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Details for Patent: 6,300,519

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Details for Patent: 6,300,519

Title: Antivirally active heterocyclic azahexane derivatives
Abstract:There are described compounds of formula I*, ##STR1## wherein R.sub.1 is lower alkoxycarbonyl, R.sub.2 is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl, R.sub.3 is phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals, or C.sub.4 -C.sub.8 cycloalkyl, R.sub.4 is phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl that is bonded by way of a ring carbon atom, has from 5 to 8 ring atoms, contains from 1 to 4 hetero atoms selected from nitrogen, oxygen, sulfur, suffinyl (--SO--) and sulfonyl (--SO.sub.2 --) and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl, R.sub.5, independently of R.sub.2, has one of the meanings mentioned for R.sub.2, and R.sub.6, independently of R.sub.1, is lower alkoxycarbonyl, or salts thereof, provided that at least one salt-forming group is present. The compounds are inhibitors of retroviral aspartate protease and can be used, for example, in the treatment of AIDS. They exhibit outstanding pharmacodynamic properties.
Inventor(s): Fassler; Alexander (Macclesfield, GB), Bold; Guido (Gipf-Oberfrick, CH), Capraro; Hans-Georg (Rheinfelden, CH), Lang; Marc (Mulhouse, FR), Khanna; Satish Chandra (Bottmingen, CH)
Assignee: Novartis Finance Corporation (New York, NY)
Filing Date:Nov 23, 1999
Application Number:09/448,328
Claims:1. A process for the preparation of a compound of the following formula I*, ##STR42##

wherein

R.sub.1 is lower alkoxycarbonyl,

R.sub.2 is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl,

R.sub.3 is phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals, or C.sub.4 -C.sub.8 cycloalkyl,

R.sub.4 is phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl that is bonded by way of a ring carbon atom, has from 5 to 8 ring atoms, contains from 1 to 4 hetero atoms selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl,

R.sub.5, independently of R.sub.2, has one of the meanings mentioned for R.sub.2, and

R.sub.6, independently of R.sub.1, is lower alkoxycarbonyl,

or a salt thereof, provided that at least one salt-forming group is present;

wherein

a) a hydrazine derivative of formula I* ##STR43##

wherein the radicals R.sub.4, R.sub.5 and R.sub.6 are as defined for compounds of formula I, is added to an epoxide of formula IV*, ##STR44##

wherein the radicals R.sub.1, R.sub.2 and R.sub.3 are as defined for compounds of formula I*, free functional groups selected from carboxy, hydroxy or amino group with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed, or

b) an amino compound of formula V*, ##STR45##

wherein the radicals R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined for compounds of formula I*, is condensed with an acid of formula ##STR46##

or with a reactive acid derivative thereof, wherein the radicals R.sub.5 and R.sub.6 are as defined for compounds of formula I*, free functional groups selected from carboxy, hydroxy or amino group with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed, or

c) an amino compound of formula VII*, ##STR47##

wherein the radicals R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined for compounds of formula I*, is condensed with an acid of formula I* ##STR48##

or with a reactive acid derivative thereof, wherein R.sub.1 and R.sub.2 are as defined for compounds of formula I*, free functional groups selected from carboxy, hydroxy or amino group with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed, or

d) to prepare a compound of formula I* wherein the pairs of substituents R.sub.1 and R.sub.6 and R.sub.2 and R.sub.5 are in each case two identical radicals, as defined for compounds of formula I*, and R.sub.3 and R.sub.4 are as defined for compounds of formula I*, a diamino compound of formula IX* ##STR49##

wherein the radicals are as just defined, is condensed with an acid of formula I* ##STR50##

or with a reactive acid derivative thereof, wherein R.sub.1 ' and R.sub.2 ' are as defined for R.sub.1 and R.sub.6 and for R.sub.2 and R.sub.5, respectively, in formula I*, the pairs R.sub.1 and R.sub.6 and R.sub.2 and R.sub.5 being in each case two identical radicals, free functional groups with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups selected from carboxy, hydroxy or amino group are removed, or

e) an imino compound of formula (I')*, ##STR51##

wherein the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are as defined for compounds of formula I*, is reacted with a compound of formula X, ##STR52##

wherein X is a leaving group and R.sub.4 is as defined for compounds of formula I*, free functional groups selected from carboxy, hydroxy or amino group with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed, or

f) an imino compound of formula (I')*, ##STR53##

wherein the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.5, and R.sub.6 are as defined for compounds of formula I*, is reacted with an aldehyde of formula X*, ##STR54##

wherein R.sub.4 is as defined for compounds of formula I*, or with a reactive derivative thereof, with reductive alkylation, free functional groups with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed,

and, a compound of formula I* having at least one salt-forming group obtainable in accordance with any one of processes a) to f) above is converted into its salt or an obtainable salt is converted into the free compound or into a different salt and/or isomeric mixtures which may be obtainable are separated and/or a compound of formula I* according to the invention is converted into a different compound of formula I* according to the invention.
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