Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-02
2001-10-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S063000
Reexamination Certificate
active
06297237
ABSTRACT:
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):
wherein R is C
2
-C
20
linear or branched alkyl, C
3
-C
7
cycloalkyl, phenyl or benzyl, which can optionally be substituted by C
1
-C
4
alkyl, halogen or C
1
-C
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;
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.
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═C═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)
wherein R
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
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:
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);
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═C═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
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
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
said process comprises:
a) hydrolysis with a mineral or an organic acid of a compound of formula (II)
wherein R
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)
b) acylation of eseroline (IIa) with an isocyanate of formula R—N═C═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:
wherein R
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
1
is isopropyl, tert-butyl, methoxymethyl, and geneseroline ethers of formula (III) wherein R
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 (1
Amari Gabriele
Chiesi Paolo
Delcanale Maurizio
Pietra Claudio
Pighi Roberto
Chiesi Farmaceutici S.p.A.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Raymond Richard L.
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