WO2004016271A1 - Pyrimidones en tant qu'agents antiviraux - Google Patents

Pyrimidones en tant qu'agents antiviraux Download PDF

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Publication number
WO2004016271A1
WO2004016271A1 PCT/EP2003/009039 EP0309039W WO2004016271A1 WO 2004016271 A1 WO2004016271 A1 WO 2004016271A1 EP 0309039 W EP0309039 W EP 0309039W WO 2004016271 A1 WO2004016271 A1 WO 2004016271A1
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WO
WIPO (PCT)
Prior art keywords
pyrimidine
trifluoromethyl
vinyl
ethenyl
phenyl
Prior art date
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PCT/EP2003/009039
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English (en)
Inventor
Andrea Missio
Thomas Herget
Andrea Aschenbrenner
Bernd Kramer
Johann Leban
Kristina Wolf
Original Assignee
Axxima Pharmaceuticals Ag
4Sc Ag
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
Priority claimed from EP02018357A external-priority patent/EP1389461A1/fr
Application filed by Axxima Pharmaceuticals Ag, 4Sc Ag filed Critical Axxima Pharmaceuticals Ag
Priority to AU2003258612A priority Critical patent/AU2003258612A1/en
Publication of WO2004016271A1 publication Critical patent/WO2004016271A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to vinylpyrimidine-2-one derivatives, the use of the vinylpyrimidine-2-one derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases including opportunistic infections, cell proliferation disorders, cardiovascular disorders, immunological diseases, inflammatory diseases, neuroimmunological diseases, autoimmune diseases, as well as compositions containing at least one vinylpyrimidine-2-one derivative and/or pharmaceutically acceptable salt thereof, and methods for preventing and/or treating such diseases. Furthermore, a process for preparing said vinylpyrimidine-2-one derivatives is disclosed using the corresponding diketones as starting materials.
  • HCMV Human Cytomegalovirus
  • HCMV infection is associated with high mortality rates (80-90% for untreated HCMV pneumonia).
  • Current approaches to develop therapeutics against Cytomegalovirus (CMV) have focused on antiviral agents per se; for example viral polymerase inhibitors. In fact, high mortality rates have been dramatically reduced by new antiviral agents.
  • Current CMV therapeutics possess severe drawbacks, however. For example, Fomivirsen (Vitravene, formerly ISIS 2922) is typically administered by injection directly into the eye every 2 or 4 weeks.
  • Ganciclovir is available for intravenous (Cytovene) or oral administration, and as an implant in the case of retinitis; unfortunately, toxic complications including leukopenia and thrombocytopenia frequently develop.
  • Foscarnet (Foscavir; phosphonoformic acid), another antiviral agent, exhibits considerable renal toxicities and is only available in intravenous form (which is also true for Cidofovir (Vistide), another CMV therapeutic).
  • CMV replication resumes soon after Ganciclovir and Foscarnet treatment is halted.
  • Ganciclovir- and Foscarnet-resistant strains of CMV are emerging.
  • Cytokines serve as messengers that bind to receptors on the surface of a target cell. As a result of the binding, the receptors activate a cascade of downstream signaling molecules, thereby transmitting the message from the exterior of the cell to its nucleus. Signal transduction to the nucleus modulates specific gene expression (i.e., transcription and translation), which results in either the upregulation or downregulation of specific proteins that carry out a particular biological function.
  • Viral infection disrupts normal signal transduction, which leads to cellular malfunctioning resulting in a disease state.
  • interference of HCMV with relevant human primary cells is necessary for the virus to create an environment that allows it to grow and replicate, and in turn cause disease in the infected individual.
  • Current research efforts have failed to elucidate all the specific intracellular signal pathways affected by HCMV infection, however. Discovery of the signal transduction pathways and specific intracellular signal transduction molecules affected by CMV infection would represent a tremendous advance in the understanding of the induction and progression of CMV infection processes and provide new avenues for the development of a novel class of effective therapeutics for the treatment of CMV.
  • the present invention is also directed to novel compounds of the general formula (I) and pharmaceutically acceptable salts thereof:
  • R 1 represents hydrogen, d-Ce-alkyl, C-i-Ce-alkenyl, C-i-Ce-alkinyl, C 3 -C 8 - cycloalkyl, C 5 -C 15 -aryl, heteroaryl, -COOR 7 or -SO 2 R 7 ;
  • R 2 represents hydrogen, C ⁇ -C 6 -alkyl, Ci-Cr-alkenyl, Ci-C ⁇ -alkinyl, C 3 -C 8 - cycloalkyl, C ⁇ -C ⁇ aryl, heteroaryl, -COOR 7 , -SO 2 R 7 ; -C(R 10 ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 10' )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 10' ) 2 , -CH 2 -CR 10 (R 10' )R 10" ,
  • R )10 , D R10' , D R1 1 0 U " represent independently of each other hydrogen, F, Cl, Br or
  • R 3 , R 4 , R 5 and R 7 represent independently of each other hydrogen, C-
  • R 6 represents Ci-C ⁇ -alkyl, Ci-C ⁇ -alkenyl, Ci-Cr-alkinyl, C 3 -C 8 -cycloalkyl, C 5 - Ci 5 -aryl or heteroaryl;
  • C 3 -C 8 -cycloalkyl, Cs-Cis-aryl, and heteroaryl group can optionally be substituted by one or more substituents R 8 .
  • R 8 represents independently of each other hydrogen, -COOR 9 , -CONHR 9 , -F, -Cl, -Br, -1, -CO-R 9 , -SO 2 NHR 9 , -SO 2 N(R 9 ) 2 , -NR 9 -CO-(C ⁇ -C 6 )-haloalkyl, -NO 2 , - Ci-Ce-aminoalkyl, -OH, -SH, C ⁇ -Cer-alkoxy, C-
  • R 9 represents hydrogen, Ci-Ce-hydroxyalkyl, Ci-C ⁇ -aminoalkyl, Cs-Cis-aryl or heteroaryl.
  • a heteroaryl group represents a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, or S.
  • This heterocyclic group can be fused to another ring.
  • this group can be selected from an oxazole-2- yl, oxazole-4-yl, oxazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, isothiazole- 3-yl, isothiazole-4-yl, isothiazole-5-yl, 1 ,2,4-oxadiazole-3-yl, 1 ,2,4-oxadiazole-5-yl, 1 ,2,4-thiadiazole-3-yl, 1 ,2,4-thiadiazole-5-yl, 1 ,2,5-oxadiazole-3-yl, 1 ,2,5- oxadiazole-4-yl, 1 ,2,5-thiadiazole-3-y
  • R 1 represents hydrogen, C -C ⁇ -alkyl, Ci-Ce-alkenyl, Ci-Cg-alkinyl, C 3 -C 8 - cycloalkyl, C 5 -C 15 -aryl, heteroaryl, -COOR 7 or -SO 2 R 7 ;
  • R 2 represents hydrogen, Ci-C ⁇ -alkyl, C -C 6 -alkenyl, d-C ⁇ -alkinyl, C 3 -C 8 - cycloalkyl, heteroaryl, -COOR 7 or -SO 2 R 7 ;
  • R 3 , R 4 , R 5 and R 7 represent independently of each other hydrogen, Ci-Ce-alkyl, C Ce-alkenyl, Ci-Ce-alkinyl, C 3 -C 8 -cycloalkyl, C 5 -C ⁇ 5 -aryl or heteroaryl;
  • R 6 represents C 5 -C ⁇ 5 -aryl or heteroaryl
  • the C 3 -C 8 -cycloalkyl, C 5 -Ci 5 -aryl, and heteroaryl group can optionally be substituted by one or more substituents R 8 .
  • R 8 represents independently of each other hydrogen, -COOR 9 , -CONHR 9 , -F, -Cl, -Br, -I, -CO-R 9 , -SO 2 NHR 9 , -SO 2 N(R 9 ) 2 , -NR 9 -CO-(C ⁇ -C 6 )-haloalkyl, -NO 2 , - NR 9 -SO 2 -(d-C 6 )-haloalkyl, -CN, d-Cs-alkyl, Ci-Ce-aminoalkyl, -OH, -SH, d-C ⁇ -alkoxy, d-Ce-alkylthio, d-C 6 -haloalkyloxy, C 5 -Ci 5 -aryl or heteroaryl Ci-Ce-alkenyloxy Ci - C 6 alkinyloxy, OR 9 .
  • R 9 represents hydrogen, Ci-C ⁇ -hydroxyalkyl, C ⁇ -C 6 -alkyl, Ci-C ⁇ -aminoalkyl, Cs-Cis-aryl or heteroaryl.
  • a heteroaryl group represents a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, or S.
  • This heterocyclic group can be fused to another ring.
  • this group can be selected from an oxazole-2- yl, oxazole-4-yl, oxazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, isothiazole- 3-yl, isothiazole-4-yl, isothiazole-5-yl, 1 ,2,4-oxadiazole-3-yl, 1 ,2,4-oxadiazole-5-yl, 1 ,2,4-thiadiazole-3-yl, 1 ,2,4-thiadiazole-5-yl, 1 ,2,5-oxadiazole-3-yl, 1 ,2,5- oxadiazole-4-yl, 1 ,2,5-thiadiazole-3-y
  • R 1 represents hydrogen, Ci-Ce-alkyl, d-C 6 -alkenyl, Ci-Cs-alkinyl, C 3 -C 8 - cycloalkyl, C 5 -C 15 -aryl, heteroaryl, -COOR 7 or -SO 2 R 7 ;
  • R 2 represents -C(R 10 ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 10' )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 0' ) 2 , -CH 2 -CR 10 (R 10' )R 10" , -C 3 (R 10 ) 7 or -C 2 H 4 -C(R 10 ) 3 ;
  • R 10 ,R 10' ,R 10" represent independently of each other H, F, Cl, Br or I;
  • R 3 , R 4 , R 5 and R 7 represent independently of each other hydrogen, C ⁇ -C 6 -alkyl, C-i- C ⁇ -alkenyl, Ci-Cs-alkinyl, C 3 -C 8 -cycloalkyl, C 5 -C ⁇ 5 -aryl or heteroaryl;
  • R 6 represents C ⁇ -C 6 -alkyl, Ci-C ⁇ -alkenyl, Ci-Ce-alkinyl, C 3 -C 8 -cycloalkyl, C 5 - Ci 5 -aryl or heteroaryl;
  • Ci-Ce-alkyl, C 3 -C 8 -cycloalkyl, C 5 -Ci 5 -aryl, and heteroaryl group can optionally be substituted by one or more substituents R 8 .
  • R 8 represents independently of each other hydrogen, -COOR 9 , -CONHR 9 , -F, -Cl, -Br, -I, -CO-R 9 , -SO 2 NHR 9 , -SO 2 N(R 9 ) 2 , -NR 9 -CO-(d-C e )-haloalkyl, -NO 2 , - NR 9 -SO 2 -(C ⁇ -C 6 )-haloalkyl, -CN, d-Ce-alkyl, Ci-Ce-aminoalkyl, -OH, -SH, C ⁇ -C 6 -alkoxy, Ci-C ⁇ -alkylthio, d-Cs-hydroxyalkylamino, Ci-Ce-haloalkyloxy, Cs-Cis-aryl, d-Ce-alkenyloxy, Ci - C 6 alkinyloxy, OR 9 , or heteroaryl;
  • R 9 represents hydrogen, Ci-Ce-hydroxyalkyl, Ci-Ce-alkyl, Ci-Ce-aminoalkyl, Cs-Cis-aryl or heteroaryl.
  • a heteroaryl group represents a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, or S.
  • This heterocyclic group can be fused to another ring.
  • this group can be selected from an oxazole-2- yl, oxazole-4-yl, oxazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, isothiazole- 3-yl, isothiazole-4-yl, isothiazole-5-yl, 1 ,2,4-oxadiazole-3-yl, 1 ,2,4-oxadiazole-5-yl, 1 ,2,4-thiadiazole-3-yl, 1 ,2,4-thiadiazole-5-yl, 1 ,2,5-oxadiazole-3-yl, 1 ,2,5- oxadiazole-4-yl, 1 ,2,5-thiadiazole-3-y
  • R 1 represents hydrogen, Ci-Ce-alkyl, Ci-Ce-alkenyl, Ci-Ce-alkinyl, C 3 -Cs- cycloalkyl, Cs-Cis-aryl, heteroaryl, -COOR 7 or-SO 2 R 7 ;
  • R 2 represents hydrogen, Ci-Ce-alkyl, Ci-Ce-alkenyl, Ci-Ce-alkinyl, C 3 -Cs- cycloalkyl, Cs-Cis-aryl, heteroaryl, -COOR 7 , -SO 2 R 7 , -C(R 10 ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 10' )R 10" , -C 2 (R 10 )s, -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 10' ) 2 , -CH 2 -CR 10 (R 10' )R 10"
  • R ,R ,R represent independently of each other hydrogen, F, Cl, Br or I;
  • R 3 , R 4 , R 5 and R 7 represent independently of each other hydrogen, Ci-Ce-alkyl, Ci- Ce-alkenyl, Ci-Ce-alkinyl, C 3 -C 8 -cycloalkyI, C 5 -C 5 -aryl or heteroaryl;
  • R 6 represents Ci-Ce-alkyl, Ci-Ce-alkenyl, Ci-Ce-alkinyl, C 3 -C 8 -cycloalkyl, Cs- Cis-aryl or heteroaryl;
  • Ci-C ⁇ -alkyl, C 3 -C 8 -cycloalkyl, C 5 -C ⁇ s-aryl, and heteroaryl group can optionally be substituted by one or more substituents R 8 .
  • R 8 represents independently of each other hydrogen, -COOR 9 , -CONHR 9 , -F, -Cl, -Br, -1, -CO-R 9 , -SO 2 NHR 9 , -SO 2 N(R 9 ) 2 , -NR 9 -CO-(d-C 6 )-haloalkyl, -NO 2 , - NR 9 -SO 2 -(C ⁇ -C 6 )-haloalkyl, -CN, d-Ce-alkyl, Ci-Ce-aminoalkyl, -OH, -SH, Ci-C ⁇ -alkoxy, Ci-Ce-alkylthio, C ⁇ -C 6 -hydroxyaIkylamino, Ci-Ce-haloalkyloxy, d-Ce-alkenyloxy Ci - C 6 alkinyloxy, -OR 9 , Cs-Cis-aryl or heteroaryl;
  • R 9 represents hydrogen, C ⁇ -C 6 -hydroxyalkyl, Ci-C ⁇ - alkyl, Ci-Ce-aminoalkyl, C 5 -Ci 5 -aryl or heteroaryl.
  • a heteroaryl group represents a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, or S.
  • This heterocyclic group can be fused to another ring.
  • this group can be selected from an oxazole-2- yl, oxazole-4-yl, oxazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, isothiazole- 3-yl, isothiazole-4-yl, isothiazole-5-yl, 1 ,2,4-oxadiazole-3-yl, 1 ,2,4-oxadiazole-5-yl, 1 ,2,4-thiadiazole-3-yl, 1 ,2,4-thiadiazole-5-yl, 1 ,2,5-oxadiazole-3-yi, 1 ,2,5- oxadiazole-4-yl, 1,2,5-thiadiazole-3-yI,
  • R 8 and R 9 have the meanings as defined above; and R 8 , R 8 ' and R 8 represent independently of each other hydrogen, -COOR 9 , -CONHR 9 , -F, -Cl, -Br, -I, -NO 2 , -CO-R 9 , -SO 2 NHR 9 , -SO 2 N(R 9 ) 2 , -NR 9 -CO-(d-C 6 )-haloalkyl, -OH, - SH, -CN, -NR 9 -SO 2 -(C ⁇ -C 6 )-haloalkyl, Ci-Ce-alkyl, Ci-Ce-aminoalkyl, d-Ce- alkoxy, C ⁇ -C 6 -alkylthio, Ci-C ⁇ -hydroxyalkylamino, Ci-Ce-haloalkyloxy, Cs-Cis- aryl or heteroaryl
  • the present invention provides also compounds of the following general formula (la) and pharmaceutically acceptable salts thereof,
  • R 1 represents hydrogen, Ci-Ce-alkyl, Ci-Ce-alkenyl, Ci-Ce-alkinyl, C 3 -C 8 - cycloalkyl, Cs-Cis-aryl, heteroaryl, -COOR 7 or -SO 2 R 7 ;
  • R 2 represents hydrogen, Ci-Ce-alkyl, Ci-Ce-alkenyl, Ci-Ce-alkinyl, C 3 -Cs- cycloalkyl, Cs-Cis-aryl, heteroaryl, -COOR 7 , -SO 2 R 7 , -C(R 10 ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 0' )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 10' ) 2 , -CH 2 -CR 10 (R 10' )R 10" , -C 3 (R 10 )7 ⁇ r -C 2 H 4 -C(R 10 ) 3 ;
  • R 10 ,R 10 ,R 10 represents independently of each other hydrogen F, Cl, Br or I;
  • R 3 , R 4 , R 5 and R 7 represent independently of each other hydrogen, Ci-C ⁇ -alkyl, Ci- Ce-alkenyl, Ci-Ce-alkinyl, C 3 -C 8 -cycloalkyl, C 5 -C ⁇ 5 -aryl or heteroaryl;
  • R 6 represents Ci-Ce-alkyl, C ⁇ -C 6 -alkenyl, C -C ⁇ -alkinyl, C 3 -Cs-cycloalkyl, C 5 - Ci 5 -ar l or heteroaryl;
  • R 5 or R 6 are pyridine or phenyl and R 2 is methyl; and 4-(2,2-Diphenylethenyl)-6-methyl-1r7-pyrimdine-2-one are excluded, for the use as pharmaceutically active agent.
  • Ci-Ce-alkyl, C 3 -Cs-cycloalkyl, C 5 -C ⁇ 5 -aryl, and heteroaryl group can optionally be substituted by one or more substituents R 8 .
  • R 8 represents independently of each other hydrogen, -COOR 9 , -CONHR 9 , -F, -Cl, -Br, -I, -CO-R 9 , -SO 2 NHR 9 , -SO 2 N(R 9 ) 2 , -NR 9 -CO-(d-C 6 )-haloalkyl, -NO 2 , - NR 9 -SO 2 -(C ⁇ -C 6 )-haloalkyl, -CN, Ci-Ce-alkyl, d-Ce-aminoalkyl, -OH, -SH, Ci-Q—alkoxy, Ci-Ce-alkylthio, C ⁇ -C 6 -hydroxyalkylamino, Ci-Ce-haloalkyloxy, C -C ⁇ -alkenyloxy Ci - C 6 alkinyloxy, -OR 9 , C5-C ⁇ 5 -aryl or heteroaryl;
  • R 9 represents hydrogen, C ⁇ -C 6 -hydroxyalkyl, C ⁇ -C 6 -alkyl, Ci-Ce-aminoalkyl, Cs-Cis-aryl or heteroaryl.
  • a heteroaryl group represents a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, or S.
  • This heterocyclic group can be fused to another ring.
  • this group can be selected from an oxazole-2- yl, oxazole-4-yl, oxazole-5-yl, thiazoIe-2-yl, thiazole-4-yl, thiazole-5-yl, isothiazole- 3-yl, isothiazole-4-yl, isothiazole-5-yl, 1 ,2,4-oxadiazole-3-yI, 1 ,2,4-oxadiazole-5-yl, 1 ,2,4-thiadiazole-3-yl, 1 ,2,4-thiadiazole-5-yl, 1 ,2,5-oxadiazole-3-yl, 1 ,2,5- oxadiazole-4-yl, 1 ,2,5-thiadiazole-3-
  • R 1 is H
  • R 2 is CF 3
  • R ⁇ is furyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 2 is CF 2 CI
  • R 6 is furyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 2 is methyl
  • R 6 is furyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 4 is methyl
  • R 2 is CF 3
  • R 6 is phenyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 2 is CF 2 CI
  • R 4 is methyl
  • R 6 is phenyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H, R 2 is methyl, R 4 is methyl and R 6 is phenyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H, R 2 is CF 3 and R 6 is phenyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 2 is CF 2 CI
  • R 6 is phenyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 2 is methyl
  • R 6 is phenyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 2 is CF 3
  • R 6 is naphthyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 2 is CF 2 CI
  • R 6 is naphthyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • R 1 is H
  • R 2 is methyl
  • R 6 is naphthyl, which can optionally be substituted by one or more substituents R 8 , wherein R 8 is as defined above.
  • the above-mentioned preferred embodiments refer both to the compounds per se as well as to the use of these compounds for the preparation of a pharmaceutical composition for the treatment of diseases.
  • the present invention provides methods for preparing the vinylpyrimidine-2-one of the general formula (I) and the vinylpyrimidine-2-one of the general formula (la). This step is described for example in D. M. Brown and G. A. R. Kon, Journal of the Chemical Society 1948, 2147-54.
  • One possibility for the synthesis of compounds of formula (I) comprises the step of reacting a pyrimidone of formula (II) with a carbonyl compound of formula (III) (R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as above defined for formula I). .
  • One possibility for the synthesis of compounds of formula (la) comprises the step of reacting a pyrimidone of formula (lla) with a carbonyl compound of formula (III) (R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as above defined for formula I).
  • Fo ⁇ nula lla Formula la One method for preparing pyrimidones of formula (II) or formula (lla) comprises the step of reacting a 1 ,3-diketone of formula (IV) with a urea of formula (V) (R 1 , R 2 , R 3 , and R 4 are as above defined for formula I).
  • pyrimidones of formula (II) or formula (Ma) can be separated by chromatography, for example by column chromarography on silica gel [A. Katoh et al., Chem. Pharm. Bull. 1994, 42(7), 1514-1517; C. Kashima, A. Katoh, J. Heterocyclic Chem. 1980, 17, 913-915].
  • vinylpyrimidine-2-one derivatives of the general formula (I) or vinylpyrimidine-2-one derivatives of the general formula (la) as new pharmaceutically active agents, especially for the preparation of a pharmaceutical composition for the treatment of diseases which are cured or relieved by the inhibition of kinases and/or phosphatases.
  • the compounds of the general formula (I) or compounds of the general formula (la) were surprisingly identified as potent inhibitors for human and viral kinases, especially of herpesviral kinases such as UL97.
  • a method for preventing and/or treating diseases which are cured or relieved by the inhibition of kinases and/or phosphatases in a mammal, including a human, which method comprises administering to the mammal an amount of at least one compound of general formula (I) or compounds of the general formula (la) and/or pharmaceutically acceptable salts thereof, effective to prevent and/or treat said diseases which are cured or relieved by the inhibition of kinases and/or phosphatases.
  • a preferred embodiment of said method involves the herpesviral kinase UL97 as a target for preventing and/or treating herpesviral infections and diseases.
  • Another method is directed to the prophylaxis and/or treatment of infectious diseases, including opportunistic infections in a mammal, including a human.
  • Said method comprises administering to the mammal an amount of at least one compound of the general formula (I) and/or at least one compound of the general formula (la) and/or pharmaceutically acceptable salts thereof, effective to prevent and/or treat said infectious disease and/or opportunistic infection.
  • the infectious disease can be selected from the group comprising AIDS, Alveolar Hydatid Disease (AHD, Echinococcosis), Amebiasis (Entamoeba histolytica Infection), Angiostrongylus infection, Anisakiasis, Anthrax, Babesiosis (Babesia Infection), Balantidium Infection (Balantidiasis), Baylisascaris Infection (Raccoon Roundworm), Bilharzia (Schistosomiasis), Blastocystis hominis Infection (Blastomycosis), Boreliosis, Botulism, Brainerd Diarrhea, Brucellosis, BSE (Bovine Spongiform Encephalopathy), Candidiasis, Capillariasis (Capillaria Infection), CFS (Chronic Fatigue Syndrome), Chagas Disease (American Trypanosomiasis), Chickenpox (Varicella-Zoster virus), Chlamydia pneumoniae
  • Cryptosporidiosis Culex mosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM), Cyclosporiasis (Cyclospora Infection), Cysticercosis (Neurocysticercosis), Cytomegalovirus Infection (CMV), Dengue / Dengue Fever, Dipylidium Infection (Dog and Cat Flea Tapeworm), Ebola Virus Hemorrhagic Fever, Echinococcosis (Alveolar Hydatid Disease), Encephalitis, Entomoeba coli Infection, Entomoeba dispar Infection, Entamoeba hartmanni Infection, Entamoeba histolytica Infection (Amebiasis), Entamoeba polecki Infection, Enterobiasis (Pinworm Infection), Enterovirus Infection (Non-Polio), Epstein-Barr Virus Infection, Escherichi
  • a method for preventing and/or treating herpesviral infections and/or associated diseases in a mammal, including a human comprises the administration of a pharmaceutically effective amount of at least one compound of general formula (I) and/or at least one compound of the general formula (la) to said mammal, wherein said compound inhibits at least partially the activity of the herpesviral kinase UL97.
  • vinylpyrimidine-2-one derivatives of the general formula (I) or vinylpyrimidine-2-one derivatives of the general formula (la) can be used for prophylaxis and/or treatment of infectious diseases, including opportunistic infections, especially of herpes and diseases caused by herpes viruses.
  • Herpesviruses may be selected from the group comprising ⁇ -herpesviruses (Simplexvirus, Varicellavirus), ⁇ -herpesviruses (Cytomegalovirus also known as human herpesvirus 5, Muromegalovirus, Roseolovirus), or ⁇ -herpesviruses
  • ⁇ -herpesviruses are Herpes simplex virus type 1 (human herpesvirus 1 ), Herpes simplex virus type 2 (human herpesvirus 2), Varicella Zoster virus (human herpesvirus 3).
  • ⁇ - herpesviruses are Epstein-Barr virus (human herpesvirus 4) or human herpesvirus type 8 (HHV8). More preferably, the herpesvirus is Herpes simplex virus type 1 , or Varicella Zoster virus, or Epstein-Barr virus (EBV), or human cytomegalovirus
  • the herpesvirus represents the ⁇ -herpesviruses Herpes simplex virus type 1 , or Varicella Zoster virus, or the ⁇ -herpesviruses
  • Epstein-Barr virus or Human Herpes virus type 8.
  • the herpesvirus family comprises the human herpesviruses 1 to 8 and different herpes viruses for various animal species as shown below in Table 1 : Table 1 : Members of the herpesvirus family
  • herpesvirus 1 bovine herpesvirus 2 (herpes simplex virus 1 ) human herpesvirus 2 cercopithecine herpes ⁇
  • herpes simplex virus 2 virus 1 virus 1
  • herpes B virus varicella virus human herpesvirus 3 pseudorabiesvirus (Varicella Zoster virus) bovine herpesvirus 1 equine-abortion virus ⁇ -herpesvirus cytomegalovirus human herpesvirus 5 (HCMV) muromegalo virus murine herpesvirus 1
  • Roseolovirus human herpesvirus 6 aotine herpesvirus 1 , 3 human herpesvirus 7
  • Rhadinovirus human herpesvirus 8 ateline herpesvirus 2 saimirine herpesvirus 1
  • the herpes virus is selected from the group comprising herpes simplex viruses, varicello viruses, cytomegalo viruses, muromegalo viruses, roseolo viruses, lymphocrypto viruses, and rhadino viruses.
  • herpes simplex viruses varicello viruses
  • cytomegalo viruses cytomegalo viruses
  • muromegalo viruses cytomegalo viruses
  • roseolo viruses roseolo viruses
  • lymphocrypto viruses rhadino viruses.
  • Herpes simplex virus type 1 Herpes simplex virus is a highly adapted human pathogen with an extremely rapid lytic replication cycle, and yet with the ability to invade sensory neurons where highly restricted gene expression occurs with the absence of cytopathology.
  • Such latent infections are subject to reactivation whereby infectious virus can be recovered in peripheral tissue enervated by the latently infected neurons following a specific physiological stress.
  • a major factor in these "switches” from lytic to latent infection and back involves the interaction between viral promoters, the viral genome, and cellular transcriptional machinery.
  • Herpes simplex virus types 1 and 2 are generally associated with mucocutaneous facial infection (herpes labialis), genital infection (herpes genitalis), ophthalmic infection (herpes keratitis) and neonatal infection. The lesions are generally self-healing, but the infection remains, with the virus establishing latent infection in the neurons.
  • HSV-1 In immunocompromised hosts, recurrence of HSV-1 may cause progressive fulminant lesions that are refractory to current antiviral therapy. Neonatal infection is usually systematically spread and may lead to encephalitis. Current antiviral therapy like Acyclovir does not eliminate viral infection. New therapies are needed to either eliminate latent virus or to suppress lesion development over the long term.
  • Epstein-Barr virus (EBV)
  • Epstein-Barr virus is a member of the herpesvirus family and one of the most common human viruses. The virus occurs worldwide, and most people become infected with EBV sometime during their lives. In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. Infants become susceptible to EBV as soon as maternal antibody protection (present at birth) disappears. In the United States and in other developed countries, many persons are not infected with EBV in their childhood years. When infection with EBV occurs during adolescence or young adulthood, it causes infectious mononucleosis 35% to 50% of the time.
  • Symptoms of infectious mononucleosis are fever, sore throat, and swollen lymph glands. Sometimes, a swollen spleen or liver involvement may develop. Heart problems or involvement of the central nervous system occurs only rarely, and infectious mononucleosis is almost never fatal. There are no known associations between active EBV infection and problems during pregnancy, such as miscarriages or birth defects. Although the symptoms of infectious mononucleosis usually resolve in 1 or 2 months, EBV remains dormant or latent in a few cells in the throat and blood for the rest of the person's life. Periodically, the virus can reactivate and is commonly found in the saliva of infected persons. This reactivation usually occurs without symptoms of illness.
  • EBV also establishes a lifelong dormant infection in some cells of the body's immune system.
  • a late event in a very few carriers of this virus is the emergence of Burkitt's lymphoma and nasopharyngeal carcinoma, two rare cancers that are not normally found in the United States.
  • EBV appears to play an important role in these malignancies, but is probably not the sole cause of disease. No antiviral drugs or vaccines for EBV except Ganciclovir are available.
  • HHV8 Human herpesvirus 8
  • KSHV Kaposi's sarcoma-associated herpesvirus
  • KSHV is a virus belonging to the family of herpesviruses. KSHV was discovered in 1994. The virus has two names that are commonly used: KSHV which is its descriptive name and HHV8 which is its formal name. Both names are essentially interchangeable. KSHV causes a blood vessel cancer called Kaposi's sarcoma (KS), a lymphoma (a cancer of the lymphocyte) called body cavity-based lymphoma and some forms of severe lymph node enlargement, called Castleman's disease. The rates of KSHV infection in the general population of Mediterranean countries (Italy, Greece, Israel, Saudi Arabia) are higher than in North America and Northern Europe. Adult populations in some portions of Africa have very infection rates (>50%). This virus can be transmitted through sexual contact.
  • KS Kaposi's sarcoma
  • lymphoma a cancer of the lymphocyte
  • Castleman's disease some forms of severe lymph node enlargement
  • KSHV is also probably transmitted to some extent through nonsexual routes, perhaps from oral contact (kissing). Once exposed to KSHV, infection is probably life-long and the immune system of healthy adults keeps the virus in check at extremely low levels.
  • the real problem with KSHV occurs when an infected person becomes immunosuppressed. This occurs among transplant patients and patients receiving chemotherapy. There is good evidence that if someone is infected with KSHV and becomes immunosuppressed, then their chances of developing clinically detectable disease due to KSHV is higher than for other common viral infections. Infection with KSHV is diagnosed by a blood test.
  • VZV Varicella-zoster virus
  • Chicken pox is an infection that is caused by the Varicella-zoster virus (VZV). VZV spreads in nasal discharge and in fluid from inside the chicken pox blisters. Chicken pox is very contagious, and 90% of people who are not immune will catch it when they are exposed. Epidemics are most common in the late winter and early spring, and children between ages 5 and 9 account for half of all cases.
  • VZV Varicella-zoster virus
  • chicken pox is a mild illness, but it can cause serious complications, including pneumonia, encephalitis, and serious bacterial infections of chicken pox blisters.
  • VZV remains in the body. It lies dormant in nerve cells and may be reactivated later in life to cause shingles. Children (and others) who develop varicella and have weakened immune systems may be treated with Acyclovir.
  • a method for the identification of potent inhibitior for UL97 comprises contacting a test compound with the herpesviral kinase UL97 and detecting a change in activity of said cellular kinase.
  • Potent inhibitors such as the vinylpyrimidin-2-one derivatives of the general formula (I) will markedly diminish the activity of the herpesviral kinase UL97.
  • Still another aspect of the present invention is related to a method for detecting herpesviral infections and/or associated diseases in an individual comprising: a) providing a sample from said individual; and b) determining activity in said sample of the herpesviral kinase UL97.
  • a similar method for detecting herpesviral infections and/or associated diseases in cells, cell cultures and/or cell lysates comprises: a) providing a sample from said cells and/or cell lysates; and b) determining activity in said sample of the herpesviral kinase UL97.
  • vinylpyrimidine-2-one compounds can also be used for the manufacture of a pharmaceutical formulation for prophylaxis and/or treatment of diseases like cell proliferation disorders, cardiovascular disorders, immunological diseases, inflammatory diseases, neuroimmunological diseases, autoimmune diseases.
  • the present invention refers to a method for preventing and/or treating diseases like cell proliferation disorders, cardiovascular disorders, immunological diseases, inflammatory diseases, neuroimmunological diseases, autoimmune diseases preferably in mammal, most preferably in human.
  • Said method comprises administering to the mammal an amount of at least one vinylpyrimidine-2-one derivative of the general formula (I) or one vinylpyrimidine-2-one derivative of the general formula (la) and/or pharmaceutically acceptable salts thereof, effective to prevent and/or treat cell proliferation disorders, cardiovascular disorders, immunological diseases, inflammatory diseases, neuroimmunological diseases, and/or autoimmune diseases.
  • the compounds of the present invention are also useful for the treatment of diseases which are caused by malignant cell proliferation, such as all forms of hematological and solid cancer. Therefore the compounds according to the invention and pharmaceutical compositions prepared therewith are generally useful for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death or to induce systemic changes in metabolism such as changes in sugar, lipid or protein metabolism.
  • cell generation poiesis including blood cell growth and generation (prohematopoietic effect) after depletion or destruction of cells, as caused by, for example, toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune dysregulation, anemia and the like or to provide a therapeutic control of tissue generation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis.
  • the compounds according to the invention and pharmaceutical compositions prepared therewith are generally useful for the treatment of cell proliferation disorders, for the treatment or prophylaxis of cardiovascular disorders, immunological diseases and conditions (as for instance inflammatory diseases, neuroimmunological diseases, autoimmune diseases or other).
  • cancer as hematological (e.g. leukemia, lymphoma, myeloma) or solid tumors (for example breast, prostate, liver, bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain, uterine, colon, head and neck, ovarian, melanoma, astrocytoma, small cell lung cancer, glioma, basal and squameous cell carcinoma, sarcomas as Kaposi's sarcoma and osteosarcoma), tumor angiogenesis or metastasis, treatment of disorders involving T-cells such as acute or chronic graft rejection or other host versus graft or graft versus host reactions, aplastic anaemia and DiGeorge syndrome, Graves' disease, lupus erythematosus, Sjogren's Syndrome, fibrosis, uveitis, rhinitis
  • hematological e.
  • inventive vinylpyrimidine-2-one compounds of the general formula (I) or vinylpyrimidine-2-one compounds of the general formula (la) and/or pharmaceutically acceptable salts thereof are administered in a dosage corresponding to an effective concentration in the range of 0.01 - 50 ⁇ M, preferably in the range of 0.02 - 10 ⁇ M, more preferably in the range of 0.03 - 1 ⁇ M, and most preferably in the range of 0.04 - 0.1 ⁇ M.
  • compositions comprising at least one compound of the general formula (I) and/or one compound of the general formula (la) as an active ingredient together with one or more pharmaceutically acceptable carriers), excipient(s) and/or diluent(s).
  • the vinylpyrimidine-2-one compounds of the present invention can form pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid and other mineral or carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • salts may be formed with inorganic as well as organic bases such as, for example, NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide, and the like.
  • the compounds of formula (I) or of formula (la) can also be used in the form of a precursor (prodrug) or a suitably modified form, that releases the active compound in vivo.
  • a precursor prodrug
  • Such precursors can be obtained for example by masking the free acid group with an ester group, which is then in turn transformed into the free acid group in vivo [F. W. Sum et. al. Bioorg. & Med. Chem. Lett. 9 (1999), 1921-1926; Ada Rephaeli et. al. Drug Development Research 50 (2000) 379-391 ; H. Ishikawa, Current Med. Chem. 6 (1999), 575-597].
  • the compounds of the general formula (I) or compounds of the general formula (la) can also be administered in form of their pharmaceutically active salts optionally using substantially nontoxic pharmaceutically acceptable carriers, excipients or diluents.
  • the medications of the present invention are prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically- made adjuvant at suitable dosage level in a known way.
  • the preferred preparations are in administratable form which is suitable for oral application. These administratable forms, for example, include pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
  • the subject of the present invention also includes pharmaceutical preparations for parenteral, including dermal, intradermal, intragastrical, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topical or transdermal application, which in addition to typical vehicles and diluents contain a vinylpyrimidine-2-one compound of the general formula (I) and/or a vinylpyrimidine- 2-one compound of the general formula (la) and/or a pharmaceutically acceptable salt thereof as active ingredient.
  • parenteral including dermal, intradermal, intragastrical, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topical or transdermal application, which in addition to typical vehicles and diluents contain a vinylpyrimidine-2-one compound of the general formula (I
  • compositions of the present invention containing vinylpyrimidine-2-one derivatives of the general formula (I) or vinylpyrimidine-2-one compound of the general formula (la) as active ingredients, will typically be administered in admixture with suitable carrier materials selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • suitable carrier materials selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral nontoxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture.
  • Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. antihistaminic activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-pro pylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidifies.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the inventive vinylpyrimidine-2-one compounds of the present invention may also be deliverable transdermally.
  • the transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients.
  • Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins.
  • the capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet means compressed or molded solid dosage form containing the active ingredients with suitable diluents.
  • the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction well known to a person skilled in the art.
  • Oral gels refers to the active ingredients dispersed or solubilized in a hydrophilic semi-solid matrix.
  • Powders for constitution refer to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
  • suitable diluents are substances that usually make up the major portion of the composition or dosage form.
  • Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn rice and potato, and celluloses such as microcrystalline cellulose.
  • the amount of diluents in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60%» by weight.
  • disintegrants refers to materials added to the composition to help it break apart (disintegrate). Suitable disintegrants include starches, "cold water soluble” modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures.
  • the amount of disintegrant in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 5 to about 10% by weight.
  • Binders characterize substances that bind or "glue” powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
  • sugars such as sucrose, starches derived from wheat, corn rice and potato
  • natural gums such as acacia, gelatin and tragacanth
  • derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate
  • the amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
  • Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine.
  • Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
  • the amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
  • Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range from about 0.1 % to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
  • Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1 %.
  • the UL-97 gene was cloned into a baculovirus vector in order to produce GST (glutathione S-transferase) fusion protein.
  • Insect cells (Sf9) were infected and GST-UL-97 purified via glutathione affinity columns according to standard procedures.
  • the UL-97 kinase reaction was performed as described (Marschall et al., 2001 , 1439-1450). Briefly, 10 ⁇ l Assay buffer (3 ⁇ M ATP, 60 ⁇ g/ml myelin basic protein (MBP) as substrate), 1 ,0 ⁇ Ci ⁇ -[ 33 P]ATP and 10 ⁇ l Basic buffer (20mM Tris-HCl 7.5, 500 ⁇ M MnCI 2 , 1 mM DTT (dithiothreitol)) were given to the test tube before adding various concentrations of the vinylpyrimidine-2-one derivatives. The reaction was started by adding 0.2 ⁇ l UL97 kinase, purified from infected Sf9- insect cells as described above.
  • the total volume was adjusted with Basic buffer to a final volume of 30 ⁇ l.
  • the reaction mix was incubated for 1 hr at 30°C.
  • 10 ⁇ l 0.1 M EDTA ethylene diamine tetraacetate
  • 10 ⁇ l 0.1 M EDTA ethylene diamine tetraacetate
  • the Immobilon plate (Millipore) was rinsed with 50 ⁇ l methanol/well. Following addition of 100 ⁇ l 0.1 M EDTA, 20 ⁇ l of each kinase reaction mix was added to one well of the Immobilon plate. Each well was washed 4x with 250 ⁇ l 0.75% phosphoric acid and 1x with 50 ⁇ l methanol. After addition of 50 ⁇ l scintillation cocktail (Roth, Germany) per well incorporation of radioactivity was measured using a Betareader (Wallac) and enzymatic activity calculated.
  • Betareader Betareader
  • the vinylpyrimidine-2-one derivatives are non-toxic up to concentrations of 10 ⁇ M in HEK293 (human embryonic kidney) cells and HFF (human foreskin fibroblasts) cells.

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Abstract

L'invention concerne des dérivés vinylpyrimidine-2-one représentés par la formule générale (I). Cette invention concerne également des dérivés vinylpyrimidine-2-one et des dérivés représentés par la formule générale (Ia). R1 à R6 de la formule (I) et de la formule (Ia) représentent, de façon indépendante, une variété de différents substituants notamment des groupes alkyle, aryle, aralkyle, alkylaryle, hétéroaryle et des groupes caractéristiques monofonctionnels.
PCT/EP2003/009039 2002-08-14 2003-08-14 Pyrimidones en tant qu'agents antiviraux WO2004016271A1 (fr)

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WO2015183989A1 (fr) * 2014-05-27 2015-12-03 Navigen, Inc. Inhibiteurrs d'arf6 et leurs méthodes de synthèse et d'utilisation
US10849901B2 (en) 2014-05-27 2020-12-01 Navigen, Inc. Arf6 inhibitors and methods of synthesis and use thereof

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