Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-10
2002-09-24
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...
C546S097000
Reexamination Certificate
active
06455538
ABSTRACT:
DESCRIPTION OF THE INVENTION
The present application relates to new substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols of general formula I:
wherein
X denotes a single bond, —O—, C
1
-C
4
-alkylene, an alkylene bridge having 1 to 8 carbon atoms which may be branched or unbranched and may have one or two oxygen atom(s) anywhere in the bridge, preferably C
1
-C
3
-alkylene—O— or —O—-CH
2
—CH
2
—O—, —O—CH
2
—CH
2
—NH—;
R
1
denotes hydrogen, methyl, ethyl, or phenyl;
R
2
denotes hydrogen or methyl;
R
3
denotes hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, or methoxy;
R
4
denotes hydrogen, methyl, or ethyl;
R
5
denotes hydrogen, methyl, or ethyl;
R
6
denotes hydrogen, methyl, or ethyl;
R
7
denotes tert-butyl, cyclohexyl, phenyl optionally substituted by R
9
and R
10
, which may be identical or different,
R
8
denotes hydrogen or C
1
-C
4
-alkyl;
Z denotes oxygen, NH, or sulfur;
R
9
denotes hydrogen, methyl, fluorine, chlorine, bromine, or methoxy;
R
10
denotes hydrogen, methyl, fluorine, chlorine, bromine, or methoxy;
optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids such as, e.g., acid addition salts with hydrohalic acids, for example, hydrochloric or hydrobromic acids, or corresponding organic acids, for example, fumaric or diglycolic acid.
Preferred compounds of general formula I are those wherein, in the above definition R
4
and R
5
either both simultaneously denote methyl or independently of one another may denote hydrogen or methyl, with at least one of the substituents denoting a methyl group.
Compounds of general formula I are preferred wherein:
X denotes oxygen;
R
1
denotes hydrogen, methyl or ethyl;
R
2
denotes hydrogen,
R
2
denotes hydrogen;
R
4
denotes hydrogen or methyl;
R
5
denotes hydrogen or methyl;
R
6
denotes methyl;
R
7
denotes phenyl;
R
8
denotes hydrogen; and
R
9
and R
10
independently of one another denote hydrogen, methyl, fluorine or methoxy,
particularly compounds of general formula I wherein, in the above definition, R
4
and R
5
either both simultaneously denote methyl or independently of one another denote hydrogen or methyl, with at least one of the substituents denoting a methyl group;
The following compounds are most particularly preferred:
(−)-(1R,2″S)-2-(2″-benzyloxy)propyl-4′-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and
(−)-(1R,2″S)-2-[2″-(2′″,6′″-difluorobenzyl)oxy]propyl-4′-hydroxy-5,9,9-trimethyl-6,7-benzomorphan in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
Unless otherwise stated, the general definitions are used in the following sense:
C
1
-C
4
-alkyl or C
1
-C
8
-alkyl generally denotes a branched or unbranched hydrocarbon group having 1 to 4 or 1 to 8 carbon atom(s), which may optionally be substituted with one or more halogen atom(s)—preferably fluorine—which may be identical to or different from one another. The following hydrocarbon groups are mentioned by way of example:
methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2,-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl are preferred.
Accordingly, alkylene denotes a branched or unbranched divalent hydrocarbon bridge having 1 to 8 carbon atoms which may optionally be substituted with one or more halogen atom(s)13 preferably fluorine—which may be identical to or different from one another.
Alkoxy generally denotes a straight-chained or branched hydrocarbon group bound via an oxygen atom; a lower alkoxy group having 1 to 4 carbon atom(s) is preferred. The methoxy group is particularly preferred.
Methods of Preparation
The compounds according to the invention may be prepared by methods known from the prior art [WO 97/06146]. The invention relates to the enantiomerically pure compounds as well as the associated racemates.
The key compounds are the nor-benzomorphans
2
a
to
5
a
, which are shown in the diagram as the corresponding (−)-enantiomers:
The synthesis of
2
where R=H is described in published German Application No.: 195 28 472.
Compound
3
can be prepared analogously to compound
2
. The starting compound is the piperidone
6
which occurs as an intermediate in the synthesis of
2
, and which is reacted for example with an ethyltriphenylphosphonium salt instead of with the corresponding ethyl derivative - as is already known from the prior art (cf. Diagram 2).
Compound
4
is prepared analogously to the process described in WO 97/06146 from 2-methoxybenzylcyanide
11
and 2-bromopropionic acid
12
.
In the first step, for example, 2-methoxybenzylcyanide
11
is reacted with ethyl 2-bromopropionate
12
to obtain the correspondingly substituted 3-amino-2-methylbutanoic acid ester derivative
13
(since in view of the desired end product the alcohol component of the partial ester structure is not important, any other C
1
-C
8
-alkyl ester or a benzyl ester may be used):
In order to carry out this conversion, of the Reformatsky reaction type, an alkylhalosilane, preferably, a trialkylchlorosilane, most preferably trimethylchlorosilane - and zinc powder are placed in a solvent which is inert under the reaction conditions used, preferably an ether, or in a halohydrocarbon, most preferably dichloromethane. After this mixture has been diluted with a polar - inert - solvent, preferably a cyclic ether, most preferably tetrahydrofuran - the reaction mixture is heated - preferably to reflux temperature - and combined with a mixture of the ethyl 2-bromopropionate of general formula 3 with the o-methoxybenzylcyanide and heated further, preferably to reflux temperature. After cooling and filtering off the zinc powder, the reaction mixture is mixed with a reducing agent which is selective regarding the reduction of imino functions - preferably a complex alkali metal borohydride derivative, most preferably sodium cyanoborohydride - and then mixed with an alkanol - preferably a straight-chained or branched C
1
-C
4
-alcohol, most preferably ethanol. Then an aqueous solution of a basically reacting compound - preferably ammonia solution, most preferably with concentrated ammonia solution - is added and the organic phase of the reaction mixture is isolated. After drying and evaporation in vacuo, the residue remaining is taken up in an inert solvent - preferably in an aliphatic or aromatic hydrocarbon, most preferably in toluene - and extracted with the aqueous solution of an acid - preferably a mineral acid, most preferably 2 N hydrochloric acid. Finally the aqueous phase is made alkaline with the aqueous solution of a basically reacting compound - preferably ammonia solution, most preferably with concentrated ammonia solution - and then extracted with an organic, water-immiscible extraction agent - preferably with a halohydrocarbon, most preferably with dichloromethane. The extract thus obtained is dried and then concentrated and the 3-amino-2-methylbutanoate derivative of general formula
4
is isolated.
In the second reaction step the ethyl 3-amino-2-methylbutanoate derivative
13
thus obtained is reacted with ethyl acrylate (as, in the light of the desired end product, the alcohol component of the ester structure is not critical, any other C
1
-C
8
-alkyl ester or even a benzyl es
Bechtel Wolf-Dietrich
Carter Adrian
Grauert Matthias
Palluk Rainer
Pschorn Uwe
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen
Huang Evelyn Mei
Raymond Robert P.
Witkowski Timothy X.
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