| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | October 2, 2001 |
| PATENT TITLE |
Process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
| PATENT ABSTRACT | A process for the preparation of compounds of formula (I), ##STR1## wherein R is C.sub.2 -C.sub.20 linear or branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl or benzyl, which can optionally be substituted by C.sub.1 -C.sub.4 alkyl, halogen or C.sub.1 -C.sub.4 alkoxy group, said process comprising: a) oxidation of eserine with hydrogen peroxide in the presence of a base and subsequent hydrolysis to geneseroline, without isolating the intermediate geneserine; b) acylation of geneseroline with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined above, in the presence of a basic catalyst; c) optional transformation into a pharmaceutically acceptable salt. Compounds of formula (I) wherein R is a phenyl or benzyl, which can be optionally substituted by alkyl, halogen or alkoxy, are selective, potent brain anticholinesterase inhibitors |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | August 2, 1999 |
| PATENT CT FILE DATE | October 7, 1998 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | April 22, 1999 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
N. Node et al.: Chemical & Pharmaceutical Bulletin, vol. 44, No. 4, 1996, pp. 715-719, XP002092652 see p. 715, left-hand column, compound 2. P. L. Julian et al.: Journal of the American Chemical Society, vol. 57, 1935, pp. 755-757, XP002092654 cited in the application see p. 756, compound (VII) see p. 757, left-hand column, last paragraph to right-hand column, first paragraph. E. Redenti et al.: Journal of Pharmaceutical Sciences, vol. 84, No. 9, Sep. 1995, pp. 1126-1133, XP002092653 see p. 1126, scheme 1; pp. 1126-1127, paragraph "Chemistry". |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A process for the preparation of compounds of formula (I): ##STR15## wherein R is C.sub.2 -C.sub.20 linear or branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl or benzyl, which can optionally be substituted by C.sub.1 -C.sub.4 alkyl, halogen or C.sub.1 -C.sub.4 alkoxy group, said process comprising: a) oxidation of eserine with hydrogen peroxide in the presence of a base and subsequent hydrolysis to geneseroline, without isolating the intermediate geneserine; b) acylation of geneseroline with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined above, in the presence of a basic catalyst; c) optional transformation into a pharmaceutically acceptable salt. 2. A process according to claim 1, wherein the catalyst in step b) is selected from the group consisting of potassium tert-butylate and potassium carbonate. 3. A process according to claim 1, wherein in step b) a phase transfer catalyst is added. 4. A process according to claim 3, wherein tetrabutylammonium bromide is the phase transfer catalyst. 5. A process according to claim 1, wherein in step b) an ultrasonic source is used. 6. A process for the preparation of compounds of formula (I): ##STR16## wherein R is C.sub.2 -C.sub.20 linear or branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl or benzyl, which can optionally be substituted by C.sub.1 -C.sub.4 alkyl, halogen or C.sub.1 -C.sub.4 alkoxy group, said process comprising: a) oxidation of a compound of formula (II) with peracids or peroxides ##STR17## wherein R.sub.1 is a protective group for the phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions without reducing the geneserino-like N-oxide group, in an alcoholic solvent or in a water-alcohol mixture to give a compound of formula (III); ##STR18## b) hydrolysis of the compound of formula (III) to geneseroline with a mineral acid or an organic acid, which does not reduce the N-oxide group; c) acylation of geneseroline with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined above, in the presence of a basic catalyst selected from the group consisting of alkali alcoholates, carbonates or hydroxides; d) optional transformation into a pharmaceutically acceptable salt. 7. A process for the preparation of compounds of formula (I): ##STR19## wherein R is C.sub.2 -C.sub.20 linear or branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl or benzyl, which can optionally be substituted by C.sub.1 -C.sub.4 alkyl, halogen or C.sub.1 -C4 alkoxy group, said process comprising a) hydrolysis of a compound of formula (II) ##STR20## wherein R.sub.1 is a protective group for the phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions to give eseroline of formula (IIa); ##STR21## b) acylation of eseroline (IIa) with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined above in the presence of a basic catalyst selected from the group consisting of alkali alcoholates, carbonates or hydroxides; c) oxidation of the so obtained eseroline aminocarbonyl derivative to the corresponding aminocarbonyl derivative of geneseroline; d) optional transformation into a pharmaceutically acceptable salt. 8. A process according to claim 6, wherein hydrolysis of compound (II) or (III) is carried out with an acid selected from the group consisting of sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, a strongly acidic ion-exchange resin. 9. A process according to claim 6, wherein hydrolysis is carried out with sulfuric acid at a concentration ranging from 10 to 85% w/w. 10. A process according to claim 6, wherein hydrolysis is carried out with hot 85% w/w phosphoric acid. 11. A process according to claim 6, wherein hydrolysis is carried out with methanesulfonic acid at 90.degree. C. 12. A process according to claim 6, wherein hydrolysis is carried out with hot trifluoroacetic acid or 10% hydrochloric acid at 40.degree. C. 13. A process according to claim 6, wherein hydrolysis is carried out with a strongly acidic ion-exchange resin. 14. A process according to claim 6, wherein, in the acylation step, the basic catalyst is added with a phase transfer catalyst or an ultrasound source is used. 15. A process according to claim 7, wherein hydrolysis of compound (II) or (III) is carried out with an acid selected from the group consisting of sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, and a strongly acidic ion-exchange resin. 16. A process according to claim 7, wherein hydrolysis is carried out with sulfuric acid at a concentration ranging from 10 to 85% w/w. 17. A process according to claim 7, wherein hydrolysis is carried out with hot 85% w/w phosphoric acid. 18. A process according to claim 7, wherein hydrolysis is carried out with methanesulfonic acid at 90.degree. C. 19. A process according to claim 7, wherein hydrolysis is carried out with hot trifluoroacetic acid or 10% hydrochloric acid at 40.degree. C. 20. A process according to claim 7, wherein hydrolysis is carried out with a strongly acidic ion-exchange resin. 21. A process according to claim 7, wherein, in the acylation step, the basic catalyst is added with a phase transfer catalyst or an ultrasound source is used. 22. Compounds of formula (Ia) ##STR22## wherein R is phenyl or benzyl group, which can optionally be substituted by C.sub.1 -C.sub.4 alkyl, halogen or C.sub.1 -C.sub.4 alkoxy group and their pharmaceutically acceptable salts. 23. Compounds according to claim 22, wherein R is selected from the group consisting of 2-ethylphenyl, 3-methylphenyl, 2-methylphenyl. 24. The compound of claim 22, wherein R is 2-ethylphenyl. 25. Pharmaceutical compositions containing an effective amount of a compound of claim 22 in admixture with pharmaceutically acceptable carriers and excipients. 26. A method of inhibiting acetylcholinesterase activity in a patient comprising administering to said patient an effective amount of the compound of claim 22 to inhibit acetylcholinesterase activity. 27. A method of treating neurodegenerative disease in a patient in need thereof comprising administering to said patient an effect amount of the compound of claim 22 to treat a neurodegenerative disease. 28. The method of claim 27, wherein said neurodegenerative disease is Alzheimer's disease. 29. A method of inhibiting acetylcholinesterase activity in a patient comprising administering to said patient an effective amount of the compound of claim 24 to inhibit acetylcholinesterase activity. 30. A method of treating neurodegenerative disease in a patient in need thereof comprising administering to said patient an effect amount of the compound of claim 24 to treat a neurodegenerative disease. 31. The method of claim 30, wherein said neurodegenerative disease is Alzheimer's disease. 32. The method of claim 27, wherein said effective amount is from 1 to 50 mg per day. 33. The method of claim 32, wherein said effective amount is from 5 to 20 mg per day. 34. The method of claim 30, wherein said effective amount is from 1 to 50 mg per day. 35. The method of claim 34, wherein said effective amount is from 5 to 20 mg per day. |
| PATENT DESCRIPTION |
DESCRIPTION The present invention relates to a process for the preparation of structural analogues of geneseroline, in particular to aminocarbonyl derivatives of geneseroline of formula (I): ##STR2## wherein R is C.sub.2 -C.sub.20 linear or branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl or benzyl, which can optionally be substituted by C.sub.1 -C.sub.4 alkyl, halogen or C.sub.1 -C.sub.4 alkoxy group. BACKGROUND OF THE INVENTION Geneseroline derivatives of the above formula (I), having anticholinesterase activity, are disclosed in the European patent 0599890, in the name of Chiesi. These compounds can be used in the treatment of disorders of central nervous system. The examples of preparation of the compounds of formula (I), as disclosed in the above patent, comprise the following steps: a) hydrolysis of eserine to eseroline; ##STR3## b) O-acylation of eseroline with reagents capable of introducing the desired function --CO--NHR, wherein R is as above defined; c) oxidation of the so obtained eseroline aminocarbonyl derivatives to give the corresponding aminocarbonyl derivatives of geneseroline. More specifically, in the examples of the patent, the preparation of only n-heptylaminocarbonylgeneseroline is disclosed. Substituted imidazolureas or isocyanates are used for the acylation reaction. Oxidation of eseroline derivatives to the corresponding geneseroline derivatives is carried out by using peracids or organic peroxides, such as m-chloroperbenzoic, monoperphthalic, peracetic acid, hydrogen peroxide, in inert solvents, such as halogenated hydrocarbons, aromatic hydrocarbons, dimethylformamide, dimethylsulfoxide. Alternatively, the compounds of formula (I) have been prepared starting from geneseroline through hydrolysis of the methylaminocarbonyloxy group, and subsequent acylation, carried out by always using N-alkylimidazoleurea. Geneseroline is a well-known compound (Yu Q.S. et al. Journal of Natural Products, 52(2), 332-336, 1989). The processes therein disclosed are unsuited to industrial scale, because of problems related to the cost of the starting alkaloid, reaction speed, yield and purity of the final product, due to side reactions. It has now been found, and it is an object of the present invention, a process for the preparation of the compounds of formula (I), which is simple, economical, safe and applicable on industrial scale with good quantitative yields. DISCLOSURE OF THE INVENTION In a first embodiment of the present invention, the compounds of formula (I) can be prepared starting from eserine, according the following reaction scheme n.1, obtaining good yields, a good purity grade of the final product and improvement of reaction times. ##STR4## The process according to this first embodiment of the present invention comprises: a) oxidation of eserine with hydrogen peroxide in the presence of a base and subsequent hydrolysis to geneseroline, without isolating the intermediate geneserine; b) acylation of geneseroline with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined in the above formula (I), in the presence of a basic catalyst; c) optional transformation into a pharmaceutically acceptable salt. The above disclosed process, comprising oxidation of eserine, followed by hydrolysis to geneseroline, without isolating the intermediate geneserine, allows a significant increase of the yields, maintaining a good purity of the final product. Besides, the use of cheaper and less dangerous reagents makes the procedure more suitable for industrial scale. Acylation reaction is carried out by using isocyanates according to classical methods, with a suitable basic catalyst, selected among alkali alcoholates, carbonates or hydroxides, such as potassium tert-butylate or potassium carbonate, the latter being particularly preferred for the application to industrial productions. In order to speed up the process, the reaction may be carried out in the presence of small amounts of a phase transfer catalyst, such as tetrabutylammonium bromide, or using an ultrasound source. In a second embodiment of the present invention, the synthesis is carried out by using as starting compounds ethers of formula (II) ##STR5## wherein R.sub.1 is a protective group for phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions without reducing the geneserine-like N-oxide group. Examples of R.sub.1 group are ethyl, tert-butyl, methoxymethyl, methoxyethoxymethyl, n-propyl, isopropyl, tetrahydropyranyl. This second embodiment of the present invention is carried out according to the following reaction scheme n.2, obtaining the compounds of formula (I) in three steps: ##STR6## said process comprises: a) oxidation of a compound of formula (II) with peracids or peroxides, preferably hydrogen peroxide, in an alcoholic solvent or in a water-alcohol mixture to give a compound of formula (III); ##STR7## b) hydrolysis of the compound of formula (III) to geneseroline with a mineral acid or an organic acid, which does not reduce the N-oxide group; c) acylation of geneseroline with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined above and in the same reaction conditions disclosed for the process outlined in scheme 1 above; d) optional transformation into a pharmaceutically acceptable salt. For the purposes of the present invention, the definition of R.sub.1 is clearly understood by the person skilled in this art, by resorting only to the general knowledge available in the pertaining literature, such as for example Greene, T. W., Wuts P. G. M. "Protective Groups in Organic Synthesis", 3, 145, Wiley, 2.sup.nd edition 1990; Kocienski P. J. "Protecting Groups" 2, 21, Ed. Thieme 1994. This process can be applied to both enantiomers of the ethers of formula (II), allowing obtaining both products with structure (I) and the corresponding enantiomers. In a further embodiment of the present invention, compounds (I) can be prepared according to the following scheme 3 ##STR8## said process comprises: a) hydrolysis with a mineral or an organic acid of a compound of formula (II) ##STR9## wherein R.sub.1 is a protective group for the phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions, such as for example ethyl, tert-butyl, methoxymethyl, methoxyethoxymethyl, n-propyl, isopropyl, tetrahydropyranyl; to give eseroline (IIa) ##STR10## b) acylation of eseroline (IIa) with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined above and in the same reaction conditions disclosed for the process outlined in scheme 1 above; c) oxidation of the so obtained eseroline aminocarbonyl derivative to the corresponding geneseroline aminocarbonyl derivative; d) optional transformation into a pharmaceutically acceptable salt. Eseretole is one of the ethers that can be used in this invention and is commercially available at low cost and suitable quantities. Other ethers, which proved to be particularly suited as starting compounds for the preparation of compounds (I), are for example: ##STR11## wherein R.sub.1 is tert-butyl, methoxymethyl, methoxyethoxymethyl, n-propyl, isopropyl, tetrahydropyranyl. These ethers may be prepared according to methods available in the literature. Eseroline ethers of formula (II) and geneseroline ethers of formula (III), wherein R.sub.1 is isopropyl, tert-butyl, methoxymethyl, and geneseroline ethers of formula (III) wherein R.sub.1 is alkyl or alkoxylalkyl, among which tetrahydropyranyl are per se new, since they have never been disclosed before. Compounds (II) and (III) are within the scope of the present invention as intermediates in the process above disclosed. The embodiments of the present invention according to the reaction schemes 2 and 3 are characterised by the step comprising the hydrolysis of eseroline ethers of formula (II) or geneseroline ethers of formula (III) to eseroline or geneseroline, respectively. Technical literature provides many examples of hydrolysis of this kind of alkaloids, in particular esermetol and eseretole: Polonovsky M., Nitzerg C., Bull. Soc. Chim. Fr., 19, 33-37 (1916); Julian P., Pikl J., J. Am. Chem. Soc. 57, 755-757 (1935); Yu Q. S., Brossi A., Heterocycles, 27, 745-750 (1988). However, in all the earlier documents, scientific papers and patents, hydrolysis of these ethers is carried out by using classical dealkylating agents, such as BBr.sub.3, BCl.sub.3, AlCl.sub.3 (Lewis acids), HBr or other halogenhydric acids. For example, U.S. Pat. No. 5310935 discloses the preparation of (3aS-cis)-eseroline by hydrolysing its methyl ether (or similar ethers) with AlCl.sub.3 or BBr.sub.3 ; International patent application WO 9427963 enables for the conversion of eseretole to physostigmin or its derivatives, according to the teaching by Julian P., PikI J., J. Am. Chem. Soc. 57, 755-757 (1935); in European patent application n. 0253372 eseroline ether hydrolysis is carried out with AlCl.sub.3 or BBr.sub.3. The application of the methods disclosed in the above references to the hydrolysis of the ethers of formula (III) to geneseroline did not give good results, since other reduction side reactions occur, with formation of unwanted by-products and consequent difficult purification of the obtained geneseroline and low yields. On the contrary, the method disclosed in the present invention allows to obtain highly pure geneseroline with good yields. The application of this method offers relevant work-and-cost effective advantages also in the presence of compounds of formula (II) with respect to Lewis acid uses. A particular aspect of the present invention relates to the use of a mineral or organic acid for the hydrolysis of alkyl ethers of indole derivatives, such as for example eseroline, geneseroline or physovenol. Suitable acids for the hydrolysis of compounds (II) or (III) are those having non-reducing properties, in particular with respect to compounds of formula (III), wherein the N--O group is sensitive to reducing agents. In the process according to the present invention, the acid is preferably selected from the group consisting of: sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, a strongly acidic ion-exchange resin, such as Amberlyst.RTM.. Hydrolysis conditions will be selected according to the R.sub.1 group present in the molecule, in particular the choice will be made on the kind of acid, its concentration and hydrolysis temperature. Sulfuric acid can be used at different concentrations from 10 to 85%, preferably at a temperature ranging from 50 to 90.degree. C. Phosphoric acid is generally used at the concentration of 85%, hot, preferably at a temperature of about 90.degree. C. Methanesulfonic acid is used as such and is made to react hot, preferably at a temperature of about 90.degree. C. Trifluoroacetic acid as such and 10% hydrochloric acid can be made to react warm at a temperature of about 40.degree. C. Compounds of formula (I) can be suitably transformed into their salts with pharmaceutically acceptable acids. Derivatives of formula (I), similarly to their parent compound geneserine, when in the form of free base have a 1,2-oxazine structure, while in the respective salified forms they have a N-oxide structure (see Scheme 4) ##STR12## The process according to the present invention allows for the first time and contrarily to the process disclosed in EP 0599890 to prepare in industrial scale compounds of formula (I), in particular wherein R is an aromatic group, preferably phenyl and benzyl, optionally substituted by C.sub.1 -C.sub.4 alkyl, halogen or C.sub.1 -C.sub.4 alkoxy. It has surprisingly been found that the compounds of formula (I), wherein R is an aromatic group, in particular phenyl and benzyl, optionally substituted by C.sub.1 -C4 alkyl, halogen or C.sub.1 -C4 alkoxy, have potent anticholinesterase activity, which is selective at cerebral level. These compounds, whose pharmacological properties were not effectively disclosed in EP 0599890, therefore represent a selection with respect to the earlier European patent and are a further object of the present invention. In fact, European patent 0599890 relates to aminocarbonyl derivatives of geneseroline of formula (I): ##STR13## wherein R is C.sub.2 -C20 linear or branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl or benzyl, which can optionally be substituted by C.sub.1 -C4 alkyl, halogen or C.sub.1 -C.sub.4 alkoxy group. The teaching of this patent enables the pharmacological properties only of n-heptylaminocarbonylgeneseroline (named also CHF 2060), which is an inhibitor of brain acetylcholinesterase characterised by a long action. Symptomatic therapy of senile dementia associated to Alzheimer disease can be done with substances having anticholinesterase activity, with the purpose to raise acetylcholine brain levels and restore cholinergic neurons functionality. Tacrine was the first compound endowed with these properties to come into clinical practice (Cognex; Davis K. L. et al., N. Eng. J. Med., 327: 1253-1259, 1993). However, hepatic side effects and poor selectivity at central level of this product stimulated pharmacological research to find out new compounds having higher activity and higher selectivity of action toward central level. Briefly, there is the need to have available a compound having high anticholinesterase activity, long duration of action, higher affinity on acetylcholinesterase enzyme (AChE) with respect to butyrylcholinesterase (BuChE) and at the same time to be selective "in vivo" in inhibiting brain AChE with respect to the same enzyme present in other peripheral organs, for example in the heart. SDZ-ENA 713 (commercial name Exelon), described in Enz A. et al. Progress in Brain Res. 98, 431-438, 1993, can be considered one of the selective anticholinesterase substances. This compound has been used by the applicant as comparison in some studies. It has now been found that compounds of formula (Ia) ##STR14## wherein R is phenyl or benzyl group, which can optionally be substituted by C.sub.1 -C4 alkyl, halogen or C.sub.1 -C4 alkoxy group are endowed with better pharmacological properties than the compounds of formula (I) wherein R is C.sub.2 -C.sub.20 linear or branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, in particular n-heptyl. Accordingly, the present invention further relates to compounds of formula (Ia) as new compounds when used as medicaments. It is another object of the present invention compounds of formula (Ia) and their pharmaceutically acceptable salts. Still another object of the present invention is a pharmaceutical composition containing a therapeutically effective amount of at least a compound of formula (Ia). The use of said compounds as active ingredient for the manufacture of a medicament is also within the scope of the present invention. According this further aspect of the present invention, examples of phenyl or benzyl group substituted with C.sub.1 -C4 alkyl group are 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, 2-propylbenzyl, 3-propylbenzyl, 4-propylbenzyl, 2-butylphenyl, 3-butylphenyl, 4-butylphenyl, 2-butylbenzyl, 3-butylbenzyl, 4-butylbenzyl, being intended that the terms propyl and butyl comprise both linear and branched isomers. Examples of phenyl or benzyl group substituted with halogen atoms are 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodiophenyl, 3-iodiophenyl, 4-iodiophenyl, 2-iodiobenzyl, 3-iodiobenzyl, 4-iodiobenzyl. Examples of phenyl or benzyl group substituted with C.sub.1 -C4 alkoxy group are 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 2-propoxyphenyl, 3-propoxyphenyl, 4-propoxyphenyl, 2-propoxybenzyl, 3-propoxybenzyl, 4-propoxybenzyl, 2-butoxyphenyl, 3-butoxyphenyl, 4-butoxyphenyl, 2-butoxybenzyl, 3-butoxybenzyl, 4-butoxybenzyl, being intended that the terms propoxy and butoxy comprise both linear and branched isomers. Preferred compound according to the present invention are those in which R is selected from the group consisting of: 2-ethylphenyl (named also CHF2819), 3-methylphenyl (CHF 2957) and 2-methylphenyl (CHF 2822). In a Declaration filed with United States Patent and Trademark Office, during the prosecution of U.S. Pat. No. 5,538,968, corresponding to EP 0599890, it was shown for the compounds of the present invention a particular selectivity with respect to brain acetylcholinesterase (AChE) in comparison with plasma acetylcholinesterase (AChE), therefore a higher selectivity for the brain than the one for the peripheral system. It has now been found that aminocarbonyl derivatives of geneseroline of formula (Ia) show a higher inhibition potency for brain acetylcholinesterase (AChE) with respect to the derivatives substituted with an alkyl residue at the same position, such as disclosed in the above cited European patent and in particular to n-heptylgeneseroline. The potency increase observed occurs at the same efficacy of enzymatic inhibition. Besides, the compounds of formula (Ia) evidenced not only a higher potency, but also a higher selectivity of enzymatic inhibition. In fact, these compounds demonstrate both a higher selectivity at tissue level, (brain tissue with respect to heart tissue) and a higher selectivity for acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). This selectivity is superior than the n-heptylgeneseroline one and to the reference compounds, such as physostigmine and SDZ-ENA 713. |
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