- Design, biologic evaluation, and SAR of novel pseudo-peptide incorporating benzheterocycles as HIV-1 protease inhibitors
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A series of novel HIV-1 protease inhibitors based on the (hydroxyethylamino)-sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P 2 ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the -CH2- of P1-P2 linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P 1′group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV-1 protease with an IC50 value of 5 nm, also exhibited good anti-SIV activity (EC50 = 0.8 μm) with low toxicity (TC 50 > 100 μm). The flexible docking of inhibitor 23 to HIV-1 protease active site rationalized the interactions with protease.
- He, Meizi,Zhang, Hang,Yao, Xiaojian,Eckart, Michael,Zuo, Elizabeth,Yang, Ming
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p. 174 - 180
(2011/03/20)
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- Highly diastereoselective catalytic Meerwein-Ponndorf-Verley reductions
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Very practical synthesis of ephedrine analogues in high yields and enantiopurity was realized by a highly diastereoselective Meerwein-Ponndorf- Verley (MPV) reduction of protected α-amino aromatic ketones using catalytic aluminum isopropoxide. The high anti selectivity resulted from the chelation of the nitrogen anion to the aluminum. In contrast, high syn selectivity was obtained with α-alkoxy ketones and other compounds via Felkin-Ahn control.
- Yin, Jingjun,Huffman, Mark A.,Conrad, Karen M.,Armstrong III, Joseph D.
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p. 840 - 843
(2007/10/03)
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- HIV protease inhibitors
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Combinatorial libraries of HIV and FIV protease inhibitors are characterized by alpha-keto amide or hydroxyethylamine core structures flanked by on one side by substituted pyrrolidines, piperidines, or azasugars and on the other side by phenylalanine, tyrosine, or substituted tyrosines. The libraries are synthesized via a one step coupling reaction. Highly efficacious drug candidates are identified by screening the libraries for binding and inhibitory activity against both HIV and FIV protease. Drug candidates displaying clinically useful activity against both HIV and FIV protease are identified as being potentially resistive against a loss of inhibitory activity due to development of resistant strains of HIV.
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Page/Page column 30
(2010/02/11)
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- New approaches to the industrial synthesis of HIV protease inhibitors
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Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.
- Honda, Yutaka,Katayama, Satoshi,Kojima, Mitsuhiko,Suzuki, Takayuki,Kishibata, Naomi,Izawa, Kunisuke
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p. 2061 - 2070
(2007/10/03)
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- Retroviral protease inhibitors
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N-heterocyclic moiety-containing hydroxyethylamine protease inhibitor compounds, methods for making the compounds, and intermediates useful in the method. Also, a method for inhibiting retroviral proteases and for treatment or prophylaxis of a retroviral infection.
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- α-and β-amino acid hydroxyethlamino sulfonamides useful as retroviral protease inhibitors
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α- and β-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
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Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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Page column 45,51
(2008/06/13)
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- Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
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Succinoylamino hydroxyethylamino sulfonyl urea derivatives of the formula: wherein the substituents are as defined in the specification, are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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Page column 21
(2010/01/30)
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- HETEROCYCLECARBONYL AMINO ACID HYDROXYETHYLAMINO SULFONAMIDE RETROVIRAL PROTEASE INHIBITORS
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Selected heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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- Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors
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PCT No. PCT/US94/09139 Sec. 371 Date Jan. 24, 1996 Sec. 102(e) Date Jan. 24, 1996 PCT Filed Aug. 23, 1994 PCT Pub. No. WO95/06030 PCT Pub. Date Mar. 2, 1995The invention relates to sulfonamide-containing hydroxyethylamine protease inhibitor compounds, their process of making, composition and method of use for inhibiting retroviral proteases such as human immunodeficiency virus.
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- alpha - and beta -amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
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alpha - and beta -amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- Synthesis of benzo fused heterocyclic sulfonyl chlorides
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A process for preparing a benzo fused heterocyclic sulfonyl halide comprising reacting a benzo fused heterocyclic compound with an SO3 complex in the presence of a water immiscible, non-reactive solvent, at a temperature of from about 0 DEG C. to about 75 DEG C., cooling, if necessary, to a temperature of from about -25 DEG C. to about 65 DEG C. and then adding oxalyl halide.
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- Alpha- and beta-amino acid hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
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PCT No. PCT/US93/10552 Sec. 371 Date Feb. 2, 1995 Sec. 102(e) Date Feb. 2, 1995 PCT Filed Oct. 29, 1993 PCT Pub. No. WO94/10134 PCT Pub. Date May 11, 1994Certain Alpha- and Beta-amino acid hydroxyethylamino sulfamic acid derivatives represented by the following formula are useful as retroviral protease inhibitors:
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- Bis-amino acid hydroxyethlamino sulfonamide retroviral protease inhibitors
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PCT No. PCT/US96/02685 Sec. 371 Date Jan. 21, 1997 Sec. 102(e) Date Jan. 21, 1997 PCT Filed Mar. 7, 1996 PCT Pub. No. WO96/28464 PCT Pub. Date Sep. 19, 1996Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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- Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors
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PCT No. PCT/US96/00607 Sec. 371 Date Feb. 26, 1998 Sec. 102(e) Date Feb. 26, 1998 PCT Filed Jan. 18, 1996 PCT Pub. No. WO96/22287 PCT Pub. Date Jul. 25, 1996Bis-sulfonamido hydroxyethylamino compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to retroviral protease inhibiting compounds of the formula: or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein the variables are as defined herein.
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- Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
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Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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- Development of a new type of protease inhibitors, efficacious against FIV and HIV variants
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Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.
- Lee, Taekyu,Le, Van-Duc,Lim, Dongyeol,Lin, Ying-Chuan,Morris, Garrett M.,Wong, Andrew L.,Olson, Arthur J.,Elder, John H.,Wong, Chi-Huey
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p. 1145 - 1155
(2007/10/03)
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- AMINO ACID HYDROXYETHYLAMINO SULFONAMIDE RETROVIRAL PROTEASE INHIBITORS
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Described herein is a retroviral protease inhibiting compound of the formula: STR1 or a pharmaceutically acceptable salt, prodrug or ester thereof.
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- SULFONYLALKANOYLAMINO HYDROXYETHYLAMINO SULFONAMIDE RETROVIRAL PROTEASE INHIBITORS
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Selected sulfonylalkanoylamino hydroxyethylamine sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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- A totally stereocontrolled route to N-methyl-γ-amino-β-hydroxy acids: Asymmetric synthesis of the amino acid component of hapalosin
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A new approach to the synthesis of N-methyl-γ-amino-β-hydroxy acids, compounds that are essential components of several depsipeptides exhibiting highly interesting therapeutic profiles, is presented. Relevant steps in the synthetic sequence involve the totally stereoselective preparation of a protected aminoalkyl epoxide from a highly enantiopure 2,3-epoxy alcohol, efficient N-methylation and three-step conversion to the desired N-methyl amino acid. The method is exemplified by the enantioselective synthesis of (3R,4S)-4-(N-methylamino)-3-hydroxy-5-phenylpentanoic acid in two differently protected forms.
- Catasus, Monica,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni
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p. 9309 - 9312
(2007/10/03)
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- β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
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α- and β-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- Sulfonylalkanoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
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Sulfonylalkanoylamino hydroxyethylamino sulfonyl urea derivative compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. In accordance with the present invention, compounds of Formula (I) are disclosed STR1 wherein the substituents are as defined in the specification.
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- SULFONYLALKANOYLAMINO HYDROXYETHYLAMINO SULFONAMIDE RETROVIRAL PROTEASE INHIBITORS
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Selected sulfonylalkanoylamino hydroxyethylamine sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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- HETEROCYCLECARBONYL AMINO ACID HYDROXYETHYLAMINO SULFONAMIDE RETROVIRAL PROTEASE INHIBITORS
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Selected heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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- Substituted sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
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Selected sulfonylalkanoylamino hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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- Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
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Selected amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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- Retroviral protease inhibitors and combinations thereof
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The present invention is directed to the preparation and use of retroviral protease inhibitors and combinations of retroviral protease inhibitors which are effective in preventing the replication of mammalian retroviruses, such as human immunodeficiency virus (HIV).
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- Process for producing 3-amino-2-oxo-1-halogenopropane derivatives
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Compounds formed by reacting a protected amino acid with an alkali metal enolate of an alkyl acetate are reacted with a halogenating agent for halogenation of the 2-position, or a protected amino acid is reacted with an alkali metal enolate of an alkyl halogenoacetate, to form a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative, and hydrolysis and decarboxylation are conducted to produce a 3-amino-2-oxo-1-halogenopropane derivative or its salt. The present method is a useful process for producing a 3-amino-2-oxo-1-halogenopropane derivatives which can easily be converted to a 3-amino-1,2-epoxypropane.
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- Process for preparing oxiranemethanamine derivatives
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A process for preparing oxiranemethane derivatives which are useful as intermediates for preparing aspartyl protease inhibitors comprising the steps of activating an aminodiol, acylating the aminodiol and reacting the acylated aminodiol with a base to form an epoxy compound.
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- SUCCINOYLAMINO HYDROXYETHYLAMINO SULFAMIC ACID DERIVATIVES USEFUL AS RETROVIRAL PROTEASE INHIBITORS
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Succinoylamino hydroxyethylamino sulfamic acid derivative compounds which are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- RETROVIRAL PROTEASE INHIBITORS
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N-heterocyclic moiety containing hydroxyethylamine compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- SULFONYLALKANOYLAMINO HYDROXYETHLAMINO SULFONAMIDES USEFUL AS RETROVIRAL PROTEASE INHIBITORS
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Sulfonamide-containing hydroxethylamine compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
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Sulfonamide-containing hydroxyethylamine compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- Process for producing optically active erythro-3-amino-1,2-epoxy compound
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The present invention relates to a process for producing an optically active erythro-3-amino-1,2-epoxy compound represented by the following general formula (3): STR1 wherein R1 represents a hydrocarbon residue having 3 to 12 carbon atoms; and R2 represents optionally protected amino, provided that when the carbon atom at the *3-position has an S configuration, then the carbon atom at the *2-position has an S configuration, and when the carbon atom at the *3-position has an R configuration, then the carbon atom at the *2-position has an R configuration.
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- CYCLIC SULFONE CONTAINING RETROVIRAL PROTEASE INHIBITORS
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The present invention relates to cyclic sulfone moiety-containing hydroxyethylamine protease inhibitor compounds and pharmaceutical or method of use therefor, particularly as an inhibitor of HIV protease.
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- Synthesis of N-protection erythro-phenylalanylepoxides
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The synthesis of erythro-isomers of N-α-t-Boc, N-α-Fmoc- and N-α-Cbz-L-phenylalanylepoxides from the appropriate N-α-protected L-phenylalanines via bromomethyl-ketone intermediates is described.
- Heinsoo,Raidaru,Linask,Jarv,Zetterstrom,Langel
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p. 2245 - 2247
(2007/10/03)
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- SUCCINOYLAMINO HYDROXYETHYLAMINO SULFONAMIDES USEFUL AS RETROVIRAL PROTEASE INHIBITORS
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Succinoylamino hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- RETROVIRAL PROTEASE INHIBITORS
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Urea-containing hydroxyethylamine peptide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- A Practical Synthesis of an HIV Protease Inhibitor Intermediate - Diastreoselective Epoxide Formation from Chiral α-Aminoaldehydes
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A practical and efficient synthesis of an HIV protease inhibitor intermediate has been developed based on the diastereoselective epoxide formation from a chiral α-aminoaldehyde and an in situ generated halomethyllithium reagent.
- Ng, John S.,Przybyla, Claire A.,Liu, Chin,Yen, Joe C.,Muellner, Frank W.,Weyker, Cara L.
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p. 6397 - 6410
(2007/10/02)
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- Aminodiol HIV Protease Inhibitors. 1. Design, Synthesis, and Preliminary SAR
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A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials.The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds.Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50(HIV-1) = 80 nM) containing P1/P1' benzyl and P2/P2' Boc substituents.Compound 9a is a selective inhibito r of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin.In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs.After iv and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40percent) and a promising plasma elimination half-life (4 h).
- Barrish, Joel C.,Gordon, Eric,Alam, Masud,Lin, Pin-Fang,Bisacchi, Gregory S.,et al.
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p. 1758 - 1768
(2007/10/02)
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- Stereocontrolled synthesis of erythro N-protected α-amino epoxides and peptidyl epoxides
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N-protected α-amino epoxides of erythro configuration, derived from α-amino acids, were synthesized in a stereoselective manner. The erythro (2S,3S), configuration was achieved by the synthetic sequence: amino acid -> haloketone -> halohydrin -> epoxide. A mechanistic explanation for the observed stereoselectivity is presented. This stereoselective synthetic approach was applied to the synthesis of a variety of short peptidyl epoxides, bearing a predefined absolute configuration of the chiral epoxide moiety.
- Albeck, Amnon,Persky, Rachel
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p. 6333 - 6346
(2007/10/02)
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- Facile Synthesis of Potent HIV-1 Protease Inhibitors containing a Novel Pseudo-symmetric Dipeptide Isostere
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A series of potent inhibitors of the HIV-1 protease containing a novel pseudo-symmetric dipeptide isostere 3 was synthesized via ring opening of a protected epoxide with various substituted hydrazines.
- Sham, Hing L.,Betebenner, David A.,Zhao, Chen,Wideburg, Norman E.,Saldivar, Ayda,et al.
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p. 1052 - 1053
(2007/10/02)
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- Amino acid derivatives
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Compounds of the formula STR1 wherein R1 is alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl, alkylsulphonyl, arylsulphonyl, monoaralkylcarbamoyl, cinnamoyl or α-aralkoxycarbonylaminoalkanoyl and R2 is hydrogen or R1 and R2 together with the nitrogen atom to which they are attached represent a cyclic imide group of the formula STR2 in which P and Q together represent an aromatic system; R3 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkyl- sulphinylalkyl, carbamoylalkyl or alkoxycarbonylalkyl or, when n stands for zero, R3 can also represent alkylthioalkyl or, when n stands for 1, R3 can also represent alkylsulphonylalkyl; R4 is alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R5 is hydrogen and R6 is hydroxy or R5 and R6 together represent oxo; R7 and R8 together represent a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonylamino or acylamino or in which one --CH2 -- group is replaced by --NH--, --N(alkoxycar- bonyl)--, --N(alkyl)-- or --S-- or which carries a fused cycloalkane, aromatic or heteroaromatic ring; and R9 is alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula STR3 in which R10 and R11 each represent alkyl; and their pharmaceutically acceptable acid addition salts inhibit proteases of viral origin and can be used as medicaments for the treatment or prophylaxis of viral infections. They can be manufactured according to generally known procedures.
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