EP2240504A1 - Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation - Google Patents

Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation

Info

Publication number
EP2240504A1
EP2240504A1 EP08867782A EP08867782A EP2240504A1 EP 2240504 A1 EP2240504 A1 EP 2240504A1 EP 08867782 A EP08867782 A EP 08867782A EP 08867782 A EP08867782 A EP 08867782A EP 2240504 A1 EP2240504 A1 EP 2240504A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
dimethylsuccinyl
oxolup
oic acid
acetamide
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP08867782A
Other languages
German (de)
English (en)
Inventor
Christophe Moinet
Laval Chan Chun Kong
Marc Courchesne
Liliane Halab
Nathalie Chauret
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Virochem Pharma Inc
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
Publication of EP2240504A1 publication Critical patent/EP2240504A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
  • HIV primarily infects T cells, macrophages and other important components of -the immune system resulting in the gradual loss of cell-mediated immunity and as result, HIV patients become increasingly more susceptible to numerous opportunistic infections and tumors and if left untreated, death usually results within 10 years following infection.
  • 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) and pharmaceutically acceptable salts:
  • R 1 is H, a hydroxy protecting group or
  • A is d. 8 alkyl, C 2 . 8 alkenyl, or -(CH 2 ) L2 0(CH 2 ) L2 -;
  • R y1 and R y2 are each independently H or -CH 3 ;
  • R 2 is H, C 1 -I2 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 is H, 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 6-14 aryl which is unsubstituted or substituted one or more times by R 11 , C 7 .
  • 1 6 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 2 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 10 is halogen, oxo, C 1 * alkoxy, -NH 2 , -NH(C 4 alkyl), -N(C 4 alkyl) 2 , -C(O)NH 2 , - C(0)NH(d.
  • R 11 is halogen, C 1 -O alkyl, halogenated C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 1-6 alkoxy, - NH 2 , -NH(C 4 alkyl), -N(C 4 alkyl) 2 , -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 4 alkyl) 2 , -NHC(O)H, -N(C 1-4 alkyl)C(O)H, -N(C 1-4 alkyl)C(0)C 4 alkyl, -NHC(O)C 1 .
  • R 12 is halogen, oxo, CLO alkyl, halogenated CL6 alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, CL6 alkoxy, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), - C(O)N(C 1-4 alkyl) 2 , -NHC(O)H, -N(C 1-4 alkyl)C(O)H, -N(C 1-4 alkyl)C(O)C 1 . 4 alkyl, - NHC(O)C 1-4 alkyl, -NHC(O)OC 1-4 alkyl, -N(C 1-4 alkyl)C(O)Od. 4 alkyl, -NHC(O)C 1-4 alkyl, -NHC(O)OC 1-4
  • Y is C-R y1 R y2 and R y1 and R y2 are -CH 3
  • Y is C-R y iR y2 and R y i and R y2 are H.
  • R 1 is succinyl, glutaryl, 3'-methylglutaryl, 3'-methylsucctnyl, 3', 3'- dimethylsuccinyl, 3',3'- dimethylglutaryl, 2',2'-dinnethylmalonyl, 2',3'- dihydroxysuccinyl, 2',3'-dimethylsuccinyl, 2',2 1 ,3 I ,3'-tetramethylsuccinyl, X- methylsuccinyl, or 2',2'- dimethylsuccinyl.
  • R 1 is succinyl, glutaryl, 3'-methylglutaryl, 3'- methylsuccinyl, 3',3'- dimethylsuccinyl, 3',3'- dimethylglutaryl, 2',2"-dimethylmalonyl, 2 ,3' dihydroxysuccinyl, 2',2 l ,3',3'-tetramethylsuccinyl or 2', 2'- dimethylsuccinyl.
  • R 1 is 3',3'-dimethylsuccinyl.
  • R 1 is H, or a hydroxy protecting group.
  • R 1 is H.
  • R 2 is H or C 1 . 12 alkyl which is unsubstituted or substituted one or more times by R 10 .
  • R 2 is H or d- 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, ter ⁇ -butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.
  • R 2 is methyl
  • R 2 is H.
  • R 2 and R 3 taken together 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 2 and R 3 taken together form a piperidyl, a piperazinyl, or a morpholinyl which is unsubstituted or substituted one or more times by R 11 .
  • R 2 and R 3 taken together form a diazabicyclo[3.2.1]octane which is unsubstituted or substituted one or more times by R 11 .
  • R 3 is C 1 . 12 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 , C7. 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 C 1 - 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 is C 1-6 alkyl which is unsubstituted or substituted one or more times by R 10 , benzyl 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 C 1-6 alkyl which is unsubstituted or substituted one or more times by R 10 , benzyl which is unsubstituted or substituted one or more times by Rn, 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 3 is C 1-6 alkyl which is unsubstituted or substituted one or more times by R 10 , benzyl which is unsubstituted or substituted one or more times by R 11 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 3 is C 1-6 alkyl which is unsubstituted or substituted one or more times by R 10 .
  • 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 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .
  • R 3 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl(CH 2 )-.
  • R 3 is benzyl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 is benzyl
  • R 3 is pyridinyl(CH 2 )- which is unsubstituted or substituted one or more times by R 11 .
  • R 3 is pyridinyl(CH 2 )-.
  • R 3 is ethyl, iso-propyl, tert-butyl, cyclopentyl, cyclopentyl(CH 2 )-, cyclohexyl, cyclohexyl(CH 2 )-, phenyl, benzyl, pyridinyl, pyridinyl(CH 2 )-, piperidynyl, piperazinyl, thiophenyl, morpholino, oxadiazole, pyrimidinyl, pyranyl, pyrazinyl, thiazole, and pyrazole, which are unsubstituted or substituted by one or more substituents chosen from a halogen, d.
  • R 3 is piperidinyl which is unsubstituted or substituted one or more times by
  • R 3 is piperidinyl.
  • R 3 is pyrimidinyl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 is pyrimidinyl
  • R 3 is pyridine which is unsubstituted or substituted one or more times by
  • R 3 is pyridine.
  • R 3 is pyrazole which is unsubstituted or substituted one or more times by R 11 .
  • R 3 is methyl pyrazole
  • R 3 is pyperazinyl
  • R 3 is phenyl which is unsubstituted or substituted one or more times by R 11 .
  • R 3 is fluorophenyl
  • R 3 is phenyl
  • R 3 is cyclohexyl(CH 2 )- which is unsubstituted or substituted one or more times by R 10 .
  • R 3 is cyclohexyl(CH 2 )- which is unsubstituted or substituted one or more times by halogen.
  • R 10 is halogen, oxo, C 1 * alkoxy, -NH 2 , -NH(C 1 4 alkyl), -N(C 1-4 alkyl) 2 , -CONH 2 , - CONH(C 1-4 alkyl), -CON(C 4 alkyl) 2 , -NHCOH, -N(d. 4 alkyl)COH, -N(C 1-4 alkyl)COd. 4 alkyl, -NHCOC 1-4 alkyl, -NHCOOC 1-4 alkyl, -NHCONHC 1-4 alkyl, -
  • R 10 is halogen, oxo, d. 6 alkoxy, -NH 2 , -NH(C 1-4 alkyl), -N(d. 4 alkyl) 2 , -CONH 2 , - CONH(C 1-4 alkyl), -CON(C 4 alkyl) 2 , -NHCOH, -N(C 1-4 alkyl)COH, -N(C 1-4 alkyl)COd.
  • R 10 is halogen, oxo, -NH 2 , -NH(C 4 alkyl), -N(CM alkyl) 2 , -CONH 2 , -CONH(C 4 alkyl), -CON(C 4 alkyl) 2 , -NHCOH, -N(CL 4 alkyl)COH, -N(C 4 alkyl)COC 4 alkyl, - NHCOC 1-4 alkyl, -NHCOOC 1-4 alkyl, -NHCONHCL 4 alkyl, -C(O)H, -C(O)CL 4 alkyl, carboxy, -C(O)OC 1-4 alkyl, hydroxyl, C 4 alkoxy, nitro, nitroso, azido, or cyano.
  • R 10 is halogen, oxo, -NH 2 , -NH(CL 4 alkyl), -N(C 1-4 alkyl) 2 , -CONH 2 , -CONH(CL 4 alkyl), -CON(CL 4 alkyl) 2 , -NHCOH, -N(C 1-4 alkyl)COH, -N(C 1-4 alkyl)C0C 4 alkyl, - NHCOC 1-4 alkyl, -NHCOOC 1-4 alkyl, -NHCONHCL 4 alkyl, -C(O)H, -C(O)CL 4 alkyl, carboxy, -C(O)OCL 4 alkyl, hydroxyl, C 1-4 alkoxy, nitro, azido, or cyano.
  • R 10 is halogen, oxo, -NH 2 , -NH(C 1-4 alkyl), -N(C 4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(CL 4 alkyl) 2 , -NHCOH, -N(C 4 alkyl)COH, -N(C 1-4 alkyl)COC 1-4 alkyl, - NHCOCL 4 alkyl, -NHCOOCL 4 alkyl, -NHCONHCL 4 alkyl, -C(O)H, -C(O)CL 4 alkyl, carboxy, -C(O)OC 1-4 alkyl, hydroxyl, or C 4 alkoxy.
  • R 10 is halogen, oxo, -NH 2 , -NH(C 1-4 alkyl), -N(CL 4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(C 1-4 alkyl) 2 , -N(C 1-4 alkyl)C0C 4 alkyl, -NHCOC 1-4 alkyl, carboxy, - C(O)OC 1-4 alkyl, hydroxyl, C 4 alkoxy, or cyano.
  • R 11 is halogen, C 1-6 alkyl, halogenated CL 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 6 alkoxy,- NH 2 , -NH(CL 4 alkyl), -N(C 1-4 alkyl) 2 , -CONH 2 , -CONH(CL 4 alkyl), -CON(CL 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, -N(C 1-4 alkyl)CONHC 4 alkyl, -N(C 1-4 alkyl)CON(C 4 alkyl) 2 , -NHCON(C 1-4 alkyl) 2 , -C(O)H, -C(O)C
  • R 11 is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2 . 6 alkenyl, C 6 alkynyl, C 1-6 alkoxy,-NH 2 , -NH(C 1-4 alkyl), -N(CL 4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(C 1-4 alkyl) 2 , -NHCOH, -N(CL 4 alkyl)COH, -N(C 4 alkyl)COC 1-4 , alkyl, -NHCOC 4 alkyl, - NHCOOCL 4 alkyl, -NHCONHCL 4 alkyl, -N(C 4 alkyl)CONHC 4 alkyl, -N(CL 4 alkyl)CON(C 4 alkyl) 2 , -NHCON(C 1-4 alkyl) 2 , -C(O)H, -C(O)C 1-4 al
  • 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,.
  • 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 ,
  • R 1 Ms 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(CM alkyl)COC 1 . 4 alkyl, -NHCOC 1-4 alkyl, carboxy, -C(O)OC 1-4 alkyl, hydroxyl, or d. 6 alkoxy.
  • R 12 is halogen, oxo, d. 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)C0d.
  • R 12 is halogen, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl,, d. 6 alkoxy,-NH 2 , -NH(C 4 alkyl), -N(C 1 ., alkyl) 2 , -CONH 2 , -CONH(C 1 ., alkyl), -CON(C 1 ., alkyl) 2 , -NHCOH, -N(C 1 ., alkyl)COH, -N(C 1 ., alkyl)COC 4 , alkyl, -NHCOC 1-4 alkyl, - NHCOOC 1 ., alkyl, -NHCONHC 4 alkyl, -N(C,.
  • R 12 is halogen, oxo, 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 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 4 alkyl)C0C 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 12 is halogen, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, -
  • R 12 is halogen, oxo, C 1-6 alkyl, halogenated C O alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, - NH 2 , -NH(C 1-4 alkyl), -N(C 4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(C 1-4 alkyl) 2 , - NHCOH, -N(C 4 alkyl)COH, -N(C 1-4 alkyl)C0C 4 alkyl, -NHCOC 1-4 alkyl, -NHCOOC 1-4 alkyl, -NHCONHC 1-4 alkyl, -C(O)H, -C(O)C 4 alkyl, carboxy, -C(O)OC 4 alkyl, hydroxyl, or C 1-6 alkoxy.
  • R 12 is halogen, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, -NH 2 , -NH(C 1-4 alkyl), - N(C 1-4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -CON(C 4 alkyl) 2 , -N(C 4 alkyl)C0C 4 alkyl, - NHCOC 1-4 alkyl, carboxy, -C(O)OC 1-4 alkyl, hydroxyl, or C 1-6 alkoxy.
  • the compounds in accordance with the present invention can exists as 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. It will be appreciated by those skilled in the art that 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 method 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, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.
  • Other 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-) .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-) .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 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, alkenyloxy and alkynyloxy 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.
  • alkoxy, alkenyloxy, and alkynyloxy groups can be optionally substituted by, for example, halogens, oxo, -NR d R 6 , -CONR d R 6 , -NR d COR 6 , carboxy, - hydroxyl, nitro, nitroso, C 1-6 alkyl, C 2 -6 alkenyl, C 2 . 6 alkynyl, -N(R h )CONR 1 R j , S(0) o .
  • 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
  • R 3 -R j are each independently H, C 1 4 alkyl, C 2 . 4 alkenyl or C 2 . 4 alkynyl.
  • 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
  • the 6-18 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.
  • a bond represented by a combination of a solid and dashed line, ie. " ' may be either a single or double bond.
  • R d , R 6 , R f and R 8 are each independently selected from H, d. 1o alkyl, C 2 . 10 alkenyl, C 2 - 10 alkynyl, C 6 . 12 aryl, and C 7-12 aralkyl, or R f and R g 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 isopropyloxycarbonyl.
  • 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 a 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 a composition of the invention.
  • 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.
  • 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 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), Trilvesr® (AZT/3TC/abacavir or zidovudine/lamivudine/abacavir combination), a
  • 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 (Isentress®, 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 (Isentress®, 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).
  • MPC-9055 Vivecon
  • PA-457 Bevirimat
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a zinc finger inhibitor and is azodicarbonamide (ADA). In another embodiment, 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'-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.
  • at least one other antiviral agent chosen from 2',3'-dideoxyadenosine, 3'-deoxythymidine, 2',3'-dideoxy-2',3'-didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir and ganciclovir; interferons such as al
  • 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, mibefradil, 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.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations 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.
  • kits for use in administering a combinations 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.
  • 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.
  • Com ounds accordin to the resent invention include:
  • the organic layer is washed successively with water (500 mL), a saturated solution of sodium carbonate (3 x 250 mL), water (500 mL) and brine (3 x 200 mL), dried over sodium sulfate and concentrated in vacuo.
  • the gummy yellow solid is triturated with methanol and filtered off to yield the title compound 4 (21.41 g, 94.8%) as a colorless solid.
  • Step 1 To a solution of compound 6 in DCM is added a solution of oxalyl chloride (2 eq.) and few drops of DMF. The reaction mixture is stirred for 1 to 2 hours at room temperature and evaporated in vacuo to yield the acid chloride used as crude.
  • Step 2 To a mixture of acid chloride in DCM is added the amine R 2 NHR 3 (1.1 to 3 eq.) and a base such as triethylamine or diisopropylamine (1.1 to 3 eq.). The reaction is stirred at room temperature until completion (microwaves at 150°C for 20 minutes in DCE is used for amines with low reactivity). The crude is purified by flash chromatography on silica gel to yield the amide 7.
  • a base such as triethylamine or diisopropylamine
  • Step 3 The amide 7 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° C to give the alcohol 8.
  • 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° C to give the alcohol 8.
  • Step 4 To the alcohol 8 in pyridine is added a cyclic anhydride and DMAP (3 to 10 equivalents). The reaction mixture is heated at temperature ranging from 90 to 140° C until completion to yield after standard acidic aqueous work up and purification by flash chromatography on silica gel the acid 9.
  • Step 1 To a solution of compound 6 (500 mg, 0.975 mmol) in 5 mL of anhydrous DCM is added a solution of oxalyl chloride (2M in DCM, 0.975 mL, 1.95 mmol) and 2 drops of DMF. The reaction mixture is stirred for 1 hour at room temperature and evaporated in vacuo to yield 3/3-acetoxy-21 -oxolup-18-en-28-oic acid chloride as an orange solid used as crude material.
  • oxalyl chloride 2M in DCM, 0.975 mL, 1.95 mmol
  • Step 2 To a solution of previously prepared 3/?-acetoxy-21 -oxolup-18-en-28-oic acid chloride in 5 mL of anhydrous DCM is added triethylamine (150 ⁇ l_, 1.073 mmol) and benzylamine (112 ⁇ l_, 1.024 mmol). The reaction mixture is stirred at room temperature until completion, diluted with DCM, washed with HCl 1 N and dried over sodium sulfate.
  • Step 3 To a solution of 3/?-acetoxy-21 -oxolup-18-en-28-oic acid N-benzylamide (574 mg, 0.953 mmol) in a 4:1 mixture of dioxane / water (25 ml.) is added an aqueous solution of 4N NaOH (2.38 mL). The mixture is stirred for 4 hours at 50°C, then HCl 4N (2.38 mL) is added and dioxane is evaporated in vacuo. The remaining aqueous solution is extracted with ethyl acetate (3x) and the combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated.
  • the crude material is purified by flash chromatography (Biotage) on silica gel (ethyl acetate / hexanes 0 to 80%) to isolate 3/?-hydroxy-21 -oxolup-18-en-28-oic acid N- benzylamide 8-1 (307 mg, 58%) as a white solid.
  • Step 4 To a solution of 3/?-hydroxy-21 -oxolup-18-en-28-oic acid N-benzylamide (110 mg, 0.196 mmol) in 3 mL of pyridine is added 2,2-dimethyl succinic anhydride (75.3 mg, 0.588 mmol) and DMAP (28.6 mg, 0.235 mmol). The reaction mixture is stirred overnight under reflux. Then 75.3 mg of 2,2-dimethyl succinic anhydride is added twice every 3 hours to complete the reaction. The solvent is evaporated in vacuo and the residue is taken up with ethyl acetate (50 mL) and HCl 1 N (10 mL).
  • Step 1 Selenium dioxide (4 to 6 eq.) is added to a solution of compound 7 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 1 1.
  • Step 2 The ester 1 1 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°C to give the alcohol 12.
  • 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°C to give the alcohol 12.
  • Step 3 To the alcohol 12 in pyridine is added a cyclic anhydride (5 to 10 eq.) and DMAP (1.1 to 2 eq.). The reaction mixture is heated at temperature ranging from 90 to 140°C until completion to yield after standard acidic aqueous work up and purification by flash chromatography on silica gel the acid 10.
  • Tables 1 , 2 and 3 of compounds illustrate some of the compounds of the present invention which may be synthesized using the procedures described in scheme 2.
  • Retention time (t R ) for each compound are measured using the standard analytical HPLC or LC/MS methods described above.
  • 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 * 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°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.
  • the IC 50 of the compounds tested in accordance with the HIV replication activity assay MT-2 (HlVmu) are represented in Table 4 (without HS) and Table 5 (with 30% HS)
  • the average IC 50 is provided.
  • 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 °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-IiIiB at a MOI of 5.0 for 3 hours at 37 °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 °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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (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 le descriptif, ainsi que des sels et des solvates de ceux-ci pharmaceutiquement acceptables. Ces composés présentent une activité anti-VIH importante. Ainsi, 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 de celui-ci pharmaceutiquement acceptable, au patient nécessitant un tel traitement.
EP08867782A 2008-01-03 2008-12-23 Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation Withdrawn EP2240504A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US1876608P 2008-01-03 2008-01-03
US3968008P 2008-03-26 2008-03-26
PCT/CA2008/002290 WO2009082818A1 (fr) 2008-01-03 2008-12-23 Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation

Publications (1)

Publication Number Publication Date
EP2240504A1 true EP2240504A1 (fr) 2010-10-20

Family

ID=40823728

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08867782A Withdrawn EP2240504A1 (fr) 2008-01-03 2008-12-23 Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation

Country Status (7)

Country Link
EP (1) EP2240504A1 (fr)
JP (1) JP2011508747A (fr)
CN (1) CN101977924A (fr)
AU (1) AU2008342536A1 (fr)
CA (1) CA2711420A1 (fr)
MX (1) MX2010007374A (fr)
WO (1) WO2009082818A1 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3085377A1 (fr) * 2008-01-25 2016-10-26 Chimerix, Inc. Méthodes de traitement d'infections virales
US9067966B2 (en) 2009-07-14 2015-06-30 Hetero Research Foundation, Hetero Drugs Ltd. Lupeol-type triterpene derivatives as antivirals
HUE026849T2 (en) 2010-01-27 2016-08-29 Viiv Healthcare Company Corp Service Company Therapeutic combination containing dolutegravir, abacavir and lamivudine
SG182769A1 (en) * 2010-02-11 2012-09-27 Glaxosmithkline Llc Derivatives of betulin
EP3216789A1 (fr) 2010-02-12 2017-09-13 Chimerix, Inc. Procédés de traitement d'une infection virale
WO2011139709A2 (fr) 2010-04-26 2011-11-10 Chimerix, Inc. Méthodes de traitement d'infections rétrovirales et régimes posologiques associés
WO2013020245A1 (fr) * 2011-08-08 2013-02-14 Glaxosmithkline Llc Dérivés carbonyles de bétuline
CN104844679B (zh) * 2011-12-16 2017-03-01 葛兰素史克有限责任公司 白桦脂醇的衍生物
JO3387B1 (ar) * 2011-12-16 2019-03-13 Glaxosmithkline Llc مشتقات بيتولين
CN103242413B (zh) * 2012-02-08 2015-08-26 江西青峰药业有限公司 Lupane三萜系衍生物及其药学用途
BR112015013695A2 (pt) * 2012-12-14 2017-07-11 Glaxosmithkline Llc composição farmacêutica, e, métodos para tratamento e para prevenção de uma infecção por hiv
US9637516B2 (en) 2012-12-31 2017-05-02 Hetero Research Foundation Betulinic acid proline derivatives as HIV inhibitors
US20170129916A1 (en) 2014-06-26 2017-05-11 Hetero Research Foundation Novel betulinic proline imidazole derivatives as hiv inhibitors
AU2015323321A1 (en) 2014-09-26 2017-04-13 Glaxosmithkline Intellectual Property (No.2) Limited Long acting pharmaceutical compositions
MA40886B1 (fr) 2015-02-09 2020-03-31 Hetero Research Foundation Nouveau triterpénone en c-3 avec des dérivés d'amide inverse en c-28 en tant qu'inhibiteurs du vih
WO2016147099A2 (fr) * 2015-03-16 2016-09-22 Hetero Research Foundation Nouveaux triterpénone c-3 avec des dérivés amide c-28 servant d'inhibiteurs de vih
WO2017115329A1 (fr) * 2015-12-30 2017-07-06 Hetero Research Foundation Nouveaux dérivés de triterpénone en c-3 en tant qu'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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009082818A1 *

Also Published As

Publication number Publication date
CA2711420A1 (fr) 2009-07-09
JP2011508747A (ja) 2011-03-17
WO2009082818A1 (fr) 2009-07-09
AU2008342536A1 (en) 2009-07-09
MX2010007374A (es) 2010-10-05
CN101977924A (zh) 2011-02-16
WO2009082818A8 (fr) 2009-09-03

Similar Documents

Publication Publication Date Title
EP2240504A1 (fr) Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation
US20110077251A1 (en) Novel 17 beta lupane derivatives
EP2250185A1 (fr) Nouveaux dérivés de lupane
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
CA2634499A1 (fr) Hydroxydihydropyridopy razine-1,8-diones et procedes d'inhibition de l'integrase du vih
US20060205697A1 (en) Novel betulin derivatives, preparation thereof and use thereof
US11464790B2 (en) Triterpenoids with HIV maturation inhibitory activity
US8431556B2 (en) C-21-keto lupane derivatives preparation and use thereof
US11084845B2 (en) C-3 and C-17 modified triterpenoids as HIV-1 inhibitors
CA3101643C (fr) Derives d'amine triterpenique
JP2014505103A (ja) ネコ免疫不全ウイルスの治療に使用するための大環状インテグラーゼ阻害剤
US9914747B2 (en) Extended betulinic acid analogs

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100803

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20120703