Process for preparing scopine esters

Details Process for preparing scopine esters Process for preparing scopine esters

2003-01-09

2004-06-08

Huang, Evelyn Mei (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S059000, C549S060000, C549S473000, C560S100000, C560S101000, C562S468000

Reexamination Certificate

active

06747154

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a new process for preparing scopine esters of general formula 1
wherein X
−
and the groups R
1
and Ar may have the meanings given in the claims and in the specification.
BACKGROUND OF THE INVENTION
Anticholinergics may appropriately be used to treat a number of diseases. Particular mention should be made, for example, of the treatment of asthma or chronic obstructive pulmonary disease (COPD). For treating these diseases, WO 92/16528 proposes, for example, anticholinergics which have a scopine, tropenol, or tropine basic structure.
The problem on which WO 92/16528 is based is the preparation of anticholinergically active compounds which are characterized by their long-lasting activity. To solve this problem, WO 92/16528 discloses inter alia benzilic acid esters of scopine, tropenol, or tropine.
For treating chronic diseases, it is often desirable to prepare pharmaceutical compositions with a longer-lasting effect. This will generally ensure that the concentration of the active substance needed to achieve the therapeutic effect is present in the body for a longer period of time without the need for the pharmaceutical composition to be administered repeatedly and all too frequently. Moreover, if an active substance is administered at longer intervals of time, this contributes to the feeling of well-being of the patient to a considerable degree. It is particularly desirable to provide a pharmaceutical composition which can be used to therapeutically good effect by administering it once a day (single dose). A single application per day has the advantage that the patient can become accustomed relatively quickly to the regular taking of the medicament at a particular time of the day.
If it is to be used as a medicament for administration once a day, the active substance which is to be given must meet particular requirements. First of all, the desired onset of the activity after the administration of the pharmaceutical composition should occur relatively quickly and ideally the activity should remain as constant as possible over a fairly lengthy ensuing period. On the other hand, the duration of activity of the pharmaceutical composition should not greatly exceed a period of about one day. Ideally, an active substance should have an activity profile such that the preparation of a pharmaceutical composition which is intended to be administered once a day and contains the active substance in therapeutically appropriate doses can be properly controlled.
It has been found that the esters of scopine, tropenol, or tropine disclosed in WO 92/16528 do not meet these more stringent requirements. Because of their extremely long duration of activity, significantly exceeding the period of about one day specified above, they cannot be used therapeutically in a single once-a-day dose.
In contrast to the compounds disclosed in WO 92/16528, for example, it is possible to prepare anticholinergically active pharmaceutical compositions which can be administered once a day if scopine esters of formula 1
wherein X
−
and the groups R
1
and Ar may have the meanings specified hereinafter.
In addition to the methods of synthesis disclosed in WO 92/16528 for preparing scopine esters, processes for preparing esters of scopine are also disclosed in EP 418 716 A1, for example. These processes known in the art may also be used to prepare the compounds of formula 1. However, these methods of synthesis are in some cases more complex procedures involving a number of synthesis steps.
The aim of the present invention is to provide a method of synthesis which allows the compounds of general formula 1 to be synthesized more easily.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that compounds of formula 1
wherein X
−
and the groups R
1
and Ar may have the meanings specified hereinafter, may be obtained in a single reaction step if compounds of formula 2
are used as starting material.
Accordingly, the present invention relates to a process for preparing compounds of formula 1
wherein:
X
−
may represent chlorine, bromine, iodine, methanesulfonate, or trifluoromethanesulfonate;
R
1
may represent hydroxy, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, CF
3
, or fluorine;
Ar may represent a group selected from among phenyl, naphthyl, thienyl, and furyl, which may optionally be mono- or disubstituted by one or two groups selected from among C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, hydroxy, fluorine, chlorine, bromine, or CF
3
,
characterized in that a compound of formula 2
wherein:
Y
−
may denote chlorine, bromine, iodine, methanesulfonate, or trifluoromethanesulfonate is reacted in one step with a compound of formula 3
wherein:
R denotes a group selected from among hydroxy, methoxy, ethoxy, O—N-succinimide, O—N-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, 2-allyloxy, —S-methyl, —S-ethyl, and —S-phenyl; and
the groups R
1
and Ar may have one of the above meanings.
Preferably, the present invention relates to a process for preparing compounds of formula 1
wherein:
X
−
may represent bromine, methanesulfonate, or trifluoromethanesulfonate;
R
1
may represent hydroxy, methyl, CF
3
, or fluorine;
Ar may represent a group selected from among phenyl, thienyl, and furyl, characterized in that a compound of formula 2
wherein:
Y
−
may denote bromine, methanesulfonate, or trifluoromethanesulfonate is reacted in one step with a compound of formula 3
wherein:
R denotes a group selected from among hydroxy, O—N-succinimide, O—N-phthalimide, vinyloxy, and 2-allyloxy; and
the groups R
1
and Ar may have one of the above meanings.
More preferably, the present invention relates to a process for preparing compounds of formula 1
wherein:
X
−
may represent bromine, methanesulfonate, or trifluoromethanesulfonate;
R
1
may represent hydroxy or methyl; and
Ar may represent phenyl or thienyl,
characterized in that a compound of formula 2
wherein:
Y
−
may represent bromine, methanesulfonate, or trifluoromethanesulfonate, is reacted in one step with a compound of formula 3
wherein:
R denotes a group selected from among hydroxy, O—N-succinimide, O—N-phthalimide, vinyloxy, and 2-allyloxy, preferably vinyloxy and 2-allyloxy; and
the groups R
1
and Ar may have one of the above meanings.
To perform the process according to the invention the following procedure may be used.
In a first step the compound of formula 3 is taken up in a suitable organic solvent, preferably in a polar organic solvent, most preferably in a solvent selected from among acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide, and dimethylacetamide, while of the abovementioned solvents dimethylformamide, N-methylpyrrolidinone, and dimethylacetamide are particularly preferred. Of particular importance according to the invention are dimethylformamide and N-methylpyrrolidinone, the latter being particularly preferred.
Preferably, between 0.5 L and 2 L, most preferably between 0.75 L and 1.5 L of the abovementioned solvent are used per mol of the compound of formula 3 used.
Depending on the choice of the compound of formula 3, it may be useful in some cases to activate it before the reaction with the compound of formula 2. If derivatives wherein R denotes H are used as the compound of formula 3, it is preferable according to the invention to use, for example, corresponding activating reagents such as carbonyldiimidazole, carbonyldi-1,2,4-triazole, dicyclohexylcarbodiimide, or ethyldimethylaminopropylcarbodiimide, while in this context the use of carbonyldiimidazole is particularly preferred. Between 1 mol and 2 mol of the coupling reagent are used per mol of the compound 3 used wherein R is hydroxy. Preferably, 1 mol to 1.5 mol of the coupling reagent are used. If the abovementioned coupling reagents are used, as is preferred when R is hydroxy, the reaction mixture then obtained is preferably stirred for a period of 1 to 8 hours, preferably 3 to 7 hours, at a temperature i

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