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Claims for Patent: 5,849,911

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Claims for Patent: 5,849,911

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, sulfinyl (--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, GB3), Bold; Guido (Gipf-Oberfrick, CH), Capraro; Hans-Georg (Rheinfelden, CH), Lang; Marc (Mulhouse, FR), Khanna; Satish Chandra (Bottmingen, CH)
Assignee: Novartis Finance Corporation (Summit, NJ)
Application Number:08/831,630
Patent Claims: 1. A compound of the 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.

2. A compound according to claim 1 of formula Ia, ##STR43## wherein the radicals are as defined in claim 1, or a salt thereof.

3. A compound of formula Ia according to claim 2, wherein

R.sub.1 is lower alkoxycarbonyl,

R.sub.2 is isopropyl, sec-butyl or tert-butyl,

R.sub.3 is phenyl or cyclohexyl,

R.sub.4 is phenyl substituted in the 4-position by one of the following radicals bonded by way of a ring carbon atom: thienyl; oxazolyl; thiazolyl; imidazolyl; 1,4-thiazinyl; triazolyl that is unsubstituted or substituted by 1-methyl-1-phenyl-ethyl, tert-butyl or by methyl; tetrazolyl that is unsubstituted or substituted by 1-methyl-1-phenyl-ethyl, tert-butyl or by methyl; pyridinyl; pyrazinyl; and pyrimidinyl;

R.sub.5 is isopropyl, sec-butyl, tert-butyl or methylthiomethyl, and

R.sub.6 is lower alkoxycarbonyl,

or a salt thereof.

4. A compound of formula Ia according to claim 2, wherein

R.sub.1 is methoxycarbonyl or ethoxycarbonyl,

R.sub.2 is isopropyl, sec-butyl or tert-butyl,

R.sub.3 is phenyl,

R.sub.4 is phenyl substituted in the 4-position of the phenyl ring by 2- or 3-thienyl; thiazol-5-yl; thiazol-2-yl; 2H-tetrazol-5-yl that is unsubstituted or substituted in the 2-position by 1-methyl-1-phenyl-ethyl, tert-butyl or by methyl; 1H-tetrazol-5-yl substituted in the 1-position by methyl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; or by pyrazin-2-yl;

R.sub.5 is isopropyl, sec-butyl, tert-butyl or methylthiomethyl; and

R.sub.6 is methoxycarbonyl or ethoxycarbonyl;

with the proviso that at least one of the two radicals R.sub.2 and R.sub.5 is tert-butyl, provided that R.sub.4 is phenyl substituted in the 4-position of the phenyl ring by 2- or 3-thienyl; thiazol-5-yl; thiazol-2-yl; 2H-tetrazol-5-yl that is unsubstituted or substituted in the 2-position by 1-methyl-1-phenyl-ethyl, tert-butyl or by methyl; 1H-tetrazol-5-yl substituted in the 1-position by methyl; pyridin-3-yl; pyridin-4-yl; or by pyrazin-2-yl;

or a salt thereof.

5. A compound of formula Ia according to claim 2, wherein

R.sub.1 is methoxycarbonyl or ethoxycarbonyl,

R.sub.2 is isopropyl, sec-butyl or tert-butyl,

R.sub.3 is phenyl,

R.sub.4 is 4-(thiazol-2-yl)-phenyl, 4-(thiazol-5-yl)-phenyl, 4-(pyridin-2-yl)-phenyl or 4-(2-methyl-tetrazol-5-yl)-phenyl;

R.sub.5 is isopropyl, sec-butyl, tert-butyl or methylthiomethyl; and

R.sub.6 is methoxycarbonyl or ethoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

6. A compound of formula Ia according to claim 2, selected from the following compounds:

1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycartionyl-(L)-valyl) amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexare;

1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-iso-leu cyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahex ane;

1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycartonyl-(L)-S-methy lcysteinyl)-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl- 2-azahexane;

1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-N-(N-ethoxycarboiyl-(L)-valyl)am ino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane;

1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert-le ucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane;

1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert-le ucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahex ane;

1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis-[N-(N-methoxycarbonyl -(L)-tert-leucyl)-amino]-6-phenyl-2-azahexane;

1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert-le ucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane;

1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert-le ucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahex ane;

1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis-[N-(N-methoxycarbonyl -(L)-valyl)amino]-6-phenyl-2-azahexane;

1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-valyl)a mino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane; and

1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert-le ucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane;

or in each case a pharmaceutically acceptable salt thereof.

7. A compound of formula Ia according to claim 2 named 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis-[N-(N-methoxycarbony l-(L)-tert-leucyl)-amino]-6-phenyl-2-azahexane, or a salt thereof.

8. A compound of formula Ia according to claim 2 named 1-[4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis-[N-(N-m ethoxycarbonyl-(L)-tert-leucyl)amino]-6-phenyl-2-azahexane, or a salt thereof.

9. A compound of formula Ia according to claim 2 named 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis-[N-(N-methoxycarbony l-(L)-tert-leucyl)-amino]-6-phenyl-2-azahexane, or a salt thereof.

10. A pharmaceutical composition suitable for administration to a warm-blooded animal for the treatment of AIDS or its preliminary stages, comprising a compound of formula I* according to claim 1, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.

11. A method for the treatment of AIDS or its preliminary stages, wherein a therapeutically effective amount of a compound of formula I* according to claim 1, or a pharmaceutically acceptable salt thereof, is administered to a human, who on account of said disease requires such treatment, in a dose that is effective in the treatment of said disease.
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