Azahexane derivatives as substrate isosters of retroviral...

Details Azahexane derivatives as substrate isosters of retroviral... Azahexane derivatives as substrate isosters of retroviral...

1998-05-21

2001-05-01

Kumar, Shailendra (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C514S934000, C558S417000, C560S025000, C560S026000

Reexamination Certificate

active

06225345

ABSTRACT:

BRIEF DESCRIPTION OF THE INVENTION
The invention relates to azahexane derivatives having the property of being substrate isosteres of retroviral aspartate proteases, to salts thereof, to processes for the preparation of those compounds and their salts, to pharmaceutical compositions comprising those compounds or their salts, and to the use of those compounds or their salts (alone or in combination with other antiretrovirally active compounds) in the therapeutic or diagnostic treatment of the human or animal body or in the preparation of pharmaceutical compositions.
BACKGROUND TO THE INVENTION
According to WHO estimates there are clearly more than 20 million people infected by HIV-1 or HIV-2. Sooner or later that infection manifests itself 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-ribofuranoxyl-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 in 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.
Also reported are advanced clinical experiments with a hydroxyethylene isostere as an inhibitor of HIV-protease, 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). That compound exhibits an inhibitory action against HIV-protease in vitro, suppression of virus replication in cell experiments and, in experiments on rodents, blood levels that are still usable are achieved even in the case of oral administration (see Roberts, N. A., et al., Biochemical Soc. Transactions 20, 513-516 (1992)); usable blood levels have also been achieved in humans (see e.g. G. J. Muirhead et al., Brit. J. Clin. Pharmacol. 34, 170P-171 P (1992)). A so-called “surrogate-marker” (titre of the CD4-lymphocytes in the blood, the decrease in which in untreated patients is a measure of the advance of the AIDS disease) has shown initial positive effects in AIDS patients (see “Roche Statement on HIV Proteinase Inhibitor (Ro 31-8959) European Trials Results”, distributed to participants in the 9th International Congress on AIDS in Berlin, Jun. 7-11, 1993). A disadvantage of that compound, Ro 31-8959, is that it is expensive to synthesise.
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. Corresponding inhibitors 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 and indinavir, and especially advantageous pharmacological properties, for example good pharmacokinetics, such as high bioavailabilty 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
wherein
R
1
and R
10
are each independently of the other lower alkoxycarbonyl;
either R
2
, R
3
and R
4
are each independently of the other C
1
-C
4
alkyl and R
7
, R
8
and R
9
are each selected from hydrogen and C
1
-C
4
alkyl, with not more than 2 of the radicals being hydrogen;
or R
7
, R
8
and R
9
are each independently of the other C
1
-C
4
alkyl and R
2
, R
3
and R
4
are each selected from hydrogen and C
1
-C
4
alkyl, with 1 or 2 of the radicals being hydrogen;
R
5
is phenyl or cyclohexyl; and
R
6
is phenyl or cyanophenyl;
or salts thereof.
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 especially 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
, R
3
and R
4
and to R
7
, R
8
and R
9
and the carbon atoms carrying the radical [(R
2
)(R
3
)(R
4
)C]— or [(R
7
)(R
8
)(R
9
)C]— in compounds of formula I, 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
)(R
3
)(R
4
)C]— or [(R
7
)(R
8
)(R
9
)C]— 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 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 more especially methoxycarbonyl.
As R
5
, phenyl is preferred to cyclohexyl.
Cyanophenyl is preferably 4-, 3- or especially 2-cyanophenyl.
The compounds of formula I preferably have the formula Ia
wherein the radicals are as defined.
Salts are especially the pharmaceutically acceptable, non-toxic salts of compounds of formula I.
Such salts are formed, for example, by compounds of formula I with their basic imino group as acid addition salts, preferably with inorganic acids, for example hydrohalic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with strong organic sulfonic, sulfo or phospho acids or N-substituted sulfamic acids (preferably: pKa<1).
For the purposes of isolation or purification it is also possible to use pharmaceutically unacceptable salts, for example perchlorates. Only the pharmaceutically acceptable salts or the free compounds of formula I are used therapeutically and they are therefore preferred.
The compounds of formula I have valuable pharmacological propert

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