Patent EA-001794-B1 (EA)
Title: Antivirally active heterocyclic azahexane derivatives
Inventor: FASSLER ALEXANDER
IPC: C07C233/21
Filed: 1997-04-14
Abstract: 1. A compound of the formula l*,   wherein R1 is C1-C7 alkoxycarbonyl, R2 is -CH(CH3)2, -C(CH3)3, -CH(C2H5)CH3 or CH2-S-CH3; R3 is phenyl that is unsubstituted, C4-C8cycloalkyl, R4 is phenyl substituted in the 4-position by pyridyl, thienyl, pyrazolyl, thiazolyl, or tetrazolyl substituted by C1-C7 alkyl or fenyl C1-C7 alkyl, R5, independently of R2, has one of the meanings mentioned for R2, and R6, independently of R1, is C1-C7 alkoxycarbonyl, or a salt thereof, provided that at least one salt-forming group is present. 2. A compound according to Claim 1, selected from the following compounds: 1-[4-(thiazol-5-yl)phenyl]-4(S)-hydroxy-2-N-[N-methoxycarbonyl-(L)-valyl]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-methoxycarbonyl-(L)-isoleucyl]amino-5(S)-N-[N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane; 1-[4-(thiazol-5-yl)phenyll-4(S)-hydroxy-2-N-[N-methoxycarbonyl-(L)-S-methylcysteinyl]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-ethoxycarbonyl-(L)-valyl]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-methoxycarbonyl-(L)-tert-leucyl)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-leucyl]amino-5(S)-N-[N-methoxycarbonyl-(L)-isoleucyl]amino-6-phenyl-2-azahexane; 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-leucyl]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-leucyl]amino-5(S)-N-[N-methoxycarbonyl-(L)-isoteucyl]amino-6-phenyl-2-azahexane; 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]amino-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-leucyl]amino-5(S)-N-[N-methoxycarbonyl-(L)-valyl]amino-6-phenyl-2-azahexane; or in each case a pharmaceutically acceptable salt thereof, provided that a salt-forming group is present. 3. A pharmaceutical composition comprising a compound according to Claim 1 or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, together with a pharmaceutically acceptable carrier. 4. A process for the preparation of a compound according to Claim 1, or of a pharmaceutically acceptable salt thereof, wherein a hydrazine derivative of formula   wherein the radicals R4, R5 and R6 are as defined for compounds of formula I, is added to an epoxide of formula IV*,   wherein the radicals R1, R2 and R3 are as defined for compounds of formula I, free from functional groups with the exception of those participating in the reaction being, if necessary in protected form, and any protecting groups are removed, and, if desired, a compound of formula I having at least one salt-forming group obtainable in accordance with above-mentioned process 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. 5. A process for the preparation of a compound according to Claim 1, or of a pharmaceutically acceptable salt thereof, wherein an amino compound of formula V*,   wherein the radicals R1, R2, R3 and R4 are as defined for compounds of formula I, are condensed with an acid of formula   or with a reactive derivative thereof, wherein the radicals R5 and R6 are as defined for compounds of formula I, free from functional groups with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed and, if desired, a compound of formula I having at least one salt-forming group obtainable in accordance with above-mentioned process 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. 6. A process for the preparation of a compound according to Claim 1, or of a pharmaceutically acceptable salt thereof, wherein an amino compound of formula VII*,   wherein the radicals R3, R4, R5 and R6 are as defined for compounds of formula I, are condensed with an acid of formula   or with a reactive derivative thereof, wherein the radicals R1 and R2 are as defined for compounds of formula I, free from functional groups with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed and, if desired, a compound of formula I having at least one salt-forming group obtainable in accordance with above-mentioned process 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. 7. A process for the preparation of a compound according to Claim 1, or of a pharmaceutically acceptable salt thereof, wherein for preparation of a compound of formula I wherein the pairs of substituents R1 and R6 and R2 and R5 are in each case two identical radicals, as defined for compounds of formula I, and R3 and R4 are as defined for compounds of formula I, a diamino compound of formula IX*   wherein the radicals are as just defined, are condensed with an acid of formula   or with a reactive derivative thereof, wherein the radicals R1' and R2' are as defined for compounds of formula I, correspondingly for radicals R1 and R6 and for R2 and R5, wherein pairs R1 and R6 and R2 and R5 in each case are identical radicals free from functional groups with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed and, if desired, a compound of formula I having at least one salt-forming group obtainable in accordance with above-mentioned process 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. 8. A process for the preparation of a compound according to Claim 1, or of a pharmaceutically acceptable salt thereof, wherein an imino compound of formula (I)*   wherein the radicals R1, R2, R3, R5 and R6 are as defined for compounds of formula I, is reacted with a compound of formula X,   wherein X is a leaving group and R4 is as defined for compounds of formula I, free from functional groups with the exception of those participating in the reaction being, if necessary, in protected form, and any protecting groups are removed, if desired, a compound of formula I having at least one salt-forming group obtainable in accordance with above-mentioned process 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. 9. A process for the preparation of a compound according to Claim 1, or of a pharmaceutically acceptable salt thereof, wherein an imino compound of formula (I')*,   wherein the radicals R1, R2, R3, R5 and R6 are as defined for compounds of formula I, , is reacted with an aldehyde of formula X*,    wherein R4 is as defined for compounds of formula I, or with a reactive derivative thereof, free from functional groups with the exception of those participating in the reaction being, if necessary, in protected form, with reductive alkylation,  and any protecting groups are removed, if desired, a compound of formula I having at least one salt-forming group obtainable in accordance with above-mentioned process 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.