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WO2000029399A1 - Composes antiherpes - Google Patents

Composes antiherpes Download PDF

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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
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Prior art keywords
nhc
compound according
group
nhch
lower alkyl
Prior art date
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PCT/CA1999/001066
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English (en)
Inventor
Bruno Simoneau
James J. Crute
Anne-Marie Faucher
Christine A. Grygon
Karl D. Hargrave
Bounkham Thavonekham
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Boehringer Ingelheim (Canada) Ltd.
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Publication of WO2000029399A1 publication Critical patent/WO2000029399A1/fr

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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07D277/40—Unsubstituted amino or imino radicals
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07D285/15—Six-membered rings
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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.

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Abstract

L'invention concerne des composés représentés par la formule générale X-Aryle-Y-Z dans laquelle X représente un composé hétérocyclique aromatique à cinq ou six éléments relié à un groupe Aryle, par exemple, un groupe phényle; Y est absent ou représente un gro upe de liaison NHC(O)CH2; Z représente un groupe terminal NHCO (O)OC(CH3)3 ou (I). Ces composés inhibent l'enzyme hélicase-prima se de l'herpès, ce qui rend ces composés utiles en tant qu'agents antiviraux. Elle concerne également des compositions pharmaceutiques comprenant ces composés, ainsi que des procédés servant à préparer et à utiliser ces composés.
PCT/CA1999/001066 1998-11-12 1999-11-09 Composes antiherpes WO2000029399A1 (fr)

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WO2001068609A1 (fr) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. Derives de 1,2,3,4-tetrahydroisoquinoline
WO2002038554A1 (fr) * 2000-11-10 2002-05-16 Yamanouchi Pharmaceutical Co., Ltd. Derives amides
WO2003095435A1 (fr) * 2002-05-09 2003-11-20 Yamanouchi Pharmaceutical Co., Ltd. Derives d'amides
JP2006512321A (ja) * 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 カルボキサミド
JP4732757B2 (ja) * 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 カルボキサミド
WO2004069805A1 (fr) * 2003-02-10 2004-08-19 Bayer Healthcare Ag Derives de bis(hetero)aryle carboxamide destines a etre utilises en tant qu'antagonistes de la pg12
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 (ko) * 2003-08-08 2012-06-22 아스텔라스세이야쿠 가부시키가이샤 아미드 유도체
JPWO2005014559A1 (ja) * 2003-08-08 2006-10-05 アステラス製薬株式会社 アミド誘導体
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AU2004263448B2 (en) * 2003-08-08 2009-02-05 Astellas Pharma Inc Amide derivatives
WO2005014559A1 (fr) * 2003-08-08 2005-02-17 Astellas Pharma Inc. Derives d'amide
JP4549974B2 (ja) * 2003-08-08 2010-09-22 アステラス製薬株式会社 アミド誘導体
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2006066948A1 (fr) * 2004-12-20 2006-06-29 Schering Aktiengesellschaft Derives de piperidine utilises comme antagonistes des recepteurs aux cc chimiokines ccr1 et utilisation de ceux-ci comme agents anti-inflammatoires
JP2006241144A (ja) * 2005-02-03 2006-09-14 Astellas Pharma Inc テトラヒドロ−２ｈ−チオピラン−４−カルボキサミド誘導体を含有する医薬組成物
WO2006102645A1 (fr) * 2005-03-24 2006-09-28 Janssen Pharmaceutica, N.V. Amides derives de biaryle modulateurs de recepteur vanilloide vr1
JP2009523748A (ja) * 2006-01-18 2009-06-25 シエナ ビオテク ソシエタ ペル アチオニ α７ニコチン性アセチルコリン受容体の調節物質およびそれらの治療への使用
JP2010502579A (ja) * 2006-08-30 2010-01-28 エフ．ホフマン−ラ ロシュ アーゲー Ｇｌｙｔ−１の阻害薬
WO2010047295A1 (fr) 2008-10-20 2010-04-29 アステラス製薬株式会社 Médicament destiné à la prévention ou au traitement de la douleur associée à un zona
EP3388429A1 (fr) * 2010-11-16 2018-10-17 Texas Heart Institute Agonistes qui améliorent la liaison des cellules exprimant l'intégrine avec des récepteurs de l'intégrine
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
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CN108147972B (zh) * 2016-12-05 2020-07-10 成都西岭源药业有限公司 一种维帕他韦中间体及其类似物的制备方法
WO2020127685A1 (fr) * 2018-12-19 2020-06-25 Leo Pharma A/S Anilides d'acides aminés en tant que modulateurs à petites molécules d'il-17
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