Antivirally active heterocyclic azahexane derivatives

Details Antivirally active heterocyclic azahexane derivatives Antivirally active heterocyclic azahexane derivatives

1999-11-23

2001-10-09

Rotman, Alan L. (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S153000, C514S579000, C514S614000, C514S615000, C546S152000, C546S176000, C548S507000

Reexamination Certificate

active

06300519

ABSTRACT:

BACKGROUND OF THE INVENTION
According to WHO estimates there are clearly more than 20 million people infected by the “Human Immuno Deficiency Virus”, HIV-1 or HIV-2. With very few exceptions, in infected subjects the disease results, by way of preliminary stages, such as ARDS, in a manifest disease of the immune system which is known as “Acquired Immunodeficiency Syndrome” or AIDS. In the overwhelming number of cases the disease sooner or later leads to the death of the infected patients.
Hitherto, the treatment of retroviral diseases, such as AIDS, has involved principally the use of inhibitors of reverse transcriptase, an enzyme effective in the conversion of retroviral RNA into DNA, such as 3′-azido-3′-deoxythymidine (AZT) or dideoxyinosine (DDI), and also trisodium phosphonoformate, ammonium-21-tungstenato-9-antimonate, 1-&bgr;-D-ribofuran-oxyl-1,2,4-triazole-3-carboxamide and dideoxycytidine and also adriamycin. Attempts have also been made to introduce into the body, for example in the form of a recombinant molecule or molecule fragment, the T4-cell receptor which is present on certain cells of the defence system of the human body and is responsible for the anchoring and introduction of infectious virus particles into those cells and thus for their infection, the objective being that binding sites for the virus will be blocked so that the virions will no longer be able to bind to the cells. Compounds that prevent the virus penetrating the cell membrane in some other way, such as polymannoacetate, are also used.
The first inhibitor of so-called retroviral aspartate protease to be approved for combatting the infection was saquinavir, [N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-2-quinolyl-carbonyl-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (Ro 31-8959)]. Since then others have followed (indinavir (Merck) and ritonavir (Abbott)).
Also under development are a number of further inhibitors of retroviral aspartate protease, an enzyme the function of which can be characterised as follows:
In the AIDS viruses, HIV-1 and HIV-2, and other retroviruses, for example corresponding viruses in cats (FIV) and apes (SIV), the proteolytic maturation of, for example, the core proteins of the virus is brought about by an aspartate protease, such as HIV-protease. Without that proteolytic maturation, infectious virus particles cannot be formed. Owing to the central role of the said aspartate proteases, such as HIV-1- or HIV-2-protease, in the maturation of viruses and on the basis of experimental results, for example on infected cell cultures, it has become plausible that effective suppression of the maturation step brought about by that protease will suppress the assembly of mature virions in vivo. Inhibitors of that protease can therefore be used therapeutically.
The aim of the present invention is to provide a novel type of compound that is equipped, especially, with a high degree of inhibitory activity against virus replication in cells, high anti-viral activity against numerous virus strains, including those which are resistant to known compounds, such as saquinavir, ritonavir and indinavir, and especially advantageous pharmacological properties, for example good pharmacokinetics, such as high bioavailability and high blood levels, and/or high selectivity.
FULL DESCRIPTION OF THE INVENTION
The azahexane derivatives according to the invention are compounds of formula I*,
especially of formula I,
wherein
R
1
is lower alkoxycarbonyl,
R
2
is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl,
R
3
is phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals, or C
4
-C
8
cycloalkyl,
R
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 (—SO—) and sulfonyl (—SO
2
—) and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl,
R
5
, independently of R
2
, has one of the meanings mentioned for R
2
, and
R
6
, independently of R
1
, is lower alkoxycarbonyl,
or a salt thereof, provided that at least one salt-forming group is present.
Those compounds exhibit unexpectedly good and surprisingly positive pharmacological properties, as indicated in detail below, and are relatively simple to synthesise.
Unless indicated to the contrary, the general terms used hereinabove and hereinbelow preferably have the following meanings within the scope of this disclosure:
The term “lower” indicates a radical having up to and including a maximum of 7 carbon atoms, preferably up to and including a maximum of 4 carbon atoms, the radicals in question being unbranched or branched one or more times.
Lower alkyl and C
1
-C
4
alkyl are especially tert-butyl, sec-butyl, isobutyl, n-butyl, isopropyl, n-propyl, ethyl and methyl.
Any reference to compounds, salts and the like in the plural also includes a compound, a salt and the like.
Any asymmetric carbon atoms present, for example the carbon atoms bonded to the radicals R
2
and R
5
, may be in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration, the (S)-configuration being especially preferred in the case of the carbon atoms carrying the radical R
2
and/or R
5
in compounds of formula I. Accordingly, the compounds in question may be in the form of isomeric mixtures or in the form of pure isomers, preferably in the form of enantiomerically pure diastereoisomers.
Lower alkoxycarbonyl is preferably C
1
-C
4
alkoxycarbonyl wherein the alkyl radical may be branched or unbranched, and is especially ethoxycarbonyl or methoxycarbonyl.
Secondary or tertiary lower alkyl is especially sec-butyl, tert-butyl or isopropyl.
Lower alkylthio-lower alkyl is especially methylthiomethyl.
Phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals is especially phenyl that is unsubstituted or substituted by from one to three lower alkoxy radicals, especially methoxy. In the case when there are three methoxy substituents, these are especially in the 2,3,4-positions of the phenyl ring and in the case when there is one methoxy substituent, that substituent is especially in the 2-, 3- or, more especially, in the 4-position. Unsubstituted phenyl is preferred.
C
4
-C
8
cycloalkyl is especially cyclopentyl or, more especially, cyclohexyl.
As R
3
phenyl is preferred to cyclohexyl.
In phenyl or cyclohexyl 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 (—SO—) and sulfonyl (—SO
2
—) and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl, the corresponding heterocyclyl has especially the following meanings:
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 (—SO—) and sulfonyl (—SO
2
—) and is unsubstituted or substituted by lower alkyl, especially by methyl, or by phenyl-lower alkyl wherein the lower alkyl radical is unbranched or branched, especially by 1-methyl-1-phenylethyl, is especially one of the following radicals bonded by way of a ring carbon atom: thienyl (=thiophenyl); oxazolyl; thiazolyl; imidazolyl; 1,4-thiazinyl; triazolyl that is unsubstituted or, especially, substituted by 1-methyl-1-phenyl-ethyl or preferably by tert-butyl or especially by methyl, such as 1-, 2- or 4-(methyl or tert-butyl)-triazol-3-yl; tetrazolyl that is unsubstituted or, especially, substituted by 1-methyl-1-phenyl-ethyl or preferably by lower alkyl, such as by tert-butyl or especially by methyl, such as 2H-tetrazol-5-yl substituted by 1-methyl-1-phenyl-ethyl or preferably by lower alkyl, such as by tert-butyl or especially by methyl, or 1H-tetrazol-5-yl substituted by tert-butyl or especially by methyl; pyridiny

Affiliated with

Also associated with

Rating

Antivirally active heterocyclic azahexane derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Antivirally active heterocyclic azahexane derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antivirally active heterocyclic azahexane derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2576254