AP950A - THF-containing sulfonamide inhibitors of aspartyl protease. - Google Patents

THF-containing sulfonamide inhibitors of aspartyl protease. Download PDF

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AP950A
AP950A APAP/P/1997/001119A AP9701119A AP950A AP 950 A AP950 A AP 950A AP 9701119 A AP9701119 A AP 9701119A AP 950 A AP950 A AP 950A
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hiv
compounds
aspartyl protease
thf
viral
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APAP/P/1997/001119A
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AP9701119A0 (en
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Roger D Tung
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Vertex Pharma
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Abstract

The present invention relates to a class of TKF-containing sulfonamide aspartyl protease inhibitors having the structure of formula I: D OH D1 I I ITHF—R-NH—CH—CH—CH2——N—S02E (I) . This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention.

Description

THF-CONTAINING SULFONAMIDE INHIBITORS OF ASPARTYL PROTEASE TECHNICAL FIELD OF THE INVENTION The present invention relates to a class of THF-containing sulfonamides which are aspartyl protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-l and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-l and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention. BACKGROUND OF THE INVENTION The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS") -- a disease characterized by the destruction of the immune system, particularly of CD4“ T-cells, with attendant susceptibility to opportunistic infections -- and its precursor' AIDS-related complex i"ARC") -- a syndrome characterized by symptoms such as oersistent generalized lymphadenopathy, fever and weight loss.
As m the case cf several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., "A Deletion Mutation in the 5' Part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processing of the gag and pol Polyproteins", J. Virol.. 53, p. 899 (1985)). These gene products include pol. which encodes the virion ENA-dependent DNA polymerase (reverse transcriptase), an endonuclease, HIV protease, and gag, which encodes the core-proteins of the virion (H. Toh et al., "Close Structural Resemblance Between Putative Polymerase of a Drosophila Transposable Genetic Element 17.6 and pol gene product of Moloney Murine Leukemia Virus", EMBO J.. 4, p. 1267 (1985); L.H. Pearl et al., "A Structural Model for the Retroviral Proteases", Nature. pp. 329-351 (1987); M.D. Power et al., "Nucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirus", Science. 231, p. 1567 (1986)). A number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4+ T-lymphocytes (for example, soluble CD4), and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA (M.S. Hirsh and R.T. D'Aqulia, "Therapy for Human Immunodeficiency Virus Infection", N.Eng.J.Med.. 328, p. 1686 (1993)). However, such agents, which are directed primarily to early stages of viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
More recently, drug design efforts have been directed toward creating compounds which inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N.E. et al. "Active HIV Protease is Required for Viral Infectivity" Proc, Natl, Acad. Sci. USA, 85, p. 4686 (1988)). The anti-viral potential of HIV protease inhibition has been demonstrated using peptidal inhibitors. Such peptidal compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally consistent with oral administration. Accordingly, the need still exists for compounds that can effectively inhibit the action of viral proteases, for use as agents for preventing and treating chronic and acute viral infections. Such agents would be expected to act as effective therapeutic agents in their own right. In addition, since they act at a separate stage in the virus life cycle from previously described antiretroviral agents, the administration of a combination of agents would be expected to result in increased therapeutic efficacy.
SUMMARY OF THE INVENTION
The present invention provides a novel class of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of aspartyl proteases, in particular, HIV aspartyl protease. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, -UUUUU~Hk>UU-JV-4.l-i-LCUk-.V>X. O * s*'— «*»**>·* w I — »- — w»i»w>*. w prophylaxis of viral infection.
According to a preferred embodiment, the compounds of this invention are capable of inhibiting HIV viral replication in human CD4+ cells including T-cells, monocytic lines including macrophages and dendrocytes and other permissive cells. These compounds are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-l and related viruses which may result in asymptomatic infection, AIDS-related complex ("ARC"), acquired immunodeficiency syndrome ("AIDS"), or similar-disease of the immune system.
It is a principal object of this invention to provide a class of THF-containing sulfonamides which are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. This class of THF-containing sulfonamides is represented by formula I:
(I) wherein: each Rl is independently selected from the group consisting of -C (0)-, -S(0)2-, -C(0)-C (0)-, -0-C (0)-, -0-S(0)2, -NR2-S(O)2-, -NR2-C (0) - and -NR2-C(0)-C(0)-; each Het is independently selected from the group consisting of C3-C, carbocycle; C6-C,0 aryl; phenyl fused with heterocycle; and heterocycle; wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, -OR2, -R2, -N(R2)(R2), -NHOH, -R2-0H, -CN, -CO2R2, -C(0)-N(R2) (R2) , -3 (0) 2-N (R2) (R2) , -N(R2)-
C(O)-R2, -C(O)-R2, -S{O)„-R2, -OCFj, -S(O)„-R6, -N(R2)-S(O)2(R2), halo, -CF3, -NOj, -R6 and -O-R6; each R2 is independently selected from the group consisting of H and C,-C3 alkyl optionally substituted with R6; each R3 is independently selected from the group consisting of H, Het, C,-Ce alkyl and Cj-Ce alkenyl wherein any member of said R3, except H, may be optionally substituted with one or more substituents selected from the group consisting of -OR2, -C(O)-NH-R2, -S (0) B-N(R2) (R2) , Het, -CN, -SR2, -COjR2, NR2-C(O)-R2; each n is independently 1 or 2; each D and D' is independently selected from the group consisting of R6; C,-Cj alkyl, which may be optionally substituted with one or more groups selected from -OR2, -R3, -0-R6, -S-R6 and R6; C2-C4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of -OR2, -R3, -0-R6 and R6; and C3-Ce carbocycle, which may be optionally substituted with or fused with R6; each E is independently selected from the group consisting of Het; -Ο-Het; Het-Het; -0-R3; -NR2R3; Cj-Ce alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Het; and C2-C6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R* and Het; each R4. is independently selected from the group consisting of -OR2, -C(O)-NHR2, -S(O)2-NHR2, halo, -NR2-C(O)-R2 and -CN; and each R3 is independently selected from the group consisting of H and Ci~C4 alkyl optionally substituted with aryl; and each R6 is independently selected from the group consisting of aryl, carbocycle and heterocycle, wherein said aryl, carbocycle or heterocycle may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR5, -R5, -N(R5) (R5) , -N(Rs)-C(0)-R5, -RS-OH, -CN, -COjR5, -C (Ο)-N (R5) (R5) , halo and -CFj.
It is also an object of this invention to provide pharmaceutical compositions comprising the THF-containing sulfonamides of formula I and methods for their use as inhibitors of HIV aspartyl protease.
DETAILED DESCRIPT.IQN_QF . THE INVENTION
In order that the invention herein described may be more fully understood, the following detailed description is set forth. In the description, the following abbreviations are used:
Reagent or Fragment Ac acetyl
Me methyl
Et ethyl
Bn benzyl
Trityl triphenylmethyl
Asn D- or L-asparagine
He D- or L-isoleucine
Phe D- or L-phenylalanine
Val D- or L-valine
Boc tert-butoxycarbonyl
Cbz benzyloxycarbonyl (carbobenzyloxy) DCC dieyelohexylcarbodiimide DBU l,8-diazabicyclo(5.4.0)undec-7-ene DIC diisopropylcarbodiimide DIEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EDC 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
EtOAc ethyl acetate
Fmoc 9-fluorenylmethoxycarbonyl HOBt l-hydroxybenzotriazole HOSu 1-hydroxysuccinimide iBu iso-butyl NCA N-carboxyanhydride t-Bu tert-butyl TFA trifluoroacetic acid ΊΉΡ tertrahydropyran THF tetrahydrofuran TMSCl chlorotrimethylsilane
The following terms are employed herein:
Unless expressly stated to the contrary, the terms "-S02-" and "-S(0)2-" as used herein refer to a sulfone or sulfone derivative (i.e., both appended groups linked to the S), and not a sulfinate ester.
The term "backbone" refers to the structural representation of a compound of this invention, as set forth in the figures drawn in this application. The term "backbone" does not encompass the variables drawn in those figures.
For the compounds of formula I, and intermediates thereof, the stereochemistry of the explicitly shown hydroxyl is defined relative to D on the adjacent carbon atom, when the molecule is drawn in an extended zig-zag representation (such as that drawn for compounds of formula VI). If both OH and D reside on the same side of the plane defined by the extended backbone of the compound, the stereochemistry of the hydroxyl will be referred to as "syn". If OH and D reside on opposite sides of that plane, the stereochemistry of the hydroxyl will be referred to as "anti".
As used herein, the term "alkyl", alone or in combination with any other term, refers to a straight-chain or branch-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 1-10 and more preferably from 1-5 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
The term "alkenyl", alone or in combination with any other term, refers to a straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 2-10 carbon atoms and more preferably, from 2-6 carbon atoms. Examples of alkenyl radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, Ε,Ε-, Ε,Ζ-, Z,E- and Z,Z-hexadienyl and the like.
The term "aryl", alone or in combination with any other term, refers to a carbocyciic aromatic radical (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms. Examples'of aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
The term "cycloalkyl", alone or in combination with any other term, refers to a cyclic saturated hydrocarbon radical containing the specified number of carbon atoms, preferably from 3-7 carbon

Claims (1)

  1. Original document published without claims.
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