperidin-1-yl)butoxy)-6H-benzo[c]chromen-6-one

3-(4-(4-(3-methoxybenzyl)piperidin-1 -yl)butoxy) 6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 75.4. H NMR (300 MHz, CDCI₃, ppm): δ 1.20-1.38 (m, 2H), 1.39-1.54 (m, 1 H), 1.55-1.82 (m, 8H), 2.33 (t, 2H), 2.45 (d, 2H), 2.88 (d, 2H), 3.73 (s, 3H), 3.98 (t, 2H), 6.57-6.73 (m, 3H), 6-75-6.88 (m, 2H), 7.07-7.17 (m, 1 H), 7.45 (t, 1H), 7.72 (t, 1H), 7.82-7.99 (m, 2H), 8.29 (d, 1 H).

Example 76: URO-4C-MBPP.HCI

3-(4-(4-(3-methoxybenzyl)piperidin-1-yl)butoxy)-6H-benzo[c]chromen-6-one hydrochloride

3-(4-(4-(3-methoxybenzyl)piperidin-1 -yl)butoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 82.2 %, HPLC purity: 99.01 %, HRMS(ESI) C30H34NO4 calcd 472.2488 [M+H]⁺, found 472.2490, DSC: 177.8°C.

Example 77: URO-4C-BPZ

3-(4-(4-benzylpiperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one

3-(4-(4-benzylpiperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 68.3%. ¹H NMR (300 MHz, CDCI3 , ppm): 61.56-1.84 (m, 4H), 2.24-2.67 (m, 10H), 3.46 (s, 2H), 3.97 (t, 2H), 6.78 (d,1H), 6.83 (dd, 1H), 7.14-7.28 ( m, 5H), 7.44 (dt, 1 H), 7.72 (dt, 1 H), 7.87 (d, 1H), 7.94 (d, 1H), 8.29 (dd, 1H).

Example 78: URO-4C-BPZ.2HCI

3-(4-(4-benzylpiperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one dihydrochloride

3-(4-(4-benzylpiperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 84.3%, HPLC purity: 99.77%, HRMS(ESI) C28H31N2O3 calcd 443.2335 [M+H]⁺, found 443.2350, DSC: 263.6°C.

Example 79: URO-4C-MBPZ

3-(4-(4-(3-methoxybenzyl)piperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one 3-(4-(4-(3-methoxybenzyl)piperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 9. Yield obtained: 75.2%. ¹H NMR (300 MHz, CDCI3, ppm): 51.63 (p, 2H), 1.77 (p, 2H), 2.28-2.65 (m, 10H), 3.43 (s, 2H), 3.74 (s, 3H), 3.97 (t, 2H), 6.69 -6.87 (m, 5H), 7.15 (t, 1 H), 7.43 (dt, 1 H), 7.72 (dt, 1 H), 7.86 (d, 1 H), 7.93 (d, 1 H), 8.29 (dd, 1 H). Example 80: URO-4C-MBPZ.2HCI

3-(4-(4-(3-methoxybenzyl)piperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one dihydrochloride

3-(4-(4-(3-methoxybenzyl)piperazin-1-yl)butoxy)-6H-benzo[c]chromen-6-one dihydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 78.4%, HPLC purity: 98.48 %, HRMS (ESI) C29H33N2O4 calcd 473.2440 [M+H]⁺, found 473.2448, DSC: 251.2°C.

The compounds of the present invention concomitant with the pharmaceutical salts thereof represented by the general formula II and the general formula III are useful in the treatment of various kinds of senile dementia, in particular Alzheimer's Disease accompanying senile dementia. Related pharmacological experimental data are described.

Experimental (Pharmacology)

The potential of the compounds of the present invention to inhibit acetylcholinesterase and butyrylcholinesterase enzymes were tested according to the method of Ellman et.al. (i.e., Ellman, G. L, Courtney, K. D., Andres, V., and Featherstone, R. M., Biochem. Pharmacol., 1961 , 7, 88-95). Human recombinant acetylcholinesterase and human recombinant butyrylcholinesterase were employed. Each reaction mixture contained the enzyme (either ACHE or BCHE) solution, DTNB and sample in Tris HCl buffer solution. The reactions were initiated by the addition of the substrate (either acetylthiocholine iodide or butyrylthiocholine iodide, respectively for ACHE and BCHE enzymes). The enzyme catalyzed formation of the yellow color was measured at 412 nm in terms of the calculation of enzyme activity concomitant to the presence of an inhibitor activity. The acetylcholinesterase and butyrylcholinesterase inhibitory activity of each sample was expressed in terms of inhibitory concentration 50% (ICso). Representative examples are shown in Table I:

Table I In general, the compounds of the present invention displayed strong potential for the inhibition of both ACHE and BCHE enzymes. As seen in the examples in Table 1 , most of the compounds have IC50 values for ACHE close to 1. This finding definitely points out these compounds more active than rivastigmine in terms of the potential to inhibit ACHE. On the other hand, these results also reveal that the compounds of the present invention possess comparable potential with respect to galantamine, another ACHE inhibitor drug, for the inhibition of ACHE.

Another important discovery of the present research is on the IC50 values obtained for some of the compounds on the inhibition of BCHE. There are several compounds which possess strong inhibition towards BCHE. In comparison to the current drugs (i.e., galantamine, rivastigmine, and donepezil), the compounds such as THU-3C- BPZ, URO-3C-BPZ have exhibited strong inhibitory potential towards BCHE, which makes them better inhibitors of the BCHE.

Although, the selectivity of the compounds of the present invention seems to be bias for the ACHE enzyme the selectivity ratio for some compounds have been found close to 1 which also definitely points out their difference from the current ACHE and/or BCHE inhibitor drug molecules. Indeed, compounds such as THU-3C-BA, THU-3C-BPP, THU-3C-MBPP, THU-3C-BPZ, THU-4C-BPZ, URO-3C-BPP, URO- 3C-BPZ, and URO-4C-BA have selectivity ratio considerably less than current drugs such as donepezil and galantamine.

Experimental (Passive avoidance learning test)

The passive avoidance test evaluates the ability of a rat to learn and memorize. Male Wistar rats, at an age of approximately 2 months, and around 250 g body weight were used. For learning, the rats were placed into the illuminated compartment while the door closed and allowed a habituation phase (30 seconds). Then the door automatically opened and stayed open for 5 minutes experimental time. Two seconds after the rat entering the dark compartment of the apparatus the door closed and after 2 seconds latency an electric stimulus took place lasting for 3 or 6 seconds. The rat stayed in the dark compartment for another 30 seconds delay before it was placed into the home cage.

For testing, the rats were treated with 1 mg/kg (i.p.) of scopolamine, half an hour before the administration of the each test compound. Half an hour after the oral administration of the each compound, the rats were placed into the illuminated compartment with the door closed again for a habituation time of 30 seconds. Following the opening of the door automatically, the time for the rats visiting the dark box (latency) was measured for 5 minutes. The time difference between the no scopolamine administered group and the only scopolamine administered group was taken as 100% and the effect of each compound of the present invention was calculated accordingly in terms of the percentage antagonism. Each test compound was assessed employing ten animals per dose.

The results are shown Table II:

Table II

As seen in the Table II, the compounds of the present invention have considerable effect in the test of passive avoidance learning impairment induced by scopolamine. The results obtained through both the in-vitro acetylcholinesterase and butyrylcholinesterase inhibition tests and the in-vivo passive avoidance test present the compounds of this invention as powerful, promising, and novel compounds effective for various kinds of dementia, particularly the Alzheimer senile dementia..

Claims

1. A compound having the following formula I or a pharmaceutical acceptable salt thereof:

Formula I wherein:

A and B together form benzene or cyclohexane; n is the number of carbon atoms; preferably n is from 2 to 6, most preferably n is from 2 to 4;

R is selected from:

CH₃

N

\

Ri

wherein Ri is a lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof.

2. A 3-aminoalkyloxy-substituted-6H-benzo[c]chromen-6-one compound having the following formula II or a pharmaceutical acceptable salt thereof according to Claim 1 ,

Formula II wherein: n is the number of carbon atoms, preferably n is from 2 to 6, most-preferably n is from 2 to 4; R is selected from:

CH₃

N

\

<1

-N N-R, wherein Ri is a lower alkyl group, cyclohexyi group, benzyl group, or 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof.

3. A 3-aminoalkyloxy-substituted-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one compound having the following formula III or a pharmaceutical acceptable salt thereof according to Claim 1 ,

Formula III wherein: n is the number of carbon atoms, preferably n is from 2 to 6, most preferably n is from 2 to 4;

R is selected from:

CH₃ — -N

\

R₁

4. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(2- (benzyl(methyl)amino)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

5. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(2-((3- methoxybenzyl)(methyl)amino)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

6. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(2-(4- benzylpiperazin-1-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

7. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahyclro-benzo[c]chrorrien-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(3- (benzyl(methyl)amino)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

8. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(3-((3- methoxybenzyl)(methyl)amino)propoxy)-7, 8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

9. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(3-(4- benzylpiperidin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

10. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(3-(4-(3- methoxybenzyl)piperidin-1-yl)propoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

11. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(3-(4- benzylpiperazin-1 -yl)propoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one.

12. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(4- (benzyl(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

13. A 3-aminoalkyloxy-substituted-6H-7,8,9,10-tetrahydro-benzo[c]chrornen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(4-((3- methoxybenzyl)(methyl)amino)butoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

14. A 3-aminoalkyloxy-substituted-6H-7,8,9, 10-tetrahydro-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, which is 3-(4-(4- benzylpiperazin-1-yl)butoxy)-7,8,9, 0-tetrahydro-6H-benzo[c]chromen-6-one.

15. A 3-aminoalkyloxy-substituted- 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2, which is 3-(2-(4- benzylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one.

16. A 3-aminoalkyloxy-substituted 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2, which is 3-(3-(4- benzylpiperidin-1-yl)propoxy)-6H-benzo[c]chromen-6-one.

17. A 3-aminoalkyloxy-substituted 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2, which is 3-(3-(4- benzylpiperazin-1-yl)propoxy)-6H-benzo[c]chromen-6-one.

18. A 3-aminoalkyloxy-substituted 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2, which is 3-(4- (benzyl(methyl)amino)butoxy)-6H-benzo[c]chromen-6-one.

19. The use of a 3-aminoalkyloxy-substituted 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2 for preparing a medicament for the treatment of a disease due to acetylcholinesterase and/or butyrylcholinesterase activity.

20. The use of a 3~aminoalkyloxy-substituted-7, 8, 9, 10-tetrahydro-6H-benzo[c]chromen-6- one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3 for preparing a medicament for the treatment of a disease due to acetylcholinesterase and/or butyrylcholinesterase activity.

21. The use of a 3-aminoalkyloxy-substituted 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2 for the treatment of senile dementia.

22. The use of a 3--aminoalkyloxy-substituted-7,8,9_l10-tetrahydro-6H-benzo[c]chromen-6- one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3 for the treatment of senile dementia.

23. The use of a 3-aminoalkyloxy-substituted 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2 for the treatment of senile dementia of the Alzheimer type.

24. The use of a 3-aminoalkyloxy-substituted-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3 for the treatment of senile dementia of the Alzheimer type.

25. The use of a 3-aminoalkyloxy-substituted 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2 thereof for preparing a medicament for the treatment of any central nervous system disease.

26. The use of a 3-aminoalkyloxy-substituted-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6- one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3 for preparing a medicament for the treatment of any central nervous system disease.

27. A therapeutical composition comprising a pharmacologically active amount of a 3- aminoalkyloxy-substituted 6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 2, and a pharmacologically acceptable carrier.

28. A therapeutical composition comprising a pharmacologically active amount of a 3- aminoalkyloxy-substituted-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one compound or a pharmaceutical acceptable salt thereof according to Claim 1 and 3, and a pharmacologically acceptable carrier.

29. According to Claim 2, a process for the preparation of formula II

wherein: n is the number of carbon atoms, preferably n is from 2 to 6, most preferably n is from 2 to 4; R is selected from:

-N N-R-, and Ri is a lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof, comprises the steps where resorcinol is reacted with halo benzoic acid compound to obtain the compound of formula IV;

IV alkylation of the compound with appropriate atkyl halide to obtain the compound of formula V

V

n=2,3,4

30. According to Claim 3, a process for the preparation of formula

III wherein: n is the number of carbon atoms, preferably n is from 2 to 6, most preferably n is from 2 to 4; R is selected from:

CH₃

N

\

and Ri is a lower alkyl group, cyciohexyl group, benzyl group, or 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof, comprises the steps where resorcinol is reacted with ethyl 2-oxocyclohexanecarboxylate to obtain the compound of formula VI;

VI alkylation of the compound with appropriate alkyl haiide to obtain the compound of formula VII;

VII

n=2,3,4

31. 3- 2-chloroethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

32. 3- 2-iodoethoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one.

33. 3- 3-chloropropoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

34. 3- 3-iodopropoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one.

35. 3- -chlorobutoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.

36. 3- 4-iodobutoxy)-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one.

37. 3- 2-chloroethoxy)-6H-benzo[c]chromen-6-one.

38. 3- 2-iodoethoxy)-6H-benzo[c]chromen-6-one.

39. 3- 3-chloropropoxy)-6H-benzo[c]chromen-6-one.

40. 3- 3-iodopropoxy)-6H-benzo[c]chromen-6-one.

41. 3- 4-chlorobutoxy)-6H-benzo[c]chromen-6-one.

42. 3-(4-iodobutoxy)-6H-benzo[c]chromen-6-one.

43. A process for the preparation of a compound or a pharmaceutical acceptable salt thereof, according to Claim 1 , including the in-situ preparation and the employment of the intermediates as defined in Claims through 31 to 42.