Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-16
2004-02-24
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...
C546S094000
Reexamination Certificate
active
06696462
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to new anticholinergics of general formula 1
wherein X
−
and the groups A, B, R, R
1
, R
2
, R
3
, R
3′
, R
4
, R
4′
, R
X
, and R
X′
, may have the meanings given in the claims and in the specification, processes for preparing them, and their use as pharmaceutical compositions.
DESCRIPTION OF THE INVENTION
The present invention relates to compounds of general formula 1
wherein:
X
−
denotes 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;
A and B, which may be identical or different, preferably identical, denote —O—, —S—, —NH—, —CH
2
—, —CH═CH, or —N(C
1
-C
4
-alkyl)—;
R denotes hydrogen, hydroxy, —C
1
-C
4
-alkyl, —C
1
-C
4
-alkyloxy, —C
1
-C
4
-alkylene-halogen, —O—C
1
-C
4
-alkylene-halogen, —C
1
-C
4
-alkylene-OH, —CF
3
, —CHF
2
, —C
1
-C
4
-alkylene-C
1
-C
4
-alkyloxy, —O—COC
1
-C
4
-alkyl, —O—COC
1
-C
4
-alkylene-halogen, —C
1
-C
4
-alkylene-C
3
-C
6
-cycloalkyl, —O—COCF
3
, or halogen;
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;
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; and
R
X
and R
X′
, 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, or
R
X
and R
X′
together denote a single bond or a bridging group selected from among the bridges —O—, —S—, —NH—, —CH
2
—, —CH
2
—CH
2
—, —N(C
1
-C
4
-alkyl)—, —CH(C
1
-C
4
-alkyl)—, and —C(C
1
-C
4
-alkyl)
2
—.
Preferred compounds of general formula 1 are those wherein:
X
−
denotes an anion with a single negative charge selected from among chloride, bromide, 4-toluenesulfonate, and methanesulfonate, preferably bromide;
A and B, which may be identical or different, preferably identical, denote —O—, —S—, —NH—, or —CH═CH—;
R denotes hydrogen, hydroxy, —C
1
-C
4
-alkyl, —C
1
-C
4
-alkyloxy, —CF
3
, —CHF
2
, fluorine, chlorine, or bromine;
R
1
and R
2
, which may be identical or different, denote C
1
-C
4
-alkyl, which may optionally be substituted by hydroxy, fluorine, chlorine, or bromine, or
R
1
and R
2
together denote a —C
3
-C
4
-alkylene-bridge;
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
, fluorine, chlorine, or bromine; and
R
X
and R
X′
, 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
, fluorine, chlorine, or bromine, or
R
X
and R
X′
together denote a single bond or a bridging group selected from among the bridges —O—, —S—, —NH—, and —CH
2
—
Particularly preferred compounds of general formula 1 are those wherein:
X
−
denotes an anion with a single negative charge selected from among chloride, bromide, and methanesulfonate, preferably bromide;
A and B, which may be identical or different, preferably identical, denote —S— or —CH═CH—;
R denotes hydrogen, hydroxy, methyl, ethyl, methyloxy, ethyloxy, —CF
3
, or fluorine;
R
1
and R
2
, which may be identical or different, denote methyl, ethyl, —CH
2
F, or —CH
2
CH
2
F, preferably methyl or ethyl;
R
3
, R
4
, R
3′
, and R
4′
, which may be identical or different, denote hydrogen, methyl, methyloxy, —CF
3
, or fluorine;
R
X
and R
X′
, which may be identical or different, denote hydrogen, methyl, methyloxy, —CF
3
, or fluorine, or
R
X
and R
X′
together denote a single bond or the bridging group —O—.
Of particular importance according to the invention are compounds of general formula 1, wherein:
X
−
denotes an anion with a single negative charge selected from among chloride, bromide, and methanesulfonate, preferably bromide;
A and B, which may be identical or different, preferably identical, denote —S— or —CH═CH—;
R denotes hydrogen, hydroxy, or methyl;
R
1
and R
2
, which may be identical or different, denote methyl or ethyl;
R
3
, R
4
, R
3′
, and R
4′
, which may be identical or different, denote hydrogen, —CF
3
, or fluorine, preferably hydrogen;
R
X
and R
X′
, which may be identical or different, denote hydrogen, —CF
3
, or fluorine, preferably hydrogen, or
R
X
and R
X′
together denote a single bond or the bridging group —O—.
Also preferred according to the invention are compounds of general formula 1, wherein:
X
−
denotes bromide;
A and B denote —CH═CH—;
R denotes hydrogen, hydroxy, or methyl;
R
1
and R
2
denote methyl;
R
3
, R
4
, R
3′
, and R
4′
, which may be identical or different, denote hydrogen or fluorine, preferably hydrogen;
R
X
and R
X′
, which may be identical or different, denote hydrogen or fluorine, preferably hydrogen, or
R
X
and R
X′
together denote a single bond or the bridging group —O—.
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, as well as optionally in the form of the pharmacologically acceptable acid addition salts thereof.
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.
Of particular importance according to the invention are the compounds of general formula 1 wherein the two rings which contain A and B are arranged so that A and B are each in the ortho configuration relative to the bond to the “C—R” carbon. This preferred configuration is particularly important when A and B do not represent —CH═CH—. These compounds correspond to the general formula ortho-1.
Of particular importance according to the invention are the compounds of general formula 1 wherein A represents —CH═CH— and B represents —CH═CH—. These compounds correspond to general formula 1′.
Of particular importance according to the invention are the compounds of general formula 1 wherein the ester substituent at the nitrogen bicyclic group is in the a configuration. These compounds correspond to general formula 1-&agr;
The compounds of general formula 1 preferred according to the invention wherein the two rings which contain A and B are arranged so that A and B in each case ortho-configured relative to the bond to the “C—R” carbon and wherein, moreover, the ester substituent at the nitrogen bicyclic group is &agr;-configured correspond to general formula ortho-1-&agr;
The compounds of general formula 1 which are particularly preferred according to the invention wherein A represents —CH═CH— and B represents —CH═CH— and wherein the ester substituent at the nitrogen bicyclic group is &agr;-configured correspond to general formula 1′-&agr;.
The following compounds are particularly impor
Breitfelder Steffen
Eickmeier Christian
Germeyer Sabine
Grauert Matthias
Pestel Sabine
Aulakh Charanjit S.
Boehringer Ingelheim Pharma GmbH & Co. KG
Bottino Anthony P.
Raymond Robert P.
Witkowski Timothy X.
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