+

WO2009082819A1 - Nouveaux dérivés de lupane - Google Patents

Nouveaux dérivés de lupane Download PDF

Info

Publication number
WO2009082819A1
WO2009082819A1 PCT/CA2008/002291 CA2008002291W WO2009082819A1 WO 2009082819 A1 WO2009082819 A1 WO 2009082819A1 CA 2008002291 W CA2008002291 W CA 2008002291W WO 2009082819 A1 WO2009082819 A1 WO 2009082819A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
oxolup
ene
dimethylsuccinyl
unsubstituted
Prior art date
Application number
PCT/CA2008/002291
Other languages
English (en)
Other versions
WO2009082819A8 (fr
Inventor
Christophe Moinet
Liliane Halab
Nathalie Turcotte
Monica Bubenik
Marc Courchesne
Carl Poisson
Oswy Z. Pereira
Paul Nguyen-Ba
Bingean Liu
Nathalie Chauret
Caroline Cadilhac
Laval Chan Chun Kong
Original Assignee
Virochem Pharma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Virochem Pharma Inc. filed Critical Virochem Pharma Inc.
Priority to EP08869088A priority Critical patent/EP2250185A4/fr
Priority to JP2010540997A priority patent/JP2011508748A/ja
Priority to AU2008342537A priority patent/AU2008342537A1/en
Priority to CA2711424A priority patent/CA2711424A1/fr
Priority to CN2008801275273A priority patent/CN101981047A/zh
Priority to MX2010007375A priority patent/MX2010007375A/es
Publication of WO2009082819A1 publication Critical patent/WO2009082819A1/fr
Publication of WO2009082819A8 publication Critical patent/WO2009082819A8/fr
Priority to US12/830,293 priority patent/US8269026B2/en
Priority to US12/830,294 priority patent/US8431556B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • HIV Human immunodeficiency virus
  • AIDS Acquired ImmunoDeficiency Syndrome
  • the viral life cycle initiates with attachment of HIV gp120 surface protein to the CD4 receptors present of the T-cells. This event triggers a conformational change which exposes an additional binding site on gp120 and results with an interaction with the chemokine co-receptors (CCR5 and CXCR4). Another conformational change arising from co-receptor binding results in fusion of the cellular and viral membranes and release of the virion into the cell. After uncoating and release of the viral genome in the cytoplasm, viral reverse transcriptase (RT) then converts RNA into double stranded DNA which is then integrated into the host genome by the action of HIV integrase.
  • RT viral reverse transcriptase
  • the proviral DNA is then transcribed and translated by host cellular system to express HIV RNA and HIV proteins which are then directed to the cell membrane where they assemble and bud as immature virions.
  • the viral protease cleaves specific sites in Gag and Gag-Pol releasing essential viral proteins and enzymes such as capsid, nucleocapsid, reverse transcriptase, integrase and spacer peptides SP1 and SP2. This last step is crucial for generating functional viral enzymes and also for the formation of the mature conical HIV capsid.
  • a number of antiviral agents have been developed to interfere with various stages of viral replication.
  • viral entry can be blocked with T-20 or Maraviroc and post entry steps such as reverse transcription can be blocked with nucleoside RT inhibitors (examples: Lamivudine, Tenofovir, Zidovudine, Didanosine, Emtricitabine, Abacavir) or nonnucleoside RT inhibitors (examples: Nevirapine, Efavirenz and Delavirdine).
  • Integration can be blocked by Raltegravir and HIV proteolytic activity can be inhibited by protease inhibitors such as Saquinavir, Indinavir, Amprenavir, Darunavir, Lopinavir, Atazanavir, and Nelfinavir.
  • Triterpenoid derivatives have been shown to possess anti -retroviral properties.
  • moronic acid D. Yu, et al. J. Med. Chem. 2006, 49, 5462- 5469
  • oleanolic acid H. Assefa, et al. Bioorg. Med. Chem. Lett. 1999, 9, 1889- 1894
  • platanic acid T. Fujioka, et al. J. Nat. Prod. 1994, 57, 243-247
  • betulonic acid O. B. Flekhter, et al. Russ. J. Bioorg. Chem. 2004, 30, 80-88
  • betulinic acid I. -C. Sun, et al. Bioorg. Med. Chem.
  • This invention relates to 21 -keto triterpenes and the discovery that these novel modified triterpenoid derivatives possess significant anti-HIV activity.
  • the present invention relates to a compound of formula (I):
  • R 1 is H, hydroxy protecting group or O O
  • A is d. 8 alkyl, C 2 . 8 alkenyl, or -(CH 2 ⁇ 2 O(CH 2 ) L2 -;
  • Ry 1 and R y2 are each independently H or -CH 3 ;
  • X is NR 2 R 3 ;
  • R 2 is H, d. 12 alkyl which is unsubstituted or substituted one or more times by R 10 , C 2 . 12 alkenyl which is unsubstituted or substituted one or more times by R 10 , or C 2 . 12 alkynyl which is unsubstituted or substituted one or more times by R 10 ;
  • R 3 and R 3 ' are each independently H, C 1 ⁇ 2 alkyl which is unsubstituted or substituted one or more times by R 10 , C 2 . 12 alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2 . 12 alkynyl which is unsubstituted or substituted one or more times by R 10 , C 6 -i 4 aryl which is unsubstituted or substituted one or more times by R 11 , C 7 .
  • 16 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ;
  • R 3 and R 3 ' can also be taken together to form 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , or a 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 ;
  • R 4 is C M2 alkyl which is unsubstituted or substituted one or more times by R 10 , C 2 - 12 alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2 . n alkynyl which is unsubstituted or substituted one or more times by R 10 , C 6 -i 4 aryl which is unsubstituted or substituted one or more times by R 11 , C 7 .
  • 16 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ;
  • R 5 and R 6 are each independently C M2 alkyl which is unsubstituted or substituted one or more times by R 10 , C 2 .i 2 alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2 .i 2 alkynyl which is unsubstituted or substituted one or more times by R 10 , C 6 .i 4 aryl which is unsubstituted or substituted one or more times by R 11 , C 7 .
  • R 16 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ;
  • R 10 is halogen, oxo, d.
  • R 11 is halogen, C L6 alkyl, halogenated C L6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, d. 6 alkoxy, - NH 2 , -NH(C L4 alkyl), -N(d. 4 alkyl) 2 , -C(O)NH 2 , -C(O)NH(CL 4 alkyl), -C(O)N(C L4 alkylh, -NHC(O)H, -N(CL 4 alkyl)C(O)H, -N(C L4 alkyl)C(O)d. 4 alkyl, -NHC(O)C 1 .
  • R 12 is halogen, oxo, d_ 6 alkyl, halogenated C L6 alkyl, C 6 alkenyl, C 6 alkynyl, C L6 alkoxy, -NH 2 , -NH(C L4 alkyl), -N(C L4 alkyl) 2 , -C(O)NH 2 , -C(O)NH(C L4 alkyl), - C(O)N (C L4 alkylh, -NHC(O)H, -N(C L4 alkyl)C(O)H, -N(C L4 alkyl)C(O)d. 4 alkyl, - NHC(O)CL 4 alkyl, -NHC(O)OC L4 alkyl, -N(d. 4 alkyl)C(0)0C 4 alkyl, -
  • Y is C-Ry 1 R y2 and R y1 and R y2 are each -CH 3
  • Y is C-Ry 1 R y2 and R y1 and R y2 are each H.
  • R 1 is succinyl, glutaryl, 3'-methylglutaryl, 3'-methylsuccinyl, 3', 3 ' - dimethylsuccinyl, 3',3'- dimethylglutaryl, 2',2 1 -dimethylmalonyl, 2 ' , 3'- dihydroxysuccinyl, 2',3'-dimethylsuccinyl, 2',2',3',3'-tetramethylsuccinyl, 2 - methylsuccinyl, or 2',2'- dimethylsuccinyl.
  • R 1 is succinyl, glutaryl, 3'-methylglutaryl, 3'-methylsuccinyl, 3',3'- dimethylsuccinyl, 3', 3'- dimethylglutaryl, 2 1 ,2'-dimethylmalonyl, 2', 3'- dihydroxysuccinyl, 2 I ,2',3',3 l -tetramethylsuccinyl or 2',2'- dimethylsuccinyl.
  • R 1 is 3',3"-dimethylsuccinyt.
  • R 1 is H, or a hydroxy protecting group.
  • R 1 is H.
  • R 2 is H or C 1-I2 alkyl which is unsubstituted or substituted one or more times by R 10 .
  • R 2 is H or C 1 . 6 alkyl which is unsubstituted or substituted one or more times by R 10 .
  • R 2 is H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.
  • R 2 is H.
  • R 3 1 is H.
  • R 3 and R 3 ' can also be taken together to form a 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R 11 or a 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 .
  • R 3 and R 3 1 can also be taken together to form a piperidyl, a piperazinyl, or a morpholinyl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 is CM 2 alkyl which is unsubstituted or substituted one or more times by R 10 , C 2 - U alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2 .
  • n alkynyl which is unsubstituted or substituted one or more times by R 10 , C 6 - I4 aryl which is unsubstituted or substituted one or more times by R 11 , C 7 .
  • 16 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 3 is C M2 alkyl which is unsubstituted or substituted one or more times by R 10 , C 6 aryl which is unsubstituted or substituted one or more times by R 11 , C 7 . 9 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 3 is Ci- 6 alkyl which is unsubstituted or substituted one or more times by R 10 , phenyl which is unsubstituted or substituted one or more times by R 11 , benzyl which is unsubstituted or substituted one or more times by R 11 , 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 4 is Ci -12 alkyl which is unsubstituted or substituted one or more times by R 10 , C 2 . 12 alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2 . 12 alkynyl which is unsubstituted or substituted one or more times by R 10 , C 6 . 14 aryl which is unsubstituted or substituted one or more times by R 11 , C 7 .
  • 16 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 4 is C 1 - U alkyl which is unsubstituted or substituted one or more times by R 10 , C 6 aryl which is unsubstituted or substituted one or more times by R 11 , C 7 . 9 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 4 is Ci- 6 alkyl which is unsubstituted or substituted one or more times by R 10 , phenyl which is unsubstituted or substituted one or more times by R 11 , benzyl which is unsubstituted or substituted one or more times by R 11 , 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 3 , R 4 , R 5 or R 6 are CM 2 alkyl which is unsubstituted or substituted one or more times by R 10 .
  • R 3 , R 4 , R 5 or R 6 are C 1-6 alkyl which is unsubstituted or substituted one or more times by R 10 .
  • R 3 , R 4 , R 5 or R 6 are each independently methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 3 , R 4 , R 5 or R 6 are each independently is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.
  • R 3 , R 4 , Rs or R 6 are phenyl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 , R 4 , R 5 or R 6 are phenyl.
  • R 3 , R 4 , R 5 or R 6 are 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 , R 4 , R 5 or R 6 are is pyridyl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 , R 4 , R 5 or R 6 are is 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 , R 4 , R 5 or R 6 are -CH 2 -pyridyl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 , R 4 , R 5 or R 6 are 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 .
  • R 3 , R 4 , R 5 or R 6 are piperidine which is unsubstituted or substituted one or more times by R 12 .
  • R 3 , R 4 , R 5 or R 6 are 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12
  • R 3 , R 4 , R 5 or R 6 are -CH 2 -piperidine which is unsubstituted or substituted one or more times by R 12 .
  • R 3 , R 4 , R 5 or R 6 are each independently ethyl, iso-propyl, tert-butyl, cyclopentyl, -CH 2 -cyclopentyl, cyclohexyl, -CH 2 -cyclohexyl, phenyl, benzyl, pyridinyl, -CH 2 -pyridinyl, piperidynyl, piperazinyl, thienyl, morpholino, oxadiazole, pyrimidinyl, pyranyl, pyrazinyl, thiazole, and pyrazole, which are unsubstituted or substituted by one or more substituents chosen from a halogen, C L4 alkyl, d.
  • R 3 is 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 is 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 .
  • R 3 is pyridine which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1 ⁇ alkyl.
  • R 3 is pyrimidine which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl.
  • R 3 is pyrazole which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C,. 3 alkyl.
  • R 3 is phenyl which is unsubstituted or substituted one or more times by halogen, alkyl.
  • R 3 is benzyl which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1 ⁇ alkoxy, or halogenated C 1 -3 alkyl.
  • R 3 is oxadiazole which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1 ⁇ alkyl.
  • R 3 is imidazole which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 10 alkoxy, or halogenated C 1-3 alkyl.
  • R 3 is pyrrolidine which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1 ⁇ alkoxy, or halogenated C 1-3 alkyl.
  • R 3 is piperidine which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1 ⁇ alkoxy, or halogenated C 1 ⁇ alkyl.
  • R 3 is cyclohexyl which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl.
  • R 3 is pyridine.
  • R 3 is methylpyridine.
  • R 3 is pyrimidine.
  • R 3 is pyrazine
  • R 3 is pyrazole.
  • R 3 is methylpyrazole.
  • R 3 is thiadiazole.
  • R 3 is methylthiadiazole.
  • R 3 is oxadiazole.
  • R 3 is methyloxadiazole.
  • R 3 is piperidine.
  • R 3 is methylpiperidine.
  • R 3 is N-acetyl piperidine.
  • R 3 is cyclohexyl
  • R 3 is difluorocyclohexyl.
  • R 4 is 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R 11 .
  • R 4 is 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 .
  • R 4 is pyridine which is unsubstituted or substituted one or more times by halogen, d. 3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl.
  • R 4 is pyrimidine which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyt, C 1-3 alkoxy, or halogenated C 1-3 alkyl.
  • R 4 is pyrazine which which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated Ci -3 alkyl.
  • R 4 is pyrazole which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl.
  • R 4 is phenyl which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 10 alkoxy, or halogenated C 1-3 alkyl.
  • R 4 is benzyl which is unsubstituted or substituted one or more times by halogen, Ci -3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl.
  • R 4 is thiazole which is unsubstituted or substituted one or more times by halogen, Ci. 3 alkyl, C 1-3 alkoxy, or halogenated Ci- 3 alkyl.
  • R 4 is oxadiazole which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated Ci- 3 alkyl.
  • R 4 is imidazole which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl.
  • R 4 is pyrrolidine which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1 -3 alkyl.
  • R 4 is piperidine which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl.
  • R 4 is cyclohexyl which is unsubstituted or substituted one or more times by halogen, C 1-3 alkyl, Ci. 3 alkoxy, or halogenated C 1-3 alkyl.
  • R 4 is pyridine.
  • R 4 is methylpyridine.
  • R 4 is pyrimidine.
  • R 4 is pyrazine.
  • R 4 is pyrazole.
  • R 4 is methylpyrazole.
  • R 4 is phenyl
  • R 4 is fluorophenyl
  • R 4 is benzyl.
  • R 4 is fluorobenzyl.
  • R 4 is thiazole.
  • R 4 is methylthiazole.
  • R 4 is oxadiazole
  • R 4 is methyloxadiazole.
  • R 4 is imidazole.
  • R 4 is methylimidazole.
  • R 4 is piperidine.
  • R 4 is methylpiperidine.
  • R 4 is N-acetyl piperidine.
  • R 4 is thienyl
  • R 5 is C 12 alkyl which is unsubstituted or substituted one or more times by
  • R 5 is C 1 - O alkyl which is unsubstituted or substituted one or more times by R 10 .
  • R 5 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 5 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.
  • R 6 is C 1 - 12 alkyl which is unsubstituted or substituted one or more times by R 10 .
  • R 6 is C 1 - O alkyl which is unsubstituted or substituted one or more times by
  • R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.
  • R 10 is halogen, oxo, C 6 alkoxy, -NH 2 , -NH(Ci. 4 alkyl), -N(C 1-4 alkyl) 2 , -CONH 2 , - CONH(CM alkyl), -CON(C 4 alkyl) 2 , -NHCOH, -N(C 4 alkyl)COH, -N(C 4 alkyl)COC M , alkyl, -NHCOC M alkyl, -NHCOOC L4 alkyl, -NHCONHC L4 alkyl, -N(C 1 ., alkyl)CONHC M alkyl,-N(C 4 atkyl)CON(C 4 alkyl) 2 , -NHCON(C 4 alkyl) 2 , -C(O)H, -C(O)C M alkyl, carboxy, -C(O)OCL 4 alkyl, -C(NOH)C L4 alkyl,
  • R 10 is halogen, oxo, C L6 alkoxy,-NH 2 , -NH(C L4 alkyl), -N(Cv 4 alkyl) 2 , - CONH 2 , -CONH(d.
  • R 10 is halogen, oxo, -NH 2 , -NH(C L4 alkyl), -N(C 4 alkylh, -CONH 2 , -CONH(C L4 - alkyl), -CON(C L4 alkyl) 2 , -NHCOH, -N(C L4 alkyl)COH, -N(C M alkyl)COd. 4 alkyl, - NHCOC L4 alkyl, -NHCOOC L4 alkyl, -NHCONHC L4 alkyl, -C(O)H, -C(O)CL 4 alkyl, carboxy, -C(O)OC L4 alkyl, hydroxyl, d. 4 alkoxy, nitro, nitroso, azido, or cyano.
  • R 10 is halogen, oxo, -NH 2 , -NH(C L4 alkyl), -N(C M alkylh, -CONH 2 , -CONH(C L4 alkyl), -CON(C L4 alkylh, -NHCOH, -N(C L4 alkyl)COH, -N(C L4 alkyl)COC 1 4 alkyl, - NHCOC L4 alkyl, -NHCOOC M alkyl, -NHCONHC L4 alkyl, -C(O)H, -C(O)C L4 alkyl, carboxy, -C(O)OC L4 alkyl, hydroxyl, Ci. 4 alkoxy, nitro, azido, or cyano.
  • R 10 is halogen, oxo, -NH 2 , -NH(C L4 alkyl), -N(C M alkyl) 2 , -CONH 2 , -CONH(C L4 alkyl), -CON(C 4 alkylh, -NHCOH, -N(C L4 alkyl)COH, -N(CL 4 alkyl)COC M alkyl, - NHCOCL 4 alkyl, -NHCOOCL 4 alkyl, -NHCONHCL 4 alkyl, -C(O)H, -C(O)C L4 alkyl, carboxy, -C(O)OCL 4 alkyl, hydroxyl, or d. 4 alkoxy.
  • R 10 is halogen, oxo, -NH 2 , -NH(C L4 alkyl), -N(C M alkylh, -CONH 2 , -CONH(C L4 alkyl), -CON(CL 4 alkylh, -N(CL 4 alkyl)COC M alkyl, -NHCOCL 4 alkyl, carboxy, - C(O)OC L4 alkyl, hydroxyl, d. 4 alkoxy, or cyano.
  • R 11 is halogen, C L6 alkyl, halogenated d. & alKyl, C 6 alkenyl, C 2 . 6 alkynyl, C L6 alkoxy,-NH 2 , -NH(C L4 alkyl), -N(C M alkylh, -CONH 2 , -CONH(C L4 alkyl), -CON(C M alkylh, -NHCOH, -N(CL 4 alkyl)COH, -N(CL 4 alkyl)COd.
  • R 11 is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2 .
  • R 11 is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NH 2 , - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(C 1-4 alkyl) 2 , -NHCOH, - N(C 1-4 alkyl)COH, -N(C 1-4 alkyl)COC 1-4 alkyl, -NHCOC 1-4 alkyl, -NHCOOC 1-4 alkyl, - NHCONHC 1-4 alkyl, -C(O)H, -C(O)C 1-4 alkyl, carboxy, -C(O)OC 1-4 alkyl, hydroxyl, C 1-6 alkoxy, nitro, nitroso, azido, or cyano.
  • R 11 is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NH 2 , -
  • R 11 is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(C 1-4 alkyl) 2 , -NHCOH, -N(C 1-4 alkyl)COH, -N(C 1-4 alkyl)COC 1-4 alkyl, -NHCOC 1-4 alkyl, -NHCOOC 1-4 alkyl, - NHCONHC 1-4 alkyl, -C(O)H, -C(O)C 1-4 alkyl, carboxy, -C(O)OC 1-4 alkyl, hydroxyl, or C 1-6 alkoxy.
  • R 11 is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(C 1-4 alkyl) 2 , -N(C 1-4 alkyl)COC 1-4 alkyl, -NHCOC 1-4 alkyl, carboxy, -C(O)OC 1-4 alkyl, hydroxyl, or C 1-6 alkoxy.
  • R 12 is halogen, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(C 1-4 alkyl) 2 , -NHCOH, -N(C 1-4 alkyl)COH, -N(C 1-4 alkyl)COC 1-4 , alkyl, -NHCOC 1-4 alkyl, - NHCOOCL 4 alkyl, -NHCONHCL 4 alkyl, -N(CL 4 alkyl)C0NHd.
  • R 12 is halogen, oxo, d. 6 alkyl, halogenated C 1 * alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, d. 6 alkoxy, -NH 2 , -NH(C 1 ., alkyl), -N(CL 4 alkyl) 2 , -CONH 2 , -CONH(CL 4 alkyl), -CON(CL 4 alkyl) 2 , -NHCOH, -N(C M alkyl)COH, -N(CL 4 alkyl)COC,. 4 , alkyl, -
  • NHCOCL 4 alkyl -NHCOOC M alkyl, -NHCONHCL 4 alkyl, -N(C M alkyl)CONHC M alkyl, -N (CL 4 alkyl)CON(d. 4 alkyl) 2 , -NHCON(CL 4 alkyl) 2 , -C(O)H, -C(O)CL 4 alkyl, carboxy, -C(O)O C M alkyl, -C(NOH) CL 4 alkyl, -C(NOH)H, hydroxyl, nitro, azido, cyano, -S(O) 0 . 2 H, -S(O) 0 .
  • R 12 is halogen, oxo, CLO alkyl, halogenated d. 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, -
  • R 12 is halogen, oxo, C 1 * alkyl, halogenated CL 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, - NH 2 , -NH(CL 4 alkyl), -N(CM alkyl) 2 , -CONH 2 , -CONH(CL 4 alkyl), -CON(CL 4 alkyl) 2 , - NHCOH, -N(CL 4 alkyl)COH, -N(CL 4 alkyl)COd.
  • R 12 Is halogen, oxo, C 1 * alkyl, halogenated C 1 * alkyl, C 2 * alkenyl, C 2 * alkynyl, - NH 2 , -NH(CL 4 alkyl), -N(CL 4 alkyl) 2 , -CONH 2 , -CONH(CL 4 alkyl), -CON(C 4 alkyl) 2 , -
  • R 12 is halogen, oxo, C 1 ⁇ alkyl, halogenated Cv 6 alkyl, -NH 2 , -NH(Cv 4 alkyl), - N(C L4 alkylh, -CONH 2 , -CONH(C 1 ., alkyl), -CON(C 4 alkyl) 2 , -N(CM alkylJCOCM alkyl, - NHC0d. 4 alkyl, carboxy, -C(O)OCi. 4 alkyl, hydroxyl, or C ⁇ alkoxy.
  • the present invention relates to a compound of formula (II) or formula (Ha):
  • the present invention relates to a compound of formula (II) :
  • the present invention relates to a compound of formula
  • the present invention relates to a compound of formula (IV) :
  • stereoisomers for example, optical (+ and -), geometrical (cis and trans) and conformational isomers (axial and equatorial). All such stereoisomers are included in the scope of the present invention.
  • the compounds in accordance with the present invention can contain a chiral center.
  • the compounds of formula (I) may thus exist in the form of two different optical isomers (i.e. (+) or (-) enantiomers). All such enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
  • the single optical isomers or enantiomers can be obtained by methods well known in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary.
  • the compounds of the present invention are provided in the form of a single enantiomer at least 95%, at least 97% and at least 99% free of the corresponding enantiomer.
  • the compound of the present invention are in the form of the (+) enantiomer at least 95% free of the corresponding (-) enantiomer.
  • the compound of the present invention are in the form of the (+) enantiomer at least 97% free of the corresponding (-) enantiomer.
  • the compound of the present invention are in the form of the (+) enantiomer at least 99% free of the corresponding (-) enantiomer.
  • the compounds of the present invention are in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer.
  • the compound of the present invention are in the form of the (-) enantiomer at least 97% free of the corresponding (+) enantiomer.
  • the compound of the present invention are in the form of the (-) enantiomer at least 99% free of the corresponding (+) enantiomer.
  • pharmaceutically acceptable salts of the compounds of the present invention are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.
  • acids such as oxalic, while not themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from amino acids are also included (e.g. L-Arginine, L-Lysine).
  • Salts derived from appropriate bases include alkali metals (e.g. sodium, lithium, potassium), alkaline earth metals (e.g. calcium, magnesium), ammonium, NR4+ (where R is C-1.4 alkyl) salts, choline, meglumine and tromethamine.
  • alkali metals e.g. sodium, lithium, potassium
  • alkaline earth metals e.g. calcium, magnesium
  • ammonium NR4+ (where R is C-1.4 alkyl) salts
  • choline meglumine and tromethamine.
  • a reference hereinafter to a compound according to the invention includes that compound and its pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salt is a sodium salt.
  • the pharmaceutically acceptable salt is a lithium salt.
  • the pharmaceutically acceptable salt is a potassium salt.
  • the pharmaceutically acceptable salt is a tromethamine salt.
  • the pharmaceutically acceptable salt is an L-Arginine salt.
  • the pharmaceutically acceptable salt is a meglumine salt.
  • polymorphism is the ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
  • a polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
  • Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds.
  • the compounds in accordance with the present invention can exist in different solvate forms, for example hydrates.
  • Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process.
  • alkyl represents a linear, branched or cyclic hydrocarbon moiety.
  • alkenyl and alkynyl represent a linear, branched or cyclic hydrocarbon moiety which has one or more double bonds or triple bonds in the chain, respectively.
  • alkyl, alkenyl, and alkynyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl, allyl, vinyl, acetylenyl, ethylenyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, hexatrienyl, heptenyl, heptadienyl, heptatrienyl, octenyl, octadienyl, octat
  • alkyl alkenyl
  • alkynyl can be optionally substituted such as in the case of haloalkyls in which one or more hydrogen atom is replaced by a halogen, e.g., an alkylhalide.
  • haloalkyls include but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloroethyl, dichloroethyl, chloroethyl, chlorofluoromethyl, chlorodifluoromethyl, dichlorofluoroethyl.
  • cycloalkyl and “cycloalkenyl” represent a cyclic hydrocarbon alkyl or alkenyl, respectively, and are meant to include monocyclic (e.g., cyclohexyl), spiro (e.g., spiro [2.3]hexanyl), fused (e.g., bicyclo[4.4.0]decanyl), and bridged (e.g., bicyclo[2.2.1]heptanyl) hydrocarbon moieties.
  • the "cycloalkyl”, and “cycloalkenyl” groups can also be optionally substituted as defined in “alkyl” and “alkenyl” definition,
  • alkoxy represents an alkyl, alkenyl or alkynyl moiety, respectively, which is covalently bonded to the adjacent atom through an oxygen atom.
  • alkenyl and alkynyl groups where indicated the alkoxy (-O-alkyl), alkenyloxy (-0-alkenyl) and alkynyloxy (-O-alkynyl) groups can also be optionally substituted.
  • Examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy and neohexyloxy.
  • aryl represents a carbocyclic moiety containing at least one benzenoid-type ring (i.e., may be monocyclic or polycyclic), and which where indicated may be optionally substituted with one or more substituents. Examples include but are not limited to phenyl, tolyl, dimethylphenyl, aminophenyl, anilinyl, naphthyl, anthryl, phenanthryl or biphenyl.
  • aryloxy represent an aryl moiety substituted with an oxygen, wherein the point of attachement to the molecule it substitutes is on the oxygen.
  • aralkyl represents an aryl group attached to the adjacent atom by an alkyl, alkenyl, or alkynyl. Like the aryl groups, where indicated the aralkyl groups can also be optionally substituted. Examples include but are not limited to benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2- phenylpropyl, 4-phenylbutyl and naphthylmethyl.
  • heterocycle represents an optionally substituted, non aromatic, saturated or partially saturated wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (O), sulfur (S) or nitrogen (N). It is understood that in a 3-12 member heterocycle moiety, the 3-12 member represents the total of the ring atoms present in the heterocycle moiety. Heterocycles may be monocyclic or polycyclic rings.
  • Examples include but are not limited to azetidinyl, dioxolanyl, morpholinyl, morpholino, oxetanyl, piperazinyl, piperidyl, piperidino, cyclopentapyrazolyl, cyclopentaoxazinyl, cyclopentafuranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl dioxyde, thiazolinyl, oxazolinyl, pyranyl, thiopyranyl, aziridinyl, azepinyl, dioxazepinyl, diazepinyl, oxyranyl, oxazinyl, pyrrolidinyl, thiopyranyl, thiolane, pyr
  • heterocycle-alkyl represents an optionally substituted heterocycle group attached to the adjacent atom by an alkyl, alkenyl, or alkynyl group. It is understood that in a 5-18 member heterocycle-alkyl moiety, the 5-18 member represents the total of the ring atoms present in the heterocycle moiety and the carbon atoms present in the alkyl, alkenyl or alkynyl group. For example, the following groups are encompassed by a 7 member heterocycle-alkyl ( * represents the attachment point):
  • heteroaryl represents an optionally substituted aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0), sulfur (S) or nitrogen (N). It is understood that in a 5-12 member heteroaryl moiety, the 5-12 member represents the total of the ring atoms present in the heteroaryl moiety. Heteroaryls may be monocyclic or polycyclic rings.
  • Examples include but are not limited to dithiadiazinyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, dioxazole, oxatriazole, oxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl, pyrazolyl, pyrrolyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidinyl, thia
  • heteroaralkyl represents an optionally substituted heteroaryl group attached to the adjacent atom by an alkyl, alkenyl, or alkynyl group.
  • heteroaralkyl in a 6-18 member heteroaralkyl moiety, the 5-18 member represents the total of the ring atoms present in the heteroaryl moiety and the carbon atoms present in the alkyl, alkenyl or alkynyl group.
  • the following groups are encompassed by a 7 member heteroaralkyl ( * represents the attachment point):
  • Halogen atom is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachement for a substitutent.
  • -CONR d R e is attached through the carbon of the amide.
  • R d , R e and R f are each independently selected from H, C M0 alkyl, C 2 -i 0 alkenyl, C 2 . 10 alkynyl, Q 6 . n aryl, and C 7 . n aralkyl, or R e and R f are taken together with the nitrogen to which they are attached to form an optionally substituted 4 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
  • hydroxyl protecting group is well known in the field of organic chemistry. Such protecting groups may be found in "Protective Groups in Organic Synthesis” second edition, Wiley-interscience publication, by T. W. Greene and P. G. M. Wuts. Examples of hydroxy protecting groups include but are not limited to benzyl, acetyl, benzoyl, pivaloyl and isopropy loxycarbony I .
  • the sulfur atom can be at different oxidation levels, i.e., S, SO, or SO 2 . All such oxidation levels are within the scope of the present invention.
  • a method for prevention or treatment of HIV infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.
  • a method for delaying the onset of AIDS or treating AIDS in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.
  • a compound, composition or combination of the invention for the manufacture of a medicament for treating or preventing HIV infections in a subject in need of such treatment.
  • a compound, composition or combination of the invention for the manufacture of a medicament for delaying the onset of AIDS or treating AIDS in a subject in need of such treatment.
  • a method for blocking cellular entry of HIV in a subject or for the prevention or treatment of HIV infections in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound of formula (I) and at least one further therapeutic agent.
  • AIDS or treating AIDS in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound of formula (I) and at least one further therapeutic agent.
  • the pharmaceutical combination of this invention may contain at least one further therapeutic agent which is an antiviral agent.
  • the pharmaceutical combination of this invention may contain at least one further antiviral agent which is chosen from nucleoside and nucleotide analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, attachment and fusion inhibitors, integrase inhibitors, and maturation inhibitors.
  • at least one further antiviral agent which is chosen from nucleoside and nucleotide analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, attachment and fusion inhibitors, integrase inhibitors, and maturation inhibitors.
  • the pharmaceutical combinations of this invention may contain at least one other antiviral agent which is a nucleoside and nucleotide analog reverse transcriptase inhibitors chosen from 3TC (lamivudine, Epivir®), AZT (zidovudine, Retrovir®), Emtricitabine (Coviracil®, formerly FTC), d4T (2',3'- dideoxy-2',3'-didehydro-thymidine, stavudine and Zerit®), tenofovir (Viread®), 2',3'-dideoxyinosine (ddl, didanosine, Videx®), 2',3'-dideoxycytidine (ddC, zalcitabine, Hivid®), Combivir® (AZT/3TC or zidovudine/lamivudine combination), Trilusr® (AZT/3TC/abacavir or zidovudine/ lamivudine/abacavir combination), a nucleo
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a non-nucleoside reverse transcriptase inhibitor chosen from Nevirapine (Viramune®, NVP, BI-RG-587), delavirdine (Rescriptor®, DLV), efavirenz (DMP 266, Sustiva®), (+)-Calanolide A, Capravirine (AG1549, formerly S-1153), DPC083, MIV-150, TMC120, lntelence (etravirine®, TMC125), TMC-278 or BHAP (delavirdine), calanolides, GW695634, RDEA806, RDEA427, RDEA640, UK-453061 , BILR355, VRX 840773 and L-697,661 (2- Pyridinone 3benzoxazolMeNH derivative).
  • a non-nucleoside reverse transcriptase inhibitor chosen from Nevirapine (Viramune®, NVP, BI-RG
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a protease inhibitor chosen from nelfinavir (Viracept®, NFV), amprenavir (141W94, Agenerase®), indinavir (MK-639, IDV, Crixivan®), saquinavir (Invirase®, Fortovase®, SQV), ritonavir (Norvir®, RTV), lopinavir (ABT-378, Kaletra®), Atazanavir (Reyataz®, BMS232632), mozenavir (DMP-450), fosamprenavir (GW433908), RO033-4649, Tipranavir (Aptivus®, PNU-140690), Darunavir (Prezista®, TMC114), SPI-256, Brecanavir (GW640385), P- 1946, MK-8122 (formerly PPL-100)and VX-385.
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an attachment and fusion inhibitor chosen from T-20 (enfuvirtide, Fuzeon®), T-1249, TRI-999, TRI-1144, Schering C (SCH-C), Vicriviroc (Schering D, SCH-D), FP21399, PRO-140, PRO 542, PRO 452, TNX-355, Aplaviroc (GW873140, AK602), TBR-220 (formerly TAK-220), TBR-652 (formerly TAK-652), PF-232798, Maraviroc (Selzentry®, UK-427,857) or soluble CD4, CD4 fragments, CD4-hybrid molecules, BMS-806, BMS-488043, AMD3100, AMD070, AMD887, INCB9471 , INCB15050, KRH-2731 , KRH-3140, SJ-3366, SP-01A, sifuvirtide, and KRH
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an integrase inhibitor chosen from S-1360, L-870,810, elvitegravir (GS9137, JKT 303), GS9137, L-870,812, raltegravir (Isentressdb, MK-0518), MK-2048, GSK1349572, and C-2507.
  • an integrase inhibitor chosen from S-1360, L-870,810, elvitegravir (GS9137, JKT 303), GS9137, L-870,812, raltegravir (Isentressdb, MK-0518), MK-2048, GSK1349572, and C-2507.
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a maturation inhibitor chosen from Vivecon (MPC-9055) and Bevirimat PA-457.
  • a maturation inhibitor chosen from Vivecon (MPC-9055) and Bevirimat PA-457.
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a zinc finger inhibitor and is azodicarbonamide (ADA).
  • ADA azodicarbonamide
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an antisense drug and is HGTV43.
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an immunomodulator, immune stimulator or cytokine chosen from interleukin-2 (IL-2, Aldesleukin, Proleukin), granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin, Multikine, Ampligen, thymomodulin, thymopentin, foscamet, HE2000, Reticulose, Murabutide, Resveratrol, HRG214, HIV-1 lmmunogen (Remune), WF10 and EP HIV-1090.
  • an immunomodulator immune stimulator or cytokine chosen from interleukin-2 (IL-2, Aldesleukin, Proleukin
  • GM-CSF granulocyte macrophage colony stimulating factor
  • erythropoietin erythropoietin
  • Multikine erythropoietin
  • Ampligen thymomodulin
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent chosen from: 2',3'-dideoxyadenosine, 3'-deoxythymidine, 2',3'-dideoxy-2',3 1 -didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir, and ganciclovir; interferons such as alpha-, beta-and gamma-interferon; glucuronation inhibitors such as probenecid; and TIBO drugs, HEPT, Pictovir® (VGX-410) and TSAO derivatives.
  • the pharmaceutical combination of this invention may contain an inhibitor of the cytochrome P450.
  • the pharmaceutical combination of this invention may contain an inhibitor of the cytochrome P450 chosen from atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, erythromycin, fluconazole, fosamprenavir, grapefruit juice, fluvoxamine, fluoxetine, macrolide antibiotics, sertraline sulfaphenazole, Troleandomycin, cyclosporine, clomethiazole, atazanavir, mibef radii, vitamin E, bergamottin, dihydroxybergamottin, and pharmaceutically acceptable salts thereof.
  • an inhibitor of the cytochrome P450 chosen from atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir,
  • the pharmaceutical combination of this invention may contain an inhibitor of the cytochrome P450 which is ritonavir or a pharmaceutically acceptable salt thereof.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprises a further aspect of the invention.
  • the compound of formula (I) and at least one further therapeutic agent are administered sequentially.
  • the compound of formula (I) and at least one further therapeutic agent are administered simultaneously.
  • a further embodiment of the invention is a kit for use in administering a combination, the kit comprising: a first containment means for storing a compound according to formula I in the form of a pharmaceutical formulation further comprising a pharmaceutically acceptable carrier; and a second containment means for storing at least one further therapeutic agent in the form of a pharmaceutical formulation further comprising a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound having the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • host or "patient” or “subject” means a human, male or female, for example, a child, an adolescent, or an adult.
  • a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, for example, in the range of 0.5 to 60 mg/kg/day, or, for example, in the range of 1 to 20 mg/kg/day.
  • the desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
  • the compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 ⁇ M, about 2 to 50 ⁇ M, about 3 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 500 mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
  • each compound may be either the same as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical composition.
  • the invention thus further provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension, or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles ⁇ which may include edible oils), or preservatives.
  • the compounds according to the invention may also be formulated for parenteral administration (e.g. by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre- filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for rectal administration wherein the carrier is a solid are, for example, presented as unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one more dispersing agents, solubilizing agents, or suspending agents.
  • Liquid sprays are conveniently delivered from pressurized packs.
  • the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • Compounds according to the present invention include: 3/?-0-(3',3'-Dimethylsuccinyl)-17/?-[(4-amino-piperidine-1 --24 carbonyl)-amino]-21 -oxolup-18-ene;
  • Analytical HPLC is carried out under standard conditions using a Phenomenex Gemini C18 column, 250 x 4.6 mm, 3 ⁇ m, 110A for the methods A, B, C, D and E, a Varian pursuit XRs C18 column, 50 x 4.6 mm, 3 ⁇ m, for the methods F, G, H and I and a Waters SymmetryShield C18 column, 250 x 4.6 mm, 5 ⁇ m for the method J. Elution is performed using a linear gradient with a flow rate of 1 mL/min. as described in the following table (Solvent A is 0.01% TFA in H 2 O; solvent B is 0.01% TFA in CH 3 CN):
  • a suspension of compound 5 (10.24 g, 20.5 mmol) in ethyl acetate (720 mL) is added to a mixture of ruthenium oxide (IV) hydrate (272 mg, 2.05 mmol) and sodium periodate (26.3 g, 123 mmol) in water (650 mL) and TFA (11 mL).
  • the biphasic mixture is stirred vigorously overnight at room temperature.
  • Ethanol (100 mL) is added and the separated organic layer is filtered through a short column of silica gel. Water (400 mL) is added and the organic layer is dried over sodium sulfate, and concentrated in vacuo.
  • the yellow solid is taken up with diethyl ether, filtered off and washed with diethyl ether to give the title compound 6 (4.96 g, 47.2%) as a colorless solid.
  • An alkyl R 2 group is introduced to compound 15 by conventional reductive amination with an aldehyde or a ketone (see A. F. Abdel-Magid, et al. J. Org. Chem. (1996), 61, 3849-3862) or by alkylation with an alkyl halide in presence of a base such as TEA, DIPEA or NaH in a solvent such as THF or DMF to give compound 16.
  • Ureas 17 are made by treatment of compound 15 or 16 with an isocyanate (1 to 3 eq.), carbamoyl chloride or phosgene or triphosgene followed by an amine in a solvent such as toluene or THF.
  • Sulfonamides 18 are obtained by coupling compound 15 or 16 with the appropriate sulfonyl chloride (1 to 3 eq.) in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA.
  • Amides 19 are prepared by coupling compound 15 or 16 with the appropriate acyl chloride (1 to 3 eq.), preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA.
  • Carbamates 20 are obtained by reacting compound 15 or 16 with the appropriate chloroformate (1 to 3 eq.) in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA.
  • Step 1 Compound 14 is treated with acetyl chloride in methanol and stirred at room temperature to give compound 35.
  • Step 2 An alkyl R 2 group is introduced to compound 35 by conventional reductive amination with an aldehyde or a ketone or by alkylation with an alkyl halide in presence of a base such as TEA, DIPEA or NaH in a solvent such as THF or DMF to give compound 36.
  • a base such as TEA, DIPEA or NaH
  • a solvent such as THF or DMF
  • Step 3 The deprotection of the ester group occurs in solvents such as methanol, THF or dioxane using an aqueous solution of inorganic base such as lithium hydroxide or potassium hydroxide (3 to 10 eq.) at temperature ranging from 20 to 60 0 C.
  • Step 4 Amides 19 are prepared by coupling compound 16 with the appropriate acyl chloride (1 to 3 eq.), preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF, DMF or DCM and in the presence of a base such as TEA or DIPEA.
  • Step 1 To an ice-cold stirring suspension of 14-1 (146.8 mg, 0.22 mmol) in MeOH (2 mL) is added acetyl chloride (0.16 ml_, 2.19 mmol). The mixture is stirred at room temperature overnight and the solvent is removed by evaporation. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 8%) to yield the title compound 3/?-O-(3',3'-Dimethylsuccinyl-methyl-ester)-17/j- amino-21 -oxolup-18-ene hydrochloride 35-1 (118 mg, 86%).
  • Step 2 To an ice-cold stirring solution of 35-1 (101 mg, 0.164 mmol) in dry THF (1.6 mL) is added sodium hydride (14 mg, 0.345 mmol, as a 60% dispersion in mineral oil). The mixture is stirred 15 minutes at 0 0 C then methyl iodide (0.012 mL, 0.196 mmol) is added. The resulting mixture is stirred at 0 0 C for 30 minutes then at room temperature overnight. The mixture is diluted with ethyl acetate, washed with aqueous ammonium chloride, water, aqueous sodium thiosulfate 5% and brine, dried over sodium sulfate.
  • Step 3 To a stirring solution of 36-1 (80 mg, 0.134 mmol) in 1 ,4-dioxane (1 mL) and water (0.5 mL) is added LiOH 1 N (0.401 mL, 0.401 mmol); The mixture is stirred overnight at room temperature, neutralized to pH 7 with HCl 1 N, extracted with ethyl acetate (1X), DCM (containing few drops of methanol) (3X). The organic extracts are combined and dried over sodium sulfate. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to yield 16-2 (43 mg, 55%) as a white solid.
  • Step 4 To an ice-cold stirring solution of potassium 5-methyl-[1 ,3,4]oxadiazole-2- carboxylate (13.4 mg, 0.081 mmol) in dry acetonitrile (1.0 mL) is added a catalytic amount of DMF followed by oxalyl chloride (0.037 mL, 0.074 mmol). The mixture is stirred 50 minutes at 0 "C, it is then added to an ice-cold stirring suspension of 16- 2 (42.9 mg, 0.074 mmol) and TEA (0.021 mL, 0.147 mmol) in dry THF (1.3 mL).
  • Step 1 Amides 19 are prepared by coupling compound 35 with the appropriate acyl chloride, preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF, DCM or DMF and in the presence of a base such as TEA or
  • Step 2 The deprotection occurs in solvents such as methanol, THF or dioxane using an aqueous solution of inorganic base such as lithium hydroxide or potassium hydroxide (3 to 10 eq.) at temperature ranging from 20 to 6O 0 C.
  • solvents such as methanol, THF or dioxane
  • inorganic base such as lithium hydroxide or potassium hydroxide (3 to 10 eq.) at temperature ranging from 20 to 6O 0 C.
  • Step 1 To a stirring suspension of compound 35-1 (85.3 mg, 0.14 mmol) and 4- hydroxynicotinic acid (28.7 mg, 0.21 mmol) in DMF (1.5 ml_) is added TEA (53 ⁇ l_, 0.41 mmol) and HATU (78.4 mg, 0.21 mmol). The mixture is stirred for 2 hours at room temperature.
  • Step 2 To a stirring solution of 37-1 (70 mg, 0.10 mmol) in 1 ,4-dioxane (0.8 ml.) and water (0.2 mL) is added LiOH-H 2 O (12.5 mg, 0.30 mmol). The mixture is stirred overnight at room temperature, acidifed to pH 3 with HCl 1 N, and the precipitate formed is collected by filtration. The product is purified by flash column chromatography on silica gel (methanol/DCM 0% to 15%) to yield 19-50 (31 mg) as a white solid.
  • lsocyanates 26 are made by treatment of compound 15 with phosgene or triphosgene.
  • Ureas 17 are obtained by treatment of the isocyanates 26 with an amine in a solvent such as toluene or THF in the presence of a base such as TEA or DIPEA.
  • Step 1 To an ice-cold stirring solution of triphosgene (335 mg, 1.129 mmol) in dry THF (5 ml.) is added drop wise over 10 minutes a solution of compound 15-1 (456 mg, 0.753 mmol) and DIPEA (0.33 ml_, 1.881 mmol) in dry THF (6 mL). The resulting mixture is stirred at room temperature for 3 hours. Water is added drop wise at 0 0 C and the mixture is diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate.
  • Step 2 To a stirring solution of 3/?-O-(3',3'-dimethylsuccinyl)-21 -oxolup-18-ene- 17/%isocyanate 26-1 (151 mg, 0.253 mmol) in dry toluene (6 ml.) is added 4-amino- 1 -Boc-piperidine (203 mg, 1.014 mmol). The mixture is stirred 2 hours at 8O 0 C, cooled down and diluted with ethyl acetate, washed with HCl 1 N, water and brine, dried over sodium sulfate. The residue is purified by flash column chromatography on silica gel (methanol/ DCM 0% to 10%) to yield the title compound 17-9 (173 mg) as a white solid.
  • An alkyl R 2 group is introduced to compound 1 1 or 12 by conventional reductive amination with an aldehyde (see A. F. Abdel-Magid, et al. J. Or ⁇ . Chem. (1996), 61, 3849-3862) or by alkylation with an alkyl halide in presence of a base such as TEA, DIPEA or NaH in a solvent such as THF or DMF to give compound 21.
  • a base such as TEA, DIPEA or NaH
  • a solvent such as THF or DMF
  • solvents such as methanol, THF or dioxane
  • a base such as DMAP, TEA, DABCO or DIPEA
  • solvents such as pyridine, TEA or toluene (0.2-1.0 M)
  • Step 1 A solution of compound 11 , 12 or 21 and the appropriate sulfonyl chloride in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA is stirred for 4 to 20 hours at room temperature or under reflux. The residue obtained is purified by flash chromatography on silica gel to afford the desired amide 23.
  • solvents such as methanol, THF or dioxane
  • a base such as DMAP, TEA, DABCO or DIPEA
  • solvents such as pyridine, TEA or toluene (0.2-1.0 M)
  • Step 1 A solution of compound 11 , 12 or 21 and the appropriate acyl chloride or anhydride in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA is stirred for 4 to 20 hours at room temperature or under reflux. The residue obtained is purified by flash chromatography on silica gel to afford the desired amide 24.
  • solvents such as methanol, THF or dioxane
  • a base such as DMAP, TEA, DABCO or DIPEA
  • solvents such as pyridine, TEA or toluene (0.2-1.0 M)
  • a base such as DMAP, TEA, DABCO or DIPEA
  • solvents such as pyridine, TEA or toluene (0.2-1.0 M)
  • Ureas 17 and carbamates 20 can also be prepared from the isocyanate 8 as described in scheme 9.
  • a base such as DMAP, TEA, DABCO or DIPEA
  • solvents such as pyridine, TEA or toluene (0.2-1.0 M)
  • solvents such as methanol, THF or dioxane
  • a base such as DMAP, TEA, DABCO or DIPEA
  • solvents such as pyridine, TEA or toluene (0.2-1.0 M)
  • Step 1 To a stirring solution of compound 10 (300 mg, 0.59 mmol) in toluene (3 mL) is added isopropanol (68 ⁇ l_, 0.88 mmol) and titanium (IV) tert-butoxide (23 ⁇ l_, 0.06 mmol). The mixture is stirred for 1 hour at room temperature. A saturated solution of ammonium chloride and ethyl acetate are added and the organic layer is dried over sodium sulfate and concentrated to dryness.
  • Step 2 To a solution of 17/ ⁇ (isopropylcarbonylamino)-3/?-acetoxy-21 -oxolup-18-ene (349 mg, 0.6 mmol) in 2 mL of methanol and 6 mL of THF is added an aqueous 4N solution of potassium hydroxide (1.5 mL, 6 mmol). The reaction mixture is stirred for 24 hours at room temperature, acidified with 4N HCl and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness to yield the title compound 25-1 (330 mg).
  • Table 1 illustrates some intermediateswhich are synthesized using the procedures described herein.
  • the precipitate formed is collected by filtration to yield the title compound 14-1 as a white solid (39 g) in a ratio of 97:3 of 14-1 : 14-4 respectively.
  • the organic layer of the filtrate is dried over sodium sulfate and concentrated to dryness.
  • the solid obtained (16 g) is recristallized twice with ethyl methyl ketone to give the title compound 14-1 (3.6g) in a ratio of 98:2 of 14-1 : 14-4 respectively.
  • Step 1 Selenium dioxide (4 to 6 eq.) is added to a solution of compound 14 previously dissolved in dioxane, acetic acid and acetic anhydride. The reaction mixture is refluxed overnight, then cooled to room temperature and filtered through Celite. The residue is dissolved in DCM, washed with water, brine, dried over sodium sulfate and evaporated to dryness. The crude material is purified by flash chromatography on silica gel to yield the compound 27.
  • Step 2 The compound 27 is deprotected in solvents such as THF or dioxane and 4N HCl. The mixture is stirred for 12 to 24 hours at room temperature then concentrated to dryness to give 28.
  • solvents such as THF or dioxane and 4N HCl.
  • Ureas 29 are made by treatment of compound 28 with an isocyanate (1 to 3 eq.) or phosgene or triphosgene followed by an amine (R 3 IVNH 2 ) in a solvent such as toluene or THF.
  • Sulfonamides 30 are obtained by coupling compound 28 with the appropriate sulfonyl chloride (1 to 3 eq.) in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA.
  • Amides 31 are prepared by coupling compound 28 with the appropriate acyl chloride (1 to 3 eq.), preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA.
  • Carbamates 32 are obtained by reacting compound 28 with the appropriate chloroformate (1 to 3 eq.) in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA.
  • Step 1 Selenium dioxide (4 to 6 eq.) is added to a solution of compound 22, 23, 24 or 25 previously dissolved in dioxane, acetic acid and acetic anhydride. The reaction mixture is refluxed overnight, then cooled to room temperature and filtered through Celite. The residue is dissolved in DCM, washed with water, brine, dried over sodium sulfate and evaporated to dryness. The crude material is purified by flash chromatography on silica gel to yield the compound 33.
  • Step 2 The ester 33 is deprotected in solvents such as methanol, THF or dioxane using an aqueous solution of inorganic base such as sodium hydroxide or potassium hydroxide (10 to 20 eq.) at temperature ranging from 20 to 60 0 C to give the alcohol 34.
  • solvents such as methanol, THF or dioxane
  • inorganic base such as sodium hydroxide or potassium hydroxide (10 to 20 eq.) at temperature ranging from 20 to 60 0 C to give the alcohol 34.
  • Step 3 To the alcohol 34 in solvents such as pyridine, TEA or toluene (0.2-1.0 M) is added a cyclic anhydride (2 to 10 eq.) and base such as DMAP, TEA, DABCO or DIPEA (1.1 to 2 eq.).
  • solvents such as pyridine
  • TEA or toluene 0.2-1.0 M
  • base such as DMAP, TEA, DABCO or DIPEA
  • the reaction mixture is heated at temperature ranging from 90 to 140 0 C until completion to yield after standard acidic aqueous work up and purification by flash chromatography on silica gel the acid 29, 30, 31 or 32.
  • HIV Replication Activity HIV-1 Replication in MT2 cell line with and without 30% human serum The cells are infected at a Multiciplicity of Infection (MOI) of 0.5 for 3h and then washed twice with complete media to remove residual virus. Cells are then resuspended at 0.5 x 10 6 /ml in complete medium (RPMI, 10% FBS, 1% sodium pyruvate), and seeded into 96-well plates (6.25 * 10 4 /well). The cells are cultured in the presence or absence of various concentrations of test compounds in serial dilutions for 3 days at 37 0 C. The test compounds are serially diluted in complete medium supplemented or not with 30% human serum.
  • MOI Multiciplicity of Infection
  • IC 50 and IC 90 values for the virus replication are determined by using GRAPHPAD PRISM software.
  • PBMCs are separated from healthy donors' blood by standard density gradient centrifugation, resuspended at a cell density of 1.5 X 10 6 cells/ml in culture medium containing 2 ⁇ g/mL of phytohaemagglutinin (PHA), and thereafter incubated for 3 days at 37 0 C in a humidified 5% CO 2 atmosphere.
  • PHA- stimulated PBMCs are adjusted at a concentration of 5x10 6 / mL and then infected with HIV-1iii B at a MOI of 5.0 for 3 hours at 37 0 C in a humidified 5% CO 2 atmosphere and then washed to remove any residual virus.
  • cells are resuspended in culture medium supplemented with interleukin-2 (IL-2) at a concentration of 50 units/mL (2X) and seeded at a density of 0.2 X 10 6 cells/well into 96-well plates in the absence or presence of various concentrations of the test compound.
  • IL-2 interleukin-2
  • infected-cells are cultured for 4 days at 37 0 C in a humidified 5% CO 2 atmosphere in the absence or presence of 30% human serum after which an aliquot of cultured medium supernatant is replaced with fresh medium supplemented with human serum (when necessary) containing the serially diluted test compound.
  • the IC 50 and IC 90 values for the virus replication are determined at day 6 post-infection by measuring the reverse transcriptase activity in the harvested supernatant by using GRAPHPAD PRISM software.
  • HIV replication activity assay MT2 HIV replication activity assay MT2
  • Table 2 of compounds illustrates some of the compounds of the present invention which are synthesized and tested using the procedures described herein. Retention time (t R ) for each compound are measured using the standard analytical HPLC methods described above.
  • the average IC50 is provided.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des composés de 21-céto triterpènes de formule (I) : R1, X, et Y étant tels que définis dans la description, et des sels et des solvates de ceux-ci pharmaceutiquement acceptables. Ces composés présentent une activité anti-VIH significative. L'invention concerne également des procédés de prévention ou de traitement des infections par le VIH par administration de quantités thérapeutiquement efficaces d'un composé de formule (I), ou d'un sel ou solvate pharmaceutiquement acceptable de celui-ci, à un sujet ayant besoin d'un tel traitement.
PCT/CA2008/002291 2008-01-03 2008-12-23 Nouveaux dérivés de lupane WO2009082819A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP08869088A EP2250185A4 (fr) 2008-01-03 2008-12-23 Nouveaux dérivés de lupane
JP2010540997A JP2011508748A (ja) 2008-01-03 2008-12-23 新規のルパン誘導体
AU2008342537A AU2008342537A1 (en) 2008-01-03 2008-12-23 Novel lupane derivatives
CA2711424A CA2711424A1 (fr) 2008-01-03 2008-12-23 Nouveaux derives de lupane
CN2008801275273A CN101981047A (zh) 2008-01-03 2008-12-23 新的羽扇烷衍生物
MX2010007375A MX2010007375A (es) 2008-01-03 2008-12-23 Nuevos derivados de lupano.
US12/830,293 US8269026B2 (en) 2008-01-03 2010-07-03 Lupane derivatives useful for treating HIV
US12/830,294 US8431556B2 (en) 2008-03-26 2010-07-03 C-21-keto lupane derivatives preparation and use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1875908P 2008-01-03 2008-01-03
US61/018,759 2008-01-03
US3966008P 2008-03-26 2008-03-26
US61/039,660 2008-03-26

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US12/830,294 Continuation US8431556B2 (en) 2008-03-26 2010-07-03 C-21-keto lupane derivatives preparation and use thereof
US12/830,293 Continuation US8269026B2 (en) 2008-01-03 2010-07-03 Lupane derivatives useful for treating HIV

Publications (2)

Publication Number Publication Date
WO2009082819A1 true WO2009082819A1 (fr) 2009-07-09
WO2009082819A8 WO2009082819A8 (fr) 2009-10-22

Family

ID=40823729

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2008/002291 WO2009082819A1 (fr) 2008-01-03 2008-12-23 Nouveaux dérivés de lupane

Country Status (7)

Country Link
EP (1) EP2250185A4 (fr)
JP (1) JP2011508748A (fr)
CN (1) CN101981047A (fr)
AU (1) AU2008342537A1 (fr)
CA (1) CA2711424A1 (fr)
MX (1) MX2010007375A (fr)
WO (1) WO2009082819A1 (fr)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011007230A2 (fr) 2009-07-14 2011-01-20 Hetero Research Foundation Dérivés de triterpène de type lupéol comme antiviraux
US20120295898A1 (en) * 2010-01-27 2012-11-22 Mark Richard Underwood Antiviral Therapy
EP2533643A1 (fr) * 2010-02-11 2012-12-19 GlaxoSmithKline LLC Dérivés de bétuline
CN103242413A (zh) * 2012-02-08 2013-08-14 陆峰 Lupane三萜系衍生物及其药学用途
WO2014105926A1 (fr) 2012-12-31 2014-07-03 Hetero Research Foundation Nouveaux dérivés proline de l'acide bétulinique utilisés comme inhibiteurs du vih
US8802727B2 (en) 2009-07-14 2014-08-12 Hetero Research Foundation, Hetero Drugs Limited Pharmaceutically acceptable salts of betulinic acid derivatives
US8993542B2 (en) 2008-01-25 2015-03-31 Chimerix Inc. Methods of treating viral infections
US9102685B2 (en) 2011-12-16 2015-08-11 Glaxosmithkline Llc Derivatives of betulin
US9278135B2 (en) 2010-04-26 2016-03-08 Chimerix Inc. Methods of treating retroviral infections and related dosage regimes
WO2016147099A3 (fr) * 2015-03-16 2016-11-03 Hetero Research Foundation Nouveaux triterpénone c-3 avec des dérivés amide c-28 servant d'inhibiteurs de vih
WO2016178092A2 (fr) 2015-02-09 2016-11-10 Hetero Research Foundation Nouveau triterpénone en c-3 avec des dérivés d'amide inverse en c-28 en tant qu'inhibiteurs du vih
RU2613554C2 (ru) * 2011-12-14 2017-03-17 ГЛАКСОСМИТКЛАЙН ЭлЭлСи Пропеноатные производные бетулина
WO2017125870A1 (fr) * 2016-01-20 2017-07-27 Glaxosmithkline Intellectual Property (No.2) Limited Dérivés amine de lupanes ayant une activité inhibitrice de la maturation du vih
EP3210603A1 (fr) * 2008-12-11 2017-08-30 Shionogi & Co., Ltd Synthèse d'inhibiteurs carbamoylpyridone de l'intégrase du vih et intermédiaires
US9765100B2 (en) 2010-02-12 2017-09-19 Chimerix, Inc. Nucleoside phosphonate salts
US9795619B2 (en) 2012-12-14 2017-10-24 Glaxosmithkline Llc Pharmaceutical compositions
US9868758B2 (en) 2014-06-30 2018-01-16 Hetero Labs Limited Betulinic proline imidazole derivatives as HIV inhibitors
WO2018025247A1 (fr) * 2016-08-05 2018-02-08 Hetero Labs Limited Nouvelle triterpénone en c-3 avec des dérivés de diamide en c-28 en tant qu'inhibiteurs du vih
WO2018029604A1 (fr) * 2016-08-08 2018-02-15 Hetero Labs Limited Nouveau triterpénone en c-3 avec des dérivés d'amide inverse en c-17 en tant qu'inhibiteurs du vih
WO2018029610A1 (fr) * 2016-08-09 2018-02-15 Hetero Labs Limited Nouvelle triterpénone en c-3 avec des dérivés de n-amide en c-17 en tant qu'inhibiteurs du vih
WO2018065930A1 (fr) * 2016-10-05 2018-04-12 Hetero Labs Limited Triterpénone en c-3 avec des dérivés amides inversés en c-17 en tant qu'inhibiteurs du vih
WO2018069857A1 (fr) * 2016-10-12 2018-04-19 Hetero Labs Limited Nouvelle triterpénone en c-3 à dérivés hétérocycliques d'amide inverse en c-17 utilisés comme inhibiteurs du vih
US10092523B2 (en) 2014-09-26 2018-10-09 Glaxosmithkline Intellectual Property (No. 2) Limited Long acting pharmaceutical compositions
US20180305398A1 (en) * 2015-10-13 2018-10-25 Hetero Research Foundation C-3 novel triterpenone with c-28 urea derivatives as hiv inhibitors
US11116737B1 (en) 2020-04-10 2021-09-14 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8906889B2 (en) * 2012-02-15 2014-12-09 Bristol-Myers Squibb Company C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity
JP2017533937A (ja) * 2014-11-14 2017-11-16 ヴィーブ ヘルスケア ユーケー（ナンバー５）リミテッド オキソルペン誘導体

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0012528D0 (en) * 2000-05-23 2000-07-12 Univ Palackeho Triterpenoid derivatives
AU2001262489A1 (en) * 2000-05-23 2001-12-03 Univerzita Karlova V Praze Triterpenoid derivatives
US20060019934A1 (en) * 2004-05-20 2006-01-26 Saxena Brij B Anti-HIV-1 activity of betulinol derivatives
TW200628161A (en) * 2004-11-12 2006-08-16 Panacos Pharmaceuticals Inc Novel betulin derivatives, preparation thereof and use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KASHIWADA ET AL.: "3,28-Di-O-(dimethylsuccinyl)-betulin Isomers as Anti-HIV Agents", BIOORG. MED. CHEM. LETT., vol. 11, no. 2, 2001, pages 183 - 185, XP004314843 *
See also references of EP2250185A4 *
SUN ET AL.: "Anti-AIDS Agents. 32. Synthesis and Anti-HIV Activity of Betulin Derivatives", BIOORG. MED. CHEM. LETT., vol. 8, no. 10, 1998, pages 1267 - 1272, XP004137059 *
SUN ET AL.: "Anti-AIDS Agents. 34. Synthesis and Structure-Activity Relationships of Betulin Derivatives as Anti-HIV Agents", J. MED CHEM., vol. 41, no. 23, 1998, pages 4648 - 4657, XP002184894 *

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8993542B2 (en) 2008-01-25 2015-03-31 Chimerix Inc. Methods of treating viral infections
EP3210603A1 (fr) * 2008-12-11 2017-08-30 Shionogi & Co., Ltd Synthèse d'inhibiteurs carbamoylpyridone de l'intégrase du vih et intermédiaires
US8802727B2 (en) 2009-07-14 2014-08-12 Hetero Research Foundation, Hetero Drugs Limited Pharmaceutically acceptable salts of betulinic acid derivatives
WO2011007230A3 (fr) * 2009-07-14 2011-06-03 Hetero Research Foundation Dérivés de triterpène de type lupéol comme antiviraux
KR20120037985A (ko) * 2009-07-14 2012-04-20 헤테로 리서치 파운데이션 항 바이러스성 루페올-형 트리테르펜 유도체
WO2011007230A2 (fr) 2009-07-14 2011-01-20 Hetero Research Foundation Dérivés de triterpène de type lupéol comme antiviraux
KR101582856B1 (ko) * 2009-07-14 2016-01-07 헤테로 리서치 파운데이션 항 바이러스성 루페올-형 트리테르펜 유도체
RU2561604C2 (ru) * 2009-07-14 2015-08-27 Хетеро Рисерч Фаундейшн Тритерпеновые производные лупеольного типа как противовирусные препараты
US9067966B2 (en) 2009-07-14 2015-06-30 Hetero Research Foundation, Hetero Drugs Ltd. Lupeol-type triterpene derivatives as antivirals
US20120295898A1 (en) * 2010-01-27 2012-11-22 Mark Richard Underwood Antiviral Therapy
US10426780B2 (en) 2010-01-27 2019-10-01 Viiv Healthcare Company Antiviral therapy
US11234985B2 (en) 2010-01-27 2022-02-01 Viiv Healthcare Company Antiviral therapy
EP2533643A4 (fr) * 2010-02-11 2013-07-10 Glaxosmithkline Llc Dérivés de bétuline
EP2533643A1 (fr) * 2010-02-11 2012-12-19 GlaxoSmithKline LLC Dérivés de bétuline
US9765100B2 (en) 2010-02-12 2017-09-19 Chimerix, Inc. Nucleoside phosphonate salts
US9694024B2 (en) 2010-04-26 2017-07-04 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
US9956239B2 (en) 2010-04-26 2018-05-01 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
US9278135B2 (en) 2010-04-26 2016-03-08 Chimerix Inc. Methods of treating retroviral infections and related dosage regimes
RU2613554C2 (ru) * 2011-12-14 2017-03-17 ГЛАКСОСМИТКЛАЙН ЭлЭлСи Пропеноатные производные бетулина
US10064873B2 (en) 2011-12-16 2018-09-04 Glaxosmithkline Llc Compounds and compositions for treating HIV with derivatives of Betulin
US9102685B2 (en) 2011-12-16 2015-08-11 Glaxosmithkline Llc Derivatives of betulin
CN103242413A (zh) * 2012-02-08 2013-08-14 陆峰 Lupane三萜系衍生物及其药学用途
WO2013117137A1 (fr) * 2012-02-08 2013-08-15 Jiangxi Qingfeng Pharmaceutical Inc. Dérivés de triterpénoïdes de lupane et leur utilisation pharmaceutique
US9428542B2 (en) 2012-02-08 2016-08-30 Jiangxi Qingfeng Pharmaceutical Inc. Lupane triterpenoid derivatives and pharmaceutical use thereof
US9795619B2 (en) 2012-12-14 2017-10-24 Glaxosmithkline Llc Pharmaceutical compositions
US9637516B2 (en) 2012-12-31 2017-05-02 Hetero Research Foundation Betulinic acid proline derivatives as HIV inhibitors
WO2014105926A1 (fr) 2012-12-31 2014-07-03 Hetero Research Foundation Nouveaux dérivés proline de l'acide bétulinique utilisés comme inhibiteurs du vih
US9868758B2 (en) 2014-06-30 2018-01-16 Hetero Labs Limited Betulinic proline imidazole derivatives as HIV inhibitors
US10092523B2 (en) 2014-09-26 2018-10-09 Glaxosmithkline Intellectual Property (No. 2) Limited Long acting pharmaceutical compositions
US11034718B2 (en) 2015-02-09 2021-06-15 Hetero Labs Limited C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
US10533035B2 (en) 2015-02-09 2020-01-14 Hetero Labs Ltd. C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
AU2016258274B2 (en) * 2015-02-09 2019-12-05 Dfh Therapeutics, Inc. C-3 novel triterpenone with c-17 reverse amide derivatives as hiv inhibitors
WO2016178092A2 (fr) 2015-02-09 2016-11-10 Hetero Research Foundation Nouveau triterpénone en c-3 avec des dérivés d'amide inverse en c-28 en tant qu'inhibiteurs du vih
WO2016178092A3 (fr) * 2015-02-09 2017-01-05 Hetero Research Foundation Nouveau triterpénone en c-3 avec des dérivés d'amide inverse en c-28 en tant qu'inhibiteurs du vih
EA033264B1 (ru) * 2015-02-09 2019-09-30 Хетеро Лабз Лимитед Новый тритерпенон по с-3 с обратными амидными производными по с-17 в качестве ингибиторов вич
WO2016147099A3 (fr) * 2015-03-16 2016-11-03 Hetero Research Foundation Nouveaux triterpénone c-3 avec des dérivés amide c-28 servant d'inhibiteurs de vih
US10370405B2 (en) 2015-03-16 2019-08-06 Hetero Labs Limited C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors
US10669305B2 (en) * 2015-10-13 2020-06-02 Hetero Labs Limited C-3 novel triterpenone with C-28 urea derivatives as HIV inhibitors
US20180305398A1 (en) * 2015-10-13 2018-10-25 Hetero Research Foundation C-3 novel triterpenone with c-28 urea derivatives as hiv inhibitors
WO2017125870A1 (fr) * 2016-01-20 2017-07-27 Glaxosmithkline Intellectual Property (No.2) Limited Dérivés amine de lupanes ayant une activité inhibitrice de la maturation du vih
WO2018025247A1 (fr) * 2016-08-05 2018-02-08 Hetero Labs Limited Nouvelle triterpénone en c-3 avec des dérivés de diamide en c-28 en tant qu'inhibiteurs du vih
WO2018029604A1 (fr) * 2016-08-08 2018-02-15 Hetero Labs Limited Nouveau triterpénone en c-3 avec des dérivés d'amide inverse en c-17 en tant qu'inhibiteurs du vih
WO2018029610A1 (fr) * 2016-08-09 2018-02-15 Hetero Labs Limited Nouvelle triterpénone en c-3 avec des dérivés de n-amide en c-17 en tant qu'inhibiteurs du vih
WO2018065930A1 (fr) * 2016-10-05 2018-04-12 Hetero Labs Limited Triterpénone en c-3 avec des dérivés amides inversés en c-17 en tant qu'inhibiteurs du vih
WO2018069857A1 (fr) * 2016-10-12 2018-04-19 Hetero Labs Limited Nouvelle triterpénone en c-3 à dérivés hétérocycliques d'amide inverse en c-17 utilisés comme inhibiteurs du vih
US11116737B1 (en) 2020-04-10 2021-09-14 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections
US11903916B2 (en) 2020-04-10 2024-02-20 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections

Also Published As

Publication number Publication date
EP2250185A4 (fr) 2011-11-16
CA2711424A1 (fr) 2009-07-09
AU2008342537A1 (en) 2009-07-09
MX2010007375A (es) 2010-09-30
WO2009082819A8 (fr) 2009-10-22
CN101981047A (zh) 2011-02-23
JP2011508748A (ja) 2011-03-17
EP2250185A1 (fr) 2010-11-17

Similar Documents

Publication Publication Date Title
WO2009082819A1 (fr) Nouveaux dérivés de lupane
US20110077251A1 (en) Novel 17 beta lupane derivatives
WO2009082818A1 (fr) Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation
JP5755731B2 (ja) Ｈｉｖ成熟阻害剤としての修飾ｃ−３ベツリン酸誘導体のｃ−２８アミド
US20060205697A1 (en) Novel betulin derivatives, preparation thereof and use thereof
US10780102B2 (en) Triterpenoids with HIV maturation inhibitory activity
CA2634499A1 (fr) Hydroxydihydropyridopy razine-1,8-diones et procedes d'inhibition de l'integrase du vih
US11084845B2 (en) C-3 and C-17 modified triterpenoids as HIV-1 inhibitors
US8269026B2 (en) Lupane derivatives useful for treating HIV
CA3101643C (fr) Derives d'amine triterpenique

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200880127527.3

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08869088

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2711424

Country of ref document: CA

Ref document number: 2010540997

Country of ref document: JP

Ref document number: MX/A/2010/007375

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2574/KOLNP/2010

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2008342537

Country of ref document: AU

Ref document number: 586814

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2008869088

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2008342537

Country of ref document: AU

Date of ref document: 20081223

Kind code of ref document: A

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载