+

WO2000029399A1 - Antiherpes compounds - Google Patents

Antiherpes compounds Download PDF

Info

Publication number
WO2000029399A1
WO2000029399A1 PCT/CA1999/001066 CA9901066W WO0029399A1 WO 2000029399 A1 WO2000029399 A1 WO 2000029399A1 CA 9901066 W CA9901066 W CA 9901066W WO 0029399 A1 WO0029399 A1 WO 0029399A1
Authority
WO
WIPO (PCT)
Prior art keywords
nhc
compound according
group
nhch
lower alkyl
Prior art date
Application number
PCT/CA1999/001066
Other languages
French (fr)
Inventor
Bruno Simoneau
James J. Crute
Anne-Marie Faucher
Christine A. Grygon
Karl D. Hargrave
Bounkham Thavonekham
Original Assignee
Boehringer Ingelheim (Canada) Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim (Canada) Ltd. filed Critical Boehringer Ingelheim (Canada) Ltd.
Publication of WO2000029399A1 publication Critical patent/WO2000029399A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • 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
    • C07C271/22—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 carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or 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
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or 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
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to methods for inhibiting herpes replication and for treating herpes infection in a mammal
  • this invention relates to compounds that inhibit the herpes helicase-primase enzyme complex.
  • This invention also relates to pharmaceutical compositions comprising the compounds, to methods of using and producing the compounds
  • Herpesviruses inflict a wide range of diseases against humans and animals
  • herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2)
  • VZV varicella zoster virus
  • HCMV human cytomegalovirus
  • Herpesviruses are complex double-stranded DNA viruses that encode all the enzymes that directly mediate viral chromosomal replication Seven DNA replication-associated polypeptides are required for human herpesvirus replication Six of these seven polypeptides show a high degree of homology across all studied human herpesviruses. These six polypeptides, when expressed by the virus, constitute a heterodime ⁇ c DNA-dependent DNA polymerase, a monome ⁇ c single-stranded DNA binding protein, and a heterotrime ⁇ c helicase-primase complex. The seventh DNA replication- associated polypeptide does not display sequence or functional conservation and is involved in the initiation of lytic viral replication
  • herpesvirus chromosomal replication will not initiate or propagate This has been demonstrated in two ways for DNA replication in HSV-1.
  • temperature sensitive HSV-1 strains have been developed and the complementation groups within these strains mapped on a one-to- one correspondence to the seven HSV DNA replication genes.
  • transient replication assays that utilized recombinant DNA plasmids containing single DNA replication genes have found that the presence of each of the seven genes was required for the efficient replication of a tester plasmid containing an HSV-1 origin of DNA replication.
  • helicase-primase complex two of the three polypeptides (e.g., the expression products of the UL5 and UL52 genes of HSV-1 ) promote catalysis of duplex DNA unwinding and RNA primer biosynthesis.
  • the assembled helicase-primase enzyme complex functions both in the initiation and propagation stages of herpesvirus DNA replication. It is responsible for the synthesis of RNA primers necessary for the initiation of all new DNA synthesis by the herpesvirus DNA polymerase.
  • duplex viral chromosomal DNA must first be unwound to the single-stranded replicative intermediate because the herpesvirus DNA polymerase is inactive on fully duplex DNA.
  • the helicase- primase is also responsible for this important DNA unwinding event.
  • nucleoside analogues must first be activated to the nucleoside monophosphate by a virally-encoded thymidine kinase enzyme. It should be pointed out that only HSV and varicella zoster virus encode thymidine kinase enzymes. This may, in part, explain the inability to adapt nucleoside-based therapies to the treatment of other human herpesviruses.
  • the nucleoside analogue monophosphate must be further phosphorylated to the triphosphate by human-encoded enzymes prior to its action.
  • the triphosphorylated nucleoside analogue is incorporated into a nascent DNA chain during viral genomic replication, thereby inhibiting the elongation of that DNA chain by the herpes DNA polymerase.
  • the final incorporation step of the nucleoside-based therapies has been characterized as "competitive" because the herpes DNA polymerase does not display a preference for the activated nucleoside drug versus normal deoxynucleoside triphosphates.
  • the action of the DNA polymerase is not considered rate-limiting for herpesvirus DNA replication, the utility of nucleoside-derived compounds in treating herpesvirus infections is necessarily limited. Accordingly, the need for effective, safe therapeutic agents for treating herpesvirus infections continues to exist.
  • the present non-nucleoside-based compounds can be distinguished from the prior art compounds by their different chemical structures and biological activities.
  • non-nucleoside- based compounds which are inhibitors of herpes viral replication, such as for example inhibitors that act directly in interfering with the likely rate- limiting process in herpesvirus DNA replication: the action of the helicase- primase enzyme.
  • the herpesvirus helicase-primase enzyme is conserved across the human herpesviruses, such compounds of this invention are effective against the full spectrum of herpesviruses, including HSV, varicella zoster virus and cytomegalovirus, and also against nucleoside-nonresponsive and nucleoside-resistant herpes infections.
  • non-nucleoside-based compounds may be characterized by having a five- or six-membered heterocycle attached to a phenyl or pyridinyl ring.
  • Compounds possessing such a moiety have been reported previously, for example:
  • the non-nucleoside-based compounds are represented by formula 1
  • Aryl is selected from the group consisting of:
  • Y is N C(0) CH wherein R 2 is H or lower alkyl
  • R 3 is H; lower alkyl; (lower cycloalkyl)-(lower alkyl) (e.g. CH 2 -(cyclohexyl); phenyl(lower alkyl); phenyl(lower alkyl) monosubstituted, disubstituted or trisubstituted on the aromatic portion thereof with a substituent or substituents selected independently from the group consisting of halo, hydroxy, lower alkoxy, lower alkoxy, lower alkyl, azido and t fluoromethyl; CH 2 -Het; or CH 2 -(bicyclic heterocyclic system); and
  • Z is NR 4 R 5 wherein
  • R 4 is H, phenyl(lower alkyl) (e.g. CH 2 Ph) or phenyl(lower alkyl) monosubstituted, disubstituted or trisubstituted on the aromatic portion thereof with a substituent or substituents selected independently from the group consisting of halo, hydroxy, lower alkoxy, lower alkyl, azido and thfluoromethyl, or
  • R 4 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • R is or a mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl;
  • R is or a mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl;
  • R 5 is selected from the group consisting of:
  • R 5 is ox C(O)OCMe 3 when R 3 is CH 2 CH 2 CH2NH2,
  • R 5 is C(O)Ph, when X is NH 2 S(O) 2 , H 2 NC(O)NHCHMe,
  • R 5 is phenyl(lower alkyl) or mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl,
  • l _ Y is N C(0) wherein R 2 is H or lower alkyl
  • Z is selected from the group consisting of:
  • CH 2 OCH 2 Ph, CH 2 OPh, OCH 2 CHMe 2 , CH 2 CH 2 Ph, CH 2 CH 2 CH 2 Ph, CH 2 SCH 2 Ph, CH CHPh, CH 2 CH 2 CH 2 CH 2 C(O)NPh 2> CH 2 CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 NH 2 , CH(NH 2 )(CH 2 ) 4 NHC(O)OCH 2 Ph, (S)- CH(NHCH 2 Ph)(CH 2 ) 4 NHC(O)OCH 2 Ph,
  • X and Aryl are as defined above; Y is absent (i.e. a valence bond); and Z is selected from the group consisting of:
  • Z is selected from the group consisting of: NHC(0)NH-CHPr 2 , NHC(S)NBu 2 , NHC(0)NBu 2 , NHC(O)CH 2 CH 2 N(CH 2 Ph) 2 ,
  • a preferred group of compounds is represented by formula 1 wherein X is
  • Y is N— C(0) CH wherein R 2 is hydrogen and R 3 is H,
  • Z is NR 4 R 5 wherein
  • R 4 is H, CH 2 Ph,
  • Aryl is wherein R 2 is H and R 3 is H
  • a most preferred group is represented by formula 1 wherein X is
  • Z is NR 4 R 5 wherein R 4 is H, CH 2 Ph,
  • Still another most preferred group is represented by formula 1 wherein X is
  • Aryl is Y is R 2 R 3
  • Z is NR R 5 wherein R 4 is H or CH 2 Ph, and R 5 is
  • X is , Aryl is , Y is NH-C(O) and Z is
  • Still another more preferred group of compounds is represented by formula 1 wherein X, Aryl and Y are defined in the last instance and Z is
  • Z is NHC(O)NBu 2 .
  • R 3 is H or PnC H 2j Y js as defined hereinbefore and Z is NR 4 R 5 wherein R 4 is H or CH 2 Ph and R 5 is C(O)OCMe 3 .
  • a further aspect of this invention is to provide compounds useful in the methods of this invention and for pharmaceutical compositions comprising those compounds.
  • Another aspect of this invention is to provide processes for preparing the compounds of this invention.
  • Still a further aspect of this invention is to provide pharmaceutical compositions containing the compounds of this invention and methods for treating herpes infection in a mammal using those pharmaceutical compositions.
  • halo as used herein means a halo radical selected from bromo, chloro, fluoro or iodo.
  • herpes refers to any virus in the herpes family of viruses and particularly, to those herpesviruses that encode a herpes helicase-primase homologous to the herpes helicase-primase of HSV-1.
  • the herpes family of viruses includes, but is not limited to, HSV-1 , HSV-2, cytomegalovirus, varicella zoster virus and Epstein-Barr virus.
  • lower alkanoyl as used herein, either alone or in combination with another radical, means a straight chain 1-oxoalkyl containing from one to six carbon atoms or a branched chain 1 -oxoalkyl containing from four to six carbon atoms; for example, acetyl, propionyl(1 -oxopropyl), 2-methyl-1- oxopropyl, 2-methylpropionyl and 2-ethylbutyryl. Note that the term “lower alkanoyl” when used in combination with “lower cycloalkyl” would include “(lower cycloalkyl)carbonyl".
  • (1-3C)alkyl as used herein, either alone or in combination with another radical, means alkyl radicals containing from one to three carbon atoms and includes methyl, ethyl, propyl and 1-methylethyl.
  • lower alkyl as used herein, either alone or in combination with another radical, means straight chain alkyl radicals containing one to four carbon atoms and branched chain alkyl radicals containing three to four carbon atoms and includes methyl, ethyl, propyl, butyl, 1-methylethyl, 1 - methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl and 2,2-dimethylpropyl.
  • (1-8C)alkyl as used herein means straight and branched chain alkyl radicals containing from one to eight carbon atoms and includes ethyl, butyl, 1-methylpropyi, 1 -ethylpropyl, 2,2-dimethylpropyl, 1-ethylbutyl, 2-ethyl- 2-methylbutyl, 2-ethylbutyl, 1 -propylbutyl, 2-propylpentyl and the like.
  • lower alkenyl as used herein means an aliphatic hydrocarbon containing two to four carbon atoms and one double bond and includes ethenyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.
  • lower alkynyi as used herein means an aliphatic hydrocarbon containing two to four carbon atoms and one triple bond and includes ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.
  • ⁇ 1 -(lower alkyl)-(lower cycloalkyl) ⁇ means a lower cycloalkyl radical bearing a lower alkyl substituent at position 1 ; for example, 1 -ethylcyclopropyl, 1 -propylcyclopentyl and 1-propylcyclohexyl.
  • lower cycloalkyl as used herein, either alone or in combination with another radical, means saturated cyclic hydrocarbon radicals containing from three to seven carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • lower alkoxy as used herein means straight chain alkoxy radicals containing one to four carbon atoms and branched chain alkoxy radicals containing three to four carbon atoms and includes methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy and 1 ,1 -dimethylethoxy.
  • the latter radical is known commonly as tert-butoxy.
  • amino as used herein means an amino radical of formula -NH2.
  • lower alkylamino as used herein means alkylamino radicals containing one to six carbon atoms and includes methylamino, propylamino, (l -methylethyl)amino and (2-methylbutyl)amino.
  • di(iower alkyl)amino means an amino radical having two lower alkyl substituents each of which contains one to six carbon atoms and includes dimethylamino, diethylamino, ethylmethylamino and the like.
  • Het as used herein means a monovalent radical derived by removal of a hydrogen from a five- or six-membered saturated or unsaturated heterocycle; said five-membered heterocycle containing from one to four nitrogen atoms (for example tetrazolyl), or said five- or six- membered heterocycle containing from one to three heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocycle may bear one or two substituents; for example, ⁇ /-oxido, lower alkyl, phenyl-(1-3C)alkyl, lower alkoxy, halo, amino or lower alkylamino.
  • heterocycles and optionally substituted heterocycles include pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, 1 H-imidazole, 1 -methyl-1 H-imidazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, 2-methylthiazole, 2- aminothiazole, 2-(methylamino)-thiazole, piperidine, 1-methylpipehdine, 1- methylpiperazine, 1 ,4-dioxane, morpholine, pyridine, pyridine ⁇ /-oxide, pyrimidine, 2,4-dihydroxypyrimidine and 2,4-dimethylpyrimidine.
  • bicyclic heterocyclic system as used herein, either alone or in combination with another radical, means a heterocycle as defined above fused to one or more other cycle be it a heterocycle or a lower cycloalkyl.
  • suitable heterocyclic systems include: thiazolo[4,-b]pyridine, quinoline, or indole.
  • pharmaceutically acceptable carrier or “veterinarily acceptable carrier” as used herein means a non-toxic, generally inert vehicle for the active ingredient which does not adversely affect the ingredient.
  • an effective amount means a predetermined antiviral amount of the antiviral agent, i.e. an amount of the agent sufficient to be effective against the virus in vivo.
  • inhibitor when used in connection with enzymatic activity, refers generally to inhibiting the enzymatic activity by at least about 50% at a concentration of about 100 ⁇ M (and preferably at a concentration of about 50 ⁇ M, more preferably, at a concentration of about 25 ⁇ M, even more preferably, at a concentration of about 10 ⁇ M and most preferably, at a concentration of about 5 ⁇ M or less) in a conventional in vitro assay for enzymatic inhibition.
  • inability to inhibit refers generally to inhibiting enzymatic activity by no more than about 50% at concentration of about 100 ⁇ M.
  • a compound with an HSV-1 helicase-primase IC50 value of 1.5 ⁇ M inhibits HSV-1 helicase-primase activity by 50% at a concentration of 1.5 ⁇ M. Therefore, this compound is an HSV-1 helicase-primase inhibitor, as the term is used herein.
  • a compound having an IC50 value of 150 ⁇ M inhibits enzymatic activity by 50% at a concentration of 150 ⁇ M and therefore, is not considered an inhibitor of that enzyme.
  • the compounds of this invention can be prepared by a variety of processes. Description of some such methods are found in standard textbooks such as "Annual Reports In Organic Synthesis - 1994", P.M. Weintraub et al., Eds., Academic Press, Inc., San Diego, CA, USA, 1994 (and the preceding annual reports), "Vogel's Textbook of Practical Organic Chemistry", B.S. Furniss et al., Eds., Longman Group Limited, Essex, UK, 1986, and “Comprehensive Organic Synthesis", B.M. Trost and I. Fleming, Eds., Pergamon Press, Oxford, UK, 1991 , Volumes 1 to 8.
  • R R 2 , R 3 and R 5 are as defined herein, Q is absent (i.e. a valance bond) or methylene, and R4AA J S an am j no protecting group or a radical as defined for R 4 hereinbefore other than hydrogen.
  • a thiazolylaniline derivative of formula 2 is coupled with an amino acid derivative of formula 3 to give a corresponding aminoamide of formula 4.
  • the aminoamide of formula 4 so obtained is a compound of formula 1.
  • R4AA J S an amino protecting group
  • the compound of formula 4 so obtained can be deprotected to give the corresponding compound of formula 1 in which R 4 is hydrogen.
  • the latter product albeit a compound of formula 1 , can also serve as an intermediate for further elaboration by standard methods to yield compounds of formula 1 in which R 4 is other than hydrogen.
  • the coupling of the 4-thiazolylaniline derivative of formula 2 and the amino acid of formula 3 is effected by the classical dehydrative coupling of a free carboxyl of one reactant with the free amino group of the other reactant in the presence of coupling agent to form a linking amide bond.
  • coupling agents are found in general textbooks on peptide chemistry; for example, M. Bodanszky, "Peptide Chemistry", 2nd rev ed, Springer- Verlag, Berlin, Germany, 1993.
  • Suitable coupling agents are ⁇ /, ⁇ /'-dicyclohexyl-carbodiimide, 1 -hydroxybenzotriazole in the presence of ⁇ /, ⁇ /'-dicyclohexylcarbodiimide or ⁇ /-ethyl- ⁇ /'- ⁇ (3- dimethylamino)propyl ⁇ carbodiimide.
  • a very practical and useful coupling agent is the commercially available (benzotriazol-1 -yloxy)tri-
  • the coupling reaction is conducted in an inert solvent, e.g. dichloromethane, dimethylformamide, tetrahydrofuran or acetonitrile.
  • An excess of a tertiary amine, e.g. diisopropylethylamine or ⁇ /-methylmorpholine, is added to maintain the reaction mixture at a pH of about eight.
  • the reaction temperature usually ranges between 0° and 50 °C and the reaction time usually ranges between 15 minutes and 24 hours.
  • Scheme 1 A practical and convenient variation of the preceding process (Scheme 1) can be practiced by replacing the 4-thiazolylaniline derivative 2 with 4'- aminoacetophenone. This process is illustrated by Scheme 2:
  • R 2AA is lower alkyl and R 3 , R 4 A ) R5 and Q are as defined hereinbefore.
  • the compound of formula 5, namely 4'-aminoacetophenone is coupled with amino acid derivative of formula 3, noted hereinbefore, to give a corresponding terminal methyl ketone of formula 6.
  • the methyl ketone 6 can be used to prepare corresponding compounds of formula 1 wherein R 2 is hydrogen as follows: The methyl ketone was reacted with thiourea and iodine according to the method of R.M. Dodson and L.C. King, J. Amer. Chem Soc. 1945, 67, 2242 to give the corresponding aminothiazole derivative of formula 7. In the instance where R4AA nas th e same significance as R 4 but excluding hydrogen, then the aminothiazole derivative of formula 7 so obtained is a compound of formula 1.
  • the derivative of formula 7 so obtained can be deprotected to give a corresponding compound of Group 1 -formula 1 wherein R 4 is hydrogen.
  • the latter derivative can be converted by standard methods (e.g., N- alkylation, acylation, carbamate formation, etc.) with the appropriate agent to give corresponding compounds of formula 1 wherein R 4 is as defined hereinbefore other than hydrogen.
  • the methyl ketone of formula 6 can be used to prepare compounds of formula 1 wherein R 2 is lower alkyl. Accordingly, the methyl ketone of formula 6 is subjected to ⁇ /-alkylation with an appropriate lower alkyl bromide, chloride or iodide in the presence of a base to give the corresponding ⁇ /-alkylated derivative of formula 8 wherein R 2AA is lower alkyl and Q, R 3 , R4AA and R5 are as de fined hereinbefore.
  • R 1 is NH 2 , R 2 and R 3 each is H, Q is absent, R 4 is as defined herein, and R 5 is R 55 which is as defined herein for R 5 with the exception that it is not an acyl group
  • PG is an amino protecting group
  • R 1 is amino
  • R 2 and R 3 each is hydrogen
  • Q is absent
  • R 4 and R 55 are as defined hereinbefore.
  • the amino acid derivative of formula 3, noted in Schemes 1 and 2 can be prepared readily by methods used in peptide chemistry.
  • the ⁇ /-monosubstituted and ⁇ /, ⁇ /-disubstituted glycine derivatives of formula 3, wherein Q is absent can be prepared by substituting the bromine of the appropriate ethyl bromoacetate with an appropriate primary or secondary amine in the presence of a tertiary amine for example, triethylamine or N- methylmorpholine, to obtain the corresponding ⁇ -aminoester having either a monosubstituted or disubstituted amino group.
  • amino protective groups suitable for use in the above schemes include benzyloxycarbonyl, terf-butoxycarbonyl, 4- methoxybenzyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl.
  • reaction may not be applicable as described to each compound included within the disclosed scope.
  • the compounds for which this occurs will be readily recognized by those skilled in the art.
  • the reaction can be successfully performed by conventional modification known to those skilled in the art, e.g. by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, or by modification illustrated in the examples herein.
  • the compound of formula 1 can be obtained in the form of a therapeutically acceptable acid addition salt.
  • Such salts can be considered as biological equivalent of the compounds of formula 1. Examples of such salts are those formed with hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid or citric acid.
  • the antiviral activity of the compounds of formula 1 can be demonstrated by biochemical, microbiological and biological procedures showing the inhibitory effect of the compounds on the replication of herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), cytomegalovirus, as well as acyclovir-resistant herpes simplex viruses and ganciclovir-resistant cytomegaloviruses.
  • a biochemical procedure for demonstrating antiherpes activity for compounds of formula 1 is described in the examples hereinafter. This particular assay is based on the evaluation of the ability of the test compound to inhibit HSV-1 helicase-primase, an essential enzyme for viral DNA replication. Methods for demonstrating the inhibitory effect of the compounds of formula 1 on herpes viral replication involving in vitro and cell culture techniques are described in the examples.
  • the therapeutic effect of the compounds of formula 1 can be demonstrated in laboratory animals, for instance, the hairless mouse model for the topical treatment of cutaneous HSV-1 infections, P.H. Lee et al., International Journal of Pharmaceutics, 1993, 93, 139; the (HSV-2)-induced genitalis mouse model, R.W. Sidewell et al., Chemotherapy, 1990, 36, 58; and BALB/C mouse model infected with murine cytomegalovirus, D.L. Barnard et al., Antiviral Res., 1993, 22, 77, and J. Neyts et al., Journal of Medical Virology, 1992, 37, 67.
  • a compound of formula 1 When a compound of formula 1 , or one of its therapeutically acceptable acid addition salts, is employed as an antiviral agent, it is administered orally, topically or systemically to warm-blooded animals, e.g. humans, pigs or horses, in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice.
  • the compound or a therapeutically acceptable salt thereof can be formulated in unit dosage forms such as capsules or tablets each containing a predetermined amount of the active ingredient, ranging from about 25 to 500 mg, in a pharmaceutically acceptable carrier.
  • the compound For topical administration, the compound can be formulated in pharmaceutically accepted vehicles containing 0.1 to 5 percent, preferably 0.5 to 5 percent, of the active agent. Such formulations can be in the form of a solution, cream or lotion.
  • the compound of formula 1 is administered by either intravenous, subcutaneous or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers.
  • pharmaceutically acceptable vehicles or carriers for parenteral administration, it is preferred to use the compounds in solution in a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic.
  • Suitable vehicles or carriers for the above noted formulations are described in standard pharmaceutical texts, e.g. in "Remington's The Science and Pratice of Pharmacy", 19th ed., Mack Publishing Company, Easton, Penn., 1995, or in “Pharmaceutical Dosage Forms And Drugs Delivery Systems", 6th ed., H.C. Ansel et al., Eds., Williams & Wilkins, Baltimore, Maryland, 1995.
  • the dosage of the compound will vary with the form of administration and the particular active agent chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small increments until the optimum effect under the circumstance is reached. In general, the compound of formula 1 is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
  • the compound or a therapeutically acceptable salt is administered in the range of 10 to 200 mg per kilogram of body weight per day, with a preferred range of 25 to 150 mg per kilogram.
  • the compound of formula 1 is administered topically in a suitable formulation to the infected area of the body e.g. the skin, the eye, the genitalia or part of the oral cavity, in an amount sufficient to cover the infected area.
  • the treatment should be repeated, for example, every four to six hours until lesions heal.
  • the compound of formula 1 is administered either topically or intraocularly (injection or implant) in a suitable preparation.
  • an implant containing the compound in a suitable formulation can be surgically placed in the posterior segment of the eye through a small incision.
  • the compound of formula 1 is administered at a dosage of 10 mg to 150 mg per kilogram of body weight per day, although the aforementioned variations will occur. However, a dosage level that is in the range of from about 10 mg to 100 mg per kilogram of body weight per day is most desirably employed in order to achieve effective results.
  • formulations disclosed hereinabove are indicated to be effective and relatively safe medications for treating herpes viral infections, the possible concurrent administration of these formulations with other antiviral medications or agents to obtain beneficial results also included.
  • other antiviral medications or agents include the antiviral nucleosides, for example, acyciovir, penciclovir, famciclovir, valacyclovir and ganciclovir, and antiviral surface active agents or antiviral interferons such as those disclosed by S.S. Asculai and F. Rapp in U.S. patent 4,507,281 , March 26, 1985.
  • ATP adenosine triphosphate
  • Boc tert-butoxycarbonyl or 1 ,1-dimethylethoxycarbonyl
  • BOP (benzotriazole-l -yloxy)tris- (dimethylamino)phosphonium hexafluorophosphate
  • Bu butyl
  • DIPEA diisopropyiethylamine
  • DMAP 4-(dimethylamino)pyridine
  • DMF dimethyl- formamide
  • DMSO dimethylsulphoxide
  • Et ethyl
  • EtOAc ethyl acetate
  • Et_2 ⁇ diethyl ether
  • Et 3 N triethylamine
  • EtOH ethanol
  • FAB/MS fast atom bombardment mass spectrometry
  • Hex hexane
  • mAb monoclonal antibody
  • Me methyl
  • MeOH methanol
  • PFU plaque forming units
  • Ph phenyl
  • Pr propyl
  • TBTU 2-(1 H-benzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ ',/V'- tetramethyluronium tetrafluoroborate
  • TFA t ⁇ fluoroacetic acid
  • THF- tetrahydrofuran tetrahydrofuran.
  • Phenyl trimethylammoniumtribromide (3.52 g, 4.37 mmol) was added portion wise to a stirred solution of N- ⁇ 2- ⁇ (4-acetylphenyl)amino ⁇ -2-oxoethyl ⁇ -N- (benzyl)benzam ⁇ de (2.5 g, 6.46 mmol) in THF (150 mL) at room temperature. The resulting mixture was then stirred for 2h. The reaction was stopped by the addition of EtOAc (300 mL).
  • 2,2,2-Tr ⁇ chloroethyl ⁇ /- ⁇ 4-(2-am ⁇ no-4-th ⁇ azolyl)-phenyl ⁇ carbamate 2,2,2- Trichloroethyl chloroformate (72.3 mL, 0.52 mol) was added (5 mm) to an ice cold suspension of 4'-am ⁇ noacetophenone (67.6 g, 0.50 mol) and pyridine (50.5 mL, 0.62 mol). The reaction mixture was stirred at 0° for 15 mm and then at room temperature (20-22°) for 45 mm. The solvent was removed under reduced pressure. Et ⁇ O (500 mL) and 1 N aqueous HCl (500 mL) were added to the residue.
  • the following four assays (A, B and Ci and C11) were used to evaluate antiherpes activity, and a fifth assay (D) was used to measure the stabilization of the DNA-herpes helicase-primase interaction.
  • HSV-1 DNA-Depende ⁇ t ATP Assay an in vitro assay based on the inhibition of HSV-1 helicase-primase.
  • the reaction mixtures (80 ⁇ L each) contained 40 mM 4-(2- hydroxyethyl)-1-p ⁇ peraz ⁇ neethanesulfon ⁇ c acid (HEPES, pH 7.5), 10% (v/v) glycerol, 5.5 mM MgCl2, 1 mM DL-dithiothreitol (DTT), 50 ⁇ g/mL acetylated bovine serum albumin, 3.3% (v/v) DMSO, 4 mM ATP, 25 ⁇ M single-stranded M13 DNA hybridized to double-tailed 68- ⁇ mer oligonucleotide and 3 ⁇ g/mL HSV-1 helicase-primase.
  • HSV-1 Herpes Simplex Virus
  • Assay BHK-21 cells clone 13 (ATCC CCL10) were incubated for two days in 850 cm 2 roller bottles (2x10 7 cells/bottle) with ⁇ -MEM medium (Gibco Canada Inc., Burlington, Ontario, Canada) supplemented with 8% (v/v) fetal bovine serum (FBS, Gibco Canada, Inc ).
  • the cells were trypsinized and then 3,000 ceils in 100 ⁇ L of fresh medium were transferred into each well of a 96-well microtiter plate.
  • the cells were incubated at 37° for a period of 3 days to reach a density of 50,000 ceils per well.
  • the cells were washed twice with 100 ⁇ L of ⁇ -MEM supplemented with 2% heat inactivated FBS and incubated for 1 -2 hours in 100 ⁇ L of the same medium.
  • the plate was washed three times with 200 ⁇ L of the above-noted phosphate buffer saline preparation, and then once with 0.1 M sodium citrate (pH 4.5). Thereafter, 100 ⁇ L of orthophenylenediamine dihydrochlo ⁇ de (OPD, Gibco, Canada Inc.) was added to each well. The plate was agitated on a microplate shaker for 30 mm in the dark. Color development was monitored at 450 nm using a microplate spectrophotometer
  • SAS was used to calculate % inhibition of viral replication and to generate EC50 values.
  • ELISA ELISA-based assay
  • PRA plaque reduction assay
  • Hs-68 cells (ATCC # CRL 1635) were seeded in 96 well microtiter plates at 10,000 ceils/well in 100 ⁇ L of DMEM medium (Gibco Canada Inc.) supplemented with 10% fetal bovine serum (FBS, Gibco Canada Inc.). The plates were incubated for 3 days at 37° to allow the cells to reach 80-90% confluency prior to the assay.
  • DMEM medium Gibco Canada Inc.
  • FBS fetal bovine serum
  • the medium was removed from wells by aspiration.
  • the cells then were infected at a multiplicity of infection (MOI) of 0.01 PFU/cell with 50 ⁇ L of HCMV (strain AD169, ATCC VR-538) in DMEM medium supplemented with 5% heat inactivated FBS (assay medium).
  • MOI multiplicity of infection
  • the virus was allowed to adsorb to cells for 2 h at 37°.
  • the medium was removed from the wells by aspiration.
  • the cells were washed twice with 200 ⁇ L of assay medium to remove unabsorbed virus.
  • the cells were then incubated with or without 100 ⁇ L of appropriate concentrations of test reagent in assay medium. After 8 days of incubation at 37°, the extent of viral replication was determined by an ELISA assay which detects the late structural protein p28 of HCMV.
  • the medium was aspirated from the wells. Nonspecific binding sites were blocked by adding 200 ⁇ L of phosphate buffered saline containing 1 % (w/v) bovine serum albumin (blocking buffer) to each well and incubating the plates for 30 mm at room temperature After removal of the blocking buffer by aspiration, the cells were fixed with 100 ⁇ L of cold ethanol-acetone solution (95.5) per well. The plates were placed at - 20° for 30 mm. The plates were washed 4 times with phosphate buffered saline containing 0.05% (v/v) polyoxyethylene sorbitan monoiaurate (Tween 20®).
  • mAb UL99 Advanced Biotechnologies Inc., # 13-130-100 recognizing HCMV protein p28 was added to each wells and plates were incubated for 2 h at room temperature. The plates were washed four times with 200 ⁇ L of the above-noted phosphate buffered sal e/Tween- 20® solution. The cells were then incubated with 100 ⁇ L of sheep anti- mouse IgG ⁇ horseradish peroxidase conjugated for 2 h at room temperature. The plates were then washed four times with 200 ⁇ L of above- noted phosphate buffered sal ⁇ ne/Tween-20® solution.
  • the SAS program was used to calculate the % inhibition of viral replication and to generate EC50 values.
  • Hs-68 cells ( ATCC # CRL 1635) were seeded in 12-weil plates at 83,000 cells/well in 1 mL of DMEM medium (Gibco Canada Inc.) supplemented with 10% fetal bovine serum (FBS, Gibco Canada Inc.). The plates were incubated for 3 days at 37° to allow the cells to reach 80-90% confluency prior to the assay.
  • DMEM medium Gibco Canada Inc.
  • FBS fetal bovine serum
  • the medium was removed from the cells by aspiration.
  • the cells were then infected with approximately 50 PFU of HCMV (strain AD169, ATCC VR-538) in DMEM medium supplemented with 5% inactivated FBS (assay medium).
  • the virus was allowed to adsorb to cells for 2 h at 37°. Following viral adsorption, the medium was removed from the wells by aspiration.
  • the cells were then incubated with or without 1 mL of appropriate concentrations of test reagent in assay medium. After 4 days of incubation at 37°, the medium was exchanged with fresh medium containing test compound and 4 days later the cells were fixed with 1% aqueous formaldehyde and stained with a 2% crystal violet solution in 20% ethanol in water.
  • a preferred group of compound of preceding TABLES 1 to 6 are those designated as entry numbers 107, 109, 1 1 1 and 1 14 in TABLE 1 ; as entry numbers 201 , 203, 205, 206 and 207 in TABLE 2; as entry numbers 305, 308, 313 and 314 in TABLE 3; as entry numbers 407, 412, 413, 427 and 438 in TABLE 4; and as entry numbers 51 1 and 536 in TABLE 5.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed herein are compounds of the general formula X-Aryl-Y-Z wherein X is a five or six-membered aromatic heterocycle attached to an Aryl group, for example a phenyl group; Y is absent or a bridging group, for example NHC(O)CH2; and Z is a terminal group, for example NHC(O)OC(CH3)3 or (I). The compounds inhibit the herpes helicase-primase enzyme, rendering the compounds useful as antiviral agents. Also disclosed are pharmaceutical compositions comprising the compounds, as well as methods of preparing and using the compounds.

Description

ANTIHERPES COMPOUNDS
Technical Field of the Invention
This invention relates to methods for inhibiting herpes replication and for treating herpes infection in a mammal In a preferred embodiment, this invention relates to compounds that inhibit the herpes helicase-primase enzyme complex. This invention also relates to pharmaceutical compositions comprising the compounds, to methods of using and producing the compounds
Background of the Invention
Herpesviruses inflict a wide range of diseases against humans and animals For instance, herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), are responsible for cold sores and genital lesions, respectively; varicella zoster virus (VZV) causes chicken pox and shingles; and the human cytomegalovirus (HCMV) is a leading cause of opportunistic infections in immunosuppressed individuals
Herpesviruses are complex double-stranded DNA viruses that encode all the enzymes that directly mediate viral chromosomal replication Seven DNA replication-associated polypeptides are required for human herpesvirus replication Six of these seven polypeptides show a high degree of homology across all studied human herpesviruses. These six polypeptides, when expressed by the virus, constitute a heterodimeπc DNA-dependent DNA polymerase, a monomeπc single-stranded DNA binding protein, and a heterotrimeπc helicase-primase complex. The seventh DNA replication- associated polypeptide does not display sequence or functional conservation and is involved in the initiation of lytic viral replication
Without the function of each of the seven herpesvirus-specific DNA replication proteins, herpesvirus chromosomal replication will not initiate or propagate This has been demonstrated in two ways for DNA replication in HSV-1. First, temperature sensitive HSV-1 strains have been developed and the complementation groups within these strains mapped on a one-to- one correspondence to the seven HSV DNA replication genes. Additionally, transient replication assays that utilized recombinant DNA plasmids containing single DNA replication genes have found that the presence of each of the seven genes was required for the efficient replication of a tester plasmid containing an HSV-1 origin of DNA replication.
More recently, the DNA replication genes in other herpesviruses (i.e., Epstein-Barr virus, cytomegalovirus and varicella zoster virus) have been delineated. These gene sequences were identified as homologous to the HSV-1 DNA replication genes. Furthermore, transient replication assays containing either an Epstein-Barr virus or cytomegalovirus lytic origin of DNA replication confirmed their identity. In varicella zoster virus (the human herpesvirus most closely related to HSV-1 ) DNA replication genes were found to be highly homologous to HSV-1 (>50% at the amino acid level) and present at identical relative locations on the two viral chromosomes. Although no follow-up analysis on varicella zoster virus DNA replication genes has been presented to date, it is highly unlikely that differences in the varicella zoster virus and HSV-1 DNA replication programs exist.
From the above, it is clear that human DNA replication proteins are unable to substitute for the HSV-1 encoded enzymes. Otherwise, temperature- sensitive viral polypeptides would have been complemented by human counterparts and the defective viruses would have continued to grow and replicate, even at elevated temperatures. Similarly, in transient replication assays, if human proteins were capable of complementing any of the seven herpesvirus-encoded polypeptides, an absolute dependence on the presence of each of these herpesvirus DNA replication-specific genes would not have been observed. Therefore, inhibiting the activity of those virally- encoded proteins represents an effective way of preventing herpesviral replication. The helicase-primase enzyme occupies a key and critical place in the herpesvirus DNA replication program. The observation that the genes encoding the herpes helicase-primase are not only essential for replication, but are also highly conserved across the range of known herpesviruses underscores the importance of this enzyme in mediating viral chromosomal replication.
In the helicase-primase complex, two of the three polypeptides (e.g., the expression products of the UL5 and UL52 genes of HSV-1 ) promote catalysis of duplex DNA unwinding and RNA primer biosynthesis. The third polypeptide, encoded by the UL8 gene, appears to modulate primase activity. The assembled helicase-primase enzyme complex functions both in the initiation and propagation stages of herpesvirus DNA replication. It is responsible for the synthesis of RNA primers necessary for the initiation of all new DNA synthesis by the herpesvirus DNA polymerase. Additionally, for DNA replication to proceed, duplex viral chromosomal DNA must first be unwound to the single-stranded replicative intermediate because the herpesvirus DNA polymerase is inactive on fully duplex DNA. The helicase- primase is also responsible for this important DNA unwinding event.
Conventional anti-herpes therapies have not focused on inhibiting the activity of the herpes helicase-primase(see R.E. Boehme et al., Annual Reports in Medicinal Chemistry, 1995, 30, 139). The most widely used anti- herpes agents to date are purine and pyrimidine nucleoside analogs, such as acyciovir and ganciclovir. These nucleoside analogues inhibit replication of viral DNA by their incorporation into a growing DNA strand. The nucleoside analogue-based inhibitors of HSV-1 growth have found only limited success and are not generally useful in treating recurring infections in the majority of patients. In addition, the infection of humans by other herpesviruses, such as varicella zoster virus or cytomegalovirus, show little or no responsiveness to nucleoside-based therapies.
The lack of broad spectrum anti-herpesvirus activity by the nucleoside- based therapies is not surprising because these compounds act by indirect biological mechanisms. Nucleoside analogues must first be activated to the nucleoside monophosphate by a virally-encoded thymidine kinase enzyme. It should be pointed out that only HSV and varicella zoster virus encode thymidine kinase enzymes. This may, in part, explain the inability to adapt nucleoside-based therapies to the treatment of other human herpesviruses. After initial phosphorylation, the nucleoside analogue monophosphate must be further phosphorylated to the triphosphate by human-encoded enzymes prior to its action. Ultimately, the triphosphorylated nucleoside analogue is incorporated into a nascent DNA chain during viral genomic replication, thereby inhibiting the elongation of that DNA chain by the herpes DNA polymerase.
The final incorporation step of the nucleoside-based therapies has been characterized as "competitive" because the herpes DNA polymerase does not display a preference for the activated nucleoside drug versus normal deoxynucleoside triphosphates. However, because the action of the DNA polymerase is not considered rate-limiting for herpesvirus DNA replication, the utility of nucleoside-derived compounds in treating herpesvirus infections is necessarily limited. Accordingly, the need for effective, safe therapeutic agents for treating herpesvirus infections continues to exist.
Y. Kawamatsu et al., Eur. J. Med. Chem.-Chimica Therapeutica, 1981 , 16,
355;
K.D. Hargrave et al., J. Med. Chem., 1983, 26, 1158; T. Nakao et al., Japanese patent application 63-060978, published
September 1 , 1986; Chem. Abstr., 1989, 110, 716, 135228r;
C.G. Caldwell et al., US patent 4,746,669, issued May 24, 1988;
J.A. Lowe, European patent application 279,598, published August 24,
1988; A.A. Nagel, European patent application 372,776 published June 13, 1990;
J.A. Lowe et al., J. Med. Chem., 1991 , 34, 1860;
A. Bernat et al., Canadian patent application 2,046,883, publisehd June 30,
1991 ;
A. Wissner, US patent 5,077,409, issued December 31 , 1991 ; Y. Katsura et al., European patent application 545,376, published June 9,
1993;
J.E. Macor and J.T. Nowakowski, PCT patent application WO 93/18032, published September 16, 1993; D.I.C. Scopes et al., UK patent application 2,276,164, published September
21 , 1994;
A. Leonardi et al., PCT patent application WO 95/04049, published February
9, 1995;
G.D. Hartman et al., PCT patent application WO 95/32710, published December 7, 1995;
J.J. Crute et al., PCT patent application WO 97/24343, published July 10,
1997;
CN. Selway and N.K. Terret, Bioorganic & Medicinal Chemistry, 1996, 4,
645; and F.C. Spector et al., J. Virol. 1998, 72, 6979.
The present non-nucleoside-based compounds can be distinguished from the prior art compounds by their different chemical structures and biological activities.
Summary of the Invention
The invention described herein overcomes the above-mentioned limitations and satisfies the above-mentioned needs by providing non-nucleoside- based compounds, which are inhibitors of herpes viral replication, such as for example inhibitors that act directly in interfering with the likely rate- limiting process in herpesvirus DNA replication: the action of the helicase- primase enzyme. Furthermore, since the herpesvirus helicase-primase enzyme is conserved across the human herpesviruses, such compounds of this invention are effective against the full spectrum of herpesviruses, including HSV, varicella zoster virus and cytomegalovirus, and also against nucleoside-nonresponsive and nucleoside-resistant herpes infections. The non-nucleoside-based compounds may be characterized by having a five- or six-membered heterocycle attached to a phenyl or pyridinyl ring. Compounds possessing such a moiety have been reported previously, for example:
The non-nucleoside-based compounds are represented by formula 1
X-Aryl-Y-Z (1 ) wherein (i) X is selected from the group consisting of:
H, H2NC(O)NHCHMe, NH2S(0)2— ,
Figure imgf000008_0001
Aryl is selected from the group consisting of:
Figure imgf000009_0001
Y is N C(0) CH wherein R2 is H or lower alkyl, and
R3 is H; lower alkyl; (lower cycloalkyl)-(lower alkyl) (e.g. CH2-(cyclohexyl); phenyl(lower alkyl); phenyl(lower alkyl) monosubstituted, disubstituted or trisubstituted on the aromatic portion thereof with a substituent or substituents selected independently from the group consisting of halo, hydroxy, lower alkoxy, lower alkoxy, lower alkyl, azido and t fluoromethyl; CH2-Het; or CH2-(bicyclic heterocyclic system); and
Z is NR4R5 wherein
R4 is H, phenyl(lower alkyl) (e.g. CH2Ph) or phenyl(lower alkyl) monosubstituted, disubstituted or trisubstituted on the aromatic portion thereof with a substituent or substituents selected independently from the group consisting of halo, hydroxy, lower alkoxy, lower alkyl, azido and thfluoromethyl, or
R4 is selected from the group consisting of:
Figure imgf000009_0002
and R5 is selected from the group consisting of:
C(O)(CH2)5NH2; CH2C(O)N(Me)CH2Ph; CH2C(0)NHCH2Ph; C(O)CH2OH;
Figure imgf000010_0001
or R5 is
when R is
Figure imgf000010_0002
or a mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl;
or R5 is
Figure imgf000010_0003
when R is
Figure imgf000011_0001
or a mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl;
or R5 is selected from the group consisting of:
Figure imgf000011_0002
when R3 is CH2-(cyclohexyl);
Figure imgf000011_0003
or R5 is ox C(O)OCMe3 when R3 is CH2CH2CH2NH2,
Figure imgf000011_0004
or R5 is C(O)Ph, when X is NH2S(O)2, H2NC(O)NHCHMe,
Figure imgf000011_0005
or R5 is phenyl(lower alkyl) or mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl,
Figure imgf000012_0001
or R3 is C(0)OCMe3
Figure imgf000012_0002
when X is
or
(ii) X and Aryl are as defined above;
l _ Y is N C(0) wherein R2 is H or lower alkyl, and
Z is selected from the group consisting of:
CH2OCH2Ph, CH2OPh, OCH2CHMe2, CH2CH2Ph, CH2CH2CH2Ph, CH2SCH2Ph, CH=CHPh, CH2CH2CH2CH2C(O)NPh2> CH2CH2CH2CH2CH2NH2, CH2CH2NH2, CH(NH2)(CH2)4NHC(O)OCH2Ph, (S)- CH(NHCH2Ph)(CH2)4NHC(O)OCH2Ph,
(S)-CH2C(O)NHCH(Me)Ph, (f?)-CH(NH2)(CH2)4NHC(O)OCH2Ph, CH2CH2NH2, CH2CH2NHC(O)CH2N(CH2Ph)2, CH2CH2NHC(O)N(CH2Ph)2, CH2CH2CH2C(O)N(CH2Ph)2, CH2CH2C(O)N(CH2Ph)2,
Figure imgf000013_0001
Figure imgf000014_0001
XH2Ph
CH2CH2NHC(Q)CH2N C(0)Ph
Figure imgf000014_0002
CH2OH
Figure imgf000014_0003
or
(iii) X and Aryl are as defined above; Y is absent (i.e. a valence bond); and Z is selected from the group consisting of:
NHCH2C(O)N(Me)CH2Ph, NHCH2C(O)NHCH2Ph, OCH2C(O)N(Me)CMe3, OCH2C(S)NHCH2Ph, NHC(S)NHCH2Ph, C(O)OMe, CH2CH2NH-S(O)2-CH2Ph, CH2CH2NHC(O)CH2CH2C(O)Ph, CH2CH2N(CH2Ph)C(O)CH2Ph, CH2CH2N(CH2Ph)S(0)2CH2Ph, CH2CH2NHC(O)CH2CH2C(O)NHCH2Ph,
CH2CH2NHC(0)CH2NHC(O)OCMe3, CH2CH2NHCH2C(0)N(CH2Ph)2, CH2NHCH2C(O)N(CH2Ph)2,
Figure imgf000015_0001
C(0)N(CH2Ph)CH2C(0)
Figure imgf000015_0002
Figure imgf000016_0001
Figure imgf000017_0001
CH2CH2NHC(0)- -C(0)NHCH2Ph ,CH2Ph
CH2CH2N
C(0)C(0)Ph
CH2Ph
CH2CH2Ph
CH2CH2N ^
CH2CH2NHC(0)CH-NHC(0)OCMe3 C(0)CH2NHC(0)CH2Ph
)
CH,Ph
CH2CH2N ^
C(0)CH2NHC(0)OCMe3
Figure imgf000017_0002
H2Ph H2Ph
C(0)NHCH2CH2N^ CH2CH2N \
CH2C(0)OCMe3 C(0)CH2NHC(0)NHPh ,CH2Ph H2Ph
C(0)NHCH2CH2Nχ C(0)NHCH2CH2N^
CH2C(0)NHPh CH2C(Q)NHCH2Ph H2Ph CH2CH2N ^
C(0)CH2NHC(0)NHCMe3
Figure imgf000018_0001
or
(iv) X is selected from the group consisting of:
Figure imgf000018_0002
Figure imgf000019_0001
Figure imgf000019_0002
Y is absent; and
Z is selected from the group consisting of: NHC(0)NH-CHPr2, NHC(S)NBu2, NHC(0)NBu2, NHC(O)CH2CH2N(CH2Ph)2,
Figure imgf000019_0003
or
(v) X and Aryl together form X' which is defined as
Figure imgf000019_0004
and Y and Z are as defined in paragraph (i).
A preferred group of compounds is represented by formula 1 wherein X is
Figure imgf000019_0005
Figure imgf000020_0001
Y is N— C(0) CH wherein R2 is hydrogen and R3 is H,
Figure imgf000020_0002
Z is NR4R5 wherein
R4 is H, CH2Ph,
Figure imgf000020_0003
R5 is
Figure imgf000021_0001
Figure imgf000021_0002
A more preferred group is represented by formula 1 wherein X is as defined
Figure imgf000021_0003
in the last instance, Aryl is wherein R2 is H and R3 is H,
Figure imgf000021_0004
Z is NR R wherein
Figure imgf000021_0005
A most preferred group is represented by formula 1 wherein X is
Figure imgf000022_0001
RJ
Y is N— (°) CH wnerein R 2 is hydrogen and R 3 is H)
Figure imgf000022_0002
Z is NR4R5 wherein R4 is H, CH2Ph,
Figure imgf000022_0003
R5is
Figure imgf000023_0001
Figure imgf000023_0002
Still another most preferred group is represented by formula 1 wherein X is
Figure imgf000023_0003
as defined in the last instance, Aryl is Y is R2 R3
I I
N— C(O) CH wnerein R2 js H and R3 is H Qr
Figure imgf000023_0004
and Z is NR R5 wherein R4 is H or CH2Ph, and R5 is
Figure imgf000023_0005
Another preferred group of compounds is represented by formula 1 wherein
X is
Figure imgf000023_0006
, Aryl is , Y is NH-C(O) and Z is
Figure imgf000023_0007
Figure imgf000024_0001
CH2Ph
CH2CH2NN H2Ph
C(0)CH2N
~C(0)OCMe3 or
Figure imgf000024_0002
Another more preferred group is represented by formula 1 where X, Aryl and Y are as defined in the last instance and Z is
CH, 2OCV"H'2 CH 2,C"H',2C"H'2 CH, 2Cs"H ■,2CWH, ,,2CV"H,2
Figure imgf000024_0003
Still another preferred group of compounds is represented by formula 1
wherein X is
Figure imgf000024_0004
Aryl is and Z is
,CH2Ph
NHC(S)CH2N
C(0)OCMe3
Figure imgf000025_0001
Still another more preferred group of compounds is represented by formula 1 wherein X, Aryl and Y are defined in the last instance and Z is
Figure imgf000025_0002
Yet another preferred group of compounds is represented by formula wherein X is
Figure imgf000025_0003
defined herebefore, and Z is NHC(O)NBu2.
Again, another preferred group of compounds is represented by formula 1 wherein X and Aryl together form X1 which is defined as
Figure imgf000025_0004
wherejn R3 is H or PnCH2j Y js as defined hereinbefore and Z is NR4R5 wherein R4 is H or CH2Ph and R5 is C(O)OCMe3.
A further aspect of this invention is to provide compounds useful in the methods of this invention and for pharmaceutical compositions comprising those compounds.
Another aspect of this invention is to provide processes for preparing the compounds of this invention.
Still a further aspect of this invention is to provide pharmaceutical compositions containing the compounds of this invention and methods for treating herpes infection in a mammal using those pharmaceutical compositions.
Detailed Description of the Invention
As used herein, the following definitions apply unless otherwise noted:
With reference to the instances where (R) ox (S) is used to designate the configuration of a radical, e.g. R^ of the compound of formula 1 , the designation is done in the context of the compound and not in the context of the radical alone.
The term "halo" as used herein means a halo radical selected from bromo, chloro, fluoro or iodo.
The term "herpes" as used herein refers to any virus in the herpes family of viruses and particularly, to those herpesviruses that encode a herpes helicase-primase homologous to the herpes helicase-primase of HSV-1. The herpes family of viruses includes, but is not limited to, HSV-1 , HSV-2, cytomegalovirus, varicella zoster virus and Epstein-Barr virus. The term "lower alkanoyl" as used herein, either alone or in combination with another radical, means a straight chain 1-oxoalkyl containing from one to six carbon atoms or a branched chain 1 -oxoalkyl containing from four to six carbon atoms; for example, acetyl, propionyl(1 -oxopropyl), 2-methyl-1- oxopropyl, 2-methylpropionyl and 2-ethylbutyryl. Note that the term "lower alkanoyl" when used in combination with "lower cycloalkyl" would include "(lower cycloalkyl)carbonyl".
The term "(1-3C)alkyl" as used herein, either alone or in combination with another radical, means alkyl radicals containing from one to three carbon atoms and includes methyl, ethyl, propyl and 1-methylethyl.
The term "lower alkyl" as used herein, either alone or in combination with another radical, means straight chain alkyl radicals containing one to four carbon atoms and branched chain alkyl radicals containing three to four carbon atoms and includes methyl, ethyl, propyl, butyl, 1-methylethyl, 1 - methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl and 2,2-dimethylpropyl.
The term "(1-8C)alkyl" as used herein means straight and branched chain alkyl radicals containing from one to eight carbon atoms and includes ethyl, butyl, 1-methylpropyi, 1 -ethylpropyl, 2,2-dimethylpropyl, 1-ethylbutyl, 2-ethyl- 2-methylbutyl, 2-ethylbutyl, 1 -propylbutyl, 2-propylpentyl and the like.
The term "lower alkenyl" as used herein means an aliphatic hydrocarbon containing two to four carbon atoms and one double bond and includes ethenyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.
The term "lower alkynyi" as used herein means an aliphatic hydrocarbon containing two to four carbon atoms and one triple bond and includes ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.
The term "{1 -(lower alkyl)-(lower cycloalkyl)}" as used herein means a lower cycloalkyl radical bearing a lower alkyl substituent at position 1 ; for example, 1 -ethylcyclopropyl, 1 -propylcyclopentyl and 1-propylcyclohexyl. The term "lower cycloalkyl" as used herein, either alone or in combination with another radical, means saturated cyclic hydrocarbon radicals containing from three to seven carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "lower alkoxy" as used herein means straight chain alkoxy radicals containing one to four carbon atoms and branched chain alkoxy radicals containing three to four carbon atoms and includes methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy and 1 ,1 -dimethylethoxy. The latter radical is known commonly as tert-butoxy.
The term "amino" as used herein means an amino radical of formula -NH2. The term "lower alkylamino" as used herein means alkylamino radicals containing one to six carbon atoms and includes methylamino, propylamino, (l -methylethyl)amino and (2-methylbutyl)amino. The term "di(iower alkyl)amino" means an amino radical having two lower alkyl substituents each of which contains one to six carbon atoms and includes dimethylamino, diethylamino, ethylmethylamino and the like.
The term "Het" as used herein means a monovalent radical derived by removal of a hydrogen from a five- or six-membered saturated or unsaturated heterocycle; said five-membered heterocycle containing from one to four nitrogen atoms (for example tetrazolyl), or said five- or six- membered heterocycle containing from one to three heteroatoms selected from nitrogen, oxygen and sulfur. Optionally, the heterocycle may bear one or two substituents; for example, Λ/-oxido, lower alkyl, phenyl-(1-3C)alkyl, lower alkoxy, halo, amino or lower alkylamino. Examples of suitable heterocycles and optionally substituted heterocycles include pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, 1 H-imidazole, 1 -methyl-1 H-imidazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, 2-methylthiazole, 2- aminothiazole, 2-(methylamino)-thiazole, piperidine, 1-methylpipehdine, 1- methylpiperazine, 1 ,4-dioxane, morpholine, pyridine, pyridine Λ/-oxide, pyrimidine, 2,4-dihydroxypyrimidine and 2,4-dimethylpyrimidine. The term "bicyclic heterocyclic system" as used herein, either alone or in combination with another radical, means a heterocycle as defined above fused to one or more other cycle be it a heterocycle or a lower cycloalkyl. Examples of suitable heterocyclic systems include: thiazolo[4,-b]pyridine, quinoline, or indole.
The term "pharmaceutically acceptable carrier" or "veterinarily acceptable carrier" as used herein means a non-toxic, generally inert vehicle for the active ingredient which does not adversely affect the ingredient.
The term "effective amount" means a predetermined antiviral amount of the antiviral agent, i.e. an amount of the agent sufficient to be effective against the virus in vivo.
The term "inhibit", when used in connection with enzymatic activity, refers generally to inhibiting the enzymatic activity by at least about 50% at a concentration of about 100 μM (and preferably at a concentration of about 50 μM, more preferably, at a concentration of about 25 μM, even more preferably, at a concentration of about 10 μM and most preferably, at a concentration of about 5 μM or less) in a conventional in vitro assay for enzymatic inhibition. In contrast, the term "inability to inhibit" refers generally to inhibiting enzymatic activity by no more than about 50% at concentration of about 100 μM. For example, a compound with an HSV-1 helicase-primase IC50 value of 1.5 μM inhibits HSV-1 helicase-primase activity by 50% at a concentration of 1.5 μM. Therefore, this compound is an HSV-1 helicase-primase inhibitor, as the term is used herein. However, a compound having an IC50 value of 150 μM inhibits enzymatic activity by 50% at a concentration of 150 μM and therefore, is not considered an inhibitor of that enzyme.
Processes for preparing the compounds
The compounds of this invention can be prepared by a variety of processes. Description of some such methods are found in standard textbooks such as "Annual Reports In Organic Synthesis - 1994", P.M. Weintraub et al., Eds., Academic Press, Inc., San Diego, CA, USA, 1994 (and the preceding annual reports), "Vogel's Textbook of Practical Organic Chemistry", B.S. Furniss et al., Eds., Longman Group Limited, Essex, UK, 1986, and "Comprehensive Organic Synthesis", B.M. Trost and I. Fleming, Eds., Pergamon Press, Oxford, UK, 1991 , Volumes 1 to 8.
One general process is represented by Scheme 1 :
Scheme 1
Figure imgf000030_0001
wherein R R2, R3 and R5 are as defined herein, Q is absent (i.e. a valance bond) or methylene, and R4AA JS an amjno protecting group or a radical as defined for R4 hereinbefore other than hydrogen.
According to Scheme 1 , a thiazolylaniline derivative of formula 2 is coupled with an amino acid derivative of formula 3 to give a corresponding aminoamide of formula 4. In the instance where R4AA nas t e same significance as R4 but excluding hydrogen, then the aminoamide of formula 4 so obtained is a compound of formula 1. In the instance where R4AA JS an amino protecting group, the compound of formula 4 so obtained can be deprotected to give the corresponding compound of formula 1 in which R4 is hydrogen. The latter product, albeit a compound of formula 1 , can also serve as an intermediate for further elaboration by standard methods to yield compounds of formula 1 in which R4 is other than hydrogen.
The coupling of the 4-thiazolylaniline derivative of formula 2 and the amino acid of formula 3 is effected by the classical dehydrative coupling of a free carboxyl of one reactant with the free amino group of the other reactant in the presence of coupling agent to form a linking amide bond. Description of such coupling agents are found in general textbooks on peptide chemistry; for example, M. Bodanszky, "Peptide Chemistry", 2nd rev ed, Springer- Verlag, Berlin, Germany, 1993. Examples of suitable coupling agents are Λ/,Λ/'-dicyclohexyl-carbodiimide, 1 -hydroxybenzotriazole in the presence of Λ/,Λ/'-dicyclohexylcarbodiimide or Λ/-ethyl-Λ/'-{(3- dimethylamino)propyl}carbodiimide. A very practical and useful coupling agent is the commercially available (benzotriazol-1 -yloxy)tri-
(dimethylamino)phosphonium hexafluorophosphate, either by itself or in the presence of 1 -hydroxybenzotriazole. Still another very practical and useful coupling agent is commercially available 2-(1 H-benzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'- tetramethyl-uronium tetrafluoroborate.
The coupling reaction is conducted in an inert solvent, e.g. dichloromethane, dimethylformamide, tetrahydrofuran or acetonitrile. An excess of a tertiary amine, e.g. diisopropylethylamine or Λ/-methylmorpholine, is added to maintain the reaction mixture at a pH of about eight. The reaction temperature usually ranges between 0° and 50 °C and the reaction time usually ranges between 15 minutes and 24 hours. A practical and convenient variation of the preceding process (Scheme 1) can be practiced by replacing the 4-thiazolylaniline derivative 2 with 4'- aminoacetophenone. This process is illustrated by Scheme 2:
Scheme 2
-R5 4AA
Corre of fo
Figure imgf000032_0001
wherein R2AA is lower alkyl and R3, R4 A) R5 and Q are as defined hereinbefore. In Scheme 2, the compound of formula 5, namely 4'-aminoacetophenone, is coupled with amino acid derivative of formula 3, noted hereinbefore, to give a corresponding terminal methyl ketone of formula 6.
The methyl ketone 6 can be used to prepare corresponding compounds of formula 1 wherein R2 is hydrogen as follows: The methyl ketone was reacted with thiourea and iodine according to the method of R.M. Dodson and L.C. King, J. Amer. Chem Soc. 1945, 67, 2242 to give the corresponding aminothiazole derivative of formula 7. In the instance where R4AA nas the same significance as R4 but excluding hydrogen, then the aminothiazole derivative of formula 7 so obtained is a compound of formula 1. In the instance where R4AA JS an amino protecting group then the derivative of formula 7 so obtained can be deprotected to give a corresponding compound of Group 1 -formula 1 wherein R4 is hydrogen. If desired, the latter derivative can be converted by standard methods (e.g., N- alkylation, acylation, carbamate formation, etc.) with the appropriate agent to give corresponding compounds of formula 1 wherein R4 is as defined hereinbefore other than hydrogen.
Alternately, the methyl ketone of formula 6 can be used to prepare compounds of formula 1 wherein R2 is lower alkyl. Accordingly, the methyl ketone of formula 6 is subjected to Λ/-alkylation with an appropriate lower alkyl bromide, chloride or iodide in the presence of a base to give the corresponding Λ/-alkylated derivative of formula 8 wherein R2AA is lower alkyl and Q, R3, R4AA and R5 are as defined hereinbefore. The latter compound, when R4AA JS a radical as defined for R4 of the compound of formula 1 other than hydrogen, can be transformed directly to the corresponding compound of formula 1 , wherein R1 is amino, R2 is lower alkyl, R4 is a radical other than hydrogen and Q, R3 and R5 are as defined hereinbefore. The transformation is effected by employing the previously noted method of Dodson and King for aminothiazole formation. On the other hand, the Λ/-alkylated derivative of formula 8 wherein R4AA JS an amino protected group can be deprotected to give the corresponding compounds of formula 1 wherein R^ is amino, R2 is lower alkyl, R4 is hydrogen, and Q, R3 and R5 are as defined hereinbefore.
Still another variation is illustrated by Scheme 3:
Scheme 3
Figure imgf000034_0001
Figure imgf000034_0002
(R1 is NH2, R2 and R3 each is H, Q is absent, R4 is as defined herein, and R5 is R55 which is as defined herein for R5 with the exception that it is not an acyl group)
wherein PG is an amino protecting group, R1 is amino, R2 and R3 each is hydrogen, Q is absent and R4 and R55 are as defined hereinbefore.
According to Scheme 3, the protected aminothiazole derivative of formula 9 wherein PG represents an amino acid protecting group is reacted with bromoacetyl bromide to give the corresponding bromoacetamide 10. Displacement of the bromine of the latter compound with the appropriate primary or secondary amine gives the corresponding intermediate of formula 11. Removal of the protecting group PG from the latter intermediate gives the corresponding compound of formula 1 wherein R5 is R55 as defined hereinbefore.
Still another variation, which can be used for preparing compounds of formula 1 in which Q is methylene, is the process represented by Scheme 4:
Scheme 4
5BB
Figure imgf000035_0001
Corresponding compound of formula 1
(R1 is NH2, R2 and R3 each is hydrogen, Q is CH2, R4=H and R5 is R5BB as defined herein) wherein R1 is NH2, R2 and R3 each is hydrogen, Q is methylene, R4BB as the same significance as R4 as described herein, R5BB has the same significance as defined hereinbefore for R5 with the exception it is not an acyl group, and PG is as amino protection group.
According to Scheme 4, Λ/-(4-acetylphenyl)-2-propenamide is reacted with the appropriate primary or secondary amine to give the Michael adduct of formula 13 wherein R4BB has the same significance as defined for R4 hereinbefore, and R5BB has the same significance as defined hereinbefore for R5 with the exception that it is not an acyl group. Thereafter, the Michael adduct of formula 13 wherein R4BB JS other than hydrogen is transformed to corresponding compounds of formula 1 by the previously noted method of Dodson and King for aminothiazole formation. However, in the instance wherein R4BB 0f ^e Michael adduct is hydrogen, the transformation to corresponding compounds of formula 1 proceeds with protecting the inherent secondary amine with an amino protecting group and the resulting amino protected derivative of formula 14 then is subjected to the Dodson and King method of aminothiazole formation, whereby the amino protecting group is cleaved in situ and the corresponding compound of formula 1 wherein R4 is hydrogen is obtained. If desired, the compounds of formula 1 so obtained according to Scheme 4 can also serve as intermediates for elaboration to other compounds of formula 1 in which Q is methylene by conventional methods.
The amino acid derivative of formula 3, noted in Schemes 1 and 2, can be prepared readily by methods used in peptide chemistry. For example, the Λ/-monosubstituted and Λ/,Λ/-disubstituted glycine derivatives of formula 3, wherein Q is absent, can be prepared by substituting the bromine of the appropriate ethyl bromoacetate with an appropriate primary or secondary amine in the presence of a tertiary amine for example, triethylamine or N- methylmorpholine, to obtain the corresponding α-aminoester having either a monosubstituted or disubstituted amino group. Subsequent hydrolysis with lithium hydroxide of the latter product (or an amino protected derivative thereof in the process involving the primary amine), gives the desired protected Λ/-monosubstituted, or the desired Λ,Λ/-disubstituted amino acid derivative of formula 3 wherein Q is absent. Likewise, Λ/,Λ/-disubstituted β- amino acids of formula 3, wherein Q is methylene, can be prepared by a similar process wherein the ethyl bromoacetate derivative is replaced with the appropriate 3-bromopropionic ethyl ester derivative.
Examples of amino protective groups suitable for use in the above schemes include benzyloxycarbonyl, terf-butoxycarbonyl, 4- methoxybenzyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl.
Other starting materials for the preceding processes are known or they can readily be prepared by standard methods from known starting materials. For example, 4'-aminoacetophenone (5) is available from the Aldrich Chemical Co., Milwaukee, WI, USA; and the requisite thiazolylaniline derivatives of formula 2 can be obtained by applying the classical thiazole preparation involving reacting the appropriate thioamide or thiourea of formula H2N-C(S)-R1 wherein R1 is hydrogen, amino, lower alkylamino or di(iower alkyl)amino with 2-bromo-4'-nitroacetophenone (Aldrich Chemical Co.) according to method described by R.H. Wiley et al., Organic Reactions 1951 , 6, 369-373 followed by reducing the intermediate product (with a nitro group) with iron powder in the presence of hydrochloric acid to obtain the desired thiazolylaniline derivative of formula 2 wherein R1 is as defined in the last instance. Moreover, the preparation of Λ/-(4-acetylphenyl)-2- propenamide (12) of Scheme 4 is described in example 3 herein; and the preparation of an example of the versatile starting material of formula 9 of Scheme 3 (wherein PG is te/ϊ-butoxycarbonyl) is given in example 2 herein.
Other useful starting materials are 3-(4-nitrophenyl)pyridine (M. Ishikura et al., Heterocycles 1984, 22, 265); 4-(4-aminophenyl)imidazole (I.E. Balaban and H. King, J. Chem. Soc, 1925, 727, 2711 ); and 2-(4- aminophenyl)thiazole (B.S. Friedman et al., J. Amer. Chem. Soc, 1937, 59, 2262). Similar starting materials which are aminophenyl substituted heterocycles are commercially available. The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, the reaction can be successfully performed by conventional modification known to those skilled in the art, e.g. by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, or by modification illustrated in the examples herein.
Furthermore, if desired, the compound of formula 1 can be obtained in the form of a therapeutically acceptable acid addition salt. Such salts can be considered as biological equivalent of the compounds of formula 1. Examples of such salts are those formed with hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid or citric acid.
Anti herpes Activity
The antiviral activity of the compounds of formula 1 can be demonstrated by biochemical, microbiological and biological procedures showing the inhibitory effect of the compounds on the replication of herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), cytomegalovirus, as well as acyclovir-resistant herpes simplex viruses and ganciclovir-resistant cytomegaloviruses.
A biochemical procedure for demonstrating antiherpes activity for compounds of formula 1 is described in the examples hereinafter. This particular assay is based on the evaluation of the ability of the test compound to inhibit HSV-1 helicase-primase, an essential enzyme for viral DNA replication. Methods for demonstrating the inhibitory effect of the compounds of formula 1 on herpes viral replication involving in vitro and cell culture techniques are described in the examples.
The therapeutic effect of the compounds of formula 1 can be demonstrated in laboratory animals, for instance, the hairless mouse model for the topical treatment of cutaneous HSV-1 infections, P.H. Lee et al., International Journal of Pharmaceutics, 1993, 93, 139; the (HSV-2)-induced genitalis mouse model, R.W. Sidewell et al., Chemotherapy, 1990, 36, 58; and BALB/C mouse model infected with murine cytomegalovirus, D.L. Barnard et al., Antiviral Res., 1993, 22, 77, and J. Neyts et al., Journal of Medical Virology, 1992, 37, 67.
When a compound of formula 1 , or one of its therapeutically acceptable acid addition salts, is employed as an antiviral agent, it is administered orally, topically or systemically to warm-blooded animals, e.g. humans, pigs or horses, in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For oral administration, the compound or a therapeutically acceptable salt thereof can be formulated in unit dosage forms such as capsules or tablets each containing a predetermined amount of the active ingredient, ranging from about 25 to 500 mg, in a pharmaceutically acceptable carrier. For topical administration, the compound can be formulated in pharmaceutically accepted vehicles containing 0.1 to 5 percent, preferably 0.5 to 5 percent, of the active agent. Such formulations can be in the form of a solution, cream or lotion.
For parenteral administration, the compound of formula 1 is administered by either intravenous, subcutaneous or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers. For administration by injection, it is preferred to use the compounds in solution in a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic.
Suitable vehicles or carriers for the above noted formulations are described in standard pharmaceutical texts, e.g. in "Remington's The Science and Pratice of Pharmacy", 19th ed., Mack Publishing Company, Easton, Penn., 1995, or in "Pharmaceutical Dosage Forms And Drugs Delivery Systems", 6th ed., H.C. Ansel et al., Eds., Williams & Wilkins, Baltimore, Maryland, 1995.
The dosage of the compound will vary with the form of administration and the particular active agent chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small increments until the optimum effect under the circumstance is reached. In general, the compound of formula 1 is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
For oral administration, the compound or a therapeutically acceptable salt is administered in the range of 10 to 200 mg per kilogram of body weight per day, with a preferred range of 25 to 150 mg per kilogram.
With reference to topical application, the compound of formula 1 is administered topically in a suitable formulation to the infected area of the body e.g. the skin, the eye, the genitalia or part of the oral cavity, in an amount sufficient to cover the infected area. The treatment should be repeated, for example, every four to six hours until lesions heal.
For ocular administration, the compound of formula 1 is administered either topically or intraocularly (injection or implant) in a suitable preparation. For example, an implant containing the compound in a suitable formulation can be surgically placed in the posterior segment of the eye through a small incision. With reference to systemic administration, the compound of formula 1 is administered at a dosage of 10 mg to 150 mg per kilogram of body weight per day, although the aforementioned variations will occur. However, a dosage level that is in the range of from about 10 mg to 100 mg per kilogram of body weight per day is most desirably employed in order to achieve effective results.
Although the formulations disclosed hereinabove are indicated to be effective and relatively safe medications for treating herpes viral infections, the possible concurrent administration of these formulations with other antiviral medications or agents to obtain beneficial results also included. Such other antiviral medications or agents include the antiviral nucleosides, for example, acyciovir, penciclovir, famciclovir, valacyclovir and ganciclovir, and antiviral surface active agents or antiviral interferons such as those disclosed by S.S. Asculai and F. Rapp in U.S. patent 4,507,281 , March 26, 1985.
The following examples further illustrate and teach this invention. Temperatures are given in degrees Celsius. Solution percentages or ratios express a volume to volume relationship, unless stated otherwise. Nuclear magnetic resonance spectra were recorded on a Bruker 400 MHz spectrometer; the chemical shifts (δ) are reported in parts per million. The concentrations for the optical rotations are expressed in grams of the compound per 100 mL of solution. Abbreviations or symbols used in the examples include ATP: adenosine triphosphate; Boc: tert-butoxycarbonyl or 1 ,1-dimethylethoxycarbonyl; BOP: (benzotriazole-l -yloxy)tris- (dimethylamino)phosphonium hexafluorophosphate; Bu: butyl; DIPEA: diisopropyiethylamine; DMAP: 4-(dimethylamino)pyridine; DMF: dimethyl- formamide; DMSO: dimethylsulphoxide; Et: ethyl; EtOAc: ethyl acetate; Et_2θ: diethyl ether; Et3N: triethylamine;EtOH: ethanol; MS (FAB) or
FAB/MS: fast atom bombardment mass spectrometry; Hex: hexane; mAb: monoclonal antibody; Me: methyl; MeOH: methanol; PFU: plaque forming units; Ph: phenyl; Pr: propyl; TBTU: 2-(1 H-benzotriazol-1 -yl)-Λ/,Λ/,Λ ',/V'- tetramethyluronium tetrafluoroborate; TFA: tπfluoroacetic acid; THF- tetrahydrofuran.
EXAMPLES
Example 1
N-{2-{{4-(2-amιno-4-oxazolyi)phenyl}amιno}-2-oxoethyl}-N- (benzyl)benzamιde
Figure imgf000042_0001
(a) 2-{(benzoyl)(benzyl)amιno}acetιc acid
CH2Ph
HO(0)CH2N
C(0)Ph
To a mixture of benzylamine (54 6 mL, 0.5 mol) and triethylamine (140 mL, 1 mol) in THF (1 L) at 0° was added ethyl bromoacetate (83.5 g, 0.5 mol) over a 15 mm period. The resulting mixture was stirred at 0° for an additional 15 mm then at room temperature for 45 mm after which time, the reaction was complete as indicated by TLC. The mixture was then cooled to 0° and benzoyl chloride (58 mL, 0.5 mol) was added over a 30 mm period. Thereafter, the mixture was allowed to come to room temperature while being stirred for an additional 30 mm The reaction was complete (TLC). The reaction mixture was then added to a solution of LιOH.H2O (83.92 g, 2 mol) in H2O (500 mL) followed the addition of MeOH (500 mL). After stirring at room temperature for 16h, 10 mL of aqueous 10N NaOH was added to the mixture, and the mixture was gently heated at reflux for 3h. Thereafter, THF and MeOH were removed under reduced pressure and the resulting solution was diluted with H O to 2L. This solution was washed with EtOAc, acidified to pH 3 with concentrated aqueous HCl, and then extracted with EtOAc. The organic solution was washed with brine, dried (MgS04) and concentrated under reduced pressure to afford 108.4 g of the desired acid as a white solid. MS (FAB) 270 (MH)+. 1H NMR (400 MHz, DMSO) 10.37 (broad s,1 H), 7.22-7.44 (m, 10 H), 4.67, 4.51 (2 s, 2 H, 1 :1 mixture of 2 rotamers), 3.98, 3.82 (2 s, 2H, 2 rotamers)
b) N-{2-{(4-acetylphenyl)amιno}-2-oxoethyl}-N-(benzyl)benzamιde
Figure imgf000043_0001
To a solution of 4'-amιnoacetophenone (5.27 g, 38.98 mmol) in DMF (100 mL) was added 2-{(benzyl)-(benzoyl)amιno}acetιc acid (10 g, 37.13 mmol), BOP reagent (17.24 g, 38.98 mmol) and DIPEA (19.4 mL, 111.4 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting solution was diluted with EtOAc (1 L), washed with H20 (2 x 500 mL), aqueous 1 N HCl (2 x 250 mL), H20 (100 mL), saturated aqueous NaHC03 (2 x 220 L) and brine (200 mL). The organic solution was dried (MgS04) and concentrated to afford 10.2 g of a light orange foam which was purified by tnturation with EtOAc-hexane (1.2) to afford 8.3 g of the desired acetamide intermediate as a white solid. MS (FAB) 287 (MH)+ 1H NMR (400 MHz, DMSO) 10.18, 10.36 (2 s, 1 H, 1 :1 mixture of 2 rotamers), 7.90- 7.94 (m, 2 H), 7.62, 7.72 (2 d, J = 8.4 Hz, 1 H, 2 rotamers), 7.25-7.45 (m, 10 H), 4.56, 4.70 (2 s, 2 H, 2 rotamers), 3.98, 4.16 (2 s, 2 H, 2 rotamers).
c) N-(benzyl)-N-{{{4-(2-bromoacetyl)phenyl}amιno}-2- oxoethyljbenzamide
Figure imgf000043_0002
Phenyl trimethylammoniumtribromide (3.52 g, 4.37 mmol) was added portion wise to a stirred solution of N-{2-{(4-acetylphenyl)amino}-2-oxoethyl}-N- (benzyl)benzamιde (2.5 g, 6.46 mmol) in THF (150 mL) at room temperature. The resulting mixture was then stirred for 2h. The reaction was stopped by the addition of EtOAc (300 mL). The resulting solution was washed with aqueous 1 N HCl, H20, saturated aqueous NaHC03 and brine, dried (MgS04) and concentrated to afford 3.72 g of the desired bromoketone as a light yellow solid. MS(FAB) 467 (MH)+. 1H NMR (400 MHz, DMSO) 10.25, 10.46 (2 s, 1 H, 1 :1 mixture of 2 rotamers), 7.96 (t, J = 8.9 Hz, 2H), 7.65, 7.75 (2 d, J = 8.7 Hz, 2 H), 7.26-7.45 (m, 10 H), 4.84, 4.85 (2 s, 2 H, 2 rotamers), 4.57, 4.71 (2 s, 2 H, 2 rotamers), 3.99, 4.18 (2 s, 2 H, 2 rotamers).
d) N-{2-{{4-(2-amιno-4-oxazolyl)phenyl}amιno}-2-oxoethyl}-N- (benzyl)benzamιde
To a solution of N-(benzyl)-N-{{{4-(2-bromoacetyl)phenyl}amino}-2- oxoethyljbenzamide (3.0 g, 6.46 mmol) in DMF (60 mL) was added urea (1.93 g, 32.9 mmol). The resulting mixture was stirred at room temperature for 14 h. The reaction mixture was diluted with EtOAc (250 mL). The resulting organic solution was washed with saturated aqueous NaHC03, H20 (3 x 100 mL), brine, dried (MgS04) and concentrated under reduced pressure. The resulting crude product was purified by two successive flash column chromatography operations using 2:1 EtOAc-hexane, then 20:1 CHCI3-EtOH to afford 94 mg of the title compound. MS(FAB) 427 (MH)+. 1H NMR (400 MHz, DMSO) 9.90, 10.04 (2 s, 1 H, 1 :1 mixture of 2 rotamers), 7.77 (s, 1 H), 7.31 -7.57 (m, 14 H), 6.65 (s, 2 H), 4.56, 4.65 (2 s, 2 H, 2 rotamers), 3.93, 4.12 (2 s, 2H, 2 rotamers).
Example 2
tert-Butyl Λ/-{4-(4-Amιnophenyl)-2-thιazolyl}-carbamate (a versatile starting material of Scheme 3)
2,2,2-Trιchloroethyl Λ/-{4-(2-amιno-4-thιazolyl)-phenyl}carbamate: 2,2,2- Trichloroethyl chloroformate (72.3 mL, 0.52 mol) was added (5 mm) to an ice cold suspension of 4'-amιnoacetophenone (67.6 g, 0.50 mol) and pyridine (50.5 mL, 0.62 mol). The reaction mixture was stirred at 0° for 15 mm and then at room temperature (20-22°) for 45 mm. The solvent was removed under reduced pressure. Et^O (500 mL) and 1 N aqueous HCl (500 mL) were added to the residue. The resulting solid was collected by filtration, washed with H2O (1 L) and Et2θ (1 L), and dried over P2O5 in a desiccator under reduced pressure for 15 h to yield the expected carbamate (137.8 g, 89% yield). A mixture of the crude carbamate (137.8 g, 0.44 mol), thiourea (135.0 g, 1 .77 mol) and I2 (202.6 g, 0.80 mol) in isopropanol (670 mL) was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and EtOAc (1 L) was added. The solution was successively washed with H2O (2 x 600 mL), saturated aqueous NaHCOβ (2 x 1 L) and then H2O (2 x 1 L). A mixture of the organic layer and saturated aqueous 4N HCl (750 mL) was stirred vigorously at room temperature for 1 .5 h. Et^O (-800 mL) and H2O (-300 mL) were added to the mixture to facilitate stirring. The suspension was filtered and the solid was washed with a 1 :1 mixture of EtOAc and Et2θ (2 L). The solid was suspended in 20% aqueous NaOH (1 .2 L). The mixture was extracted with EtOAc The EtOAc extract was washed with brine (700 mL), dried (MgSθ4) and concentrated under reduced pressure to yield 2,2,2-trιchloroethyl Λ/-{4-(2-amιno-4- thιazolyl)phenyl}carbamate (1 17 7 g, 75% yield) as a pale yellow solid: 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1 H), 7 74 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7 01 (s, 2H) 6.88 (s, 1 H), 4 95 (s, 2H); MS (FAB) m/z 366/368/370/372 (MH)+.
Example 3
Λ/-(4-Acetylphenyl)-2-propenamιde (a versatile starting material of Scheme
4) A solution of acryloyl chloride (29.5 mL, 363 mmol) in CH2CI2 (50 mL) was added dropwise (30 mm) to an ice-cold solution of 4'-amιnoacetophenone (49.0 g, 363 mmol) and Et3N (50.6 mL, 363 mmol) in CH CI2 (300 mL). The reaction mixture was stirred at 0° for 15 mm and then was concentrated under reduced pressure. The residue was dissolved with EtOAc. The solution was washed successively with 10% aqueous HCl, saturated aqueous NaHCOβ and H2O. The organic phase was dried (MgSθ4) and concentrated under reduced pressure to afford the desired Λ/-(4- acetylphenyl)-2-propenamιde (52 g, 76% yield) as a yellow solid: 1 H NMR (400 MHz, CDCI3) δ 8 17 (broad s, 1 H), 7.93 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 6.47 (dd, J = 1 0, 16 9 Hz, 1 H), 6.33 (dd, J = 10.2, 16.9 Hz, 1 H), 5.80 (dd, J = 1 0, 10 2 Hz, 1 H), 2.58 (s, 3H); MS (FAB) m/z 190 (MH)+
Example 4
The following four assays (A, B and Ci and C11) were used to evaluate antiherpes activity, and a fifth assay (D) was used to measure the stabilization of the DNA-herpes helicase-primase interaction.
A) HSV-1 DNA-Dependeπt ATP Assay (an in vitro assay based on the inhibition of HSV-1 helicase-primase).
a) Preparation of enzyme- HSV-1 helicase-primase holoenzyme was produced in triply infected Sf21 cells using recombinant baculoviruses expressing the UL5, UL8 and UL52 helicase-primase subunits, as described by S. Dracheva et al., J. Biol. Chem. 1995, 270, 14148. The crude enzyme was purified by ammonium sulfate precipitation, Source 15Q® chromatography and Sephacryl® S-300 HR gel filtration (both purification systems can be obtained from Pharmacia Biotech Inc., Montreal, Quebec, Canada), see S. Dracheva et al., supra. b) Assay: The DNA-dependent ATPase assay, described by J.J. Crute et al., Nucleic Acids Res. 1988, 16, 6585, was modified and used to evaluate the capability of the compounds of formula 1 to inhibit HSV-1 helicase-primase activity. The reaction mixtures (80 μL each) contained 40 mM 4-(2- hydroxyethyl)-1-pιperazιneethanesulfonιc acid (HEPES, pH 7.5), 10% (v/v) glycerol, 5.5 mM MgCl2, 1 mM DL-dithiothreitol (DTT), 50 μg/mL acetylated bovine serum albumin, 3.3% (v/v) DMSO, 4 mM ATP, 25 μM single-stranded M13 DNA hybridized to double-tailed 68-ιmer oligonucleotide and 3 μg/mL HSV-1 helicase-primase. After incubation for 20 m at 34°, formation of inorganic phosphate from hydrolysis of ATP was monitored spectrophotometπcally at 650 nm using acidic ammonium molybdate/malachite green reagent, P. A. Lanzetta et al., Anal. Biochem 1979, 100, 95. DNA-dependent ATPase activity was calculated from the net absorbance change in the presence and absence of inhibition.
B) Inhibition of Herpes Simplex Virus (HSV-1 ) Replication in Cell Culture
Assay BHK-21 cells clone 13 (ATCC CCL10) were incubated for two days in 850 cm2 roller bottles (2x107 cells/bottle) with α-MEM medium (Gibco Canada Inc., Burlington, Ontario, Canada) supplemented with 8% (v/v) fetal bovine serum (FBS, Gibco Canada, Inc ). The cells were trypsinized and then 3,000 ceils in 100 μL of fresh medium were transferred into each well of a 96-well microtiter plate. The cells were incubated at 37° for a period of 3 days to reach a density of 50,000 ceils per well. The cells were washed twice with 100 μL of α-MEM supplemented with 2% heat inactivated FBS and incubated for 1 -2 hours in 100 μL of the same medium.
Thereafter, the cells were infected with HSV-1 strain F or KOS (multiplicity of infection = 0.05 PFU/cell) in 50 μL of α-MEM supplemented with 2% heat inactivated FBS. Following one hour of virus absorption at 37°, the medium was removed and the cells were washed with α-MEM supplemented with 2% heat inactivated FBS (2 x 100 μL). The cells were incubated with or without 100 μL of the appropriate concentration of test reagent in α-MEM medium supplemented with 2% heat inactivated FBS. After 24 hours of incubation at 37°, the extent of viral replication was determined by an ELISA assay; for instance, the following assay that detects the late glycoprotein C of HSV-1.
Cells were fixed in the microtiter plate with 100 μL of 0.063% glutaraldehyde in phosphate buffered saline for 30 mm at room temperature. The microtiter plate was then washed once with casein blocking solution and blocked with 200 μL of the same solution for one hour at room temperature. Thereafter, 100 μL of mAb C11 recognizing the glycoprotein C of HSV-1 (see E. Trybala et al., Journal of General Virology, 1994, 75, 743) was added to each well for two hours at room temperature. The plate was washed three times with phosphate buffered saline containing 0.05% polyoxyethylene (20) sorbitan monooleate. The cells were incubated with 100 μL of sheep anti-mouse IgG horseradish peroxidase for one hour at room temperature in the dark.
The plate was washed three times with 200 μL of the above-noted phosphate buffer saline preparation, and then once with 0.1 M sodium citrate (pH 4.5). Thereafter, 100 μL of orthophenylenediamine dihydrochloπde (OPD, Gibco, Canada Inc.) was added to each well. The plate was agitated on a microplate shaker for 30 mm in the dark. Color development was monitored at 450 nm using a microplate spectrophotometer
SAS was used to calculate % inhibition of viral replication and to generate EC50 values.
C) Inhibition of Human Cytomegalovirus (HCMV) replication
The effect of compounds on the replication of HCMV has been measured by using an ELISA-based assay (ELISA) and a plaque reduction assay (PRA).
Ci) ELISA ASSAY:
Hs-68 cells (ATCC # CRL 1635) were seeded in 96 well microtiter plates at 10,000 ceils/well in 100 μL of DMEM medium (Gibco Canada Inc.) supplemented with 10% fetal bovine serum (FBS, Gibco Canada Inc.). The plates were incubated for 3 days at 37° to allow the cells to reach 80-90% confluency prior to the assay.
The medium was removed from wells by aspiration. The cells then were infected at a multiplicity of infection (MOI) of 0.01 PFU/cell with 50 μL of HCMV (strain AD169, ATCC VR-538) in DMEM medium supplemented with 5% heat inactivated FBS (assay medium). The virus was allowed to adsorb to cells for 2 h at 37°. Following viral adsorption, the medium was removed from the wells by aspiration. The cells were washed twice with 200 μL of assay medium to remove unabsorbed virus. The cells were then incubated with or without 100 μL of appropriate concentrations of test reagent in assay medium. After 8 days of incubation at 37°, the extent of viral replication was determined by an ELISA assay which detects the late structural protein p28 of HCMV.
Eight days after infection, the medium was aspirated from the wells. Nonspecific binding sites were blocked by adding 200 μL of phosphate buffered saline containing 1 % (w/v) bovine serum albumin (blocking buffer) to each well and incubating the plates for 30 mm at room temperature After removal of the blocking buffer by aspiration, the cells were fixed with 100 μL of cold ethanol-acetone solution (95.5) per well. The plates were placed at - 20° for 30 mm. The plates were washed 4 times with phosphate buffered saline containing 0.05% (v/v) polyoxyethylene sorbitan monoiaurate (Tween 20®). Thereafter, 100 μL of mAb UL99 (Advanced Biotechnologies Inc., # 13-130-100) recognizing HCMV protein p28 was added to each wells and plates were incubated for 2 h at room temperature. The plates were washed four times with 200 μL of the above-noted phosphate buffered sal e/Tween- 20® solution. The cells were then incubated with 100 μL of sheep anti- mouse IgGγ horseradish peroxidase conjugated for 2 h at room temperature. The plates were then washed four times with 200 μL of above- noted phosphate buffered salιne/Tween-20® solution. Thereafter, 100 μL of ortho phenyienediamme dihydrochloπde (OPD, Gibco Canada Inc.) solution was added to each well and the plates were agitated on a microplate shaker for 30 mm in the dark. Color development was monitored at 450 nm using a microplate spectrophotometer.
The SAS program was used to calculate the % inhibition of viral replication and to generate EC50 values.
The EC50 values obtained according to this assay method for certain thiazolylphenyl derivatives of this invention are listed in the following tables under the heading ELISA CMV.
C11) PRA ASSAY:
Hs-68 cells ( ATCC # CRL 1635) were seeded in 12-weil plates at 83,000 cells/well in 1 mL of DMEM medium (Gibco Canada Inc.) supplemented with 10% fetal bovine serum (FBS, Gibco Canada Inc.). The plates were incubated for 3 days at 37° to allow the cells to reach 80-90% confluency prior to the assay.
The medium was removed from the cells by aspiration. The cells were then infected with approximately 50 PFU of HCMV (strain AD169, ATCC VR-538) in DMEM medium supplemented with 5% inactivated FBS (assay medium). The virus was allowed to adsorb to cells for 2 h at 37°. Following viral adsorption, the medium was removed from the wells by aspiration. The cells were then incubated with or without 1 mL of appropriate concentrations of test reagent in assay medium. After 4 days of incubation at 37°, the medium was exchanged with fresh medium containing test compound and 4 days later the cells were fixed with 1% aqueous formaldehyde and stained with a 2% crystal violet solution in 20% ethanol in water. Microscopic plaques were counted using a stereomicroscope. Drug effects were calculated as a percent reduction in the number of plaques in the presence of each drug concentration compared to the number observed in the absence of drug. Ganciclovir was used as a positive control in all experiments. The EC50 values obtained according to this assay for certain thiazolyl derivatives of this invention are listed in the following tables under the heading PRA CMV
Example 5
In conjunction with the appropriate starting materials and intermediates, the aforementioned procedures can be used to prepare other compounds of this invention Examples of compounds thus prepared are listed in Tables 1 to 7, together with mass spectrum data for the individual compounds and the results obtained from three assays demonstrating antiherpes activity
TABLE 1
oι o
Figure imgf000052_0001
TABLE 1
αi
Figure imgf000053_0001
TABLE 1
Figure imgf000054_0001
TABLE 1
en eo
Figure imgf000055_0001
TABLE 1
Figure imgf000056_0001
TABLE 1
en en
Figure imgf000057_0001
TABLE 2
Figure imgf000058_0001
Figure imgf000058_0002
TABLE 2
Figure imgf000059_0001
TABLE 2
Figure imgf000060_0001
Figure imgf000060_0002
TABLE 3
Figure imgf000061_0001
Figure imgf000061_0002
TABLE 3
C
Figure imgf000062_0001
TABLE 3
Figure imgf000063_0001
Figure imgf000063_0002
TABLE 3
CD
Figure imgf000064_0001
TABLE 4
Figure imgf000065_0001
Figure imgf000065_0002
TABLE 4
e
Figure imgf000066_0001
TABLE 4
Figure imgf000067_0001
TABLE 4
Figure imgf000068_0001
Figure imgf000068_0002
TABLE 4
Figure imgf000069_0001
Figure imgf000069_0002
TABLE 4
C C
Figure imgf000070_0001
TABLE 4
C
Figure imgf000071_0001
TABLE 4
-v
Figure imgf000072_0001
TABLE 4
Figure imgf000073_0001
Figure imgf000073_0002
TABLE 4
Figure imgf000074_0001
Figure imgf000074_0002
TABLE 4
-
Figure imgf000075_0001
TABLE 4
Figure imgf000076_0001
Figure imgf000076_0002
TABLE 4
e
Figure imgf000077_0001
TABLE 4
CD
Figure imgf000078_0001
TABLE 4
Figure imgf000079_0002
Figure imgf000079_0001
TABLE 4
• C
Figure imgf000080_0001
TABLE 4
^
C
Figure imgf000081_0001
TABLE 4
00 o
Figure imgf000082_0001
TABLE 5
0
Figure imgf000083_0001
TABLE 5
0
Figure imgf000084_0001
TABLE 5
Figure imgf000085_0001
Figure imgf000085_0002
TABLE 5
0
Figure imgf000086_0001
TABLE 5
Figure imgf000087_0001
Figure imgf000087_0002
TABLE 5
Figure imgf000088_0002
Figure imgf000088_0001
TABLE 5
0 ~s
Figure imgf000089_0001
TABLE 5
0 0
Figure imgf000090_0001
TABLE 5
Figure imgf000091_0001
Figure imgf000091_0002
TABLE 5
C
Figure imgf000092_0001
TABLE 5
O
Figure imgf000093_0001
TABLE 5
ho
Figure imgf000094_0001
TABLE 5
Figure imgf000095_0001
Figure imgf000095_0002
TABLE 5
O
Figure imgf000096_0001
TABLE 5
CO en
Figure imgf000097_0001
TABLE 5
C
Figure imgf000098_0001
TABLE 5
c
Figure imgf000099_0001
TABLE 5
0
Figure imgf000100_0001
TABLE 5
c c
Figure imgf000101_0001
TABLE 6
Figure imgf000102_0001
Figure imgf000103_0001
TABLE 6
Figure imgf000104_0001
TABLE 6
Figure imgf000105_0001
TABLE 6
Figure imgf000106_0001
TABLE 6
o en
Figure imgf000107_0001
TABLE 7
Figure imgf000108_0001
TABLE 7
-
Figure imgf000109_0001
TABLE 7
Figure imgf000110_0001
TABLE 7
C
Figure imgf000111_0001
TABLE 7
Figure imgf000112_0001
Additional compounds are the following:
Figure imgf000113_0001
In an embodiment of this invention, a preferred group of compound of preceding TABLES 1 to 6 are those designated as entry numbers 107, 109, 1 1 1 and 1 14 in TABLE 1 ; as entry numbers 201 , 203, 205, 206 and 207 in TABLE 2; as entry numbers 305, 308, 313 and 314 in TABLE 3; as entry numbers 407, 412, 413, 427 and 438 in TABLE 4; and as entry numbers 51 1 and 536 in TABLE 5.

Claims

Claims:
1. A compound of formula 1
X-Aryl-Y-Z (1) wherein
(i) X is selected from the group consisting of:
H, H2NC(0)NHCHMe, NH2S(0)2— ,
Figure imgf000114_0001
Aryl is selected from the group consisting of:
Figure imgf000115_0001
Y is N-C(O)— CH wnerejn
R2 is H or lower alkyl, and
R3 is H; lower alkyl; (lower cycloalkyl)-(lower alkyl) (e.g. CH2-(cyclohexyl); phenyl(lower alkyl); phenyl(lower alkyl) monosubstituted, disubstituted or trisubstituted on the aromatic portion thereof with a substituent or substituents selected independently from the group consisting of halo, hydroxy, lower alkoxy, lower alkoxy, lower alkyl, azido and trifluoromethyl; CH2-Het; or CH2-(bicyclic heterocyclic system); and
Z is NR4R5 wherein
R4 is H, phenyl(lower alkyl) (e.g. CH Ph) or phenyl(lower alkyl) monosubstituted, disubstituted or trisubstituted on the aromatic portion thereof with a substituent or substituents selected independently from the group consisting of halo, hydroxy, lower alkoxy, lower alkyl, azido and trifluoromethyl, or R4 is selected from the group consisting of:
Figure imgf000115_0002
and R5 is selected from the group consisting of:
C(0)(CH2)5NH2; CH2C(0)N(Me)CH2Ph; CH2C(0)NHCH2Ph; C(0)CH2OH;
Figure imgf000116_0001
or R5 is
when R4 is
Figure imgf000116_0002
or a mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl;
or R5 is
Figure imgf000116_0003
when R4 is
Figure imgf000117_0001
or a mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl;
or R5 is selected from the group consisting of:
C(0)Ph,
Figure imgf000117_0002
when R3 is CH2-(cyclohexyl);
Figure imgf000117_0003
or R is ox C(0)OCMe3 when R3 is CH2CH2CH2NH2,
Figure imgf000117_0004
or R5 is C(0)Ph, when X is NH2S(0)2, H2NC(0)NHCHMe,
Figure imgf000117_0005
or R5 is phenyl(lower alkyl) or mono-, di- or trisubstituted phenyl(lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl,
Figure imgf000118_0001
or R5 is C(0)OCMe3,
Figure imgf000118_0002
or
(ii) X and Aryl are as defined above;
Y is N-c(°) wherein R2 is H or lower alkyl, and
Z is selected from the group consisting of:
CH2OCH2Ph, CH2OPh, OCH2CHMe2, CH2CH2Ph, CH2CH2CH2Ph, CH2SCH2Ph, CH=CHPh, CH2CH2CH2CH2C(0)NPh2, CH2CH2CH2CH2CH2NH2, CH2CH2NH2, CH(NH2)(CH2)4NHC(0)OCH2Ph, (S)- CH(NHCH2Ph)(CH2)4NHC(O)OCH2Ph,
(S)-CH2C(0)NHCH(Me)Ph, (f?)-CH(NH2)(CH2)4NHC(0)OCH2Ph, CH2CH2NH2, CH2CH2NHC(0)CH2N(CH2Ph)2, CH2CH2NHC(0)N(CH2Ph)2) CH2CH2CH2C(0)N(CH2Ph)2, CH2CH2C(0)N(CH2Ph)2,
Figure imgf000119_0001
Figure imgf000120_0001
,CH2Ph
CH2CH2NHC(O)CH,N: C(0)Ph
CH2Ph CH.Ph
N— CH,Ph
OH A HCH2C(0)N(Me)CH2Ph CH2CHC(0)N(Me)CH2Ph
Figure imgf000120_0002
CH2OH
Figure imgf000120_0003
2
or
(iii) X and Aryl are as defined above; Y is absent (i.e. a valence bond); and Z is selected from the group consisting of:
NHCH2C(0)N(Me)CH2Ph, NHCH2C(0)NHCH2Ph, OCH2C(0)N(Me)CMe3, OCH2C(S)NHCH2Ph, NHC(S)NHCH2Ph, C(0)OMe, CH2CH2NH-S(0)2-CH2Ph, CH2CH2NHC(0)CH2CH2C(0)Ph, CH2CH2N(CH2Ph)C(0)CH2Ph, CH2CH2N(CH2Ph)S(0)2CH2Ph, CH2CH2NHC(0)CH2CH2C(0)NHCH2Ph,
CH2CH2NHC(0)CH2NHC(0)OCMe3, CH2CH2NHCH2C(0)N(CH2Ph)2, CH2NHCH2C(0)N(CH2Ph)2l
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
CH2CH2NHC(0)- -C(0)NHCH2Ph H2Ph
CH2CH2N'
C(0)C(0)Ph
Figure imgf000123_0002
CH,Ph
CH2CH2N ^
C(0)CH2NHC(0)OCMe3
Figure imgf000123_0003
H2Ph ,CH2Ph
C(0)NHCH2CH2Nr CH2CH2N ^
CH2C(0)0CMe3 C(0)CH2NHC(0)NHPh ,CH2Ph H2Ph
C(0)NHCH2CH2N^ C(0)NHCH2CH2N^
CH2C(0)NHPh CH2C(0)NHCH2Ph
-CH2Ph
CH2CH2N ^
C(0)CH2NHC(0)NHCMe3
CH2Ph CH2CH2N ,CH2Ph
C(0)CH NHC(0)CH2N C(0)OCMe3
0)OCMe3
Figure imgf000124_0001
or
(iv) X is selected from the group consisting of:
Figure imgf000124_0002
Figure imgf000125_0001
Figure imgf000125_0002
Y is absent; and
Z is selected from the group consisting of: NHC(0)NH-CHPr2,
NHC(S)NBu2, NHC(0)NBu2, NHC(0)CH2CH2N(CH2Ph)2,
CH,Ph CH,Ph
NHC(0)CH2N / NHC(0)CH2N /
C(0)Ph C(0)OCMe3
, and
Figure imgf000125_0003
or
(v) X and Aryl together form X' which is defined as
Figure imgf000125_0004
and Y and Z are as defined in paragraph (i).
2. A compound according to claim 1 , subsection (i), wherein X is
Figure imgf000125_0005
Figure imgf000126_0001
is N C(0) CH wherein R2 is hydrogen and R3 is H,
Figure imgf000126_0002
Z is NR4R5 wherein R4 is H, CH2Ph,
Figure imgf000126_0003
R5 is
Figure imgf000127_0001
Figure imgf000127_0002
A compound according to claim 2 wherein X is defined in Claim 2,
Figure imgf000127_0003
wherein R2 is H and R3 is H,
Figure imgf000127_0004
Z is NR4R5 wherein
Figure imgf000127_0005
4. A compound according to claim 2 wherein X is
Figure imgf000128_0001
Figure imgf000128_0002
5. A compound according to claim 4 wherein Aryl is Y is R2 R3
I I
N C(O) CH wherejn R2 js H and R3 js H or
Figure imgf000128_0003
wherein R* is H or CH Ph, and R° is
Figure imgf000128_0004
A compound according to claim 1 subsection (ii) wherein X is
Figure imgf000128_0005
, Aryl is , Y is NH-C(O) and Z is
Figure imgf000128_0006
CH,CH,CH "2 CH,CH,CH,CH "2
CH2Ph
CH2Ph
CH2CMe2N
CH2-^ NHC(0)OCMe3 C(0)OCH2Ph
Figure imgf000129_0001
,CH2Ph
CH,CH,N' ,CH2Ph
C(0)CH2N
~C(0)OCMe, or
Figure imgf000129_0002
7. A compound according to claim 6 wherein Z is
CH,CH,CH "2 CH2CH2CH2CH2
Figure imgf000129_0003
Figure imgf000129_0004
8. A compound according to claim 1 , subsection (iii) wherein X is
Figure imgf000129_0005
CH2Ph
NHC(S)CH.N
C(0)OCMe3
Figure imgf000129_0006
Figure imgf000130_0001
9. A compound according to claim 8 wherein Z is
Figure imgf000130_0002
10. A compound according to claim 1 , subsection (iv) wherein X is
Figure imgf000130_0003
1 1 . A compound according to claim 1 , subsection (v), wherein X and Aryl
Figure imgf000130_0004
together form X1 which is defined as Y is
O RJ
NH C CH wnerejn R3 js H or phCH2 and z js NR4Rs wnerejn R4 is H or CH2Ph and R5 is C(0)OCMe3.
12. A compound according to claim 1 , subsection (i), having the structure
Figure imgf000131_0001
wherein R is NH2, R is H, R is H, and R and R are designated as follows:
Figure imgf000131_0002
or
Figure imgf000132_0001
13. A compound according to claim 12 selected from the group consisting of compounds of entry numbers 107, 109, 111 and 114.
14. A compound according to claim 1 , subsection (i), having the stucture
Figure imgf000133_0001
wherein R1 is NH2, R2 is H, and R3, R4 and R5 are designated as follows:
, or
Figure imgf000133_0002
15. A compound according to claim 14 selected from the group consisting of compounds of entry numbers 201 , 203, 205, 206 and 207.
16. A compound according to claim 1 , subsection (i), having the structure
Figure imgf000134_0001
wherein R2 and R3 each is hydrogen and X, R4 and R5 are designated as follows:
Figure imgf000134_0002
or
Figure imgf000135_0003
17. A compound according to claim 16 selected from the group consisting of compounds of entry numbers 305, 308, 313 and 314.
18. A compound according to claim 1 , subsection (ii), having the structure
Figure imgf000135_0001
wherein R1 is NH2, R2 is H and Z is designated as follows:
Figure imgf000135_0002
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
462 .Bu
N;
CH2CH2OH or
463 CH2CH2C(0)N(CH2Ph)2
19. A compound according to claim 18 selected from the group consisting of entry numbers 407, 412, 413, 427 and 438.
20. A compound according to claim 1 , subsection (iii), having the structure
Figure imgf000141_0001
wherein Z is designated as follows:
Figure imgf000141_0002
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
or
Figure imgf000146_0001
21. A compound according to claim 20 selected from the group consisting of entry numbers 511 and 536.
22. A compound according to claim 1 , subsection (iv), having the structure
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000148_0002
23. A compound according to claim 1 , subsection (v), having the structure
Figure imgf000149_0001
wherein R2 is H, R3, R4 and R5 and X' are designated as follows:
, or
Figure imgf000149_0003
24. A compound according to claim 1 , subsection (i), having the structure
Figure imgf000149_0002
wherein R is H, R , R and R and X' are designated as follows:
Figure imgf000149_0004
Figure imgf000150_0001
25. A compound according to claim 1 , subsection (i), having the formula
Figure imgf000150_0002
Figure imgf000151_0001
26. A method for treating herpes infection in a mammal comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically acceptable carrier and a compound according to claim 1.
27. A pharmaceutical composition comprising the compound according to claim 1 and pharmaceutically acceptable carrier.
28. The pharmaceutical composition according to claim 27, wherein the composition is suitable for oral administration.
29. The pharmaceutical composition according to claim 27, wherein the composition is suitable for topical administration.
30. A method for treating herpes infection in a mammal comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of the pharmaceutical composition according to claim 28.
31. A method for treating herpes infection in a mammal comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of pharmaceutical composition according to claim 29.
PCT/CA1999/001066 1998-11-12 1999-11-09 Antiherpes compounds WO2000029399A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10827298P 1998-11-12 1998-11-12
US60/108,272 1998-11-12

Publications (1)

Publication Number Publication Date
WO2000029399A1 true WO2000029399A1 (en) 2000-05-25

Family

ID=22321236

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1999/001066 WO2000029399A1 (en) 1998-11-12 1999-11-09 Antiherpes compounds

Country Status (1)

Country Link
WO (1) WO2000029399A1 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068609A1 (en) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. 1,2,3,4-tetrahydroisoquinoline derivatives
WO2002038554A1 (en) * 2000-11-10 2002-05-16 Yamanouchi Pharmaceutical Co., Ltd. Amide derivatives
WO2003095435A1 (en) * 2002-05-09 2003-11-20 Yamanouchi Pharmaceutical Co., Ltd. Amide derivatives
WO2004069805A1 (en) * 2003-02-10 2004-08-19 Bayer Healthcare Ag Bis(hetero)aryl carboxamide derivatives for use as pgi2 antagonists
WO2005014559A1 (en) * 2003-08-08 2005-02-17 Astellas Pharma Inc. Amide derivatives
JP2006512321A (en) * 2002-11-21 2006-04-13 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Carboxamide
WO2006066948A1 (en) * 2004-12-20 2006-06-29 Schering Aktiengesellschaft Piperidine derivatives as antagonists of the cc chemokine receptor ccr1 and their use as anti-inflammatory agents
JP2006241144A (en) * 2005-02-03 2006-09-14 Astellas Pharma Inc Medicinal composition containing tetrahydro-2h-thiopyran-4-carboxamide derivative
WO2006102645A1 (en) * 2005-03-24 2006-09-28 Janssen Pharmaceutica, N.V. Biaryl derived amide modulators of vanilloid vr1 receptor
JP2009523748A (en) * 2006-01-18 2009-06-25 シエナ ビオテク ソシエタ ペル アチオニ Modulators of α7 nicotinic acetylcholine receptors and their use in therapy
JP2010502579A (en) * 2006-08-30 2010-01-28 エフ．ホフマン−ラ ロシュ アーゲー Inhibitor of GLYT-1
WO2010047295A1 (en) 2008-10-20 2010-04-29 アステラス製薬株式会社 Medicine for preventing or treating pain related to herpes zoster
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
CN108147972A (en) * 2016-12-05 2018-06-12 成都西岭源药业有限公司 A kind of preparation method of Wei Patawei intermediates and the like
EP3388429A1 (en) * 2010-11-16 2018-10-17 Texas Heart Institute Agonists that enhance binding of integrin-expressing cells to integrin receptors
CN111170983A (en) * 2019-12-26 2020-05-19 中国农业大学 A kind of benzylthioacetamide compound and its preparation method and application
WO2020127685A1 (en) * 2018-12-19 2020-06-25 Leo Pharma A/S Amino-acid anilides as small molecule modulators of il-17
RU2815505C2 (en) * 2018-12-19 2024-03-18 Лео Фарма А/С Anilides of amino acids as low-molecular modulators il-17

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0045081A2 (en) * 1980-07-25 1982-02-03 Ciba-Geigy Ag Trisubstituted imidazole derivatives, processes for preparing them, pharmaceutical compositions containing them, and their use
WO1997024343A1 (en) * 1995-12-29 1997-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Phenyl thiazole derivatives with anti herpes virus properties
FR2754258A1 (en) * 1996-10-08 1998-04-10 Sanofi Sa AMINOTHIAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
WO1999042455A1 (en) * 1998-02-19 1999-08-26 Tularik Inc. Antiviral agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0045081A2 (en) * 1980-07-25 1982-02-03 Ciba-Geigy Ag Trisubstituted imidazole derivatives, processes for preparing them, pharmaceutical compositions containing them, and their use
WO1997024343A1 (en) * 1995-12-29 1997-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Phenyl thiazole derivatives with anti herpes virus properties
FR2754258A1 (en) * 1996-10-08 1998-04-10 Sanofi Sa AMINOTHIAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
WO1999042455A1 (en) * 1998-02-19 1999-08-26 Tularik Inc. Antiviral agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
F.C. SPECTOR ET AL: "Inhibition of Herpes Simplex virus replication by a 2-amino thiazole via interactions with the helicase component of the UL5-UL8-UL52- COMPLEX", JOURNAL OF VIROLOGY., vol. 72, no. 9, September 1998 (1998-09-01), THE AMERICAN SOCIETY FOR MICROBIOLOGY., US, pages 6979 - 6987, XP002128325, ISSN: 0022-538X *

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6703392B2 (en) 2000-03-14 2004-03-09 Actelion Pharmaceuticals Ltd. 1,2,3,4-tetrahydroisoquinoline derivatives
WO2001068609A1 (en) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. 1,2,3,4-tetrahydroisoquinoline derivatives
WO2002038554A1 (en) * 2000-11-10 2002-05-16 Yamanouchi Pharmaceutical Co., Ltd. Amide derivatives
WO2003095435A1 (en) * 2002-05-09 2003-11-20 Yamanouchi Pharmaceutical Co., Ltd. Amide derivatives
JP2006512321A (en) * 2002-11-21 2006-04-13 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Carboxamide
JP4732757B2 (en) * 2002-11-21 2011-07-27 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Carboxamide
WO2004069805A1 (en) * 2003-02-10 2004-08-19 Bayer Healthcare Ag Bis(hetero)aryl carboxamide derivatives for use as pgi2 antagonists
US7465748B2 (en) 2003-08-08 2008-12-16 Astellas Pharma Inc. Amide derivative
US6903125B2 (en) 2003-08-08 2005-06-07 Yamanouchi Pharmaceutical Co., Ltd. Tetrahydro-2H-thiopyran-4-carboxamide derivative
KR101157074B1 (en) * 2003-08-08 2012-06-22 아스텔라스세이야쿠 가부시키가이샤 Amide derivatives
JPWO2005014559A1 (en) * 2003-08-08 2006-10-05 アステラス製薬株式会社 Amide derivatives
CN100445271C (en) * 2003-08-08 2008-12-24 安斯泰来制药有限公司 Amide derivative
AU2004263448B2 (en) * 2003-08-08 2009-02-05 Astellas Pharma Inc Amide derivatives
WO2005014559A1 (en) * 2003-08-08 2005-02-17 Astellas Pharma Inc. Amide derivatives
JP4549974B2 (en) * 2003-08-08 2010-09-22 アステラス製薬株式会社 Amide derivatives
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2006066948A1 (en) * 2004-12-20 2006-06-29 Schering Aktiengesellschaft Piperidine derivatives as antagonists of the cc chemokine receptor ccr1 and their use as anti-inflammatory agents
JP2006241144A (en) * 2005-02-03 2006-09-14 Astellas Pharma Inc Medicinal composition containing tetrahydro-2h-thiopyran-4-carboxamide derivative
WO2006102645A1 (en) * 2005-03-24 2006-09-28 Janssen Pharmaceutica, N.V. Biaryl derived amide modulators of vanilloid vr1 receptor
JP2009523748A (en) * 2006-01-18 2009-06-25 シエナ ビオテク ソシエタ ペル アチオニ Modulators of α7 nicotinic acetylcholine receptors and their use in therapy
JP2010502579A (en) * 2006-08-30 2010-01-28 エフ．ホフマン−ラ ロシュ アーゲー Inhibitor of GLYT-1
WO2010047295A1 (en) 2008-10-20 2010-04-29 アステラス製薬株式会社 Medicine for preventing or treating pain related to herpes zoster
EP3388429A1 (en) * 2010-11-16 2018-10-17 Texas Heart Institute Agonists that enhance binding of integrin-expressing cells to integrin receptors
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
CN108147972A (en) * 2016-12-05 2018-06-12 成都西岭源药业有限公司 A kind of preparation method of Wei Patawei intermediates and the like
CN108147972B (en) * 2016-12-05 2020-07-10 成都西岭源药业有限公司 Preparation method of vipatavir intermediate and analogue thereof
WO2020127685A1 (en) * 2018-12-19 2020-06-25 Leo Pharma A/S Amino-acid anilides as small molecule modulators of il-17
CN113164448A (en) * 2018-12-19 2021-07-23 利奥制药有限公司 Amino acid anilines as small molecule modulators of IL-17
JP2022514079A (en) * 2018-12-19 2022-02-09 レオ ファーマ アクティーゼルスカブ Amino acid anilides as a small molecule regulator of IL-17
US11377425B1 (en) 2018-12-19 2022-07-05 Leo Pharma A/S Small molecule modulators of IL-17
RU2815505C2 (en) * 2018-12-19 2024-03-18 Лео Фарма А/С Anilides of amino acids as low-molecular modulators il-17
JP7515481B2 (en) 2018-12-19 2024-07-12 レオ ファーマ アクティーゼルスカブ Amino acid anilides as small molecule modulators of IL-17
CN111170983A (en) * 2019-12-26 2020-05-19 中国农业大学 A kind of benzylthioacetamide compound and its preparation method and application
CN111170983B (en) * 2019-12-26 2021-07-09 中国农业大学 A kind of benzylthioacetamide compound and its preparation method and application

Similar Documents

Publication Publication Date Title
EP0871619B1 (en) Phenyl thiazole derivatives with anti herpes virus properties
WO2000029399A1 (en) Antiherpes compounds
CA2407428C (en) Hydantoin-containing glucokinase activators
EP2069303B1 (en) Antiviral protease inhibitors
ES2834051T3 (en) Aminothiazole derivatives useful as antiviral agents
US20100286169A1 (en) Antibacterial Sulfone and Sulfoxide Substituted Heterocyclic Urea Compounds
KR20000052775A (en) Novel heterocyclic amide compounds and medicinal uses thereof
US6288091B1 (en) Antiherpes virus compounds and methods for their preparation and use
CZ2004107A3 (en) Phenylacetamido-thiazole derivatives, process of their preparation and their use as antineoplastic pharmaceutical compositions
KR20060098374A (en) Thiazolidinones, their preparation and use as medicaments
KR20070100833A (en) Prevention or treatment of diseases involving herpes virus
EP2855470B1 (en) Novel bicyclic thiazole compounds
CA2301548C (en) Azetidinone derivatives for the treatment of hcmv infections
WO2008011191A1 (en) Antibacterial heterocyclic ureas
US6323202B1 (en) HSV primase inhibitors
WO2023049919A1 (en) Inhibitors of molluscum contagiosum infection and methods using the same
WO2003095435A1 (en) Amide derivatives
CZ20031667A3 (en) Novel compounds useful as HIV protease inhibitors
WO1992020665A1 (en) Thiazolidine derivatives and their use in therapy
JP2022506351A (en) A novel urea 6,7-dihydro-4H-thiazolo [5,4-C] pyridine with activity against hepatitis B virus (HBV)
CN1207094A (en) Phenyl thiazole derivatives with anti herpes virus properties
JP2004026818A (en) Amide derivative or its salt

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP MX US

AL Designated countries for regional patents

Kind code of ref document: A1

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

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载