EP1082121A4 - Hiv-integraseinhibitoren - Google Patents

Hiv-integraseinhibitoren

Info

Publication number
EP1082121A4
EP1082121A4 EP99926094A EP99926094A EP1082121A4 EP 1082121 A4 EP1082121 A4 EP 1082121A4 EP 99926094 A EP99926094 A EP 99926094A EP 99926094 A EP99926094 A EP 99926094A EP 1082121 A4 EP1082121 A4 EP 1082121A4
Authority
EP
European Patent Office
Prior art keywords
alkyl
phenyl
substituted
benzyl
hydroxy
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Withdrawn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
EP99926094A
Other languages
English (en)
French (fr)
Other versions
EP1082121A1 (de
Inventor
Steven D Young
Melissa Egbertson
Linda S Payne
John S Wai
Thorsten E Fisher
James P Guare Jr
Mark W Embrey
Lee Tran
Linghang Zhuang
Joseph P Vacca
Marie Langford
Jeffrey Melamed
David L Clark
Julio C Medina
Juan Jaen
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.)
Merck and Co Inc
Tularik Inc
Original Assignee
Merck and Co Inc
Tularik 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
Priority claimed from GBGB9815175.6A external-priority patent/GB9815175D0/en
Application filed by Merck and Co Inc, Tularik Inc filed Critical Merck and Co Inc
Publication of EP1082121A1 publication Critical patent/EP1082121A1/de
Publication of EP1082121A4 publication Critical patent/EP1082121A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/88—Unsaturated compounds containing keto groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
  • This virus was previously known as LAV, HTLV-III, or ARV.
  • a common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells.
  • Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site.
  • the fourth step in the process, repair synthesis of the resultant gap may be accomplished by cellular enzymes.
  • Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)].
  • Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
  • antiviral compounds which act as inhibitors of HrV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT.
  • Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication.
  • the applicants additionally demonstrate that inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV infected cells.
  • the particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication.
  • the compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.
  • Zhao et al. (J. Med Chem. vol. 40, pp. 937-941 and 1186- 1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors.
  • Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents & Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).
  • 4-phenyl-4-oxo-butenoic acid derivatives are disclosed as useful as kynurenine-3-hydroxylase inhibitors for the prevention and/or treatment of neurodegenerative diseases in PCT/ ⁇ P96/04517, which published as WO 97/17316 and in PCT/EP96/04518, which published as WO 97/17317.
  • These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines.
  • Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
  • This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
  • Compounds of formula I are defined as follows:
  • A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen heteroatoms substituted on carbon or nitrogen by Rl, R2, R8, and R9; optionally the aromatic ring may be fused with another ring system to form:
  • Rl is selected from:
  • each R3 is independently selected from: (1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on nitrogen or carbon by 1 to 5 substituents selected from: (a) halogen, (b) Ci-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
  • each R4 is independently selected from: (1) -H,
  • each R5 is independently selected from: (1) -H,
  • each R ⁇ is independently selected from:
  • each R7 is independently selected from: (1) -H, and
  • R8 is selected from:
  • R9 is selected from:
  • each n is independently selected from 0, 1 and 2.
  • Rl is not R ⁇ para to the dioxobutyric acid ester moiety; and (2) R2 is not selected from:
  • R3 wherein R3 is cycloalkyl; and (4) and when R2 is S(0) n R 6 , and R6 is CH2- 3 or R3, then R3 is not unsubstituted phenyl. Also provided for by the present invention are compounds of formula (I) wherein:
  • WHEN A is phenyl and Rl is: (a) H, (b) Ci-5 alkyl,
  • A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or
  • the aromatic or heteroaromatic ring may optionally be fused with a 5- or 6-membered aromatic or heteroaromatic ring to form a fused ring system, provided that when A is a fused ring system, the six-membered aromatic or heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety; optionally the aromatic or heteroaromatic ring may be fused with another ring system to form:
  • Rl is selected from:
  • each R3 is independently selected from:
  • a 5 or 6 membered aromatic or heteroaromatic ring containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from: (a) halogen,
  • halogen (i) Ci-6 alkyl, (iii) -CF3, and (iv) hydroxy; (2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
  • (6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
  • each R4 is independently selected from: (1) -H,
  • each R5 is independently selected from: (1) -H,
  • each R6 is independently selected from: (1) -C1-3 alkyl-R3, and
  • R7 is selected from:
  • R8 is selected from:
  • Ci-6 alkyl and each n is independently selected from 0, 1 and 2.
  • Rl is not :
  • R2 is not selected from:
  • Rl, R2, and R$ are not: (a) -H, (b) Cl-6 alkyl, or
  • Particular compounds of structural formula la include: (1) 3-biphenyl-4-yl-2,4-dioxobutanoic acid,
  • Particular compounds of structural formula (I) include:
  • One class of compounds of structural formula (I) includes:
  • Still another class of compounds of the present invention is represented by the formula below:
  • Still another class of compounds of the present invention is represented by the following structural formula:
  • Still another class of compounds of the present invention is represented by the following structural formula:
  • Still another class of compounds of the present invention is represented by the following structural formula:
  • Still another class of compounds of the present invention is represented by the following structural formula:
  • Still another class of compounds of the present invention is represented by the formula below:
  • A is selected from:
  • A is selected from:
  • A is phenyl
  • Rl is selected from:
  • phenyl Ci-3 alkyl- wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
  • Rl is selected from:
  • phenyl Ci-3 alkyl- wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
  • Rl is selected from:
  • phenyl Ci-3 alkyl- wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
  • Rl is selected from:
  • R2 is selected from:
  • Ci-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on Ci-6 alkyl may be replaced with a fluorine atom
  • R2 is selected from:
  • R2 is selected from:
  • R is selected from:
  • R3 is selected from:
  • Ci-6 alkyl wherein one or more of the hydrogen atoms may be replaced with a fluorine atom
  • R3 is selected from: (1) phenyl
  • halogen selected from -F, -Cl, -Br,
  • Cl-6 alkyl wherein one or more of the hydrogen atoms may be replaced with a fluorine atom

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP99926094A 1998-06-03 1999-06-01 Hiv-integraseinhibitoren Withdrawn EP1082121A4 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US8782098P 1998-06-03 1998-06-03
US87820P 1998-06-03
GB9815175 1998-07-13
GBGB9815175.6A GB9815175D0 (en) 1998-07-13 1998-07-13 HIV integrase inhibitors
PCT/US1999/012093 WO1999062520A1 (en) 1998-06-03 1999-06-01 Hiv integrase inhibitors

Publications (2)

Publication Number Publication Date
EP1082121A1 EP1082121A1 (de) 2001-03-14
EP1082121A4 true EP1082121A4 (de) 2003-02-05

Family

ID=26314024

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99926094A Withdrawn EP1082121A4 (de) 1998-06-03 1999-06-01 Hiv-integraseinhibitoren

Country Status (4)

Country Link
EP (1) EP1082121A4 (de)
AU (1) AU4225499A (de)
CA (1) CA2333707A1 (de)
WO (1) WO1999062520A1 (de)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ID26031A (id) 1998-03-26 2000-11-16 Shionogi & Co Turunan indol yang memiliki suatu aktivitas antiviral
JP2003525200A (ja) 1998-07-27 2003-08-26 イスティトゥト ディ リチェルケ ディ ビオロジア モレコラーレ ピー．アンジェレッティ ソチエタ ペル アツィオニ ポリメラーゼ阻害剤としてのジケト酸誘導体
ATE411286T1 (de) 1998-12-25 2008-10-15 Shionogi & Co Aromatische heterocyclen mit hiv integrase inhibierenden eigenschaften
JP2004503523A (ja) * 2000-06-16 2004-02-05 ブリストルーマイヤーズ　スクイブ　カンパニー Ｈｉｖインテグラーゼ阻害剤
JP3616628B2 (ja) 2001-03-01 2005-02-02 塩野義製薬株式会社 Ｈｉｖインテグラーゼ阻害活性を有する含窒素芳香族複素環化合物
BR0209537A (pt) 2001-05-09 2004-03-09 Bayer Cropscience Ag Arilcetonas substituìdas
KR101009472B1 (ko) 2001-06-12 2011-01-19 웰스테트 테라퓨틱스 코포레이션 대사 질환의 치료용 화합물
BR0211750A (pt) 2001-08-10 2004-10-13 Shionogi & Co Agente antiviral
WO2003016266A1 (en) * 2001-08-16 2003-02-27 Japan Tobacco Inc. β-KETOAMIDE COMPOUNDS AND MEDICINAL USE THEREOF
US7232819B2 (en) * 2001-10-26 2007-06-19 Istituto Di Ricerche Di Biologia P. Angeletti S.P.A. Dihydroxypyrimidine carboxamide inhibitors of HIV integrase
CN102219750B (zh) 2001-10-26 2013-05-29 P.安杰莱蒂分子生物学研究所 关于hiv整合酶的n-取代的羟基嘧啶酮甲酰胺抑制剂
AU2002360523A1 (en) * 2001-12-07 2003-06-23 The Government Of The United States Of America As Represented By The Secretary, Department Of Health Compounds to treat hiv infection and aids
US7323460B2 (en) 2002-03-15 2008-01-29 Merck & Co., Inc. N-(substituted benzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamides useful as HIV integrase inhibitors
WO2004024693A1 (ja) 2002-08-13 2004-03-25 Shionogi & Co., Ltd. Ｈｉｖインテグラーゼ阻害活性を有するヘテロ環化合物
US20040157804A1 (en) 2002-10-16 2004-08-12 Gilead Sciences, Inc. Pre-organized tricyclic integrase inhibitor compounds
EP1664046B1 (de) 2003-09-19 2009-06-17 Gilead Sciences, Inc. Azachinolinolphosphonatverbindungen als integraseinhibitoren
US7776883B2 (en) 2004-03-10 2010-08-17 The United States Of America As Represented By The Department Of Health And Human Services Quinolin-4-ones as inhibitors of retroviral integrase for the treatment of HIV, AIDS and AIDS related complex (ARC)
EP1732541A4 (de) 2004-04-07 2008-03-05 Takeda Pharmaceutical Cyclische verbindungen
US20090306054A1 (en) 2006-05-16 2009-12-10 Gilead Sciences ,Inc. Integrase inhibitors
JP2009543865A (ja) * 2006-07-19 2009-12-10 ユニバーシティ オブ ジョージア リサーチ ファウンデーション， インコーポレーテッド ピリジノンジケト酸：併用療法におけるｈｉｖ複製の阻害剤
ES2572631T3 (es) 2008-01-25 2016-06-01 Chimerix, Inc. Métodos de tratamiento de infecciones virales
US8664255B2 (en) 2008-10-20 2014-03-04 The Texas A&M University System Inhibitors of mycobacterium tuberculosis malate synthase, methods of making and uses thereof
KR20120094098A (ko) 2009-12-07 2012-08-23 유니버시티 오브 조지아 리서치 파운데이션, 인코포레이티드 피리디논 하이드록시사이클로펜틸 카복사미드: 치료 용도의 ｈｉｖ 인테그라제 억제제
US8283366B2 (en) 2010-01-22 2012-10-09 Ambrilia Biopharma, Inc. Derivatives of pyridoxine for inhibiting HIV integrase
DK2534150T3 (en) 2010-02-12 2017-06-12 Chimerix Inc METHODS OF TREATING VIRUS INFECTION
CN103420894A (zh) * 2012-05-22 2013-12-04 中国科学院上海药物研究所 丁-2-烯-1,4-二酮类化合物及其制备方法和用途
CN106905244B (zh) * 2017-02-27 2019-08-16 武汉工程大学 二芳基嘧啶-二酮酸类杂合型hiv-1抑制剂及其制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS51138683A (en) * 1975-05-14 1976-11-30 Fisons Ltd Nove manufacture of chromonee22carboxilic acid compounds
JPS61134346A (ja) * 1984-12-03 1986-06-21 Shionogi & Co Ltd ４−オキソカルボン酸誘導体および抗潰瘍剤
ES2039301A1 (es) * 1991-11-20 1993-09-16 Genesis Para La Investigacion Procedimiento de obtencion de nuevos intermedios de sintesis utiles para la preparacion de fluoroquinolonas.
WO1995013262A1 (en) * 1993-11-12 1995-05-18 Rhone-Poulenc Rorer Limited Substituted phenyl compounds
US5618830A (en) * 1994-10-17 1997-04-08 Merck & Co., Inc. Dioxobutanoic acid derivatives as inhibitors of influenza endonuclease
WO1997017316A1 (en) * 1995-11-03 1997-05-15 Pharmacia & Upjohn S.P.A. 4-phenyl-4-oxo-2-butenoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity
EP1069111A1 (de) * 1998-03-26 2001-01-17 SHIONOGI & CO., LTD. Indol derivate mit antiviraler aktivität

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3899508A (en) * 1974-04-12 1975-08-12 Lilly Co Eli 5-(2-Aminophenyl)pyrazole-3-carboxylic acids and esters thereof
US4336397A (en) * 1980-12-29 1982-06-22 Merck & Co., Inc. 2,4-Dioxo-4-substituted-1-butanoic acid derivatives useful in treating urinary tract calcium oxalate lithiasis
US4423063A (en) * 1980-12-29 1983-12-27 Merck & Co., Inc. 2,4-Dioxo-4-substituted-1-butaoic acid derivatives useful in treating urinary track calcium oxalate lithiasis
PH27357A (en) * 1989-09-22 1993-06-21 Fujisawa Pharmaceutical Co Pyrazole derivatives and pharmaceutical compositions comprising the same

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS51138683A (en) * 1975-05-14 1976-11-30 Fisons Ltd Nove manufacture of chromonee22carboxilic acid compounds
JPS61134346A (ja) * 1984-12-03 1986-06-21 Shionogi & Co Ltd ４−オキソカルボン酸誘導体および抗潰瘍剤
ES2039301A1 (es) * 1991-11-20 1993-09-16 Genesis Para La Investigacion Procedimiento de obtencion de nuevos intermedios de sintesis utiles para la preparacion de fluoroquinolonas.
WO1995013262A1 (en) * 1993-11-12 1995-05-18 Rhone-Poulenc Rorer Limited Substituted phenyl compounds
US5618830A (en) * 1994-10-17 1997-04-08 Merck & Co., Inc. Dioxobutanoic acid derivatives as inhibitors of influenza endonuclease
WO1997017316A1 (en) * 1995-11-03 1997-05-15 Pharmacia & Upjohn S.P.A. 4-phenyl-4-oxo-2-butenoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity
EP1069111A1 (de) * 1998-03-26 2001-01-17 SHIONOGI & CO., LTD. Indol derivate mit antiviraler aktivität

Non-Patent Citations (28)

* Cited by examiner, † Cited by third party
Title
AUST. J. CHEM. (1980), 33(10), 2317-24 *
BULL. CHEM. SOC. JAP. (1972), 45(9), 2829-34 *
BULL. SCI., CONS. ACAD. SCI. ARTS RSF YOUGOSLAVIE, SECT. A (1972), 17(5-6), 148-50 *
CROATICA CHEMICA ACTA (1985), 58(1), 87-90 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ANDREICHIKOV, YU. S. ET AL: "Chemistry of oxalyl derivatives of methyl ketones. XII. Transfer of the effect of substituents by the H-chelating ring in.beta.-dicarbonyl compounds", XP002221347, retrieved from STN Database accession no. 88:169443 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BEGLEY, MICHAEL J. ET AL: "Cyclization of arylpropiolyl chloro-oxalyl anhydrides: the chemistry of aryl(chloro)methylenetetrahydrofuran-2,4,5-triones and the x-ray crystal structure of a 3,4-methylenedioxybenzylidene representative", XP002221340, retrieved from STN Database accession no. 86:189624 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BENASSI, CARLO A.: "Derivatives of o-aminobenzoylpyruvic acid", XP002221352, retrieved from STN Database accession no. 56:79242 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BREGANT, N. ET AL: "Polyoxo compounds. XV. Oxidation of aroylpyruvic acids into dihydrofuran derivatives by iodosobenzene diacetate", XP002221351, retrieved from STN Database accession no. 78:4047 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; COOKE, RAYMOND G. ET AL: "Coloring matters of Australian plants. XXIII. A new synthesis of arylphenalenones and naphthoxanthenones", XP002221346, retrieved from STN Database accession no. 94:208597 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; FISONS LTD., UK: "Chromonecarboxylic acid derivatives", XP002221348, retrieved from STN Database accession no. 88:22627 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; GOMBAR, VIJAY K. ET AL: "Computer-assisted structure-activity relationship analysis: pattern recognition studies on hypolipidemic arylpropionic acid derivatives", XP002221343, retrieved from STN Database accession no. 110:225000 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; IWANAMI, YASUO ET AL: "Heterocycles structurally influenced by a side chain. II. 7-Phenacylxanthopterins and 6-phenacylisoxanthopterins", XP002221350, retrieved from STN Database accession no. 78:29723 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; JANCULEV, J. ET AL: "Condensation products of 5-acetylacenaphthene and 2-acetylfluorene with oxalic ester", XP002221353, retrieved from STN Database accession no. 56:38353 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KOVAC, SPOMENKA ET AL: "Synthesis and properties of p-hydroxyacetophenone derivatives", XP002221344, retrieved from STN Database accession no. 104:206847 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MATSUTANI, SHIGERU ET AL: "4-Oxoalkanoic acid derivatives", XP002221339, retrieved from STN Database accession no. 105:225805 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MURATA, TADAKAZU ET AL: "Structure-activity relations of 3-(substituted benzoyl)propionic acids, a new class of antispasmodics for biliary smooth muscle", XP002221349, retrieved from STN Database accession no. 87:47924 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PALOMO COLL, ALBERTO: "Process for preparation of new synthetic intermediates for preparation of fluoroquinolones", XP002221342, retrieved from STN Database accession no. 120:216980 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SWEENY, J. S. ET AL: "Synthesis of anthocyanidins. III. Total synthesis of apigeninidin and luteolinidin chlorides", XP002221345, retrieved from STN Database accession no. 95:132622 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; YANBORISOV, T. N. ET AL: "Synthesis and pharmacological activity of heteroylpyruvic acids and their derivatives", XP002221341, retrieved from STN Database accession no. 130:153601 *
EUR. J. MED. CHEM. - CHIM. THER. (1977), 12(1), 17-20 *
GAZZ. CHIM. ITAL. (1961), 91, 1097-1104 *
GODISEN ZBORNIK FIL. FAK. UNIV. SKOPJE, PRIROD. MAT. ODDEL. (1948), 11(NO. 4), 39-43 *
J. CHEM. SOC., PERKIN TRANS. 1 (1977), (2), 138-45 *
KHIMIKO-FARMATSEVTICHESKII ZHURNAL (1998), 32(9), 26-28 *
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (1988), 7(4), 225-34 *
See also references of WO9962520A1 *
TETRAHEDRON (1981), 37(8), 1481-3 *
ZH. ORG. KHIM. (1978), 14(2), 371-3 *

Also Published As

Publication number Publication date
EP1082121A1 (de) 2001-03-14
AU4225499A (en) 1999-12-20
WO1999062520A1 (en) 1999-12-09
CA2333707A1 (en) 1999-12-09

Similar Documents

Publication Publication Date Title
EP1082121A1 (de) Hiv-integraseinhibitoren
US6380249B1 (en) HIV integrase inhibitors
US6262055B1 (en) HIV integrase inhibitors
CA2425440C (en) Aza- and polyaza-naphthalenyl carboxamides useful as hiv integrase inhibitors
EP1326610B1 (de) Aza- und polyaza-naphthalenylcarbonsäureamide als hiv-integrase-hemmer
US6194439B1 (en) Tricyclic polyhydroxylic tyrosine kinase inhibitors
AU756826C (en) HIV integrase inhibitors
US7446222B2 (en) Phenyl compounds
US20040034221A1 (en) Aza-and polyaza-naphthalenyl-carboxamides useful as hiv integrase inhibitors
US7569573B2 (en) Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase
AU757409B2 (en) Hiv integrase inhibitors
WO2000020371A1 (en) Prostaglandin receptor ligands
MX2007007830A (es) Compuestos de piridina para el tratamiento de enfermedades mediadas por prostaglandina.
EP2013170B1 (de) 4-squarylpiperazinderivate als antivirale wirkstoffe
MXPA04009800A (es) Acido (2-((2-alcoxi)-fenil)-ciclopent-1-enil) carbociclico y heterociclico aromatico y derivados.
KR100878739B1 (ko) 발기부전 치료를 위한 신규한 화합물
JPH0351704B2 (de)
JP2935431B2 (ja) Ｄ（＋）‐２‐（４‐アセチルフェノキシ）プロピオン酸エステル類の製造方法
JP2002516863A (ja) Ｈｉｖインテグラーゼ阻害薬
JPH0737442B2 (ja) アニリン類及びベンジルアミン類から得られるベンジルセレノベンズアミド類、及びその製造方法
US4147790A (en) (4-Phenyl-piperazino alkyl)-3-benzoyl-benzene alkanoates
WO2006123648A1 (ja) ３－置換チオフェンの製法
KR20050106336A (ko) 항염증 활성을 갖는 크로멘-2-온 모핵 히드록사민 산유도체, 이의 제조방법 및 이를 포함하는 염증 질환의치료를 위한 조성물
JPH07119209B2 (ja) ナフチルチオアルキルカルボン酸誘導体
JPH07119208B2 (ja) ナフチルチオアルキルカルボン酸誘導体

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: 20010103

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20010103;LT PAYMENT 20010103;LV PAYMENT 20010103;MK PAYMENT 20010103;RO PAYMENT 20010103;SI PAYMENT 20010103

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 61K 31/535 A, 7C 07D 263/58 B, 7C 07D 265/36 B, 7C 07D 317/60 B, 7C 07D 319/18 B, 7C 07D 321/10 B, 7C 07D 209/10 B, 7C 07D 209/08 B, 7C 07D 213/64 B, 7A 61K 31/42 B, 7A 61K 31/36 B, 7A 61K 31/40 B, 7A 61K 31/44 B

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 61K 31/535 A, 7C 07D 263/58 B, 7C 07D 265/36 B, 7C 07D 317/60 B, 7C 07D 319/18 B, 7C 07D 321/10 B, 7C 07D 209/10 B, 7C 07D 209/08 B, 7C 07D 213/64 B, 7A 61K 31/42 B, 7A 61K 31/36 B, 7A 61K 31/40 B, 7A 61K 31/44 B, 7C 07C 59/84 B

A4 Supplementary search report drawn up and despatched

Effective date: 20021217

17Q First examination report despatched

Effective date: 20031017

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: 20040228