Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-09-12
2004-01-20
Davis, Brian (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S533000, C514S567000, C514S568000, C562S433000, C562S478000, C562S074000, C564S287000
Reexamination Certificate
active
06680345
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new substituted salicylic acid salts of salmeterol, processes for preparing them and their use as pharmaceutical compositions.
DETAILED DESCRIPTION OF THE INVENTION
The problem of the present invention is to prepare salts of salmeterol which are characterised by a high degree of local compatibility, particularly when administered by inhalation.
This problem is solved with the substituted salicylic acid salts of formula 1 shown below. Accordingly, the present invention relates to salts of general formula 1
wherein
R
1
and R
2
which may be identical or different, denote hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, halogen, COOH, OH, —COOC
1
-C
4
-alkyl, —CO—C
1
-C
4
-alkyl, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —SO
2
—OH, —CF
3
or phenyl;
R
3
denotes hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, halogen, —CF
3
or phenyl, while the phenyl ring may optionally be mono-, di- or trisubstituted by one, two or three groups selected from among C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, halogen or —CF
3
,
with the proviso that not all the groups R
1
, R
2
and R
3
may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Preferred are salts of formula 1, wherein
R
1
and R
2
which may be identical or different, denote hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, COOH, OH, —COOmethyl, —CO-methyl, —NH
2
, —NH(methyl), —N(methyl)
2
, —NH(ethyl), —N(ethyl)
2
, —SO
2
—OH, —CF
3
or phenyl;
R
3
denotes hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, —CF
3
or phenyl, while the phenyl ring may optionally be mono-, di- or trisubstituted by one, two or three groups selected from among methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine or —CF
3
,
with the proviso that not all the groups R
1
, R
2
and R
3
may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Particularly preferred are salts of formula 1, wherein
R
1
and R
2
which may be identical or different, denote hydrogen, methyl, ethyl, propyl, methoxy, fluorine, chlorine, bromine, iodine, —COOH, OH, —COOmethyl, —CO-methyl, —NH
2
, —SO
2
—OH or —CF
3
;
R
3
denotes hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, —CF
3
or phenyl, while the phenyl ring may optionally be mono- or disubstituted by one or two groups selected from among fluorine, chlorine, bromine or —CF
3
,
with the proviso that not all the groups R
1
, R
2
and R
3
may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Of particular importance according to the invention are compounds of formula 1 wherein
R
1
and R
2
which may be identical or different denote hydrogen, methyl, propyl, methoxy, chlorine, iodine, —COOH, OH, —COOmethyl, —CO-methyl, —NH
2
or —SO
2
—OH;
R
3
denotes hydrogen or phenyl, while the phenyl ring may optionally be mono- or disubstituted by one or two groups, preferably a group selected from among fluorine, chlorine, bromine or —CF
3
,
with the proviso that not all the groups R
1
, R
2
and R
3
may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Especially preferred according to the invention are compounds of general formula 1 wherein
R
1
and R
2
which may be identical or different, denote hydrogen, methyl, propyl, methoxy, chlorine, iodine, —COOH, OH, —COOmethyl, —CO-methyl, —NH
2
or —SO
2
—OH;
R
3
denotes hydrogen,
with the proviso that not all the groups R
1
, R
2
and R
3
may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Also of especial importance according to the invention are compounds of formula 1 wherein
R
1
and R
2
denote hydrogen;
R
3
denotes phenyl, while the phenyl ring may optionally be mono- or disubstituted by one or two groups, preferably a group selected from among fluorine, chlorine, bromine or —CF
3
, preferably fluorine,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
The alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups having 1 to 4 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 iso-propyl, butyl includes iso-butyl, sec. butyl and tert.-butyl, etc.
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 iso-propyloxy, butyloxy includes iso-butyloxy, 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.
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.
The salts of formula 1 are new acid addition salts of salmeterol, which is known from the prior art. Salmeterol has a chiral centre. The present invention relates to the salts of formula 1 in racemic or enantiomerically pure form. Both the (R)- and the (S)-enantiomer are of particular importance. Moreover the present invention relates to the salts of formula 1 in the form of the non-racemic mixtures of the two enantiomers.
In the compounds of general formula 1 the groups R
1
, R
2
and R
3
, if they do not represent hydrogen, may each be in the ortho, meta or para position relative to the linking to the carboxyl group. If none of the groups R
1
, R
2
and R
3
denotes hydrogen, the group R
3
is preferably linked in the meta position and the groups R
1
and R
2
are linked in the ortho and/or para position. If one of the groups R
1
, R
2
and R
3
denotes hydrogen, preferably at least one of the other groups is linked in the meta or para position, most preferably in the para position. Compounds wherein the group R
3
does not denote hydrogen are of particular importance according to the invention. In these compounds the group R
3
is preferably in the meta position, in relation to the carboxyl group.
The salts 1 according to the invention may be prepared starting from the free base of salmeterol analogously to processes known in the art for forming acid addition salts from secondary amines.
The preparation method comprises reacting the free base salmeterol with carboxylic acids of formula 2
wherein the groups R
1
, R
2
and R
3
are as hereinbefore defined, in suitable solvents, preferably organic solvents.
For this purpose the acid 2 is taken up in a suitable solvent, preferably an organic solvent, most preferably a solvent selected from among ethyl acetate, methanol, ethanol, iso-propanol and diethylether or mixtures thereof. If desired the abovementioned solvents may also be used in admixture with tert.-butylmethylether or cyclohexane. The acids 2 taken up in one of the abovementioned solvents are optionally dissolved with heating, preferably to the boiling temperature of the solvent. Salmeterol, optionally dissolved in o
Linz Guenter
Soyka Rainer
Steiner André
Boehringer Ingelheim Pharma KG
Davis Brian
Devlin Mary-Ellen M.
Morris Michael P.
Raymond Robert P.
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