Claims for Patent: 4,868,155

Summary for Patent: 4,868,155

Title:	Dipeptidyl 4-0-,6-0-acyl-2-amino-2-deoxy-D-glucose compositions and methods of use in AIDS-immunocompromised human hosts
Abstract:	Disclosed are specific dipeptidyl 4-0, 6-0-acyl-2-amino-2-deoxy-D-glucose derivatives which, either alone, or in combination with an anti-AIDS drug, e.g. azidothymidine, protect against opportunistic bacterial, fungal and viral infection in a human host immunocompromised by an AIDS-related virus, as well as help to suppress the AIDS-related virus itself.
Inventor(s):	Durette; Philippe L. (New Providence, NJ), Dorn; Conrad P. (Plainfield, NJ)
Assignee:	Merck & Co., Inc. (Rahway, NJ)
Application Number:	07/105,055
Patent Claims:	1. A composition for enhancing host resistance against opportunistic bacterial, fungal or viral infection in a human host immunocompromised by an AIDS-related virus comprising a compound of the formula: ##STR12## wherein: R.sub.1 is C.sub.1-7 alkyl; C.sub.1-7 alkyl substituted by hydroxy, mercapto, alkoxy of 1-3 carbons, alkyl mercapto of 1-3 carbons, hydroxy or mercapto esterified by an acid of 1-4 carbon atoms, halogen, carboxyl, or carboxyl functionally modified by esterification with a lower alcohol of 1-3 carbons or by amidation; phenyl; or phenyl substituted by one or more alkyl groups of 1-3 carbon atoms or hydroxy or mercapto groups either free or etherified by an acid of 1-4 carbons, alkylidioxy of 1-4 carbons, cycloalkyldioxy of 5-7 carbon atoms, amino, or trifluoromethyl; R.sub.2 is hydrogen; C.sub.1-7 alkyl; C.sub.1-7 alkyl substituted by hydroxy, mercapto, alkoxy of 1-3 carbons, alkyl mercapto of 1-3 carbons, hydroxy mercapto esterified by an acid of 1-4 carbon atoms, halogen, carboxyl, or carboxyl functionally modified by esterification with a lower alcohol of 1-3 carbons or by amidation; phenyl; phenyl substituted by one or more alkyl groups of 1-3 carbon atoms or hydroxy or mercapto groups either free or etherified by an alkyl group of 1-3 carbons or esterified by an acid of 1-4 carbons, alkyldioxy of 1-4 carbons, cycloalkyldioxy of 5-7 carbon atoms, amino, or triifluoromethyl; phenyl C.sub.1-4 alkyl; or phenyl C.sub.1-4 alkyl substituted by one or more alkyl groups of 1-3 carbon atoms or hydroxy or mercapto groups either free or etherified by an alklyl group of 1-3 carbons or esterified by an acid of 1-4 carbons, alkyldioxy of 1-4 carbons, cycloalkyldioxy of 5-7 carbon atoms, amino, or trifluoromethyl; R.sub.3 and R.sub.4 may be the same or different and are each independently hydrogen, provided that R.sub.3 and R.sub.4 may not both be hydrogen; or ##STR13## where X is --O--; --S--; or ##STR14## R.sub.10 is hydrogen; C.sub.1-30 alkyl; C.sub.2-30 alkenyl; C.sub.1-30 alkoxy; phenyl; C.sub.1-20 alkylsulfonyl; or cholesteryl; R.sub.11, R.sub.12, R.sub.14, and R.sub.15 may be the same or different and are each independently hydrogen; C.sub.1-20 alkyl; C.sub.1-20 alkylcarbonyloxy; amino; benzyl; C.sub.1-20 alkoxy-methyl; C.sub.1-20 alkylamido; or ##STR15## r is 0 or 1; s is 0 or 1; and t is 0 to 20; provided that s may only be 0 when both r and t are greater than 0 or when r is 0 and R.sub.10 is amino; phenyl; substituted phenyl; 1-adamantyl or hetero-cycle selected from the group consisting of 2- or 3-furyl, 2- or 3- thienyl, 2- or 3- pyrrolidinyl, 2-, 3- or 4- pyridyl, and 1-tetrazolyl, said heterocycle optionally substituted with C.sub.1-20 alkylcarbonyl; and where R.sub.3 or R.sub.4 is other than hydrogen, the other of R.sub.3 or R.sub.4 may additionally be C.sub.1-4 alkylcarbonyl; R.sub.5 is hydrogen or C.sub.1-10 alkyl; R.sub.6 is hydrogen or R.sub.6 and R.sub.7 taken together are --(CH.sub.2).sub.3 ; R.sub.7 is hydrogen; C.sub.1-7 allkyl; hydroxymethyl; mercaptomethyl; benzyl; or substituted benzyl; R.sub.8 and R.sub.9 may be the same or different and are each independently COOR, or CONR'R", where R is hydrogen or C.sub.1-7 alkyl, and R' and R" are hydrogen or C.sub.1-3 alkyl; when R.sub.5 is C.sub.1-10 alkyl, the stereochemistry at asymmetric center I is D or L; when R.sub.7 is other than hydrogen, the stereochemistry at asymmetric center II is L; and the stereochemistry at asymmetric center III is D; and acid addition and quaternary salts thereof; or pharmaceutically acceptable acid addition salts thereof; and an anti-viral, anti-aids drug selected from the group consisting of azidothumidine, ansamycin, ribavirin, deoxycytidine, HPA-23,-AL-721, foscarnet, in a physiologically acceptable medium in an amount effective to impart resistance against bacterial, fungal or viral infection. 2. The composition of claim 1 wherein said compound is selected from: 2-acetamido-6-O-behenoyloxyisobutyryl-2-deoxy-3-O-(D-2-propionyl-L-alanyl-D -isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(N,O-dipalmitoyl-D,L-seryl)-3-O-(D-2-propionyl-L-al anyl-D-isoglutamine)-D-glucose; 2-acetamido-6-O-(adamantane-1-carbonyl)-3-O-(D-2-propionyl-L-alanyl-D-isogl utamine)-D-glucose; 2-acetamido-6-O-behenoyloxyacetyl-2-deoxy-3-O-(D-2-propionyl L-alanyl-D-isoglutamine)-D-glucose; 2-acetamido-6-O-[d-2-(3-chloro-4-cyclohexylphenyl)propionyl]-2-deoxy-3-O-(D -2-propionyl-L-alanyl-D-isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(N-palmitoyl-L-prolyl)-3O-(D-2-propionyl-L-alanyl-D -isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(2-methyl-2-N-palmitoylamidopropionyl-3-O-(D-2-prop ionyl-L-alanyl-D-isoglutamine)-L-glucose; 2-acetamido-2-deoxy-6-O-(N-palmitoylglycyl)-3-O-(D-2-propionyl-L-alanyl-D-i soglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(N-palmitoyl-L-valyl)-3-O-(D-2-propionyl-L-alanyl-D -isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(N-palmitoyl-D-phenylalanyl)-3-O-(D-2-propionyl-L-a lanyl-D-isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(N,O-dihexadecyl-D,L-seryl)-3-O-(D-2-propionyl-L-al anyl-D-isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(D,L-2-palmitamidopalmitoyl)-3-O-(D-2-propionyl-L-a lanyl-D-isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(N,N'-dipalmitoyl-D-lysyl)-3-O-(D-2-propionyl-L-ala nyl-D-isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(N-hexadecanesulfonylglycyl)-3-O-(D-2-propionyl-L-a lanyl-D-isoglutamine)-D-glucose; Bis(6-O-muramyl dipeptide)O-palmitoyltartronate; 2-acetamido-6-O-cholesteryloxycarbonyl-2-deoxy-3-O-(D-2-propionyl-L-alanyl- D-isoglutamine)-D-glucose; Methyl 2-acetamido-2-deoxy-6-O-hexadecyloxycarbonyl-3-O-(D-2-propionyl-L-alanyl-D -isoglutamine)-.beta.-D-glucopyranoside; Methyl 2-acetamido-6-O-behenoyloxyisobutyryl-2-deoxy-3-O-(D-2-propionyl-L-alanyl- D-isoglutamine)-.beta.-D-glucopyranoside; 2-acetamido-2-deoxy-6-O-(16-hydroxyhexadecanoyl)-3-O-2-propionyl-L-alanyl-D -isoglutamine)-D-glucose; 2-acetamido-6-O-(16-acetoxyhexadecanoyl)-4-O-acetyl-3-O-(D-2-propionyl-L-al anyl-D-isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(2-furoyl)-3-O-(D-2-propionyl-L-alanyl-D-isoglutami ne)-D-glucose; 2-acetamido-2-deoxy-4,6-di-O-methoxyacetyl-3-O-(D-2-propionyl-L-alanyl-D-is oglutamine)-D-glucose; 2-acetamido-4,6-di-O-acetamidoacetyl-2-deoxy-3-O-2-propionyl-L-alanyl-D-iso glutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(5-ketohexanoyl)-3-O-(D-2-propionyl-L-alanyl-D-isog lutamine)-D-glucose; 2-acetamido-6-O-(6-aminohexanoyl)-2-deoxy-3-O-(D-2-propionyl-L-alanyl-D-iso glutamine)-D-glucose; 2-acetamido-6-O-(6-acetamidohexanoyl)-2-deoxy-3-O-(D-2-propionyl-L-alanyl-D -isoglutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(phenylacetyl)-3-O-(D-2-propionyl-L-alanyl-D-isoglu tamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(phenoxyacetyl)-3-O-(D-2-propionyl-L-alanyl-D-isogl utamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(ethoxycarbonyl)-3-O-(D-2-propionyl-L-alanyl-D-isog lutamine)-D-glucose; 2-acetamido-2-deoxy-6-O-(1-tetrazolylacetyl)-3-O-2-propionyl-L-alanyl-D-iso glutamine)-D-glucose. 3. A method for enhancing host resistance against opportunistic bacterial, fungal or viral infection in a human host immunocompromised by an AIDS-related virus comprising a composition containing the step of administering to said host a compound according to claim 1.

Details for Patent 4,868,155

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	June 04, 2004		2007-10-05
Schering Corporation A Subsidiary Of Merck & Co., Inc.	PEGINTRON/ REBETOL COMBO PACK	peginterferon alfa-2b and ribavirin		125196	June 13, 2008		2007-10-05