TH44626B - Heterocyclic azahexane derivatives that have antiviral effects. - Google Patents

Abstract

DC60 is a heterocyclic azahexane derivative, a compound described in detail with formula I* (chemical formula) (I*), where R1 is the lower alkoxycarbonyl, R2 is the secondary or tertiary lower alkyl or lower alkylthio-lower alkyl, R3 is the phenyl, either unsubstituted or substituted by one or more lower alkoxyradicals C1-C5 cycloalkyl, and R4 is the phenyl or cyclohexyl, each substituted at position 4 by an unsaturated heterocyclic atom connected by carbon atoms in a ring of 5 to 8 atoms, or a ring of 1 to 4 heteroatoms chosen from nitrogen, oxygen, sulfur, sulfynyl (-SO-), and sulfonyl (SO2), and either unsubstituted or substituted by a lower alkyl. Or by phenyl-lower alkyl derivatives, heterocyclic azahexane compounds described in detail with formula I (chemical formula), where R1 is the lower alkoxycarbonyl, R2 is the secondary or tertiary lower alkyl or lower alkylthio-lower alkyl, R3 is the phenyl, either unsubstituted or substituted by one or more lower alkoxeratical C1-C5 cycloalkyl, R4 is the phenyl or cyclohexyl, each substituted at position 4 by an unsaturated heterocyclic atom connected by a carbon atom in a ring of 5 to 8 atoms, with 1 to 4 heteroa chosen from nitrogen, oxygen, sulfyl, sulfynyl (-SO-), and sulfonyl (SOa), and unsubstituted. Or replaced by lower alkyls or by phenyl-lower alkyls. R5s are independent of R2, with one having the specific meaning as defined for R2, and R6 is independent of R1, i.e., lower alkoxycarbonyls or their salts, provided that at least one salt-forming group is present. This compound is an inhibitor of retroviril astartech protease and can be used, for example, in the treatment of AIDS. These compounds exhibit excellent pharmacodynamic properties.

Claims (14)

1. Compounds with formula I (chemical formula) where R1 is a C1-C7 alkoxycarbonyl and R2 is secandari or tertiary. Lower alkyls, or C1-C7 alkylthio-C1-C7 alkyls, where "lower" indicates radicals containing up to and including 7 carbon atoms. R3 is an unsubstituted phenyl or substituted by one or more C1-C7 alkoxyradiols; C4-C8 hydrolkyls. R4 is a phenyl or hydrohexyl, each substituted at position 4 by an unsaturated heterocyclic radical connected by 5 to 8 carbon atoms in a ring with 1 to 4 hetero atoms chosen from nitrogen, oxygen, sulfur, sulfinyl, and sulfonyl, and is unsubstituted or substituted by a C1-C7 alkyl or by a phenyl-C1-C7 alkyl. R5 is independent of R2, with one having the specific meaning as defined for R2, and R6 is independent of R1, i.e., C1-C7 alkoxycarbonyls. Or its salt, with the caveat that it must contain at least one group that produces salt. 2. Compounds according to claim 1 of formula Ia (chemical formula) in which the radicals are as described in claim 1 or their salts are defined as having at least one group that gives rise to the salt. 3. Compounds of formula Ia according to claim 2 where R1 is lower alkoxycarbonyl, R2 is isopropyl scheek-butyl or tert-butyl, R3 is phenyl or cyclohexyl, R4 is phenyl substituted at position 4 by one of the following ring-linked radicals: thienyl oxazolyl, thiazolyl, imidazolyl, 1,4-thiazinyl, unsubstituted triazolyl, or substituted by 1-methyl-1-phenyl-ethyl tert-butyl or by an unsubstituted methyl tetrazolyl. Or replaced by 1-methyl-1-phenyl-ethyl tert-butyl or by methylpyridinyl, pyrazinyl, and pyrimitinyl. R5 is isopropyl sec-butyl tert-butyl or methylthiomethyl, and R6 is the lower alkoxycarbonyl or its salt. It is specified that at least one group that produces a salt must be present. 4. Compounds with the formula Ia, or ethoxycarbonyls, have the following R1 and R2: isopropyl sec-butyl or tert-butyl; R3: phenyl; R4: phenyl substituted at the 4- position of the phenyl ring by 2- or 3-thienyl thiazole-5-il or thiazole-2-il at the 2- position by 1-methyl-1-phenyl-ethyl tert-butyl or by methyl 1H-tetrazole-5-il substituted at the 1- position by methyl pyridin-2-pyridin-3-il, pyridin-4-il, or by pyrazin-2-il; R5: isopropyl sec-butyl or tert-butyl or methylthiomethyl; and R6: methoxycarbonyl or ethoxycarbonyl. It is defined that at least one of the two radicals R2 and R5 is tert-butyl; it is defined that R4 is a phenyl substituted at position 4- of the phenyl ring by 2- or 3-thienyl thiazole-5-il, thiazole-2-il, 2H-tetrazole-5-il that is not substituted, or substituted at position 2- by 1-methyl-1-phenyl ethyl by tert-butyl or by methyl 1H-tetrazole 5-il that is substituted at position 1 by methyl pyridin-3-il, pyridin-4-il, or by pyrazine 2-il or its salts; it is defined that at least one of the groups that can be salted is also present. 5. A compound with the formula Ia, according to claim 2, where R1 is methoxycarbonyl or ethoxycarbonyl, R2 is isopropyl sec-butyl or tert-butyl, R3 is phenyl, R4 is 4-(thiazole-2-il) phenyl, 4-(thiazole-5-il) phenyl, 4-(pyridin-2-il) phenyl, 4-(2-methyl-tetraazole-5-il) phenyl, R5 is isopropyl sec-butyl, tert-butyl or methylthiomethyl, and R6 is methoxycarbonyl or ethoxycarbonyl or its salts (especially those pharmacologically acceptable), provided that at least one salt-forming group is present. 6. The compound with formula Ia, according to claim 2, is selected from the following compounds: 1-[4-(thiazole-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-(thiazole-5-yl)phenyl]-4-(S)-hydroxy-5-(S)-2-,5-bis-[N-(N-methoxycarbonyl(L)-tert-leucyl)amino]-6-phenyl-2-azahexane 1-[4-(thiazole-5-yl)phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-iso-leucyl) amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl) amino-6-phenyl-2-azahexane 1-[4-(thiazole-5-yl)phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-S-methylcysteine) amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl) amino-6-phenyl-2-azahexane 1-[4-(thiazole-5-yl)phenyl]-4-(S)-hydroxy-2-N-(N-ethoc cecarbonyl-(L)-valil) amino-5(S)-N(N-methoxycarbonyl-(L)-tert-leucyl) amino-6-phenyl-2-azahexane 1-[4-(thiazole-5-yl)phenyl]-4-(S)-hydroxy-2-N-(N-ethoc cecarbonyl-(L)-tert-leucyl) amino-5(S)-N-(N-methoxycarbonyl-(L)-valil) amino-6-phenyl-2-azahexane 1-[4-(thiazole-5-il) phenyl]-4-(S)-hydroxy-2-N-(N-ethoxycarbonyl-(L)-tert leucyl) amino-5-(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl) amino-6-phenyl-2-azahexane 1-[4-(thiazole-2-il) phenyl]-4-(S)-hydroxy-5(S)-2,5-bis-[N-(N-methoxycarbonyl-(L)-tert leucyl) amino-6-phenyl-2-azahexane 1-[4-(thiazole-2-il) phenyl]-4-(S)-hydroxy-2-N-(N-ethoxycarbonyl-(L)-tert leucyl) amino-6-phenyl-2-azahexane 1-[4-(thiazole-2-yl)phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert leucyl) amino-6-phenyl-2-azahexane 1-[4-(thiazole-2-yl)phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert leucyl) amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl) amino-6-phenyl-2-azahexane 1-[4-(2-methyl-2H-tetraazole-5-yl)phenyl]-4(S)-hydroxy-5(S)-2,5-bis [N-(N-methoxycarbonyl-(L)-tert-leuyl)amino]-6-phenyl-2-azahexane 1-[4-(pyridin-2-yl) phenyl]-4(S)-hydroxycee-5(S)-2,5-bis-[N-(N-methoxycarbonyl-(L)-valil)amino]-6-phenyl-2-azahexane 1-[4-(pyridin-2-yl) phenyl]-4(S)-hydroxycee-5(S)-2,5-bis-[N-(N-methoxycarbonyl-(L)-tert-leuyl)amino]-6-phenyl-2-azahexane 1-[4-(pyridin-2-yl)phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane or 1-[4-(pyridin-2-yl)phenyl]-4(S)-hydroxy-2-N(N-methoxycarbonyl-(L)-tert-leucyl)amino-5(S)-N(N-methoxycarbonyl-(L)-leucyl)amino-6-phenyl-2-azahexane, or in each case its pharmaceutically acceptable salts, provided that a salt-forming group is present. 7. The compound with formula Ia, according to claim 2, is named 1-[4-(thiazole-5-yl)phenyl]-4(S)-hydroxy-5(S)-2,5-bis-[N-(N-methoxycarbonyl-(L)-tert-leucyl)amino]-6-phenyl-2-azahexane or its salt. 8. The compound formula Ia according to claim 2, named 1-[4-(methyl-2H-tetrasol-5-yl)phenyl]-4(S)-hydroxy-5(S)-2,5-bis-[N-(N-methoxycarbonyl-(L)-tert-leucyl)amino]-6-phenyl-2-azahexane or its salts. 9. The compound with formula Ia according to claim 2, named 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis-[N-(N-methoxycarbonyl-(l)-tert-leucyl)amino]-6-phenyl-2-azahexane or its salt. 10. Any of the compounds under claims 1 through 9, or their salts, are pharmaceutically acceptable for use in therapeutic methods on humans or animals. 11. A pharmaceutical mixture containing any one of the Formula I compounds under Claims 1 through 9, or a pharmaceutically acceptable salt of such compound containing at least one salt-forming group, together with a pharmaceutically acceptable carrier. 12. The use of any one of the formulated compounds I under claims 1 through 9, or any pharmaceutically acceptable salt of such compounds containing at least one group that produces a salt, in the preparation of pharmaceutical mixtures for the purpose of blocking HIV aspartate protease. 13. The use of any one of the formula I compounds under claims 1 through 9, or a pharmaceutically acceptable salt of such compound containing at least one group that produces a salt, in the preparation of pharmaceutical mixtures for the treatment of retroviral diseases. 14. The process of preparing the compound formulated under claim 1 or its salts where a) a hydrazine derivative of the formula (chemical formula) in which radicals R4, R5, and R6 are as specified for the compound formula I is added to the epoxide of the formula IV (chemical formula) in which radicals R4, R5, and R6 are as specified for the compound formula I is added to the epoxide of the formula IV (chemical formula) in which radicals R1, R2, and R3 are as specified for the compound formula I, free functional groups, excluding those involved in the reaction, if necessary, are in a protected form and any protective groups are eliminated; or b) an amino compound of the formula V (chemical formula) in which radicals R1, R2, R3, and R4 are as specified for the compound formula I is condensed with an acid of the formula (chemical formula) or with its reactive acid derivative in which radicals R3 and R6 are as specified for the compound formula I, free functional groups, excluding those involved in the reaction, if necessary, are in a protected form. and any protective groups are eliminated, or c) to prepare an amino compound of formula VII (chemical formula) in which the radicals R3, R4, R5, and R6 are as specified for the formula I compound, condense with the group of the formula (chemical formula) or with its reactive acid derivatives in which R1 and R2 are as specified for the formula I compound, free functional groups, except those involved in the reaction, if necessary, are in a protected form and any protective groups are eliminated, or d) to prepare a formula I compound in which the pairs of substitutes R1 and R6 and R2 and R5 are two identical radicals in each case as specified for the formula I compound, and R3 and R4 are as specified for the formula I compound, to prepare a diamino compound of formula IX (chemical formula) in which the radicals are as specified. e) condense with the acid of the formula (chemical formula) or with its reactive acid derivatives where R1 and R2 are as specified for R3 and R6 and for R2 and R5 respectively. In formula 1, the pairs R1 and R6 and R2 and R5 are 2 identical radicals in each case. Free functional groups, excluding those involved in the reaction, are in a protected form if necessary, and any protective groups are eliminated; or e) give the imino compound of the formula (I) (chemical formula) where the radicals R1, R2, R3, R5, and R6 are as specified for the compound of formula I react with the compound of formula X (chemical formula) where X is the eliminated group and R4 is as specified for the compound of formula I. Free functional groups, excluding those involved in the reaction, are in a protected form if necessary. and any protective groups shall be eliminated, or f) the imino compound of formula (I) (chemical formula) in which the radical R1, R2, R3, R5 and R6 are as specified for the compound of formula I reacts with an aldehyde of formula X (chemical formula) in which R4 is as specified for the compound of formula I, or with its reactive derivatives to reductive alkylation, the free functional groups, except those involved in the reaction, if necessary, shall be in a protected form and any protective groups shall be eliminated, and if desired, the compound of formula I containing at least one salt group obtained by any of the above processes a) to f) shall be converted to its salt, or the obtained salt shall be converted to a free compound, or to a different salt, and/or any possible isomeric mixture shall be separated, and/or the compound of formula I under this invention shall be converted to a different different compound of formula I under this invention. (Clause 14, 11 pages, 0 figures)