Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-05-01
1999-08-31
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546242, C07D22112
Patent
active
059455357
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a new process for preparing norbenzomorphan--the central intermediate in the preparation of pharmaceutically useful benzomorphan derivatives of general formula 1, particularly (-)-(1R,5S,2"R)-3'-hydroxy-2-(2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan and ##STR2## wherein R.sub.1 denotes hydrogen, C.sub.1-6 -alkyl, halogen, hydroxy, C.sub.1-8 -alkoxy, a benzoyl group bound via an oxygen or an alkylcarboxyl group having a straight-chained or branched C.sub.1-6 -lower alkyl group--wherein the alkyl group may optionally be substituted by one or more halogen atoms which may be identical or different wherein the alkyl groups may be identical or different, NH-acyl-(C.sub.1-8 -alkyl), wherein acyl denotes benzoyl or an alkylcarbonyl group having a straight-chained or branched C.sub.1-6 -lower alkyl group, whilst the alkyl group may optionally be substituted by one or more halogen atoms which may be the same as one another or different from one another.
Unless otherwise specifically stated, the general definitions are used as follows:
C.sub.1-6 -alkyl or C.sub.1-8 -alkyl generally denotes a branched or unbranched hydrocarbon group having 1 to 6 or 1 to 8 carbon atoms, which may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be the same as or different from one another. The following hydrocarbon groups are mentioned by way of example: methyl, ethyl, propyl, 1-methylethyl (isopropyl), 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-ethylproypyl, 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 3 carbon atoms such as methyl, ethyl, propyl and isopropyl are preferred.
Acyl generally denotes benzoyl or alkylcarbonyl groups--such as straight-chained or branched lower alkyl having 1 to about 6 carbon atoms, which are bound via a carbonyl group, the alkyl group optionally being substituted by one or more halogen atoms which may be the same as or different from one another. Alkyl groups having up to 4 carbon atoms are preferred. Examples include: acetyl, trifluoroacetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl. The acetyl group is particularly preferred.
The benzomorphan derivatives mentioned hereinbefore constitute highly promising active substances for treating neurodegenerative disorders as well as cerebroischaemias of various origins. The following may be mentioned by way of example: status epilepticus, hypoglycaemia, hypoxia, anoxia, cerebral trauma, cerebral oedema, amorphous lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, cardiac infarct, cerebral stroke and perinatal asphyxia. The benzomorphan derivative numbered BIII 277 and related benzomorphans are described in detail in German Offenlegungsschrift DE-OS 41 21 821, inter alia.
In addition, other methods of synthesis for producing benzomorphan 077, published European Application 0 004 960!. However, with the exception of DE-OS 41 21 821, these publications merely describe methods of synthesising the racemates, which have to be cleaved and eventually 50% of unwanted isomer have to be discarded. Furthermore, in some reaction steps, there is the risk of the formation of regioisomers.
The objective of the present invention is therefore to overcome the disadvantages of the processes known from the prior art and to provide a method of production which on the one hand avoids the formation of any regioisomers during the synthesis of the basic benzomorphan structure and on the other hand makes it possible to obtain the pharmacologically active stereoisomer in higher yields.
This objective is ac
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Baltes Hanfried
Grauert Matthias
Merz Herbert
Boehringer Ingelheim KG
Daus Donald G.
Devlin Mary-Ellen
Raymond Robert P.
Stempel Alan R.
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