Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-02
2004-09-14
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S091000, C546S128000, C546S089000, C514S304000
Reexamination Certificate
active
06790856
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to new fluorenecarboxylic acid esters of general formula 1
wherein X
−
and the groups A, R, R
1
, R
2
, R
3
, R
3′
, R
4
, and R
4′
may have the meanings given in the claims and in the description, processes for preparing them and their use as pharmaceutical compositions.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to compounds of general formula 1
wherein:
A denotes a double-bonded group selected from among
X
−
is an anion with a single negative charge, preferably an anion selected from among chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate;
R denotes hydrogen, hydroxy, methyl, ethyl, —CF
3
, —CHF
2
, or fluorine;
R
1
and R
2
, which may be identical or different, denote C
1
-C
5
-alkyl which may optionally be substituted by C
3
-C
6
-cycloalkyl, hydroxy, or halogen, or
R
1
and R
2
together denote a —C
3
-C
5
-alkylene-bridge; and
R
3
, R
4
, R
3′
, and R
4′
, which may be identical or different, denote hydrogen, —C
1
-C
4
-alkyl, —C
1
-C
4
-alkyloxy, hydroxy, —CF
3
, —CHF
2
, —CN, —NO
2
, or halogen.
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, 4-toluenesulfonate, and methanesulfonate, preferably bromide;
R denotes hydroxy, methyl, or fluorine;
R
1
and R
2
, which may be identical or different, denote methyl, ethyl, or fluoroethyl;
R
3
, R
4
, R
3′
, and R
4′
, which may be identical or different, represent hydrogen, methyl, methyloxy, hydroxy, —CF
3
, —CHF
2
, or fluorine.
Particularly 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, and methanesulfonate, preferably bromide;
R denotes hydroxy, methyl, or fluorine, preferably methyl or hydroxy;
R
1
and R
2
, which may be identical or different, represent methyl or ethyl, preferably methyl;
R
3
, R
4
, R
3′
and R
4′
, which may be identical or different, represent hydrogen, —CF
3
, —CHF
2
, or fluorine, preferably hydrogen 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 denotes hydroxy or methyl, preferably methyl;
R
1
and R
2
, which may be identical or different, represent methyl or ethyl, preferably methyl; and
R
3
, R
4
, R
3′
, and R
4′
, which may be identical or different, represent hydrogen or fluorine.
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.
In the compounds of general formula 1 the groups R
3
, R
4
, R
3′
, and R
4′
, if they do not represent hydrogen, may in each case be arranged in the ortho, meta or para position relative to the bond to the “—C—R” group. If none of the groups R
3
, R
4
, R
3′
, and R
4′
denotes hydrogen, R
3
and R
3′
are preferably linked in the para position and R
4
and R
4′
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
3′
and R
4′
denotes hydrogen, the other group in each case is preferably bonded in the meta or para position, most preferably in the para position. If none of the groups R
3
, R
4
, R
3′
, and R
4′
denotes hydrogen, the compounds of general formula 1 wherein the groups R
3
, R
4
, R
3′
, and R
4′
have the same meaning are particularly preferred according to the invention.
Also of particular importance according to the invention are those compounds of general formula 1 wherein the ester substituent is in the a configuration on the nitrogen bicyclic group. These compounds correspond to general formula 1-&agr;
The following compounds are of particular importance according to the invention: tropenol 9-hydroxyfluorene-9-carboxylate methobromide; tropenol 9-fluorofluorene-9-carboxylate methobromide; scopine 9-hydroxyfluorene-9-carboxylate methobromide; scopine 9-fluorofluorene-9-carboxylate methobromide; tropenol 9-methylfluorene-9-carboxylate methobromide; and scopine 9-methylfluorene-9-carboxylate methobromide.
The alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups having 1 to 5 carbon atoms. Examples include: methyl, ethyl, propyl, or butyl. The groups methyl, ethyl, propyl, or butyl may optionally also be referred to by the abbreviations Me, Et, Prop or Bu. Unless otherwise stated, the definitions propyl and butyl also include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl, and tert-butyl, etc.
The alkylene groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, or butylene.
The alkylene-halogen groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably disubstituted, by a halogen. Accordingly, unless otherwise stated, the term alkylene-OH groups denotes branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably monosubstituted, by a hydroxy.
The alkyloxy groups used, unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an oxygen atom. The following may be mentioned, for example: methyloxy, ethyloxy, propyloxy, or butyloxy. The groups methyloxy, ethyloxy, propyloxy, or butyloxy may optionally also be referred to by the abbreviations MeO, EtO, PropO, or BuO. Unless otherwise stated, the definitions propyloxy and butyloxy also include all possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and isopropyloxy, butyloxy includes isobutyloxy, sec-butyloxy, and tert-butyloxy, etc. The word alkoxy may also possibly be used within the scope of the present invention instead of the word alkyloxy. The groups methyloxy, ethyloxy, propyloxy, or butyloxy may optionally also be referred to as methoxy, ethoxy, propoxy, or butoxy.
The alkylene-alkyloxy groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably monosubstituted, by an alkyloxy group.
The —O—CO-alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are bonded via an ester group. The alkyl groups are bonded directly to the carbonyl carbon of the ester group. The term —O—CO-alkyl-halogen group should be understood analogously. The group —O—CO—CF
3
denotes trifluoroacetate.
Within the scope of the present invention, halogen denotes fluorine, chlorine, bromine, or iodine. Unless otherwise stated, fluorine and bromine are the preferred halogens. The group CO denotes a carbonyl group.
As explained hereinafter, the compounds according to the invention may be prepared partly analogously to the methods already known in the art (Diagram 1). The carboxylic acid derivatives of formula 3 are known in the art or may be obtained by methods of synthesis known in the art. If only suitably substituted carboxylic acids are known in the art, the compounds of formula 3 may also be obtained directly from them by acid- or base-catalyzed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents.
As can be seen from Diagram 1, the compounds of formula 2 ma
Germeyer Sabine
Meissner Helmut
Morschhaeuser Gerd
Pestel Sabine
Pieper Michael P.
Aulakh Charanjit S.
Boehringer Ingelheim Pharma KG
Bottino Anthony P.
Raymond Robert P.
Witkowski Timothy X.
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