Composition and methods for treatment of HIV infection

Abstract

Method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound or asparaginase, and optionally at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HIV reverse transcriptase inhibitor compounds.

1 . A method of treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient, in need thereof, a composition comprising a synergistically effective combination of: 
 a PEG-ASNase compound or a pharmaceutically acceptable salts thereof, in amounts that are effective to inhibit T-cell synthesis of enzymes required for the competent replication and assembly of the Human Immunodeficiency Virus; and    at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds, HIV reverse transcriptase inhibitor compounds and pharmaceutically acceptable salts thereof.    
     
     
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         18 . A method according to  claim 1  wherein at least one compound is a protease inhibitor compound.  
     
     
         19 . A method according to  claim 1  wherein at least one compound is a ribonucleotide reductase inhibitor compound.  
     
     
         20 . A method according to  claim 1  wherein at least one compound is an HIV reverse transcriptase inhibitor compound  
     
     
         21 . A method according to  claim 1  wherein the protease inhibitor compounds are selected from the group consisting of Nelfinavir, Indinavir, Endinovere, Ritonavir, Crixivan, Viracept, Norvir and VX-478.  
     
     
         22 . A method according to  claim 1  wherein the ribonucleotide reductase inhibitor compounds are selected from the group consisting of Hydroxyurea (HU), BW-348U87, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) Amidox (VF 236; NSC-343341; N,3,4-trihydroxybenzenecarboximidamide), BWLD 1257 (2-benzyl-3-phenylpropionyl-L-(N-methyl)valyl-L-3-(methyl)valyl-L-(N4,N4-tetramethylene)asparaginyl-L-(3,3-tetramethylene)aspartyl-L-(4-methyl)leucine), BILD 1357 (2-benzyl-3-phenylpropionyl-L-(N-methyl)valyl-L-3-(methyl)valyl-L-(N4,N4-tetramethylene)asparaginyl-L-(3,3-tetramethylene)aspartic acid-1-[1(R)-ethyl-2,2-dimethylpropylamide]), BILD 1633, BILD 733 (3-phenylpropionyl-L-(N-methyl)valyl-L-[3-methyl)valyl-L-[3-(pyrrolidin-1-ylcarbonyl)]alanyl-L-(1-carboxycyclopentyl)glycyl-L-(4-methyl)leucinol), BILD 1263 (2-benzyl-3-phenylpropionyl-L-(N-methyl)valyl-L-3-(methyl)valyl-L-(N4,(N-methyl) valyl-L-3-(methyl)valyl-L-(N4,N4 tetramethylene)asparaginyl-L-(3,3-tetramethylene) aspartyl-L-(4-methyl)leucinol), BILD 1351 (1-[1(S)-[5(S)-[3-[(all-cis)-2,6-dimethylcyclohexyl]ureido]-2(S)-(3,3-dimethyl-2-dimethyl-4-oxoheptanoylamino]-1-[1(R)-ethyl-2,2dimethylpropylcarbamol]methyl]cyclopentanecarboxylic acid]), CI-F-araA(2-chloro-9-(2deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine, DAH(D-aspartic-beta-hydroxamate), DDFC(2′-deoxy-2′,2′-difluorocytidine), Didox (VF147; NSC324360; N,3,4trihydroxybenzamide), Eurd (3′-Ethynyluridine), GTI 2040, GTI 2501, μMHAG (1-isoquinolylmethane-N-hydroxy-N′-aminoguanine), LY 207702 (2′,2′-difluoro-2′-deoxyribofuranosyl-2,6-diaminopurine), LY 295501 (N-[[3,4-dichlorophenyl)amino]carbonyl]2,3-dihydro-5-benzofuransulfonamide), MDL 101731 (FMdC;KW 2331;(2E)-2′-deoxy-2′-(fluoromethylene)cytidine), Parabactin Sulofenur (LY186641; N-[[(4-chlorophenyl) amino]carbonyl]-2,3-dihydro-1H-indene-5-sulfonamide), TAS 106 (Ecyd; 3′-ethynylcytidine), Triapine (OCX 191; OCX 0191), Trimidox (VF 233; N, 3-4,5-tetrahydroxybenzene carboximidamide) and compounds of formula I  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is alkyl, alkenyl, alkynyl or an electron withdrawing group; and  
         R 2  is alkyl, alkenyl, alkynyl; or  
         a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.  
       
     
     
         23 . A method according to  claim 22  wherein the ribonucleotide reductase inhibitor compounds are compounds of formula I.  
     
     
         24 . A method according to  claim 23  wherein R 1  is a lower alkyl or a halogen group; and R 2  is a lower alkyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.  
     
     
         25 . A method according to  claim 22  wherein the ribonucleotide reductase inhibitor compound is  
       
         
           
           
               
               
           
         
       
     
     
         26 . A method according to  claim 1  wherein the HIV reverse transcriptase inhibitor compounds are selected from the group consisting of AZT (Retrovir, zidovudine) ddI (Videx, didanosine) ddC (Hivid, zalcitabine), d4T (Zerit, stavudine) and 3TC (Epivir and lamivudine).  
     
     
         27 . A method according to  claim 1  wherein administering the compound is concurrent.  
     
     
         28 . A method according to  claim 1  wherein administering the compound is sequential.  
     
     
         29 . A pharmaceutical composition comprising a synergistically effective combination of a PEG-ASNase compound and one or more compounds selected from the group consisting of a protease inhibitor compound, a HIV reverse transcriptase inhibitor compound, or a ribonucleotide reductase inhibitor compound, or a pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.  
     
     
         30 . A pharmaceutical kit for treating or preventing a physiological condition assoicated with HIV, said kit comprising a plurality of separate containers, wherein at least one of said containers contains a PEG-ASNase compound and at least another of said containers contains one or more compounds and at least another of said containers contains one or more compounds selected from the group consisting of protease inhibitor compounds, a HIV reverse transcriptase inhibitor compound and ribonucleotide reductase inhibitor compound, and said containers optionally contain a pharmaceutical carrier.  
     
     
         31 . A method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient, in need thereof, an amount of a composition comprising a synergistically effective combination of: 
 a PEG-ASNase compound, or pharmaceutically acceptable salts thereof, in amounts that are effective to inhibit the T-Cell synthesis of enzymes required for the competent replication and assembly of the Human Immunodeficiency Virus (HIV), and optionally including a synergistically effective amount of AZT or synergistically effective amounts of AZT and MISID or 3TC, or pharmaceutically acceptable salts thereof.    
     
     
         32 . A method of limiting the spread of HIV infection comprising the step of exposing a cell population infected with HIV to a composition comprising a synergistically effective combination of: 
 a PEG-ASNase compound, or pharmaceutically acceptable salts thereof, in amounts that are effective to inhibit the T-Cell synthesis of enzymes required for the competent replication and assembly of the Human Immunodeficiency Virus (HIV), and optionally including a synergistically effective amount of AZT or synergistically effective amounts of AZT and MISID or 3TC, or pharmaceutically acceptable salts thereof.    
     
     
         33 . A pharmaceutical composition comprising a synergistically effective combination of a PEG-ASNase compound, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, and optionally including a synergistically effective amount of AZT or synergistically effective amounts of AZT and MISID or 3TC, or pharmaceutically acceptable salts thereof.  
     
     
         34 . A pharmaceutical kit for treating or preventing a physiological condition associated with HIV, said kit comprising a plurality of containers, wherein at least one of said containers contains a PEG-ASNase compound or a pharmaceutically acceptable salt thereof, and at least another of said containers contains a pharmaceutically salt thereof, and optionally AZT, or AZT and MISID or 3TC, or pharmaceutically acceptable salts thereof, wherein the amounts of said PEG-ASNase compounds, said Saquinavir and said optional compounds in said containers consist of a synergistically effective combination, and said containers optionally contain a pharmaceutically acceptable carrier.  
     
     
         35 . The method of  claim 1  wherein the polyethylene glycol has an average molecular weight of about 1,000 and 100,000 daltons.  
     
     
         36 . The method of  claim 35  wherein the polyethylene glycol has an average molecular weight of about 4,000 and 40,000 daltons.  
     
     
         37 . The method of  claim 31  wherein the polyethylene glycol has an average molecular weight of about 1,000 and 100,000 daltons.  
     
     
         38 . The method of  claim 37  wherein the polyethylene glycol has an average molecular weight of about 4,000 and 40,000 daltons.