Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-11
2004-03-16
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S304000, C546S091000, C546S130000, C546S131000, C546S129000
Reexamination Certificate
active
06706726
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new anticholinergics of general formula 1:
wherein A, X
−
and the groups R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
may have the meanings given in the claims and specification, processes for preparing them as well as their use as medicaments.
BACKGROUND OF THE INVENTION
Anticholinergics may be used to therapeutic effect in a wide range of illnesses. Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease). For treating these complaints, WO 92/16528 proposes anticholinergics which have a scopine, tropenol or tropine basic structure.
The underlying objective of WO 92/16528 is the preparation of anticholinergically effective compounds which are characterised by their long-lasting activity. To achieve this aim WO 92/16528 discloses, inter alia, benzilic acid esters of scopine, tropenol or tropine.
For treating chronic diseases it is often desirable to prepare medicaments with a longer duration of activity. As a rule, this ensures that the concentration of the active substance in the body needed to achieve the therapeutic effect is guaranteed for a longer period without the need to re-administer the drug at frequent intervals. Moreover, giving an active substance at longer time intervals contributes to the wellbeing of the patient to a high degree. It is particularly desirable to prepare a pharmaceutical composition which can be used therapeutically by administration once a day (single dose). The use of a drug once a day has the advantage that the patient can become accustomed relatively quickly to regularly taking the drug at certain times of the day.
In order to be used as a medicament taken once a day, the active substance to be given must meet particular requirements. First of all, the onset of the desired activity should take place relatively quickly after administration of the drug and ideally should have as constant an effect as possible over a subsequent fairly long period of time. On the other hand, the duration of activity of the drug should not substantially exceed a period of about one day. Ideally, an active substance has an activity profile such that the preparation of a drug for administration once a day, which contains the active substance in therapeutically beneficial doses, can be deliberately controlled.
It has been found that the benzilic acid esters of scopine, tropenol and tropine disclosed in WO 92/16528 do not meet these stringent requirements. Because of their extremely long period of activity, which significantly exceeds the above-mentioned period of about one day, they cannot be used therapeutically for administration in a single dose per day.
The aim of the present invention is therefore to provide new anticholinergics which, by virtue of their activity profile, make it possible to prepare a drug for administration once a day. A further objective of the invention is to prepare compounds characterised by a relative rapid onset of activity. The invention further sets out to provide compounds which, after a rapid onset of activity, have as constant an activity as possible over a subsequent lengthy period of time. A further aim of the invention is to provide compounds whose duration of activity does not substantially exceed a period of about one day in therapeutically beneficial doses. Finally, the invention sets out to provide compounds which have an activity profile which ensures good control of the therapeutic effect (i.e. total therapeutic effect without side effects caused by a build-up of the substance in the body).
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that the above objectives are achieved by means of compounds of general formula 1 wherein the group R
7
does not denote hydroxy.
Accordingly the present invention relates to compounds of general formula 1:
wherein
A denotes a double-bonded group selected from among:
X
−
denotes anion with a single negative charge,
R
1
and R
2
denote C
1
-C
4
-alkyl, which may optionally be substituted by hydroxy or halogen;
R
3
, R
4
, R
5
and R
6
, which may be identical or different, denote hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
R7 denotes hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkyloxy, C
1
-C
4
-alkylene-halogen, halogen-C
1
-C
4
-alkyloxy, C
1
-C
4
-alkylene-OH, CF3, —C
1
-C
4
-alkylene-C
1
-C
4
-alkyloxy, —O—COC
1
-C
4
-alkyl, —O—COC
1
-C
4
-alkyl-halogen, —O—COCF
3
or halogen, while
if A denotes
R
1
and R
2
denote methyl and
R
3
, R
4
, R
5
and R
6
denote hydrogen,
R
7
cannot also be hydrogen.
Preferred compounds of general formula 1 are those wherein
A denotes a double-bonded group selected from among:
X
−
denotes an anion with a single negative charge selected from among chloride, bromide, methylsulphate, 4-toluenesulphonate and methanesulphonate, preferably bromide,
R
1
and R
2
which may be identical or different denote a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R
3
, R
4
, R
5
and R
6
, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF
3
or NO
2
;
R7 denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, —CH
2
—F, —CH
2
—CH
2
—F, —O—CH
2
—F, —O—CH
2
—CH
2
—F, —CH
2
—OH, —CH
2
—CH
2
—OH, CF
3
, —CH
2
—OMe, —CH
2
—CH
2
—OMe, —CH
2
—OEt, —CH
2
—CH
2
—OEt, —O—COMe, —O—COEt, —O—COCF
3
, —O—COCF
3
, fluorine, chlorine or bromine.
Particularly preferred are compounds of general formula 1, wherein
A denotes a double-bonded group selected from among:
X
−
denotes an anion with a single negative charge selected from among chloride, bromide and methanesulphonate, preferably bromide;
Rand R
2
which may be identical or different denote a group selected from methyl and ethyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R
3
, R
4
, R
5
and R
6
, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;
R
7
denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF
3
, or fluorine.
Preferred compounds of general formula 1 according to the invention are those wherein
A denotes a double-bonded group selected from among:
X
−
denotes bromide;
R
1
and R
2
which may be identical or different denote a group selected from methyl and ethyl, preferably methyl;
R
3
, R
4
, R
5
and R
6
, which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine;
R
7
denotes hydrogen, methyl or fluorine.
Of particular importance according to the invention are compounds of general formula 1, wherein
A denotes a double-bonded group selected from among:
X
−
denotes bromide;
R
1
and R
2
which may be identical or different denote methyl or ethyl, preferably methyl;
R
3
, R
4
, R
5
and R
6
, which may be identical or different, denote hydrogen or fluorine, preferably hydrogen;
R
7
denotes hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl.
The invention relates to the compounds of formula 1, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.
In the compounds of general formula 1 the groups R
3
, R
4
, R
5
and R
6
, provided that they do not denote hydrogen, may each be in the ortho, meta or para position relative to the bond to the “—C—R
7
” group. Provided that none of the groups R
3
, R
4
, R
5
and R
6
denotes hydrogen, R
3
and R
5
are preferably linked in the para-position and R
4
and R
6
are preferably linked in the ortho- or meta-position, most preferably in the meta-position. If one of the groups R
3
and R
4
and one of the groups R
5
and R
6
denotes hydrogen, the other group in each case is preferably linked in the meta- or para-position, most preferably in the para-position. If none of the groups R
3
, R
4
, R
5
and R
6
denotes h
Banholzer Rolf
Meissner Helmut
Morschhaeuser Gerd
Pieper Michael Paul
Pohl Gerald
Boehringer Ingelheim Pharma GmbH & Co. KG
Bottino Andrew P.
Huang Evelyn Mei
Raymond Robert P.
Witkowski Timothy X.
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