Title of Invention

"IMIDAZO [4,5-D] PYRIMIDINES, THEIR USES AND METHOD OF PREPARATION"

Abstract The Present invention relates to pharmaceutical compositions for the treatment of prevention of viral infections comprising as an active principle at least one imidazo[4,5-c] pyrimidine having the general formula[A], wherein the substituents are described in the specification. The invention also relates to processes for the preparation of compounds according to the invention having above mentioned general formula, their pharmaceutically acceptable formulations and their use as a medicine or to treat or prevent viral infections.
Full Text FIELD OF THE INVENTION
The present invention relates to imidazoS-djpyrimidines, their uses and
manufacture. The invention relates specifically to antiviral compounds, in
particular such compounds for the treatment of Flaviviridae and Picornaviridae.
BACKGROUND OF THE INVENTION
The family of the Flaviviridae consists of 3 genera, the pestiviruses, the
flaviviruses and the hepaciviruses and also contains the hepatitis G virus
(HGV/GBV-C) that has not yet been assigned to a genus. Pestiviruses such as the
Classical Swine Fever Virus (CSFV), the Bovine Viral Diarrhea Virus (BVDV) and
the Border Disease Virus (BDV) cause infections of domestic livestock
(respectively pigs, cattle and sheep) and are responsible for significant economic
losses world-wide. BVDV, the prototypic representative of the pestivirus genus is
ubiquitous and causes a range of clinical manifestations, including abortion,
teratogenesis, respiratory problems, chronic wasting disease, immune system
dysfunction, and predisposition to secondary viral and bacterial infections and
may also cause acute fatal disease. Fetuses of cattle can be infected persistently
with BVDV, these animals remain viremic throughout life and serve as a
continuous sources for virus spread in herds.
Vaccines are used in some countries with varying degrees of sticcess to
control pestivirus disease. In other countries, animal culling and slaughter are
used to contain pestivirus disease outbreaks.
The World Health Organization estimates that world-wide 170 million
people (3% of the world's population) are chronically infected with HCV
(Hepatitis C Virus). These chronic carriers are at risk of developing cirrhosis
and/or liver cancer. In studies with a 10 to 20 year follow-up, cirrhosis developed
in 20 - 30% of the patients, 1 to 5% of whom may develop liver cancer during the
next ten years. The only treatment option available today is the use of interferon
oc-2 (or its pegylated form) either alone or combined with ribavirin. However,
sustained response is only observed in about 40% of the patients and treatment is
associated with serious adverse effects. There is thus an urgent need for potent
and selective inhibitors of the replication of HCV in order to treat infections with
HCV. Furthermore, the study of specific inhibitors of HCV replication has been
hampered by the fact that it is not possible to propagate HCV (efficiently) in cell
culture. Since HCV and pestiviruses belong to the same virus family and share
many similarities (organization of the genome, analogous gene products and
replication cycle), pestiviruses have been adopted as a model and surrogate for
HCV. For example BVDV is closely related to hepatitis C virus (HCV) and used
as a surrogate virus hi drug development for HCV infection.
The compound 3-[((2-dipropylamino)ethyl)thio]-5H-l,2,4-triazino[5,6-
b]indole has been reported to selectively inhibit the replication of BVDV and other
pestiviruses (Baginski SG et. al., Proc. Natl. Acad. Sci. U.S.A. 2000 Jul
5;97(14):7981-6). Currently, there is no antiviral treatment for pestiviral infections.
Coxsackie viruses belong to the group of the enteroviruses, family of the
Picornaviridae. They cause a heterogeneous group of infections including
herpangina, aseptic meningitis, a common-cold-like syndrome, a non-paralytic
wherein:
the dotted lines represent optional double bonds, provided that no two
double bonds are adjacent to one another, and that the dotted lines represent at
least 3, optionally 4 double bonds;
R1 is selected from aryl, heterocycle, Cj C10 alkoxy, Cj C10 thioalkyl, C, C]0
alkyl-amino, Q C10 dialkyl-amino, C3.10 cycloalkyl, CMO cycloalkenyl, and C4.10
cycloalkynyl, wherein each are optionally substituted with 1 or more R6;
Y is selected from a single bond, O, S(O)m (where m is an integer from 0 to
2), MR11, CMO alkylene, C2.vt alkenylene, and C2.10 alkynylene, or C^ alkylene, C^
alkenylene or C2.]0 alkynylene, wherein 1 to 3 methylene groups optionally are
independently replaced by 1 to 3 heteroatoms selected from O, S or NR";
R2 and R4 are independently selected from hydrogen, C M8 alkyl,
C2.18alkenyl, C2.18 alkynyl, Ct.18 alkoxy, CW8 alkylthio, halogen, -OH, -CN, -NO2,
-NR7R8, haloalkyloxy,hatoalkyl, -C(=O)R9, -C(=S)R9, SH, aryl, aryloxy, arylthio,
arylalkyl, C,.lg hydroxyalkyl, CMO cycloalkyl, C3.10 cycloalkyloxy, C3.10
cycloalkylthio, C3.]0 cycloalkenyl, C7.10 cycloalkynyl, and heterocycle, provided that
when one of R25 or R26 is present, then either R2 or R4 is selected from =O, =S, or
X is selected from Q C,0 alkylene, CMO alkenylene or C2.10 alkynyleiie, where
each may include one or more heteroatoms selected from O, S, or NRU, provided
any such heteroatom is not adjacent to the N in the ring;
R3 is selected from aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl-N(R10)-, or heterocycle, where each said substituent is
optionally substituted with at least one R17, provided that for cycloalkenyl the
double bond is not adjacent to a nitrogen;
R5 independently is absent or is selected from hydrogen, C,.1S alkyl, C2.18
alkenyl, C^ alkynyl, Q.tt alkoxy, CW8 alkyllhio, halogen, -OH, -CN, -NO2, -NR7R8,
-1-18
laloalkyloxy, haloalkyl, -C(=O)R9, -C(=O)OR9, -C(=S)R9, SH, aryl, aryloxy,
arylthio, arylalkyl, CM8 hydroxyalkyl, CMO cycloalkyl, CMO cycloalkyloxy, C»
cycloalkylthio, C3.10 cycloalkenyl, C7.w cycloalkynyl, and heterocycle;
R6 is selected from hydrogen, Q.,, alkyl, C2.18 alkenyl, C2.18 alkynyl, C,.u
alkoxy, C^s alkylthio, C,.M alkylsulfoxide, CW8 alkylsulfone, CM, halo-alky!, C2.]8
halo-alkenyl, C2.18 halo-aikynyl, CW8 halo-alkoxy, CM8 halo-alkylthio, C3.]0
cycloalkyl, C3.10 cycloalkenyl, €,.,„ cycloalkynyl, halogen, OH, CN, cyanoalkyl,
-C(0)OR18, N02, NR7R8
; €,.„ haloalkyl, C(=O)R18, C(=S)R18, SH, aryl, aryloxy,
arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C,.]8)alkyl,
aryKCj.Jalkyloxy, aryKQ.Jalkylthio, heterocycle, and C,.M hydroxyalkyl, where
each may be optionally substituted with at least 1 R19;
R7 and R8 are independently selected from hydrogen, C^alkyl, C,.18 alkenyl,
aryl, C3.10 cycloalkyl, C4.10 cycloalkenyl, heterocycle, -C(=O)RU; -C(=S) R12, an amino
acid residue linked through a carboxyl group thereof, and the group formed
when R7 and R8 are taken together with the nitrogen to form a heterocycle;
R9 and R18 are independently selected from hydrogen, OH, C,.,8 alkyl, C2.w
alkenyl, C3.10 cycloalkyl, CV10 cycloalkenyl, CM, alkoxy, -NR15R16, aryl, an amino
acid residue linked through an amino group of the amino acid, CH2OCH(=O)Ra,
and CH2OC(=O)OR9a where R" is C,-C12 alkyl, C6-C20 aryl, C6-CW alkylaryl or C6-CX
aralkyl;
R10 and R" are independently selected from the group consisting of
hydrogen, Q.18 alkyl, C2.18 alkenyl, C3.10 cycloalkyl, C4,0 cycloalkenyl, aryl,
-C(=O)R12, heterocycle, and an amino acid residue;
R12 is selected from the group consisting of hydrogen, CM8 alkyl, C'2-18
alkenyl, aryl, C340 cycloalkyl, C4.,0 cycloalkenyl, and an amino acid residue;
R15 and R16 are independently selected from hydrogen, CM8 alkyl, C2.18
alkenyl, C,.,8alkynyl, aryl, arylalkyl (unsubstituted or substituted with C(O)OR18),
CMO cycloalkyl, C4.10 cycloalkenyl, and an amino acid residue;
R17 is independently selected from the group consisting of (a) hydrogen, Q.
„ alkyl, C2.18 alkenyl, C2.18 alkynyl, C,.u alkoxy, CM8 alkylthio, CM8 alkylsulfoxide, Q.
„ alkylsulfone, CM8 halogenated alkyl, C2.]8 halogenated alkenyl, C2.18 halogenated
alkynyl, CM8 halogenated alkoxy, C,.,, halogenated alkylthio, C3.10 cycloalkyl, C
cydoalkenyl, Q.10 cycloalkynyl, halogen, OH, CN, CO2H, CO2R18, NO2, NR7R8,
haloalkyl, C(=O)R18, C(=S)R:s, SH, aryl, aryloxy, arylthio, arylsulfoxide,
arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle,
and CM8 hydroxyalkyl, where each of said aryl, aryloxy, arylthio, arylsulfoxide,
arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle,
or C,.18 hydroxyalkyl is optionally substituted with 1 or more R19, and (b) M-Qwherein
M is a ring optionally substituted with 1 or more R19, and Q is a bond or a
linking group connecting M to R3 having 1 to 10 atoms selected from C and
optionally 1 or more O, N or S atoms and optionally substituted with 1 or more
R19 is selected from
(a) H;
(b) NO2, SH, NR^R21, OH, halogen and CN;
(c) Sulfone, sulfonamide and sulfoxide;
(d) CW8 alkyl, C2.18 alkenyl and C2.16 alkynyl;
(e) Q18 alkyl, C2.1B alkenyl and C2.18 alkynyl wherein 1 or more methylene are
replaced by 1 or more O, S, NRM, C(O)NR20R21, OC(O)R12, C(O)OR12 or
N(R2°)C(0);
(f) Substituents c), d) or e) substituted further by C3.10 cycloalkyl, C4.10
cycloalkenyl, C4.10 cycloalkynyl, aryl or heterocycle;
(g) C3.10 cycloalkyl, C4.u cycloalkenyl, C4.10 cycloalkynyl, aryl and heterocycle,
or said groups substituted with Ca.6 alkyl,. C(O)OR12 =O, halogen, CN,
C(0)NR20R21, C(0)R1B or OC(O)R18;
(h) C(0)R18, C(0)OR18, OC(0)R18, C(S)R18 and C(O)N(R12)2;
) Substituents d) or.e) substituted with =O, CN, halogen, C(O)R18,
21, OC(O)RM, heterocycle, and heterocycle substituted with CrC6
alkyl, C(0)ORUU , =O, CN, halogen, OC(O)R11BB or
(j) Substituents c) substituted further with C^w alkyl; and
(k) Substituents f) or g) substituted further with Cj.18 alkyl, =O, NR^R21, CN,
C1-18 alkoxy, heterocycle, Cj.18 haloalkyl, heterocyclealkyl or halogen;
R20 and R21 are independently selected from hydrogen, CM8 alkyl, Cz.18
alkenyl, C2.19 alkynyl, aryl, heterocycle, C3.10 cycloalkyl, C4.10 cycloalkenyl,
-C(=0)R12,and-C(=S)R12;
R25 and R26 are independently not present or are selected from hydrogen, Ct.
lg alkyl, CjnoCydoalkyl, aryl, heterocycle, where each is optionally independently
substituted with 1 to 4 of C alkyl, Cw alkoxy, halo, CHpH, benzyloxy, and OH;
R27 is selected from hydrogen, Q.,,, alkyl, C3.10 cycloalkyl, (C3.10cycloalkyl)-Cj.
6 alkyl, aryl, and arylC, 18 alkyl; and
salts, tautomers, polymorphs, isomers and solvates thereof.
In a further embodiment of the invention the compounds of the formulas
of this invention are optionally combined with pharmacologically acceptable
excipients.
In a further embodiment of the invention the compounds of the formulas
of this invention are administered in therapeutically effective amounts to subjects
(humans or animals) in need of antiviral therapy, in particular for inhibiting the
infection, growth or replication of Flaviviridae and Picornaviridae, especially
BVDV, HCV and Coxsackie virus.
The invention, further relates to a method of screening antiviral compounds
which comprises providing a compound of formula (A) and determining the antiviral
activity of said compound.
Also within the scope of the invention is a metabolite of the compounds of
the formulas of this invention made by fee process of administering a compound
of formula (A) to a subject and recovering the metabolite from the subject.
The invention also comprises a. method for structure-activity determination
of analogues of compounds of WO 04/005286 having the general structure
wherein
the R, X and Y groups are defined in WO 04/005286, comprising
(A) preparing an analogue of a compound falling within the scope of
WO 2004/005286 wherein Q is replaced by N; and
(B) determining the anti-HCV activity of the compound of step (A).
Detailed Description of the Invention
Definitions
" Alkyl" means saturated hydrocarbon moiety where the moiety may be
acyclic, cyclic or a combination of acyclic and cyclic portions. The acyclic portion
may contain 1 to 3 carbon atoms, and each ring may contain 3 to 6 carbon atoms
(for example, 3-methylcyclohexyl). Within this definition, the term "cycloalkyl"
refers to the saturated hydrocarbon moieties that are cyclic. Examples of "alkyl"
include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-l-propyl(i-Bu), 2-
butyl (s-Bu) 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-
methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l-butyl, 2-methyl-l-butyl, 1-hexyl, 2-
hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-
3-pentyl, 2-methyl-3-pentyl, 2/3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cyclopropyl, cyclobutyl,
l, cycloheptyl, cydooctyl, or a Cpolycydic saturated hydrocarbon
radical having from 7 to 10 carbon atoms such as, for instance, norbomy 1, fenchyl,
trimethyltricydoheptyl or adamantyL
"Alkenyl" means a hydrocarbon moiety with at least one site of double
bond unsaturation where the moiety may be acyclic, cyclic or a combination of
acyclic and cyclic portions. The acyclic portion may contain 1 to 3 carbon atoms,
and each cyclic portion may contain 3 to 6 carbon atoms. A site of double bond
unsaturation may be in a acyclic portion, a cyclic portion. In the instance of a
moiety having a combination of acyclic and cyclic portions, there may be a site of
double bond unsaturation in each of the portions. Within, this definition, the term
"cycloalkenyl" refers to the double bond unsaturated hydrocarbon moieties that
are cyclic. Examples the term "alkenyl" include, but are not limited to, ethylene
or vinyl (-GH=CK,), allyl (-CHCHCHJ, cydopentenyl (,-CH,), 5-hexenyl
(-CH1CH1CtliGfl2CH=CHs)/ 1-cydopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-
enyly 1-cyclohex-l-enyl, l-cydoJiex-2-enyl, and l-cydohex-3-enyl. The double
bond optionally is in the ds or trans configuration.
"Alkynyl" means a hydrocarbon moiety with a least one site of triple bond
unsaturation where the moiety maybe acyclic, cyclic or a combination of acyclic
and cyclic portions. The acyclic portion may contain contain I to 3 carbon atoms,
and each cyclic portion may contain 7 or more carbon atoms. Within this
definition, the term "cycloalkynl" refers to triple bond unsaturated hydrocarbon
moieties that are cyclic. Examples of the term "alkynyl" include, but are not
limited to, -CCH, -CHCCR, -CHjCC-cyclohexyl, or -CHj-cycloheptynyl.
The suffix'' -ene" used in connection with alky!, alkenyl and alkynyl
groups refers to such groups with at least 2 sites of substitution. Such polyvalent
:-hydrocarbon radicals include^but-are-not^inited to, methylene (-CHj-) 1,2-
ethylene (-Ct^CH,-), 1,3-propylene (-CH^Ct^CH^), 1,4-butylene (-
CHaCHICH,CHa-, 1,2-ethylene (-CH=CH-), -CC-, propargyl (-CE^CC-), and 4-
pentynyl (-CH,CH,CH,CCH-). Optionally, aikylene, alkenylene and alkynylene
are substituted with O, S or N, generally meaning that O, S or N replace a carbon
cyclopentyl, cycloheptyl, cyclooctyl and the like, or a C7.10 polycyclic saturated
hydrocarbon radical having from 7 to 10 carbon atoms such as, for instance,
norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl.
"Alkenyl" means a hydrocarbon moiety with at least one site of double
bond unsaturation where the moiety may be acyclic, cyclic or a combination of
acyclic and cyclic portions. The acyclic portion may contain 1 to 3 carbon atoms,
and each cyclic portion may contain 3 to 6 carbon atoms. A site of double bond
unsaturation may be in a acyclic portion, a cyclic portion. In the instance of a
moiety having a combination of acyclic and cyclic portions, there may be a site of
double bond unsaturation in each of the portions. Within this definition, the term
"cycloallcenyl" refers to the double bond unsaturated hydrocarbon moieties that
are cyclic. Examples the term "alkenyl" include, but are not limited to, ethylene
or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C), 5-hexenyl
(-CH2CH2CH2CH2CH=CH2)/ 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-
enyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, and l-cyclohex-3-enyl. The double
bond optionally is in. the cis or trans configuration.
"Alkynyl" means a hydrocarbon moiety with a least one site of triple bond
unsaturation where the moiety may be acyclic, cyclic or a combination of acyclic
and cyclic portions. The acyclic portion may contain contain 1 to 3 carbon atoms,
and each cyclic portion may contain 7 or more carbon atoms. Within this
definition, the term "cycloalkynl" refers to triple bond unsaturated hydrocarbon
moieties that are cyclic. Examples of the term "alkynyl" include, but are not
limited to, -CCH, -CH2CCH, -CH.CC-cyclohexyl, or -CH2-cycloheptynyl.
The suffix "-ene" used in connection with alkyl, alkenyl and alkynyl
groups refers to such groups with at least 2 sites of substitution. Such polyvalent
hydrocarbon radicals include, but are not limited to, methylene (-CH,,-) 1,2-
ethylene (-CH.CH,-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-
CH2CH2CH2CH2-), 1,2-ethylene (-CH=CH-), -CC-, propargyl (-CH.CC-), and 4-
pentynyl (-CH2CH2CH2CCH-). Optionally, alkylene, alkenylene and alkynylene
are substituted with O, S or N, generally meaning that O, S or N replace a carbon
rtd the valence appropriate number of carbon substituents (generally 1 or
2H). N in this case is generally R".
"Aryl" means an aromatic hydrocarbon containing 1 or more rings,
generally 1,2 or 3, with 4 to 6 carbon atoms in each, ordinarily 5 or 6 carbon
atoms,
"Arylalkyl," "arylalkenyl" and "arylalkynyl" means an alkyl, alkenyl or
alkynyl radical, respectively, in which one of the hydrogen atoms, typically a
terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylaJkyl
groups include, but are not limited to, benzyl 2-phenylethan-l-yl, 2-phenylethen-
1-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenayl,
2-naphtJtophenylethan-l-yl.
As noted, carbocydes optionally are found as single rings or multiple ring
systems. Ordinarily the hydrocarbons of the compounds of the formulas of this
invention are single rings. Monocyclic carbocycles generally have 3 to 6 ring
atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles typically have 7
to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or
10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
If the number of carbon atoms is unspecified for a hydrocarbon, typically
the number of carbon atoms will range from 1 to 18. except that the number of
carbons typically will range from 2 to 18 for unsaturated hydrocarbons and from 6
to 10 for aryL
"Heterocycle" or "heterocycle" means any 4, 5,6,7, 8 ox 9 membered single
or fused ring system containing one or more heteroatoms selected from the group
consisting of O, N or S. Heterocycles optionally are entirely aromatic, entirely
saturated, or contain 1 or more intra-ring sites of unsaturation, typically double
bonds. Multipleel:eT6cyclirtngs (one or more of which containshfcteTW5tmn:)—
are bridged or spiro. Generally, the heterocyclic rings will be aromatic, and
usuaDy they are single rings. Examples of heterocycles include oxazacyloalkyl,
morpholinyl, dioxacycloalkyl, thiacycloalkenyl, pyridyl, dihydroypyridyl,
tetrahydropyridyl (piperidyl), thiazolyl, terrahydrothiophenyl, fuianyl, thienyl,
pyrrolyl, pyranyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, imidazolyl, tetrazolyl,
benzofuranyl, tManaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,
benzimidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,
tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bistetrahydropyranyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-
thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl,
chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isothiazoledinyl,
isoxazolyl, oxazolinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, indolizinyl, isoindolyl, 3H-indolyl, IH-indazoly, purinyl, 4Hquinolizinyl,
isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,
quinazolinyl, cimolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, fi-carbolinyl,
phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl,
imidazolidinyl, imidazolinyl pyrazoHdinyl, pyrazolinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl,
oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl and isatinoyl. Other
suitable heterocycles are exemplified in Rigaudy et. al., Nomenclature of Organic
Chemistry, Sections A-H (1979) at pp. 53-76 and Fletcher et. al., Nomenclature of
Organic Compounds, Adv. Chem. Ser. 126 (1974) at pp 49-64.
The location on the heterocycle which provides the point of attachment(s)
to the rest of the compound of this invention is not critical, but those skilled in the
art will recognize substitution sites that are optimal for compound stability
and/or ease of synthesis. Carbon bonded heterocycles typically are bonded at
position 2,3,4,5, or 6 of a pyridine, position 3,4,5, or 6 of a pyridazine, position
2,4,5, or 6 of a pyrimidine, position 2,3,5, or 6 of a pyrazine, position 2,3,4, or 5
of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,
position 2,4, or 5 of an oxazole, imidazole or thiazole, position 3,4, or 5 of an
isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2,3, or
4 of an azetidine, position 2,3,4,5,6,7, or 8 of a quinoline or position 1,3,4,57 6,
7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include
3-pyridyl, 4-pyridyl, 5-pyridyi, 6-pyridyl 3-pyridazinyl, 4-pyridazinyl,
5-pyridazinyl, S-pyridazinyl, 2-pyrimidinyl, 4~pyrimidinyl, 5-pyrirnidinyl, 6-
pyriinidanyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazoh/l, 4-
thiazolyl, or S-thiazolyi
Nitrogen, containing heterocydes are bonded at nitrogen or a carbon,
typically a carbon atom These include., for example, position 1 of aziridine, 1-
asdridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, l-piperidinyl, 2-
pyrroline, 3-pyrrolirve, 2-imidazoline, 3-imidazoline, 9-carbazole, 4-morpholine,
alpha or fi-carbollne, 2-isoindok, 2-pyrazoUne and 3-pyrazoline7 and by analogy,
azetidine, pyrrole, pyrrpUdine piperidine, piperazine, indole, pyrazoline,
indollne, imidazole, imidazoKdine, JH-indazole and Isolndoline. These and otiaer
K-containing heterocydes are well-known to those skilled in the art, and their
linkage sites are a matter of discretion,
Sulfui containing heterocycles are bonded through carbon or sulfur. They
indude oxidized states such as -S(=O)(=O). In general, they are linked in the
compounds of the formulas of this invention analogous to N-containing
heterocycles.
"Alkoxy", "cycloalkoxy", "aryloxy", "arylalkyloxy", "oxy heterocycle",
"thioalkyl", "thioqrdoalkyl'"arylthio", and "arylalkylthio'' means substituents
wherein an alkyl, cycloalkyl, aryl, or arylalkyl, respectively, are attached to an
oxygen atom or a sulfur atom through a single bond, sudi as but not limited to
methoxy, ethoxy, propoxy, butoxy., diioethyl, thiomethyl, phenyloxy, benzyloxy,
inercaptobenzyl. . '
"Halogen" means any atom selected from the group consisting of fluorine,
chlorine, bromine and iodine.
Anytibstitaenlrdesignation that is found in morei±ian one site~irra
compound of this invention shaU be independently selected.
When a group is stated to be substituted with "one or more" of another
group, this typically means 1 to 3 substituents, ordinarily 1,2 or 3 substitutents.
Those of skill in the art will, also recognize that the compounds of the
invention may exist in many different protonation states, depending on, among
other things, the pH of their environment While the structural formulae
provided herein depict the compounds in only one of several possible protonation
states, it will be understood that these structures are illustrative only, and that the
invention is not limited to any particular protonation state-any and all
protonated forms of the compounds are intended to fall within the scope of the
invention.
Amino Adds
"Amino-acid" refers to a radical derived from a molecule having the
chemical formula HjN-CJiR-COOH/ wherein R" is a side group of a naturallyoccurring
or kttown synthetic airuno-acid. The ammo acids optionally are
substituted with hydrocarbon typically of 1 to 8 carbons at one or more carboxyl
or amino groups, whether those groups are on the side chain or are free after
linking the amino acid to the remainder of the compound of this invention.
Optionally the amino acid residue is a hydrophobic residue such as monoor
di-alkyl or aryl amino acids, cycloalkylamino acids. Optionally, the residue
does not contain a sulfhydryl or guanidino substituent.
NaturaHy-occutring amino acid residues are those residues found naturally
in plants, animals or microbes, especially proteins thereof. Polypeptides most
typically will be substantially composed of such naturally-occurring amino acid
residues. These amino acids are glycine, alanine, valine, leucine. isoleucine,
serine, threonine, cysteine, methiorune, glutamic acid, aspartic acid, lysine,
hydioxylysine, arginirie, histidine, phenylalanine, tyrosiae, tryptophan, proline,
asparagirte, glutarrdne and hydroxyproline. Additionally, unnatural amino acids,
—for-example, valanine, phenylglycine and-homoar-nine-are also included.
Generally, only one of any site in the parental molecule is substituted with
an amino acid, although it is within the scope of this invention to introduce amino
acids at more than one permitted site. In general, the alpha-amino or alphacarboxyl
group of the amino acid are bonded to the remainder of the molecule,
i.ev carboxyl or amino groups in the amino acid side chains generally are not used
to form amide bonds with the parental compound (although these groups may
need to be protected during synthesis of the conjugates).
The arnino acid esters optionally are hydrolyzable in vivo or in vitro under
acidic (pH 3) or basic (pH 10) conditions. Optionally, they are substantially
stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in
blood or in intracellular environments.
R28 usually is C,-C6 alkyl or CrC6 alkyl substituted with amino, carboxyl,
amide, carboxyl (as well as esters, as noted above), hydroxyl, C6-C7 aryl,
guanidinyl, imidazolyl, indolyl, sulfhydryl, sulf oxide, and /or alkylphosphate. R28
also is taken together with the amino acid alpha nitrogen to form a proline
residue. However, R28 is generally the side group of the naturally-occurring
amino acid disclosed above, for example H, -CH^ -CH(CHJV -CH2-CH(CH3)2, -
CHCH3-CH2-CH3, -OEVQHs, -CH2CH2-S-CH3, -CH2OH, -CH(OH)-CH,, -CH.-SH, -
CH2-C6H4OH, -CHa-CO-NH,, -CH2-CH2-CO-NH2/ -CH.-COOH, -CH2-CH2-COOH, -
(CHjX-NH, and -(CH2)3-NH-C(NH2)-NH2. R28 also includes l-guanidinoprop-3-yl,
benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and
ethoxyphenyl.
Subgeneric Embodiments
R1 is generally aryl or aromatic heterocyle (usually containing 1 or 2 O, S or
N atoms, typically O or S) substituted with 1, 2 or 3 R6 wherein R6 usually is
halogen, Cj.lg alkoxy; or CW8 haloalkyl. Typically, R1 is 6 to 10 C carbocycle having
I or 2 rings (most ordinarily phenyl) substituted with 1, 2 or 3 halogens, usually
fluoro.
Y generally is a single bond, O, C6 alkylene, C2.6 alkenylene, C2.6 alkynylene
or one of said groups containing 1 to 3, usually 1, heteroatoms selected from O, S
or MR11. Examples include -0(01-, -(CKL-CKCH, -S-fCH,)
-NR11-(CH2)1.5-, -(CHa)M-NR"-(CH2)w or CMO cycloalkylidene.
Typically, Y is -OCH,-, -CH.O-, Cj.2 alkylene, C2.3 alkenylene, C2.3 alkynylene, O or
a bond, but usually a bond.
In general, YR1 is not any one of H, an unsubstituted C3.10 cycloalkyl or C,-
C6 alkyl. Typically YR1 is halo or halomethyl-substituted (typically trihalomethyl)
phenyl (and usually 1 to 2 substituents in ortho or meta).
X usually is alkylene, alkynylene or alkenylene, typically alkylene, or said
hydrocarbons having an intrachain heteroatom, typically O or S. Examples
include -CH,-, -CH(CH3)-/ -CH.-CH,-, -CH.,-CH2-CH2-, -CH, CH, CH2 CH,, (CH
,-CKCH-, -(CH-S-tCH,),,-, -(CH2)M-NR10-(CH2)M-, C3,0 cycloalkylidene, C2.6
alkenylene (such as -CH=CH-CHj-) and CM alkynylene. Usually, X is methylene.
R3 generally is aryl or a heterocycle, typically an aromatic heterocycle. The
heterocycle generally will contain 1,2 or 3 N, S or O atoms in the ring, usually is
linked to X through a ring carbon atom and typically contains 4 to 6, usually 5,
total ring atoms. The R3 aryl or heterocycle ordinarily is substituted with 1,2 or 3,
usually 1, R17. R3 optionally is not indolyl.
When R3is substituted with R17then R17 typically is aryl or a heterocycle
further substituted with 1 or more, usually 1,2 or 3, R19.
R17 is M-Q in some embodiments of the invention. M is a ring. This means
any cyclic organic structure, whether carbocyclic or heterocycle, and whether
saturated, unsaturated or aromatic or single or fused ring systems. M is chosen
from rings that are structurally stable in biological systems. In general, M is a aryl
or aromatic heterocycle where heterocycle is defined above.
Q is a spacer group or bond, and is not critical. Typically it is not cyclic
and contains from 0 to 6 atoms, generally H, C, NR1,0 or S, usually C, H and O.
A typical embodiment is alkyl having 1 to 6 carbons, normal or secondary,
optionally with O or NR11 replacing 1 methylene group. Generally Q is 1 to 6
atoms, usually 1 to 3. Q typically is not substituted with R19, but if it is then
typically it is substituted with one R19. R19 as substituted on Q usually is alkoxy,
halogen, nitro or cyano.
R17 typically is selected from the group consisting of C3.10 cycloalkyl, C3.,0
cycloalkenyl, C7-,0 cycloalkynyl, halogen, aryl, aryloxy, arylthio, arylsulfoxide,
arylsulfone, arylsulfonamide, arylalkyl; arylalkyloxy (optionally an benzyloxy);
arylalkylthio (optionally a benzylthio); a heterocycle; C,.18 hydroxyalkyl, but
typically is an aryl or a heterocycle, and where each of said aryl, aryloxy, arylthio,
arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio,
or heterocycle is optionally substituted with 1 or more R19. R17 generally is
positioned distaily to X. Optionally, R17is not C(O) R18.
R9 and R18 typically are H, OH or alkyl. R18 optionally is not NR15R16.
R5 typically is not present.
R6 generally is halogen. Optionally, R6 is not C(O) R18.
R12and R22 typically are independently OH or alkyl.
R19 usually is H; C18 alkyl; C18 alkenyl; C2.18 alkynyl; C,.18alkoxy; alkenyloxy;
alkynyloxy; Calkylthlo; C3.10 cycloalkyl; C4.10 cydoalkenyl; C4.10 cycloalkynyl;
halogen; OH; CN; cyanoalkyl; NO2; NR20R21; haloalkyl; haloalkyloxy; C(=O)R18;
C(=O)OR18; OalkenylC(=O)OR18; -OalkylC(=O)NR20R21; aryl; heterocycle;
-OalkylOC(=O)R18; C(=O)N(CW alkyl), N(H)S(O)(O)(C,.6 alkyl); arylalkyloxy;
aryloxy; arylalkyloxy; and arylalkyl; each of which is unsubstituted or
substituted with 1 or more =O; NR20R21; CN; alkoxy; heterocycle; haloalkyl- or
alkyl-substituted heterocycle; heterocycle linked to R17 by alkyl; alkoxyalkoxy or
halogen. R18 as a subtituent in R is generally not H. R:9 typically is
independently halogen, N(R R ), unsubstituted or heterocycle (O-containing) -
substituted C-C alkyl or alkynyl where methylene is substituted with 1-3
oxygen atoms, or is halo-substituted alkyl or alkoxy.
R25 and R26 usually are not present but, if they are, then typically they are
cyclopentyl or cyclohexyl. If the compound is substituted at R25 or R26, either R2or
R4 is selected from =O, =S, and =NR27, usually =O.
M typically is an aromatic ring, usually single or two fused rings, and
containing 4 to 10 atoms. Usually, M is hydrocarbon, but also optionally
comprises 1 to 3 N, O and/or S heteroatoms.
Substituents optionally are designated with or without bonds. Regardless
of bond indications, if a substituent is polyvalent (based on its position in the
structure referred to), then any and all possible orientations of the substituent are
intended.
Haloalkyl or haloalkyloxy typically are -CF3 or -OCF3.
In certain embodiments of the compound of formula (A) (a) YR1 is not H;
(b) R2 is not OH, SH, =O or =S; (c) R4 is not =O or =S; (d) YR1 contains at least one
aryl; (e) X is CH,; (f) R3 contains at least one aryl; (g) if Y is a bond and R1 is an
aryl, this aryl is not phenyl substituted with OH and optionally substituted with
methyl, methoxy, nitro, dimethylamino, Cl, Br, or F; (h) if Y is a bond and R1 is
aryl which is para substituted with OH and optionally further substituted with
methyl, methoxy, nitro, diethylamino, Cl, Br or F and X is an alkylene, then R° is
not a heterocycle containing N; (i) if Y is a bond or (CH,), R1 is H, X is CH2 and
R3 is phenyl with 1R17, wherein R17 is C(=0)R18, then R18 is selected from H; OH; C,.,,
alkyl; C2.18 alkenyl; C,.ls alkoxy; NR15R16; aryl, or an amino acid residue linked
through an amino group thereof; (j) R18 is not a C3.10 cycloalkyl or C4.10 cycloalkenyl;
(k) if Y is a bond or (CHy then R1 is an aryl unsubstituted or substituted with
one or more R6, heterocycle unsubstituted or substituted with one or more R6, C3.
10 cycloalkyl unsubstituted or substituted with one or more R6and C4.,0
cycloalkenyl unsubstituted or substituted with one or more R6; (1) -YR1 is not H or
Cw alkyl; (m) if Y is a bond or (CH., R1 is H, and R3is a 5 membered heterocycle
with one R17, wherein R17 is C(=O)R18 and R18 is NR15R16, then R15 and R16 are not a
Cj.18 alkyl or a cycloalkyl; (n) if Y is a bond or (CHj)^, and R1 is H, and R3 is a 5
membered heterocycle with one R17, wherein R17 is C(=O)R18 then R18 is selected
from H; OH; C,.,, alkyl; C2.]8 alkenyl; C3.lo cycloalkyl; C4.]0 cycloalkenyl; C,.u alkoxy;
aryl or an amino acid residue linked through an amino group thereof; (o) R18 is
not NR15R16; (p) if Y is a bond or (CH2)W/ R1 is H, X is -CH,- and R3 is phenyl
substituted with one R1, then R17 is independently selected from the group
hydrogen; CM8 alkyl; C2.16 aflcenyl; C2.18 alkynyl; C,.u alkoxy; Q.,, alkylthio; C3.10
cycloalkyl, CMO cycloalkenyl or C3.10 cycloalkynyl; halogen; OH; CN; NO2; NR7R8;
OCFy haloalkyl; C(=S)R18; SH; aryl; aryloxy; arylthio; arylalkyl; arylalkyloxy
(optionally a oxybenzyl); arylalkylthio (optionally a benzylthio); 5 or 6 membered
heterocycle, oxyheterocycle or thioheterocycle; C,.18 hydroxyalkyl; and each of said
aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy (optionally a oxybenzyl),
arylalkylthio (optionally a benzylthio), 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle, Q.,,, hydroxyalkyl is optionally substituted
with 1 or more R19; (q) R17 is not (C=O)R18; (r) if Y is a bond or (CH2),.6, and R1 is H,
and R3 is a 5 membered heterocycle with one R17, wherein R17 is C(=O)R18, then R18
is selected from H; OH; €,.„ alkyl; aryl, NR15R16; (s) R18 is not C,.u alkoxy; (t) if Y is
a bond or (CHj), and R1 is H, and R3 is a 5 membered heterocycle with one R17,
wherein R17 is C(=O) R18, then R18 is selected from OH; CMB alkyl; CM8 alkoxy;
aryl, or NR15R16; (t) R18 is not H; (u) if Y is a bond, R1 is hydrogen, X is an alkyl and
R3 is an aryl thio substituted with 3 R17, and 1 R17 is OH in para, then the
remaining R17 are independently selected from the group consisting of hydrogen;
C2.,8 alkenyl; C2.18 alkynyl; CM8 alkoxy; CW8 alkylthio; C3.10 cycloalkyl, CMO
cycloalkenyl or Ccycloalkynyl; halogen; OH; CN; NO2; NR7R8; OCF3; haloalkyl;
C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl; arylalkyloxy (optionally a
oxybenzyl); arylalkylthio (optionally a benzylthio); 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle; CM8 hydroxyalkyl; and each of said aryl,
aryloxy, arylthio, arylalkyl, arylalkyloxy (optionally a oxybenzyl), arylalkylthio
(optionally a benzylthio), 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle, CM8 hydroxyalkyl is optionally substituted with 1 or more R19; (v)
R17 is not a Q.,, alkyl; (wl) if Y is a bond, R1 is a hydrogen, X is -(CHCH,)-, then
R3is selected from aryl; aryloxy; aryl-NR10-; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle; and each of said aryl, aryloxy, aryl-NR10-, 5 or 6
membered heterocycle, oxyheterocycle or thioheterocycle is optionally substituted
with one or more R17; Ccycloalkyl, oxycycloalkyl or thiocycloalkyl; C4.w
cycloalkenyl with the proviso that the double bond cannot be adjacent to a
nitrogen; H with the proviso that if X is an alkyler.e, 'an alkenylene or an
alkynylene, then X comprises at least 5 carbon atoms; (w2) R3 is not an arylthio; (x)
if X is -(CHjCEy-S, R3 is not an aryl; (y) if Y is a bond, R; is H, X is an alkylene
and R3 is phenoxy, R17 is independently selected from the group hydrogen; Cj.18
alkyl; C2.18 alkenyl; Q.1B alkynyl; Cwg alkoxy; CM8 alkylthio; €,.„ cycloalkyl, C3.10
cycloalkenyl or C3.10 cycloalkynyl; halogen; OH; CN; NO2; NR7R8; OCF^ haloalkyl;
C(=O)R9; C(=S)R9; SH; aryl; arylthio; arylalkyl (except benzyl); arylalkyloxy
(except oxybenzyl); arylalkylthio (optionally a benzylthio); 5 or 6 membered
heterocycle, oxyheterocycle or thioheterocycle; CW8 hydroxyalkyl; and each of said
aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy (optionally a oxybenzyl),
arylalkylthio (optionally a benzylthio), 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle or C,.18 hydroxyalkyl is optionally substituted
with 1 or more R19; (z) if R3 is phenoxy, R17 is not benzyl, phenoxy or oxybenzyl;
(aa) if XR3 is fluorobenzyl, R2, R3, R4 are R'=H and Y is NR11, Rn is selected from H;
C,.1B alkyl; CM8 alkenyl; CIQ cycloalkyl; C4.]0 cycloalkenyl; aryl; 5-6 membered
heterocycle or an amino acid residue linked through a carboxyl group thereof;
(bb) R11 is not methyl or C(=O)R12; (cc) if X is CH2 and R3 is a phenyl substituted in
para with Cl, and Y is CHj, then R1 is not piperazinyl; (dd) if X is CH2 and R3 is a
phenyl substituted in para with Cl, and Y is CH2, then R1 heterocycle is aromatic;
(ee) if R5 is an aryl, aryloxy or benzyl group, R1 is not H or C^ alkyl; (ff) if R1 is H
or Ca.10 alkyl, then R5 is absent or is selected from hydrogen, CM8 alkyl; CM8 alkenyl;
C2.18 alkynyl; C,.,, alkoxy; Ct.18 alkylthio; halogen; OH; CN; NO2; NR7R8; OCF
haloalkyl; C(=O)R9; C(=S)R9; SH; arylthio; arylalkyl (except benzyl); C,.u
hydroxyalkyl; C3.10 cycloalkyl; C3.10 cycloalkyloxy; C3.10 cycloalkylthio C3 ,„
cycloalkenyl; C3.]0 cycloalkynyl; 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle; (gg) R5 is not aryl, aryloxy or benzyl; (hh) YR1 is not hydrogen,
--unsubstituted C3.]0 cycloalkyl, or C,.6 alkyl; (ii) YR1 is not phenyl para substituted
with OH; (jj) if R1 is not H, Y is not NR11 with R" is C,.6 alkyl or methyl; (kk) YR1 is
not monomethylamino; (11) if R1 is a phenyl substituted with one R6, then R6 is
C(=O)R18 and R18 is t-butoxy; (ram) R1 is not piperidinyl and is not piperazinyl
subsituted with methyl; (nnJYR1 is not one of the substituents designated R13 in
column 5, lines 22-38 of U.S. Patent No. 5,486,525 or its family members; (oo) Rz
and/or R5 are none of the substituents collectively designated R14 and R15 in
column 5, lines 38-53 of U.S. Patent No. 5,486,525 or its family members; (pp) XR3
is not the substructure -(CHyn-Het-QC^-NCR1)^2) using the group designations
set forth on column 1, line 41 to column 2 line 24 of U.S. Patent No. 4,990,518 and
the comparable disclosure in any member of the patent family of U.S. Patent No.
4,990,518; (qq) XR3 is not the substructure -(CH2)n-Y-C(O)-N(R1)(R2) using the
group designations set forth on column 1, line 49 to column 2 line 38 of U.S.
Patent No. 5,302,601 and the comparable disclosure in any member of the patent
family of U.S. Patent No.. 5,302,601; (rr) R2 and R4 are not both =O or =S; and/or
(alone or in any combination) (ss) R5 contains none of the substituents designated
as Ar in WO 00/39127 (incorporated expressly herein by reference), in
particular aryl, aryl phenoxy, or benzyl; (tt) YR optionally is not a non-aromatic
hereocyclic ring containing 5 or 6 total ring atoms and 1 or 2 N atoms; (uu) YR
optionally is not a non-aromatic heterocyclic ring containing 1 or 2 N atoms
wherein one of the N atoms is linked to the imidazole ring; (vv) YR optionally is
not a 5-membered non-aromatic heterocyclic ring which contains 1 N atom and is
substituted with ammo; (ww) R optionally is not normal or secondary alkyl, or
benzyl.
The exclusions or embodiments herein are not to be interpreted as teaching
or suggesting any preferability or lack thereof for any use of the compounds
herein, but instead are merely subgeneric designations.
Optionally, the compounds of this invention also exclude all methylene
homologues of heretofore known compounds.
According to a particular aspect, the present invention relates to
compounds of the formula (A) wherein R1 is a phenyl optionally substituted with
a benzyloxy, and wherein R19 at meta is phenyl optionally substituted with a
halogen, (particularly chloro) in para, and R19 at ortho is H, nitre, amino, mono- or
di(Cw alkyl)-substituted amino, NHCXOXC^ alkyl); methoxysulfonamide or
C(O)R22, wherein Ra is NRR24 as defined below. Optionally R23 and R24 are C
alkyl taken together to form a hydroxy-substituted 6-membered saturated Nheterocycle.
An embodiment of the present invention relates to compounds of formula
(A) of this invention, pharmaceutically acceptable compositions, salts, tautomers,
and isomers thereof and their antiviral uses, wherein:
U is N;
R1 is selected from phenyl substituted with 0-3 R6; 5 or 6 membered
heterocycle containing 1-3 heteroatoms selected from the group O, N, and S,
substituted with 0-2 R6; 1-naphthyl substituted with 0-3 Rfi; 2-naphthyi substituted
with 0-3 R6; C3.7 cycloalkyl; C4.10 cycloalkenyl;
R2, R4 and R5 are independently selected from hydrogen; straight or
branched C,.6alkoxy; straight or branched CM alkyl; F; Cl; Br; I; OH; CN; NO2;
NR7R8; OCFy CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl, or in the
case of R optionally is unsubstituted;
X is selected from the group -CH,-; -CH(CH3)-; -CH2-CH2-CH2-; -OCH2-
CH,-; -CH=CH-CH2-;
R3 is selected from phenyl substituted with 0-3 R17; (benzoannellated) 5 or 6
membered aromatic heterocycle containing 1-3 heteroatoms selected from the
group O, N, and S, substituted with 0-2 R17; 1-naphthyl substituted with 0-3 R17; 2-
naphthyl substituted with 0-3 R17; C3.7 cycloalkyl; C4.7 cycloalkenyl with the proviso
that the double bond cannot be adjacent to a nitrogen;
R6 and R17 are independently selected from the group H; straight or
branched C^alkoxy; straight or branched CM alkyl; F; Cl; Br; I; OH; CN; NO2;
NR13R14; OCF3; CF3; C(=O)Rl8;phenyl; phenoxy; benzyl; hydroxymethyl;
R7 and R8 are indiependently selected from H; straight or branched d,^ alkyl;
phenyl; C(=O)R12; alternatively, R7 and R8, together with the nitrogen to which
they are attached, combine to form a 5-6 membered ring;
R9 and R18 are independently selected from H; OH; straight or branched Cw
alkyl; straight or branched Cw alkoxy; NR15R16; phenyl;
R12 is selected from the group H; Ct.6 straight or branched alkyl; phenyl;
R15 and R16 are independently selected from the group H; Cj.6 straight or
branched alkyl; phenyl; and
Y is a bond.
One embodiment of a second aspect of the present invention relates to
compounds according to the general formula (A), pharmaceutically acceptable
compositions, salts, tatitomers, polymorphs and isomers thereof, and their
antiviral uses, wherein:
UisN;
R1 is selected from hydrogen; aryl unsubstituted or substituted with one or
more R6, heterocycle unsubstituted or substituted with one or more R6, CMO
cycloalkyl unsubstituted or substituted with one or more R6 and C4.10 cycloalkenyl
unsubstituted or substituted with one or more R6;
Y is selected from the group consisting of a single bond, O; S(O)m (where
m is an integer from 0 to 2); NR11; and a divalent, saturated or unsaturated,
substituted or unsubstituted Cj.C10 hydrocarbon group optionally including one or
more heteroatoms in the main chain, said heteroatoms being selected from the
groups consisting of O, S, and N; such as C,.6 alkylene, C2.6 alkenylene, C2.6
alkynylene, -OCCH,),.,-, -(CH-OCH,),.,-, -S-(CEy„-, -(CH2)M-S-(CH2)M-,
-, -(CH2)M-NR11-(CH2)l.4-and C3,0 cycloalkylidene;
Each R2 and R4 is independently selected from the group consisting of
hydrogen CM8 alkyl; C2.I8 alkenyl; CM8 alkynyl; CM8 alkoxy; C,.tt alkylthio; halogen;
OH; CN; NO2; NR7R8; OCF haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy;
arylthio; arylalkyl; CM8 hydroxyalkyl; C3.10 cycloalkyl; C3.]0 cycloalkyloxy; C^
cycloalkylthio; C3.10 cycloalkenyl; C3.lo cycloalkynyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle;
X is selected from the group consisting of a divalent, saturated or
unsaturated, substituted or unsubstituted Q C10 hydrocarbon group optionally
including one or more heteroatoms in the main chain (provided that the
heteroatom is not linked to N of the nucleus), said heteroatoms being selected from
the group consisting of O, S, and N; such as Q.6 alkylene, (for example
K -CH, -CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2), -(CH2)2
CH,) -, -(CH^-l^-tCH-, C3.10 cycloalkylidene, CM alkenylene
(such as -CH=CH-CH2-), CM alkynylene;
R3 is selected from the group consisting of ary'i; aryloxy; arylthio; aryi-NR10-;
5 or 6 membered heterocycle, oxyheterocycle or thioheterocycle;; and each of said
aryl, aryloxy, arylthio, aryl-NR10-, 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle is optionally substituted with one or more R17; C3,10 cycloalkyl,
oxycycloalkyl or thiocycloalkyl; C4.10 cycloalkenyl with the proviso that the double
bond cannot be adjacent to a nitrogen; H with the proviso that if X is an alkylene,
an alkenylene or an alkynylene, then X comprises at least 5 carbon atoms;
R5 is independently absent or selected from the group consisting of
hydrogen; C,.1B alkyl; C2.18 alkenyl; C2.18 alkynyl; CM8 alkoxy; Cwg alkylthio; halogen;
OH; CN; NO2; NR7R8; OCF3; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy;
arylthio; arylalkyl; C,.,,, hydroxyalkyl; C3.]0 cycloalkyl; CMO cycloalkyloxy; C
cycloalkylthio C3.10 cycloalkenyl; C3.10 cycloalkynyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle;
Each R6 and R17 is independently selected from the group consisting of
hydrogen; C,.1B alkyl; C2.18 alkenyl; C2.18 alkynyl; CM8 alkoxy; C,.u alkylthio; CHO
cycloalkyl, C3.10 cycloalkenyl or C3.10 cycloalkynyl; halogen; OH; CN; NO2; NR7R8;
OCF3; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl;
arylalkyloxy (optionally a oxybenzyl); arylalkylthio (optionally a benzylthio); 5 or
6 membered heterocycle, oxyheterocycle or thioheterocycle; Q. hydroxyalkyl;
and each of said aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy (optionally a
oxybenzyl), arylalkylthio (optionally a benzylthio), 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycie, C,.w hydroxyalkyl is optionally substituted
with 1 or more R19.
Each R7 and R8 is independently selected from the group consisting of H;
C,.18alkyl; C,.18 alkenyl; aryl; C3.10 cycloalkyl; C4.10 cycloalkenyl; 5-6 membered
heterocycle; C(=O)RU; C(=S) R12; an amino acid residue linked through a carboxyl
group thereof; alternatively, R7 and R8, together with the nitrogen to which they
are attached, combine to form a 5-6 membered heterocycle;
Each R9 and R18 is independently selected from the group consisting of H;
OH; €,.„ alkyl; C2.18 alkenyl; C3.10 cycloalkyl; C4.10 cycloalkenyl; Ct]8 alkoxy; NR15R16;
aryl an amino acid residue linked through an amino group thereof;
Each R10 and R11 is independently selected from the group the group
consisting of H; C,.,8 alkyl; CM8 alkenyl; C3.10 cycloalkyl; C4.10 cycloalkenyl; aryl;
C(=O)R12; 5-6 membered heterocycle; an amino acid residue linked through a
carboxyl group thereof;
R12 is independently selected from the group consisting of H; CM8 alkyl; C2.;
alkenyl; aryl; C3.10 cycloalkyl; C4.10 cycloalkenyl; an amino acid residue linked
through an amino group thereof;
Each R1S and R16 is independently selected from the group consisting of H;
C,.u alkyl; C2.18 alkenyl; C2.18alkynyl; aryl; CMO cycloalkyl; CMO cycloalkenyl; an
amino acid residue linked through a carboxyl group thereof;
R19 is independently selected from the group consisting of H; C,.]8 alkyl,
preferably Cw alkyl; C2.]8 alkenyl; C2.]8 alkynyl; C,.lg alkoxy, preferably Cw alkoxy;
Q.^alkylthio; C3.10 cycloalkyl; C4.,0 cycloalkenyl; C4.10 cycloalkynyl; halogen; OH;
CN; N02; NR20R21; OCF3; haloalkyl; C(=O)R22; C(=S)R22; SH; C(=O)N(C^ alkyl),
N(H)S(O)(O)(C!.6 alkyl); aryl; asyloxy; arylthio; arylalkyl; and each of said aryl,
aryloxy, arylthio, arylalkyl substituted with 1 or more halogens, particularly a
phenyl substituted with 1-2 halogens; hydroxyalkyl; 5 or 6 mernbered heterocycle,
oxyheterocycle or thioheterocyele each unsubstituted or substituted with 1 or
more halogens;
Each R^and R21 is independently selected from the gruup consisting of H;
C,.,, alkyl, preferably C^alkyi; C2.18alkenyl; C2.18alkynyl; aryl; C3.10 cycloalkyl; Cwo
cycloalkenyl; C(=O)R12, C(=S)R12;
R is independently selected from H; OH; CW8 alkyl; C2.18 alkenyl; C1-18
alkoxy; NR23R24; aryl; C3.10 cycloalkyl,; C4.10 cycloalkenyl;
Each Raand R24 is independently selected from the group the group
consisting of H; CM8 alkyl, preferably C2.3 alkyl, wherein C2.3 alkyl taken together
with N of R22 can form a saturated heterocycle, which heterocycle is optionally
substituted with OH or myl or an amino acid residue.
An embodiment relating to a third aspect of the present invention relates to
compounds according to the general formula (A), pharmaceutically acceptable
compositions, salts, tautomers, polymorphs and isomers thereof, and their
antiviral uses, wherein:
UisN;
R1 is selected from hydrogen; phenyl unsubstituted or substituted with 1-3
R6; 5 or 6 membered heterocycle, optionally benzo-added, containing 1-3
heteroatoms selected from .the group O, N, and S, unsubstituted or substituted
with 1-2 R6; 1-naphthyl unsubstituted or substituted with 1-3 R6; 2-naphthyl
unsubstituted or substituted with 1-3 R6; C3.10 cycloalkyl, particularly C3.7
cycloalkyl; Cj.7 cycloalkenyl with the proviso that the double bond cannot be
adjacent to a nitrogen;
Y is selected from the group -(CH; O; S; NRn; -CHCCH,)-; -OCH,-;
-CHP-; -OCH2-CH2-; -CH2-CH2O-; -CH2-O-CH2-; -(CH2)0.5-S-; -S-tCH,),,,-;; -(CH
(CH2)0.5-NRn-; -CH2-NR11-CH2-; -QCH,),-; (cis or trans)
.,CH2-CH=CH-; (cis or trans) -CH=CH-CH2-;
Each R2, R4and R5 is independently selected from hydrogen; straight or
branched C,.18 alkoxy, particularly Calkoxy; straight or branched Q.,,, alkyl
particularly CM alkyl; F; Cl; Br; I; OH; CN; NO,; NR7R8; OCF,; CF?; C(=O)R9;
phenyl; phenoxy; benzyl; hydroxymethyl or, in the case of R5, optionally is
absent;
R3 is selected from unsubstituted or phenyl substituted with 1-3 R17; 5 or 6
membered heterocycle, containing 1-3 heteroatoms selected from the group O, N,
and S, unsubstituted or substituted with 1-2 R17; 1-naphthyl unsubstituted or
substituted with 1-3 R17; 2-naphthyl unsubstituted or substituted with 1-3 R17; CMO
cycloalkyl, particularly C cycloalkyl; C5.7 cycloalkenyl with the proviso that the
double bond cannot be adjacent to a nitrogen;
Each R and R1 is independently selected from the group H; straight or
branched CM alkoxy; straight or branched CM alkyl; F; Cl; Br; I; OH; CN; NO2;
NR13R14; OCF3; CF3; C(=O)R18; unsubstituted phenyl or phenyl substituted with 1-3
R19; 5 or 6 membered heterocycles, optionally benzo-added, containing 1-3
heteroatoms selected from O, N and S, unsubstituted or substitued with 1 or 2 R19;
2-naphthyl unsubstituted or substituted with 1-3 R19; C3.7 cycloalkyl; C5.7
cycloalkenyl, phenoxy; benzyl; hydroxymethyl;
Each R7 and R8 is independently selected from H; straight or branched Cj.18
alkyl, preferably CM alkyl; phenyl; C(=O)R12; alternatively, R7 and R8, together
with the nitrogen to which they are attached, combine to form a 5-6 membered
ring;
Each R9 and R18 is independently selected from H; OH; straight or branched
C8alkyl, preferably C, alkyl; straight or branched (I,.,,, alkoxy, preferably Cw
alkoxy; NR15R16; phenyl;
E?.ch R10 and Rn is independently selected from the group H; C,.,a alkyl,
preferably C,.6 straight or branched alkyl; phenyl;
Each 1" is selected from the group H; C,.18 alkyl, preferably Cw straight or
branched alkyl; phenyl;
Each R13 and R14 is independently selected from H; straight or branched C,.M
alkyl, preferably Cw alkyl; phenyl; C(=O)R12;
Each R15 and R16 is independently selected from the group H; Cw straight or
branched alkyl; phenyl;
R19 is selected from the group H; straight or branched Cw alkoxy; straight or
branched Cw alkyl; F; Cl, Br; OH; NO2; NR20R21; OCF3/ C(=O)R22; phenyl; phenoxy;
benzyl; hydroxymethyl;
Each R20 and R21 is independently selected from H; straight or branched C,.18
alkyl, preferably CM alkyl; phenyl; C(=O)R12;
R22 is selected from H; OH; straight or branched CM alkyl; straight or
branched C,.,,, alkoxy, preferably Cw alkoxy; NR^R24; phenyl;
Each R23and R24 is independently selected from the group H; CM8 alkyl,
preferably C16 straight or branched alkyl; phenyl.
An embodiment of a fourth aspect of the present invention relates to
compounds of formula (Al) wherein R1 is directly linked to the imidazo[4,5-
d]pyrimidine ring structure, pharmaceutically acceptable compositions, salts,
tautomers, polymorphs and isomers thereof and their use in a treatment of viral
infection or to manufacture a medicament to treat viral infections, wherein:
UisN;R1 is selected from phenyl substituted with 0-3 R6; 5 or 6 membered
heterocycle containing 1-3 heteroatoms selected from the group O, N, and S,
substituted with 0-2 R6; 1-naphthyl substituted with 0-3 R6; 2-naphthyl substituted
with 0-3 R6; C3.7 cycloalkyl; C4.10 cycloalkenyl;
R2, R4 and R5 are independently selected from hydrogen; straight or
branched Cv6alkoxy; straight or branched Q.6alkyl; F; Cl; Br; I; OH; CN; NO2;
NR7R8; OCF3; CFy C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl or, in the
case of R5, optionally is absent;
X is selected from the group -CH2-; -CH(CH3)-; -CH.-CH,-; -CH2-CH,-CH2-;
-CH2-CH,-CH2-CH2; -OCH.-CH,-; -SCH2-CH2-; -NR10-CH2-CH2-; C3.7
cycloalkylidene; -C(CH3)2; -CH2-CH(CH3)-CH2-; -CH(CH3)-CH2-CH2-; -CH.-CH,-
CHtCH,)-; -CHCH-CH,-;
R3 is selected from phenyl substituted with 0-3 R1; (benzoannellated) 5 or 6
membered aromatic heterocycle containing 1-3 heteroatoms selected from the
group O, N, and S, substituted with 0-2 R17; 1-naphthyl substituted with 0-3 R17; 2-
naphthyl substituted with 0-3 R17; C3.7 cycloalkyl; C4.10 cycloalkenyl with the
proviso that the double bond cannot be adjacent to a nitrogen;
R6 and R17 are independently selected from the group H; straight or
branched CM alkoxy; straight or branched CM alkyl; F; Cl; Br; I; OH; CN; NO2;
NR13R14; OCF3; CF3; C(=O)R18; phenyl; phenoxy; benzyl; hydroxymethyl;
R7 and R8 are independently selected from H; straight or branched Cj.6 alkyl;
phenyl; C(=O)R1Z or R7 and R8, together with the nitrogen to which they are
attached, combine to form a 5-6 membered ring;
R9 and R18 are independently selected from'H; OH; straight or branched C
alkyl; straight or branched C alkoxy; NR15R16; phenyl;
R10 is selected from the group H; C straight or branched alkyl; phenyl;
R12 is selected from the group H; Cw straight or branched alkyl; phenyl;
R13 and R14 are independently selected from H; straight or branched Cw
alkyl; phenyl; C(=O)R12;
R15 and R16 are independently selected from the group H; Q.6 straight or
branched alkyl; phenyl.
An embodiment of a fifth aspect of the present invention relates to
compounds of formula (Al), pharmaceutically acceptable compositions, salts,
tautomers, polymorphs and isomers and their use in a treatment of viral infection
' or to manufacture a medicament to treat viral infection, wherein:
R1 is selected from phenyl unsubstituted or substituted with 1-3 R6; 5 or 6
membered heterocyde containing 1-3 heteroatoms selected from the group O, N,
and S, unsubstituted or substituted with 1-2 R6; 1-naphthyl unsubstituted or
substituted with 1-3 R6; 2-naphthyl unsubstituted or substituted with 1-3 R6; C
cycloalkyl; Ccycloalkenyl;
R2 and R4 are hydrogen;
R5 is absent;
X is selected from the group -CH,-; -CH(CH3)-; -CH.-CH,-; -OCH,-
CH2-; -CH=CH-CH2-;
R3 is selected from phenyl unsubstituted or substituted with 1-3 R17;
(benzoannellated) 5 or 6 membered aromatic heterocycle containing 1-3
heteroatoms selected from the group O, N, and S, unsubstituted or substituted
with 1-2 R17; 1-naphthyl unsubstituted or substituted with 1-3 R17; 2-naphthyl
substituted with 0-3 R17; Q^ cycloalkyl; C^ cycloalkenyl with the proviso that the
double bond cannot be adjacent to a nitrogen;
Each R6 and R is independently selected from the group H; straight or
branched C^alkoxy; straight or branched C^alkyl; F; Cl; Br; I; OH; CN; NO2;
NR13RM; OCF3; CF3; C(=O)R'; phenyl; phenoxy; benzyl; hydroxymethyl;
R9 is selected from H; OH; straight or branched C^ alkyl; straight or
branched CM alkoxy; NRtsR16; phenyl;
R12 is selected from the group H; CM straight or branched alkyl; phenyl;
Each R13 and Rw is independently selected from H; straight or branched C
alkyl; phenyl; C(=O)R1Z; and
Each R15 and R16 is independendly selected from the group H; C^ straight
or branched alkyl; phenyl;
An embodiment of present invention in its sixth aspect comprises the
compounds of formula (Al), pharmaceutically acceptable compositions salts,
tautomers, and isomers thereof and their use in a treatment of viral infection or to
manufacture a medicament to treat viral infection, wherein:
U is N;
R1 is selected from phenyl unsubstituted or substituted with 1-3 R6; 5 or 6
membered heterocycle containing 1-3 heteroatoms selected from the group O, N,
and S, unsubstituted or substituted with 1-2 R6; 1-naphthyl unsubstituted or
substituted with 1-3 R6; 2-naphthyl unsubstituted or substituted with 1-3 R6;
R2 and R4 are hydrogen;
R5 is absent;
X is selected from -CH,-; -CH(CH3)-; -CH2-CH2-CH2-; -OCf-CH,-;
-CH=CH-CH2-;
R3 is selected from phenyl unsubstituted or substituted with 1-3 R17; 5 or 6
membered aromatic heterocycle containing 1-3 heteroatoms selected from the
group O, N, and S, unsubstituted or substituted with 1-3 R17; 1-naphthyl
unsubstituted or substituted with 1-3 R17; 2-naphthyl unsubstituted or substituted
with 1-3 R17;
Each R6 and R17 is independently selected from the group H; straight or
branched C^alkoxy; straight or branched C,., alkyl; F; Cl; Br; I; OH; CN; NO2;
NR13RU; OCF3; CF^ C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
R9 is selected from H; OH; straight or branched Cj.6 alkyl; straight or
branched Cw alkoxy; NR15R16; phenyl;
R12 is selected from the group H; Cw straight or branched alkyl; phenyl;
Each R13 and R14 is independently selected from H; straight or branched Cw
alkyl; phenyl; C(=O)R12; and
Each R15 and R1 is independently selected from the group H; C 6 straight or
branched alkyl; and phenyl.
An embodiment of present invention in its seventh aspect comprises
compounds of formula (Al), pharmaceutically acceptable compositions, salts,
tautomers, and isomers thereof and their use in a treatment of viral infection or to
manufacture a medicament to treat viral infection, wherein:
R1 is selected from phenyl unsubstituted or substituted with 1-3 R6; 5 or 6
membered heterocycle containing 1-3 heteroatoms selected from the group O, N,
and S, unsubstituted or substituted with 1-2 R6; 1-naphthyl unsubstituted or
substituted with 1-3 R6; 2-naphthyl unsubstituted or substituted with 1-3 R6;
R2 and R4 are hydrogen;
R5 is absent;
X is selected from -CH2-; -CH(CH,)-; -CH.-CH.-CH,-; -OCH.-CH,-;
-CH=CH-CH2-;
R3 is selected from phenyl unsubstituted or substituted with 1-3 R17; 5 or 6
membered aromatic heterocycle containing 1-3 heteroatoms selected from the
O, N, and S, unsubstituted or substituted with 1-2 R17; 1-naphthyl
substituted with 0-3 R17; 2-naphi:hyl unsubstituted or substituted with 1-3 R17;
Each R and R1 is independently selected from hydrogen; straight or
branched C,.6alkoxy; straight or branched Q.6 alkyl; F; Cl; Br; I; OH; CN; NO2;
NR13R14; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
R9 is selected from H; OH; straight or branched Cw alkyl; straight or
branched Q.6 alkoxy; NR15R16; phenyl;
R12 is selected from the group H; CM straight or branched alkyl; phenyl;
Each R13 and R1 is independently selected from H; straight or branched C
alkyl; phenyl; C(=O)R12; and
Each R15 and R16 is independently selected from the group H; C,.6 straight or
branched alkyl; and phenyl.
An embodiment of the present invention in its eighth aspect relates to
compounds of the formula (A2), pharmaceutically acceptable compositions, salts,
tautomers, polymorphs and isomers thereof and their use in a treatment of viral
infection or to manufacture a medicament to treat viral infection
wherein
UisN;
R1 is selected from hydrogen; aryl unsubstituted or substituted with one or
more Rs, heterocycle unsubstitv ted or substituted with one or more R6, C3.lo
cydoalkyl unsubstituted or substituted with one or more Rand C4.10 cycloalkenyl
unsubstituted or substituted with one or more R6;
X is selected from the group consisting of a divalent, saturated or
unsaturated, substituted or unsubstituted Cj.C,0 hydrocarbon group optionally
including one or more heteroatoms in the main chain (provided that the
heteroatom is not linked to N of the nucleus), said heteroatoms being selected
from the group consisting of O, S, and N; such as C,.6 alkylene, (for example -CHj-
CH(CH3)-/ -CH2-CrV, -CH.-CH.-CH,-, -CH,-CH2-CHrCH2), -(CH-O-tCH
-(CH-S-tCH-(CH2)M-NR10-(CH2)M-/ C3.10 cycloalkylidene, C2.6 alkenylene
(such as -CH=CH-CH,-), C2.6 alkynylene;
R3 is selected from the group consisting of aryl; aryloxy; arylthio; aryl-NR10-;
5 or 6 membered heterocycle, oxyheterocycle or thioheterocycle;; and each of said
aryl, aryloxy, arylthio, aryl-NR10-, 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle is optionally substituted with one or more R17; C3.10 cycloalkyl,
oxycycloalkyl or thiocycloalkyl; Cwo cycloalkenyl with the proviso that the double
bond cannot be adjacent to a nitrogen; H with the proviso that if X is an alkylene,
an alkenylene or an alkynylene, then X comprises at least 5 carbon atoms;
R4 is independently selected from the group consisting of hydrogen C,.Jg
alkyl; C2.18 alkenyl; C2.lg alkynyl; C,.u alkoxy; CM8 alkylthio; halogen; OH; CN; NO2;
NR7R8; OCF3; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl;
C,.]8 hydroxyalkyl; C3.m cycloalkyl; C3.10 cycloalkyloxy; C3.10 cycloalkylthio; Cj.10
cycloalkenyl; C^ cycloalkynyl; 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle; optionally R4 is not -OH, -SH, =O or =S;
R5 is independently absent or selected from the group consisting of
hydrogen; CW8 alkyl; C2.18 alkenyl; C2.18 alkynyl; C,.,, alkoxy; CM, alkylthio; halogen;
OH; CN; NO2; NR7R8; OCF3; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy;
arylthio; arylalkyl; Cj.18 hydroxyalkyl; CMO cycloalkyl; C3.10 cycloalkyloxy; C3.10
cycloalkylthio C3.10 cycloalkenyl; C3.10 cycloalkynyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle;
Each R6 and R17 is independently selected from the group consisting of
hydrogen; C,.tt alkyl; C2.]8 alkenyl; C2.18 alkynyl; C,.M alkoxy; C,.u allcylthio; C3.10
cycloalkyl, C3.10 cycloalkenyl or C3.10 cycloalkynyl; halogen; OH; CN; NO2; NR7R8;
y- haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl;
arylalkyloxy (optionally a oxybenzyl); arylalkylthio (optionally a benzylthio); 5 or
6 membered heterocycle, oxyheterocycle or thioheterocycle; CM8 hydroxyalkyl;
and each of said aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy (optionally a
oxybenzyl), arylalkylthio (optionally a benzylthio), 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle, CM8 hydroxyalkyl is optionally substituted
with 1 or more R19;
Each R7 and R8 is independently selected from the group consisting of H;
C,.,8alkyl; C,.18alkenyl; aryl; C3.i0 cycloalkyl; C4.]0 cycloalkenyl; 5-6 membered
heterocycle; C(=O)R12; C(=S) R12; an amino acid residue linked through a carboxyl
group thereof; alternatively, R7 and R8, together with the nitrogen to which they
are attached, combine to form a 5-6 membered heterocycle;
Each R9 and R18 is independently selected from the group consisting of H;
OH; CM8 alkyl; C2.]8 alkenyl; C3.10 cycloalkyl; C4.10 cycloalkenyl; CM8 alkoxy; NR15R16;
aryl an amino acid residue linked through an amino group thereof;
Each R10 and R11 is independently selected from the group the group
consisting of H; CMg alkyl; C,.,8 alkenyl; C3.,0 cycloalkyl; C4.10 cycloalkenyl; aryl;
C(=O)R12; 5-6 membered heterocycle; an amino acid residue linked through a
carboxyl group thereof;
R12 is independently selected from the group consisting of H; CM8 alkyl; C2.,8
alkenyl; aryl; C3.10 cycloalkyl; C4.]0 cycloalkenyl; an amino acid residue linked
through an amiiio group thereof;
Each R13 and R14 is independently selected from the group consisting of H;
C,.u alkyl; C2.18 alkenyl; aryl; C3.10 cycloalkyl; C4.10 cycloalkenyl; C(=O)R12; C(=S)R12;
an amino acid residue linked through a carboxyl group thereof;
Each R15 and R16 is independently selected from the group consisting of H;
Q.jg alkyl; C,.,, alkenyl; C2.18alkynyl; aryl; C3.,0 cycloalkyl; C4.,0 cycloalkenyl; an
amino acid residue linked through a carboxyl group thereof;
R19 is independently selected from the group consisting of H; C^g alkyl,
preferably C1-6 alkyl; C2.,8 alkenyl; CM8 alkynyl; CM8alkoxy, preferably C1-6alkoxy;
C,.18alkylthio; C3.10 cycloalkyl; Q.10 cycloalkenyl; C4.10 cycloalkynyl; halogen; OH;
CN; NO2; NRMR21; OCF3; haloalkyl; C(=O)R22; C(=S)R22; SH; C(=O)N(C,.6alkyl)/
N(H)S(O)(O)(C^ alkyl); aryl; aryloxy; arylthio; arylalkyl; and each of said aryl,
aryloxy, arylthio, arylalkyl substituted with 1 or more halogens, particularly a
phenyl substituted with 1-2 halogens; hydroxyalkyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocyde each unsubstituted or substituted with 1 or
more halogens;
Each Rzo and R21 is independently selected from the group consisting of H;
CI.M alkyl, preferably CM alkyl; C2.18 alkenyl; C2.w alkynyl; aryl; C3.10 cycloalkyl; Q10
cycloalkenyl; C(=O)R12, C(=S)R12;
R22 is independently selected from H; OH; C,.,, alkyl; C2.18 alkenyl; CM8
alkoxy; NR23R24; aryl; C3.10 cycloalkyl,; CMO cycloalkenyl;
Each R^and R24 is independently selected from the group the group
consisting of H; CW8 alkyl, preferably C2.3 alkyl, wherein C2.3 alkyl taken together
with N of R22 can form a saturated heterocycle, which heterocycle is optionally
substituted witli OH or aryl or an amino acid residue;
Z is selected from (=O), (=S), and (=NR27);
R25 is selected from the group consisting of of H, CM8 alkyl, preferably Cl-4
alkyl; C3.10 cycloalkyl, such as C5.,0bicycloalkyl; C3.10 cycloalkenyl; (C3.8cycloalkyl)-Cj.
3 alkyl; aryl, such as phenyl; 5 or 6 membered heterocycle, such as pyridyl;
alkylaryl, such as benzyl; and each of said CM8 alkyl, preferably CM alkyl, C3.10
cycloalkyl, C3.10cycloalkenyl, (C3.8cycloalkyl)-C1.3alkyl, C5.10bicycloalkyl,
adamantyl, phenyl, pyridyl and benzyl is optionally substituted with 1-4 of each
of Cw alkyl, Cw alkoxy, halo, CH2OH7 oxybenzyl, and OH; and heterocycle having
3 to 7 carbon atoms, preferably a saturated heterocycle wherein the heteroatoms
are S/ 5(0), or S(0)2 separated from the imidazopyridyl ring nitrogen atom by at
least 2 heterocycle carbon atoms;; and
R27 is selected from the group consisting of H, CM8 alkyl, C^0 cycloalkyl, (C3
10cycloalkyl)-C^alkyl; aryl; arylalkyl, such as benzyl.
An embodiment of the present invention in its ninth aspect relates to
compounds of the formula (A3), pharmaceutically acceptable compositions, salts,
tautomers, polymorphs and isomers thereof and their use in a treatment of viral
infection or to manufacture a medicament to treat viral infection
R1 is selected from hydrogen; aryl unsubstituted or substituted with one or
more R6, heterocycle unsubstituted or substituted with one or more R6, C3.10
cycloalkyl unsubstituted or substituted with one or more R6and C4.10 cycloalkenyl
unsubstituted or substituted with one or more R6;
X is selected from the group consisting of a divalent, saturated or
unsaturated, substituted or unsubstituted Q C10 hydrocarbon group optionally
including one or more heteroatoms in the main chain (provided that the
heteroatom is not linked to N of the nucleus), said heteroatoms being selected
from the group consisting of O, S, and N; such as C,.6 alkylene, (for example
, -CH(CH, -CH2-CHr, -CH2-CH2-CH2-, -CH,-CH2-CH2-CH2), -(CH
-(CH2)2.4-S-(CH2)24-, -(CH2)2.4-NR10-(CH2)2.4-, C3,0 cycloalkylidene, C2.6 alkenylene
(such as -CH=CH-CH2-), C2.6 alkynylene;
R3 is selected from the group consisting of aryl; aryloxy; arylthio; aryl-NR10-;
5 or 6 membered heterocycle, oxyheterocycle or thioheterocycle;; and each of said
aryl/ aryloxy, arylthio, aryl-NR10-, 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle is optionally substituted with one or more R17; C3.,0 cycloalkyl,
oxycycloalkyl or thiocycloalkyl; C4.10 cycloalkenyl with the proviso that the double
bond cannot be adjacent to a nitrogen; H with the proviso that if X is an alkylene,
an alkenylene or an alkynylene, then X comprises at least 5 carbon atoms;
R4 is independently selected from the group consisting of hydrogen C,.lg
alkyl; C2.18 alkenyl; C2.18 alkynyl; C,.,, alkoxy; CW8 alkylthio; halogen; OH; CN; NO2;
NR7R8; COv haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl;
CMg hydroxyalkyl; C3.10 cycloalkyl; C3.10 cycloalkyloxy; C3.10 cycloalkylthio; C^
cycloalkenyl; C3.10 cycloalkynyl; 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle; optionally, R4 is not OH, SH, thio or oxo;
R5 is independently absent or selected from the group consisting of
hydrogen; C,.]8 alkyl; C2.18 alkenyl; C208 alkynyl; C,.,, alkoxy; C,.18 alkylthio; halogen;
OH; CN; NO2; NR7R8; OCF3; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy;
arylthio; arylalkyl; C,.,8 hydroxyalkyl; C3.10 cycloalkyl; C3.10 cycloalkyloxy; C3.10
cycloalkylthio C3.10 cycloalkenyl; Cj.w cycloalkynyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle;
Each R6 and R17 is independently selected from the group consisting of
hydrogen; CM, alkyl; Cj.u alkenyl; CW8 aUcynyl; C,.]g alkoxy; C,.la alkylthio; C9.10
cycloalkyl, C,,10 cycloalkenyl or C3.10 cycloalkynyl; halogen; OH; CN; NO^ NR7R8;
OCF,; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl;
arylalkyloxy (optionally a .oxybenzyl); arylalkylthio (optionally a benzylthio); 5 or
6 membered heterocycle, oxyheterocycle or thioheterocycle; C,.,8 hydroxyalkyl;
and each of said aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy (optionally a
oxybenzyl), arylalkylthio (optionally a benzylthio), 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle, C,.,8 hydroxyalkyl is optionally substituted
with 1 or more R19;
Each R7 and R8 is independently selected from the group consisting of H;
C,.M alkyl; C,.18alkenyl; aryl; Cj.,0 cycloalkyl; C4.,0 cycloalkenyl; 5-6 membered
heterocycle; C(=O)R12; C(=S) R12; an amino acid residue linked through a carboxyl
group thereof; alternatively, R7 and R8, together with the nitrogen to which they
are attached, combine to form a 5-6 membered heterocycle;
Each R9 and R18 is independently selected from the group consisting of H;
OH; CM, alkyl; C2.18 alkenyl; C3.10 cycloalkyl; C4.10 cycloalkenyl; CM8 alkoxy; NR1SR16;
aryl an amino acid residue linked through an amino group thereof;
Each R10 and R11 is independently selected from the group the group
consisting of H; C alkyl; €,.,„ alkenyl; C3.JO cycloalkyl; C4.10 cycloalkenyl; aryl;
C(=O)R12; 5-6 membered heterocycle; an amino acid residue linked through a
carboxyl group thereof;
R12 is independently selected from the group consisting of H; ClmW alkyl; C2.w
alkenyl; aryl; C cycloalkyl; C4.10 cycloalkenyl; an amino acid residue linked
through an amino group thereof;
Each R15 and R16 is independently selected from the group consisting of H;
C,.18 alkyl; C2.18 alkenyl; C2.,aalkynyl; aryl; C3.10 cycloalkyl; C4.10 cycloalkenyl; an
amino acid residue linked through a carboxyl group thereof;
R19 is independently selected from the group consisting of H; C,.!8 alkyl,
20 preferably Q.6 alkyl; C2.,8 alkeny [; C2.18 alkynyl; C,.18 alkoxy, preferably Cj.6 alkoxy;
C,.ualkylthio; C3.10 cycloalkyl; C4.10 cycloalkenyl; C4.10 cycloalkynyl; halogen; OH;
CN; NO,; NRV; COy haloalkyl; C(=O)R22; C(=S)R22; SH; C(=O)N(C1.6 alkyl),
N(H)S(O)(O)(C,.6 alkyl); aryl; aryloxy; arylthio; arylalkyl; and each of said aryl,
' aryloxy, arylthio, arylalkyl substituted with 1 or more halogens, particularly a
phenyl substituted with 1-2 halogens; hydroxyalkyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle each unsubstituted or substituted with 1 or
more halogens;
38
Each R20 and R21 is independently selected from the group consisting of H;
C,.18 alkyl, preferably C,., alkyl; C2.18alkenyl; C2.18alkynyl; aryl; C3.10 cycloalkyl; C4.10
cycloalkenyl; C(=O)R12, C(=S)R12;
R22 is independently selected from H; OH; C,.J8 alkyl; C2.18alkenyl; C,.18
alkoxy; NRR24; aryl; C3.,0 cycloalkyl,; C4.i0 cycloalkenyl;
Each Raand R24 is independently selected from the group the group
consisting of H; C,.,8 alkyl, preferably C2.3 alkyl, wherein C2.3 alkyl taken together
with N of R22 can form a saturated heterocycle,. which heterocycle is optionally
substituted with OH or aryl or an amino acid residue;
Z is selected from (=O), (=S), and (=NR27);
R26 is selected from the group consisting of of H, Cj.18 alkyl, preferably CI-(
alkyl; C3.]0 cycloalkyl, such as CM0bicycloalkyl; C3.,0 cycloalkenyl; (CcycloalkylJ-Q.
3 alkyl; aryl, such as phenyl; 5 or 6 membered heterocycle, such as pyridyl;
alkylaryl, such as benzyl; and each of said CM8 alkyl, preferably Cw alkyl, C3.10
cycloalkyl, Cj.,,, cycloalkenyl, (C3.8 cycloalkyl)-C,.3 alkyl, C5.10bicycloalkyl,
adamantyl, phenyl, pyridyl and benzyl is optionally substituted with 1-4 of each
of CM alkyl, C,.6 alkoxy, halo, CH2OH, oxybenzyl, and OH; and heterocycle having
3 to 7 carbon atoms, preferably a saturated heterocycle wherein the heteroatoms
are S, S(O), or S(O), separated from the imidazopyridyl ring nitrogen atom by at
least 2 heterocycle carbon atoms; and
R27 is selected from the group consisting of H, C,.u alkyl, C3.]0 cycloalkyl, (Q
5 alkyl; aryl; arylalkyl, such as benzyl.
An embodiment of the present invention in its tenth aspect relates to
compounds of the formula (A2), pharmaceutically acceptable compositions, salts,
tautomers, polymorphs and isomers thereof and their use in a treatment of viral
infection or to manufacture a medicament to treat viral infection
R1 is selected from hydrogen; aryl unsubstituted or substituted with one or
more R6, heterocycle unsubstituted or substituted with one or more R6, C3.10
cycloalkyl unsubstituted or substituted with one or more R'and C4.10 cycloalkenyl
unsubstituted or substituted with one or more R6;
X is selected from the group consisting of a divalent, saturated or
unsaturated, substituted or unsubstituted C, C10 hydrocarbon group optionally
including one or more heteroatoms in the main chain (provided that the
heteroatom is not linked to N of the nucleus), said heteroatoms being selected
from the group consisting of O, S, and N; such as Cj.6 alkylene, (for example -CH2-
, -CH(CH,)-, -CIVCH,-, -CH2-CH2-CH2-, -CH-CHCH,), -(CH-CMCH,),,-,
-(CHS-tOU.,-, -(CH-NR'CH-, CMO cycloalkylidene, Cw alkenylene
(such as -CH=CH-CH2-), C2.6 alkynylene;
R2 is selected from the group consisting of hydrogen CW8 alkyl; C2.18 alkenyl;
C2.18 alkynyl; CM8 alkoxy; C, alkylthio; halogen; OH; CN; NO2; NR7R8; OCF
haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl; C,.]8
hydroxyalkyl; CMO cycloalkyl; C3.10 cycloalkyloxy; CMO cycloalkylthio; C3.10
cycloalkenyl; C,.IO cycloalkynyl; 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle;
R3 is selected from the group consisting of aryl; aryloxy; arylthio; aryl-NR10-
; 5 or 6 membered heterocycle, oxyheterocycle or thioheterocycle; and each of said
aryl, aryloxy, arylthio, aryl-NR10-, 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle is optionally substituted with one or more R17; C3.10 cycloalkyl,
oxycycloalkyl or thiocycloalkyl; C4.10 cycloalkenyl with the proviso that the double
bond cannot be adjacent to a nitrogen; H with the proviso that if X is an alkylene,
an alkenylene or an alkynylene, then X comprises at least 5 carbon atoms;
R is independently absent or selected from the group consisting of
hydrogen; alkyl; C2.lg alkenyl; C2.18 alkynyl; C,.18 alkoxy; C,.18 alkylthio; halogen;
OH; CN; NO2; NR7R8; OCFy haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy;
arylthio; arylalkyl; Q.ie hydroxyalkyl; Q.w cycloalkyl; C3.10 cycloalkyloxy; Q.I(,
cycloalkylthio €3.,,, cycloalkenyl; C3.10 cycloalkynyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle;
Each Rs and R17 is independently selected from the group consisting of
hydrogen; C,.18 alkyl; C2.18 alkenyl; C2.18 alkynyl; C,.18 alkoxy; C,.w alkylthio; C3.10
cycloalkyl, C3.10 cycloalkenyl or C3.10 cycloalkynyl; halogen; OH; CN; NO2; NR7R8;
OCF,; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl;
arylalkyloxy (optionally a oxybenzyl); arylalkylthio (optionally a benzylthio); 5 or
6 membered heterocycle, oxyheterocycle or thioheterocycle; Q.lg hydroxyalkyl;
and each of said aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy (optionally a
oxybenzyl), arylalkylthio (optio:nally a benzylthio), 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle, Cj.18 hydroxyalkyl is optionally substituted
with 1 or more R19;
Each R7 and Rflis independently selected from the group consisting of H; Q.
]8 alkyl; C,.u alkenyl; aryl; Cg.,,, cydoalkyl; Ccycloalkenyl; 5-6 membered
heterocycle; C(=O)R12; C(=S) R12; an amino acid residue linked through a carboxyl
group thereof; alternatively, R7 and R8, together with the nitrogen to which they
are attached, combine to form a 5-6 membered heterocycle;
Each R9 and R11 is independently selected from the group consisting of H;
OH; CM, alkyl; G2.)8 alkenyl; C3.w cycloalkyl; C4.10 cycloalkenyl; CW8 alkoxy; NR1SR16;
aryl an amino acid residue linked through an amino group thereof;
Each R10 and R" is independently selected from the group the group
consisting of H; Q.,, alkyl; Cj.18alkenyl; C,.,0 cycloalkyl; C4.,0 cycloalkenyl; aryl;
C(=O)R12; 5-6 membered heterocycle; an amino acid residue linked through a
carboxyl group thereof;
R12 is independently selected from the group consisting of H; C148 alkyl; C2.,8
alkenyl; aryl; C cycloalkyl; C4.10 cycloalkenyl; an amino acid residue linked
through an amino group thereof;
Each R15 and R16 is independently selected from the group consisting of H;
C,.18 alkyl; C2.J8 alkenyl; C2.18alkynyl; aryl; Cs.10 cycloalkyl; cycloalkenyl; an
amino acid residue linked through a carboxyl group thereof;
R19 is independently selected from the group consisting of H; Q.jg alkyl,
preferably C1-6 alkyl; C2.18 alkenyl; C2.16 alkynyl; C:.,8alkoxy, preferably C^alkoxy;
Q. alkylthio; Cj.w cycloalkyl; C4.10 cycloalkenyl; C4.10 cycloalkynyl; halogen; OH;
CN; NO2; NR20R21; OCF3; haloalkyl; C(=O)R22; C(=S)R22; SH; C(=O)N(CM alkyl),
N(H)S(O)(O)(CM alkyl); aryl;'aryloxy; arylthio; arylalkyl; and each of said aryl,
aryloxy, arylthio, arylalkyl substituted with 1 or more halogens, particularly a
phenyl substituted with 1-2 halogens; hydroxyalkyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle each unsubstituted or substituted with 1 or
more halogens;
Each R20 and R21 is independently selected from the group consisting of H;
C,.w alkyl, preferably C,.6 alkyl; C2.18 alkenyl; C2.18 alkynyl; aryl; C3.10 cycloalkyl;
cycloalkenyl; C(=O)RU, C(=S)R12;
R is independently selected from H; OH; CI.M alkyl; C2.,8 alkenyl; C,. 'MS
alkoxy; NR R ; aryl; CMO cycloalkyl,; C4.,0 cycloalkenyl;
Each R^and R24 is independently selected from the group the group
consisting of H; C^ alkyl, preferably CM alkyl, wherein C2.3 alkyl taken together
with N of R22 can form a saturated heterocycle, which heterocycle is optionally
substituted with OH or aryl or an amino acid residue;
Z is selected from (=O), (=S), and (=NR27);
R25 is selected from the group consisting of of H, C,.,8 alkyl, preferably Cw
alkyl; CMO cycloalkyl, such as C5.10bicycloalkyl; C^cycloalkenyl; (C^cycloalkylJ-Q.
3 alkyl; aryl, such as phenyl; 5 or 6 membered heterocycle, such as pyridyl;
alkylaryl, such as benzyl; and each of said C,.18 alkyl, preferably C^ alkyl, C3.,0
cycloalkyl, Cj.,0cycloalkenyl, (Cs.8cydoalkyl)-C,.3 alkyl, CMObicycloalkyl,
adamantyl, phenyl, pyridyl and benzyl is optionally substituted with 1-4 of each
of Cw alkyl, Cw alkoxy, halo, CH2OH, oxybenzyl, and OH; and heterocycle having
3 to 7 carbon atoms, preferably a saturated heterocycle wherein the heteroatoms
are S, S(O), or S(O)2 separated from the imidazopyridyl ring .nitrogen atom by at
least 2 heterocycle carbon atoms; and
R27 is selected from the group consisting of H, CW8 alkyl, C3.10 cycloalkyl, (Cj.
10cycloalkyl)-Cj.6alkyl; aryl; arylalkyl, such as benzyl;
An embodiment of the present invention in its eleventh aspect relates to
compounds of the formula (A3), pharmaceutically acceptable compositions, salts,
tautomers, polymorphs and isomers thereof and their use in a treatment of viral
infection or to manufacture a medicament to treat viral infection
R1 is selected from hydrogen; aryl unsubstituted or substituted with one or
more R4, heterocycle unsubstituted or substituted with one or more R(,
cycloalkyl unsubstituted or substituted with one or more R6and C«.,0 cycloalkenyl
unsubstituted or substituted with one or more R6;
X is selected from the group consisting of a divalent, saturated or
unsaturated, substituted or unsubstituted C,.C10 hydrocarbon group optionally
including one or more heteroatoms in the main chain (provided that the
heteroatom is not linked to N of the nucleus), said heteroatoms being selected
from the group consisting of O, S, and N; such as Q.6 alkylene, (for example -CHj-,
-CHtCH,)-, -OVCH,-, -CHj-CHCH,-, -CH.-CHa-CH.-CH,), -(CH2)2.4-O-(GH2)W-/
-(CH2)2Hl-S-(CH2)M-/ -(CH-NK; C3.lo cycloalkylidene, C« alkenylene
(such as -CH=CH-CH2-), Cw alkynylene;
R2 is independently selected from the group consisting of hydrogen C,.18
alkyl; C2.,8 alkenyl; C2.18 alkynyl; CW8 alkoxy; C,.,8 alkylthio; halogen; OH; CN; NOy
NR7R8; OCF3; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl;
hydroxyalkyl; C3.JO cycloalkyl; CMO cycloalkyloxy; C3.10 cycloalkylthio; C3.10
cycloalkenyl; CMO cycloalkynyl; 5 or 6 membered heterocycle, oxyheterocycle or
thioheterocycle;
R3 is selected from the group consisting of aryl; aryloxy; arylthio; aryl-NRlc-
; 5 or 6 membered heterocycle, oxyheterocycle or thioheterocycle;; and each of
said aryl, aryloxy, arylthio, aryl-NR10-, 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle is optionally substituted with one or more R7;
Q-io cycloalkyl, oxycycloalkyl or thiocycloalkyl; Q.10 cycloalkenyl with the proviso
that the double bond cannot be adjacent to a nitrogen; H with the proviso that if X
is an alkylene, an alkenylene or an alkynylene, then X comprises at least 5 carbon
atoms;
R5 is independently absent or selected from the group consisting of
hydrogen; C,.,, alkyl; C,.u alkenyl; Cw, alkynyl; Q.,, alkoxy; Q.,, alkylthio; halogen;
OH; CN; NO,; NR7R OCP,; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy;
arylthio; arylalkyl; Q.,, hydroxyalkyl; C3.,0 cycloalkyl; C3.10 cycloalkyloxy; C,.,,,
cycloalkylthio C3.w cycloalkenyl; C3.i0 cycloalkynyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle;
Each R6 and R17 is independently selected from the group consisting of
hydrogen; C,.18 alkyl; C2.J8 alkenyl; C2.18 alkynyl; €,.„ alkoxy; C,.,, alkylthio; C3.10
cycloalkyl, C3.10 cycloalkenyl or C3.10 cycloalkynyl; halogen; OH; CN; NO2; NR7R8;
OCF3; haloalkyl; C(=O)R9; C(=S)R9; SH; aryl; aryloxy; arylthio; arylalkyl;
arylalkyloxy (optionally a oxybenzyl); arylalkylthio (optionally a benzylthio); 5 or
6 membered heterocycle, oxyheterocycle or thioheterocycle; €,.,„ hydroxyalkyl;
and each of said aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy (optionally a
oxybenzyl), arylalkylthio (optionally a benzylthio), 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle, Cj.,8 hydroxyalkyl is optionally substituted
with 1 or more R19;
Each R7 and R8 is independently selected from the group consisting of H;
CW8 alkyl; CM8 alkenyl; aryl; C3.]0 cycloalkyl; C4.10 cycloalkenyl; 5-6 membered
heterocycle; C(=O)R12; C(=S) R12; an amino acid residue linked through a carboxyl
group thereof; alternatively, R7 and R8, together with the nitrogen to which they
are attached, combine to form a 5-6 membered heterocycle;
Each R9 and R18 is independently selected from the group consisting of H;
OH; Q.18 alkyl; C2.18 alkenyl; C3.10 cycloalkyl; Q10 cycloalkenyl; CM8 alkoxy; NR15R16;
aryl an amino acid residue linked through an amino group thereof;
Each R10 and R11 is independently selected from the group the group
consisting of H; CM8 alkyl; C,.,8 alkenyl; C^ cycloalkyl; C4.:o cycloalkenyl; aryl;
C(=O)R12; 5-6 membered heterocycle; an amino acid residue linked through a
carboxyl group thereof;
R12 is independently selected from the group consisting of H; Cj.,8 alkyl; C2.,8
alkenyl; aryl; C cycloalkyl; C4.]0 cycloalkenyl; an amino acid residue linked
through an amino group thereof;
Each R15 and R16 is independently selected from the group consisting of H;
C,.,, alkyl; Q. alkenyl; C,.,, alkynyl; aryl; C3.10 cycloalkyl; C4.10 cycloalkenyl; an
amino acid residue linked through a carboxyl group thereof;
R19 is independently selected from the group consisting of H; C,.,, alkyl,
preferably Cw alkyl; C2.,8 alkenyl; C2.18 alkynyl; C,.Ig alkoxy, preferably Cw alkoxy;
Cw8alkylthio; C3.w cycloalkyl; C4.10 cycloalkenyl; C4.10 cycloalkynyl; halogen; OH;
CN; N02; NRR21; OCF,; haloalkyl; C(=O)R22; C(=S)R22; SH; C(=O)N(C^alkyl)/
N(H)S(O)(O)(Q.6 alkyl); aryl; aryloxy; arylthio; arylalkyl; and each of said aryl,
aryloxy, arylthio, arylalkyl substituted with 1 or more halogens, particularly a
phenyl substituted with 1-2 halogens; hydroxyalkyl; 5 or 6 membered heterocycle,
oxyheterocycle or thioheterocycle each unsubstituted or substituted with 1 or
more halogens;
Each R20 and R21 is independently selected from the group consisting of H;
CW8 alkyl, preferably Q.6 alkyl; C2.18 alkenyl; C2.]8 alkynyl; aryl; C3.10 cycloalkyl; C4.10
cycloalkenyl; C(=O)R12, C(=S)R12;
R is independently selected from H; OH; C,.18 alkyl; C2.]8 alkenyl;' -1-18
alkoxy; NR224; aryl; C3.10 cycloalkyl,; C4.10 cycloalkenyl;
Each Raand R24 is independently selected from the group the group
consisting of H; C,.]8 alkyl, preferably C2.3 alkyl, wherein C2.3 alkyl taken together
with N of R22 can form a saturated heterocycle, which heterocycle is optionally
substituted with OH or aryl or an amino acid residue;
Z is selected from (=O), (=S), and (=NR27);
R26 is selected from the group consisting of of H, C,.18 alkyl, preferably C1M
alkyl; C0 cycloalkyl, such as Cbicycloalkyl; C cycloalkenyl; (CcycloalkylJ-Cj.
3 alkyl; aryl, such as phenyl; 5 or 6 membered heterocycle, such as pyridyl;
alkylaryl, such as benzyl; and each of said CM8 alkyl, preferably CM alkyl, C3.10
cycloalkyl, CMO cycloalkenyl, (CcycloalkylJ-C alkyl, C5.10bicycloalkyl,
adamantyl, phenyl, pyridyl and benzyl is optionally substituted with 1-4 of each
of C,.6 alkyl, Cj.6 alkoxy, halo, CHjOH, oxybenzyl, and OH; and heterocycle having
3 to 7 carbon atoms, preferably a saturated heterocycle wherein the heteroatoms
are S, S(O), or S(O)2 separated from the imidazopyridyl ring nitrogen atom by at
least 2 'heterocycle carbon atoms; and
Ris selected from the group consisting of H, Q.,, alkyl, C,, cycloalkyl, (C3.
,0cydoalkyl)-Cj.s alkyl; aryl; arylalkyl, such as benzyl.
An embodiment of this invention in its twelth aspect relates to compounds
of the general formula (B), pharmaceutically acceptable compositions, and the
R1 is selected from aryl, heterocycle, C3.10 cycloalkyl, C4.]0 cycloalkenyl, and
C4.,0 cycloalkynyl, wherein each are optionally substituted with 1 or 2 R6;
Y is a bond;
R2 and R4 are independently selected from hydrogen, CW8 alkyl,
CM, alkenyl, C2.18 alkynyl, C,.,8 alkoxy, CH8 alkylthio, halogen, -OH, -CN, -NO2,
-NR7R8, haloalkyloxy, haloalkyl, -C(=O)R9, -C(=S)R9, SH, aryl, aryloxy, arylthio,
arylalkyl, Ct.18 hydroxyalkyl, C3.,0 cycloalkyl, C3.10 cycloalkyloxy, C3.10
cycloalkylthio, C3.to cycloalkenyl, C7.i0 cycloalkynyl, or heterocycle, provided that
when one of R25 or R26 is present, then either R2 or R4 is selected from (=O), (=S),
and =NR27; provided that R2 is not OH, SH, thio or oxo;
X is selected from Cj.C3 alkylene, C2.3 alkenylene or C2.3 alkynylene;
R3 is selected from aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl-N(R10)-, or heterocycle, where each is optionally substituted
with at least one R17, provided that for cycloalkenyl the double bond is not
adjacent to a nitrogen;
R5 indpendently is absent or is selected from hydrogen, C alkyl, C2.18
alkenyl, C2.18 alkynyl, C,.]8 alkoxy, C,.l8 alkylthio/halogen, -OH, -CN, -NO2, -
haloalkyloxy, haloalkyl, -C(=O)R9, -C(=O)OR9, -C(=S)R9, SH, aryl, aryloxy,
arylthio, arylalkyl, C,.18 hydroxyalkyl, C,.,,, cycloalkyl, CMO cycloalkyloxy, CMO
cycloalkylthio, Q.,,, cycloalkenyl, C7.lo cycloalkynyl, or heterocycle;
R6 is selected from hydrogen, CM8 alkyl, C2.,8 alkenyl, C2.18 alkynyl, Q.,,
alkoxy, C,.18 alkylthio, C,.,8 alkylsulfoxide, C,.,8 alkylsulfone, C:.,8 halo-alkyl, C2.18
halo-alkenyl, C2.,8 halo-alkynyl, CMg halo-alkoxy, C,.,8 halo-alkylthio, CMO
cycloalkyl, C, cycloalkenyl, C7.:0 cycloalkynyl, halogen, OH, CN, cyanoalkyl,
-CO2R18, NO2/ -NR7R8, CM8 haloalkyl, C(=O)R18, C(=S)R18, SH, aryl, aryloxy, arylthio,
arylsulfoxide, arylsulfone, arylsulfonamide, aryl(CW8)aIkyl, aryl(C,.,8)alkyloxy,
aryl(C,.18)alkylthio, heterocycle, Ci.)8 hydroxyalkyl, where each may be optionally
substituted with at least 1 R19;
R7 and R8 are independently selected from hydrogen, C,.18 alkyl, CM8 alkenyl,
aryl, C3.,0 cycloalkyl, C4.10 cycloalkenyl, heterocycle, -C(=O)R1Z; -C(=S) R12, an amino
acid residue linked through a carboxyl group thereof, or where R7 and R8 together
with the nitrogen form a heterocycle;
R9 and R18 are independently selected from hydrogen, OH, C alkyl, C2.w
alkenyl, C,.10 cycloalkyl, C4.10 cycloalkenyl, C,.I8 alkoxy, -NR15R16, aryl, an amino acid
residue linked through an amino group of the amino acid, CH2OCH(=O)R9a
/ or
CH2OC(=O)OR9a where R9a is CrC]2 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C
aralkyl;
R10 and R" are independently selected from the group consisting of
hydrogen, C,.]8 alkyl, Q. alkenyl, C3.,0 cycloalkyl, C4.10 cycloalkenyl, aryl, -C(=O)R",
heterocycle, or an amino acid residue;
R12 is selected from the group consisting of hydrogen, CH8 alkyl, CMS
alkenyl, aryl, C cycloalkyl, C440 cycloalkenyl, or an amino acid residue;
R15 and R16 are independently selected from hydrogen, C,.,8 alkyl, C2.18
alkenyl, Q,, alkynyl, aryl, C3.,0 cycloalkyl, C4.]0 cycloalkenyl, or an amino acid
residue;
R17 is independently M-Q- wherein M is a ring optionally substituted with 1
or more R1', and Q is a bond or a linking group connecting M to R3 having 1 to 10
atoms selected from C and optionally 1 or more O, N or S atoms and optionally
substituted with 1 or more R";
R19 is selected from hydrogen, Chalky!, C2,18 alkenyl, C2.lg alkynyl, Q.
alkoxy, C2.16 alkenyloxy, C2.19 alkynyloxy, Calkylthio, C cycloalkyl, Qlo
cycloalkenyl, C4.,0 cycloalkynyl, halogen, -OH, -CN, cyanoalkyl, -NOa, -NR^R21,
C,.,. haloalkyl, C,.,, haloalkyloxy, -C(=O)R18, -C(=O)OR", -OalkenylC(=O)OR19,
-OalkylC(=0)NR20Ra, -OalkylOC(=O)R18, -C(=S)RW, SH, -C(=O)N(C1.6alkyl),
-N(H)S(O)(O)(C,.6 alkyl), aryl, heterocycle, Q.18alkylsulfone, arylsulfoxide,
arylsulfonamide, aryl(Cj.]8)alkyloxy, aryloxy, aryl(CMgalkyl)oxy, arylthio, aryl(Cj.
18)alkylthio or aryl(Cj.je)alkyl, where each may be optionally substituted with 1 or
more =O, NR20R21, CN, C,.1S alkoxy, heterocycle, C:.18 haloalkyl, heterocycle alkyl,
heterocycle connected to R17by alkyl, alkoxyalkoxy or halogen;
R20 and RM are independently selected from hydrogen, CM8 alkyl, C2.jg
alkenyl, C2.18 alkynyl, aryl, C3.10 cycloalkyl, C4.,0 cycloalkenyl, -C(=O)R12, or
-C(=S)R1Z;
R25 and RM are independently not present or are selected from hydrogen, Q.
lg alkyl, Cp cycloalkyl, aryl and heterocycle, where each is optionally
independently substituted with 1 to 4 of C14 alkyl, CM alkoxy, halo, CHjOH,
benzyloxy, and OH; and
R2?is selected from hydrogen, Calkyl, CMO cycloalkyl, (C3.,0cycloalkyl)-Cw
alkyl, aryl, and aryl C, alkyl, and
salts, tautomers, polymorphs, isomers and solvates thereof.
The various embodiments above represent subgeneric groups of
compounds. However, it will be understood that the compounds of this
invention also comprise other subgeneric classes in which various substitutent
groups are mixed and matched from any of the foregoing subgeneric groups, i.e.,
additional classes of compounds falling within the scope of this invention
optionally will contain R19 from the main embodiment (claim 1) but also a
narrower Y group (e.g., Y = bond) from another disclosed embodiment, in any
combination or permutation.
Utilities
The compounds of this invention, or the metabolites produced from these
compounds in vivo, have a large number of uses. They are useful in immunology,
chromatography, diagnostics and therapeutics, among other fields.
The compounds of the formulas of this invention are conjugated to
immunogenic polypeptides as a reagent for eliciting antibodies capable of binding
specifically to the polypeptide, to the compounds or to their metabolic products
which retain immunologically recognized epitopes (sites of antibody binding).
These immunogenic compositions therefore are useful as intermediates in the
preparation of antibodies for use in diagnostics, quality control, or the like, or in
assays for the compounds of the formulas of this invention or their novel
metabolic products. The compounds are useful for raising antibodies against
otherwise non-immunogenic polypeptides, in that the compounds serve as
haptenic sites stimulating an irr mune response which cross-reacts with the
unmodified conjugated protein.
Conjugates of the compounds of the formulas of this invention with
immunogenic polypeptides such as albumin or keyhole limpet hemocyanin
generally are useful as immunogens. The polypeptides are conjugated at the same
sites denoted for amino acids. The metabolic products described above may
retain a substantial degree of immunological cross reactivity with the compounds
of the invention. Thus, the antibodies of this invention will be capable of binding
to the unprotected compounds of the invention without binding to the protected
compounds. Alternatively the metabolic products will be capable of binding to
the protected compounds and/or the metabolitic products without binding to the
protected compounds of the Invention, or will be capable of binding specifically
to any one or all three. The antibodies desirably will not substantially cross-react
with naturally-occurring materials. Substantial cross-reactivity is reactivity under
specific assay conditions for specific analytes sufficient to interfere with the assay
results.
The immunogens of this invention contain the compound of this invention
presenting the desired epitope in association with an immunogenic substance.
Within the context of the invention such association means covalent bonding to
form an immunogenic conjugate (when applicable) or a mixture of non-covalently
bonded materials, or a combination of the above. Immunogenic substances
include adjuvants such as Freirnd's adjuvant, immunogenic proteins such as viral,
bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet
hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor,
and immunogenic polysaccharides. Typically, the compound having the
structure of the desired epitope is covalently conjugated to an immunogenic
polypeptide or polysaccharide by the use of a polyfunctional (ordinarily
bifunctional) cross-linking agent. Methods for the manufacture of hapten
immunogens are conventional per se, and any of the methods used heretofore for
conjugating haptens to immunogenic polypeptides or the like are suitably
employed here as well, taking into account the functional groups on the
precursors or hydroly tic products which are available for cross-linking and the
likelihood of producing antibodies specific to the epitope in question as opposed
to the immunogenic substance.
Typically the polypeptide is conjugated to a site on the compound of the
invention distant from the epitope to be recognized.
The conjugates are prepared in conventional fashion. For example, the
cross-linking agents N-hydroxysuccinimide, succinic anhydride or alkN=C=Nalk
are useful in preparing the conjugates of this invention. The conjugates comprise
a compound of the invention attached by a bond or a linking group of 1-100,
typically, 1-25, more typically 1-10 carbon atoms to the immunogenic substance.
The conjugates are separated from starting materials and by products using
chromatography or the like, and then are sterile filtered and vialed for storage.
Animals are typically immunized against the immunogenic conjugates or
derivatives and antisera or monoclonal antibodies prepared in conventional
fashion.
The compounds of this invention are useful as linkers, spacers or affinity
(typically hydrophobia) moieties in preparing affinity absorption matrices. The
compounds of the invention optionally are bound covalentiy to an insoluble
matrix and used for affinity chromatography separations, depending on the
nature of the groups of the compounds, for example compounds with pendant
aryi groups are useful in making hydrophobic affinity columns.
They also are useful as linkers and spacers in preparing immobilized
enzymes for process control, or in making immunoassay reagents. The
compounds herein contain functional groups that are suitable as sites for crosslinking
desired substances. For example, it is conventional to link affinity
reagents such as hormones, peprides, antibodies, drugs, to insoluble substrates.
These insolublized reagents are employed in known fashion to absorb binding
partners for the affinity reagents from manufactured preparations, diagnostic
samples and other impure mixtures. Similarly, immobilized enzymes are used to
perform catalytic conversions with facile recovery of enzyme. Bifunctional
compounds are commonly used to link analy tes to detectable groups in preparing
diagnostic reagents.
The compounds of this invention axe labeled with detectable moieties such
biotin, radioisotopes, enzymes for diagnostic purposes. Suitable techniques for
accomplishing the labeling of the compounds of the formulas of this invention are
well known and will be apparent to the artisan from consideration of this
specification as a whole. For example, one suitable site for labeling is JR.17 or R19.
- More typically, however, the compounds of the invention are employed for
the treatment or prophylaxis of viral infections such as yellow fever virus, Dengue
virus, hepatitis B virus; ^hepatitis G virus, Classical Swine Fever virus or the
Border Disease Virus, biitmore particularly Flaviviral or Picornaviral infections,,
in particular, HCV and BVDV. .
The therapeutic compound(s) of this invention are administered to a
subject mammal (including a human) by any means well known in the art,
, intranasally, subcutaneously, intramuscularly, intradermally,
irfclavenously, mtra-arterially, parenterally or by catheteiitation. The
therapeutically effective amount of the compound (s) is a Flavi viral or Picomaviral
growth inhibiting amount More preferably, it is a Flaviviral or Picornaviral
replication inhibiting amount or a Flaviviral or Picornaviral enzyme inhibiting
amount of the compounds of the formulas of this invention. This is believed to
correspond to an amount which ensures a plasma level of between about lug/ml
and 100 mg/ml, optionally of 10 mg/ml. This optionally is achieved by
administration of a dosage of in the range of 0.001 mg to 60 mg, preferably 0.01
mg to 10 mg, preferably 0.1 mg to 1 mg per day per kg bodyweight for humans.
These ore starting points for determining the optimal dosage of the compound, of
this invention. The actual amount will depend upon many factors known to the
artisan, including bioavariability of the compound, whether it contains a prodrug
functionality, its metabolism and distribution in the subject and its potency,
among others. It typically is necessary to determine the proper dosing in the
clinical setting, and this is well within the skill of the ordinary artisan. The
therapeutically effective amount of the compound(s) of this invention optionally
are divided into several sub-units per day or are administered at daily or more
than one day intervals, depending upon the pathologic condition to be treated,
the patient's condition and the nature of the compound of this invention.
As is conventional in the art, the evaluation of a synergistic effect in a drug
combination may be made by analyzing the quantification of the interactions
between individual drugs, using the median effect principle described by Chou et
aL in Adv. Enzyme Reg. (1984) 22:27 or tests such as, but not limited to, the
isobologram method, as previously described by Elion et al. in /. Biol Chem, (1954)
208:477-488 and-by^aba-et-alHn Antimicrob. Agents Chemot'her.i^9B^J2B^5-5l7--
using ECg, for calculating the fractional inhibitory concentration.
• Suitable anti-viral agents for inclusion in combination antiviral
compositions or for coadministration in a course of therapy include, for instance,,
interferon alpha, ribavirin, a compound falling within the scope of disclosure of
EP 1162196, WO 03/010141, WO 03/007915, WOOd/005286 and WO 03/010140, a
53
orally, intranasally, subcutaneously/ intramuscularly, intradermally,
intravenously, intra-arterially, parenterally or by catheterization. The
therapeutically effective amount of the compound(s) is a Flaviviral or Picornaviral
growth inhibiting amount. More preferably, it is a Flaviviral or Picornaviral
replication inhibiting amount or a Flaviviral or Picornaviral enzyme inhibiting
amount of the compounds of the formulas of this invention. This is believed to
correspond to an amount which ensures a plasma level of between about lug/ml
and 100 mg/ml, optionally of 10 mg/ml. This optionally is achieved by
administration of a dosage of in the range of 0.001 mg to 60 mg, preferably 0.01
mg to 10 mg, preferably 0.1 mg to 1 mg per day per kg bodyweight for humans.
These are starting points for determining the optimal dosage of the compound of
this invention. The actual amount will depend upon many factors known to the
artisan, including bioavailability of the compound, whether it contains a prodrug
functionality, its metabolism ard distribution in the subject and its potency,
among others. It typically is necessary to determine the proper dosing in the
clinical setting, and this is well within the skill of the ordinary artisan. The
therapeutically effective amount of the compound(s) of this invention optionally
are divided into several sub-units per day or are administered at daily or more
than one day intervals, depending upon the pathologic condition to be treated,
the patient's condition and the nature of the compound of this invention.
As is conventional in the aft, the evaluation of a synergistic effect in a drug
combination may be made by analyzing the quantification of the interactions
between individual drugs, using the median effect principle described by Chou et
al. in Adv. Enzyme Reg. (1984) 22:27 or tests such as, but not limited to, the
isobologram method, as previously described by Elion et al. in /. Bio/. Chem. (1954)
208:477-488 and by Eaba et al. mAntimicrob. Agents Chemother. (1984) 25:515-517,
using EC50 for calculating the fractional inhibitory concentration.
/
Suitable anti-viral agents for inclusion in combination antiviral
compositions or for coadministration in a course of therapy include, for instance,
interferon alpha, ribavirin, a compound falling within the scope of disclosure of
EP1162196, WO 03/010141, WO 03/007945, WO04/005286 and WO 03/010140, a
compound falling within the scope of disclosure of WO 00/204425, and other
patents or patent applications within their patent families, in amounts of 1 to
99.9% by weight compound of this invention, preferably from 1 to 99% by weight,
more preferably from 5 to 95% by weight as can be readily determined by one
skilled in the art. Such co-administered agents need not be formulated in the
same dosage form as the compound of the invention. They optionally are simply
administered to the subject in the course of treatment along with a course of
treatment with a compound of formula (A).
The present invention further provides veterinary compositions
comprising at least one active ingredient as above defined together with a
veterinary carrier therefore, for example in the treatment of BVDV. Veterinary
carriers are materials useful for the purpose of administering the composition and
are excipients which are otherwise inert or acceptable in the veterinary art and are
compatible with the compound of this invention. These veterinary compositions
may be administered orally, parenterally or by any other desired route.
The compounds of the invention optionally are bound covalently to an
insoluble matrix and used for affinity chromatography (separations, depending
on the nature of the groups of the compounds, for example compounds with
pendant aryl are useful in hydrophobic affinity separations.
The compounds of the invention are employed for the treatment or
prophylaxis of viral infections, more particularly Flaviviral or Picornaviral
infections, in particular, HCV and BVDV. When using one or more derivatives of
the formula (A) as defined herein:
- the active ingredients of the compound (s) may be administered to the
mammal (including a human) to be treated by any means well known in the
art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally,
intravenously, intra-arterially, parenterally or by catheterization.
the therapeutically effective Jimount of the preparation of the compound(s),
especially for the treatment of viral infections in humans and other mammals,
preferably is a Flaviviral or Picornaviral enzyme inhibiting amount. More
preferably, it is a Flaviviral or Picornaviral replication inhibiting amount or a
Flaviviral or Picornaviral enzyme inhibiting amount of the derivative(s) of
formula (A) as defined herein corresponds to an amount which ensures a
plasma level of between lug/ml and 100 mg/ml, optionally of 10 mg/ml. This
can be achieved by administration of a dosage of in the range of 0.001 mg to 20
mg, preferably 0.01 mg to 5 mg, preferably O.lmg to 1 mg per day per kg
bodyweight for humans. Depending upon the pathologic condition to be
treated and the patient's condition, the said effective amount may be divided
into several sub-units per day or may be administered at more than one day
intervals.
The present invention further relates to a method for preventing or treating
a viral infections in a subject or patient by administering to the patient in need
thereof a therapeutically effective amount imidazo[4,5-d]pyrimidine derivatives
of the present invention. The therapeutically effective amount of the preparation
of the compound(s), especially for the treatment of viral infections in humans and
other mammals, preferably is a Flaviviral or Picornaviral enzyme inhibiting
amount. More preferably, it is a Flaviviral or Picornaviral replication inhibiting
amount or a Flaviviral or Picornaviral enzyme inhibiting amount of the
derivative(s) of formula (A) as defined herein. Suitable dosage is usually in the
range of 0.001 mg to 60 mg, optionally 0.01 mg to 10 mg, optionally O.lmg to 1 mg
per day per kg bodyweight for humans. Depending upon the pathologic
condition to be treated and the patient's condition, the said effective amount may
be divided into several sub-units per day or may be administered at more than
one day intervals.
This principle may be applied to a combination of different antiviral drugs
of the invention or to a combination of the antiviral drugs of the invention with
other drugs that exhibit anti-BVDV or anti-HCV activity.
The invention thus relates to a pharmaceutical composition or combined
preparation having synergistic effects against a viral infection and containing:
Either:
A) a combination of two or more of the imidazo[4,5-d]pyrimidine
derivatives of the present invention/ and
B) optionally one or more pharmaceutical excipients or
pharmaceutically acceptable carriers, for simultaneous, separate or sequential use
in the treatment or prevention of a viral infection, or
C) one or more anti-viral agents, and
D) at least one of the imidazo[4,5-d]pyrimidine derivatives of the
present invention, and
E) optionally one or more pharmaceutical excipients or
pharmaceutically acceptable carriers, for simultaneous, separate or sequential use
in the treatment or prevention of a viral infection.
Suitable anti-viral agents for inclusion into the synergistic antiviral
compositions or combined preparations of this invention include, for instance,
interferon-alfa (either pegylated or not), ribavirin and other selective inhibitors of
the replication of BVDV or HCV.
The pharmaceutical composition or combined preparation with synergistic
activity against viral infection a ccording to this invention may contain the
imidazo[4,5-d]pyrimidine derivatives of the present invention over a broad
content range depending on the contemplated use and the expected effect of the
preparation. Generally, the content of the imidazo[4,5-d]pyrimidine derivatives of
the present invention of the combined preparation is within the range of 0.1 to
99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to
95% by weight.
According to a particular embodiment of the invention, the compounds of
the invention may be employed in combination with other therapeutic agents for
the treatment or prophylaxis of Flaviviral or Picornaviral infections, optionally,
HCV and BVDV. The invention therefore relates to the use of a composition
comprising:
(a) one or more compounds of the formulas of this invention, and
(b) one or more Flaviviral or Picornaviral enzyme inhibitors as
biologically active agents in respective proportions such as to provide a
synergistic effect against a viral infection, particularly a Flaviviral or Picornaviral
infection in a mammal, for instance in the form of a combined preparation for
simultaneous, separate or sequential use in viral infection therapy, such as of
HCv, BVDV and Coxsackie virus. Examples of such further therapeutic agents for
use in combinations include agents that are effective for the treatment or
prophylaxis of these infections, including interferon alpha, ribavirin, a compound
faiing within the scope of disclosure EP 1162196, WO 03/010141, WO 03/007945,
WO04/005286 and WO 03/010140, a compound falling within the scope of
disclosure WO 0/204425, and other patents or patent applications within their
patent families or all the foregoing filings and/or an inhibitor of Haviviral
protease and/or one or more additional Ravivirus polyinerase inhibitors.
When using a combined preparation of (aj and (b):
the active ingredients (a) and (b) may be administered to the mammal
(including a human) to be treated by any means well known in the art, i.e.
orally, intranasally, subcutaneously, intramuscularly, Intradermally,
intravenously, intra-arterially, parenterally or by catheterization.
the therapeutically effective amount of the combined preparation of (a) and
(b), especially for the treatment of viral infections in humans and other
mammals, particularly is a Flaviviral or Picornaviral enzyme inhibiting
amount. More particularly, it is a Haviviral or Picornaviral replication
inhibiting amount of derivative (a) and a Flaviviral or Picornaviral enzyme
inhibiting amount of inhibitor (b). Still more particularly when the said
Flaviviral or Picornaviral enzyme inhibitor (b) is a polymerase inhibitor, its
effective amount is a polymerase inhibiting amount. When the said Flaviviral
or Picornaviral enzyme inhibitor (b) is a protease inhibitor, its effective
amount is a protease Inhibiting amount.
ingredients (a) and (b) may be administered simultaneously but it is also
-benefieial^o-administer them, separately or sequeniially7-fe4?-instance within
relatively short period of time (e-g, within about 24 hours) HI order to achieve
their functional fusion in the body to be treated.
The invention also relates to die compounds of the formulas of this
invention being used for inhibition of the proliferation of other viruses than
BVDV, HCV or Coxsackie virus, particularly for the inhibition of other
flaviviruses or picornaviruses, with in particular yellow fever virus, Dengue
virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the
Border Disease Virus, and also for the inhibition of HIV and other retroviruses or
lentiviruses.
More generally, the invention relates to the compounds of tKe formulas of
this invention being useful as agents having biological activity (particularly
antiviral activity) or as diagnostic agents. Any of the uses mentioned with respect
to the present invention may be restricted to a non-medical use, a non-therapeutic
use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells
remote from, an animal,
Salts and Sofoafgg
The term "pharmaceutically acceptable salts" as used herein means the
therapeutically active non-toxic salt forms formed by the compounds of the
compounds of this invention. Such salts may include those derived by
combination of appropriate cations such as alkali and alkaline earth metal ions or
ammonium and quaternary amino ions with an acid anion moiety, typically a
carboxylic acid.
The compounds of the invention may bear multiple positive or negative
charges. The net charge of the compounds of the invention may be either positive
or negative. Any associated counter ions are typically dictated by the synthesis
and/or isolation methods by which the compounds are obtained. Typical counter
ions include, but are not limited to ammonium, sodium, potassium, lithium,
halides, acetate, trifjuoroacecate, and mixtures thereof. It will be understood that
the identity of any associated counter ion is not a critical feature of the invention.,
--and-that the invention encompasses-thecompeunds-in association with any type
of eauftfer ion. Moreover, as the compounds ran exist in a variety of different
forms, the invention is intended to encompass not only forms of the compounds
that are in association, with counter ions (e.g., dry salts), but also forms that are
not in association with counter ions (e.g., aqueous or organic solutions),
flaviviruses or picornaviruses, with in particular yellow fever virus, Dengue
virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the
Border Disease Virus, and also for the inhibition of HTV and other retroviruses or
lentiviruses.
More generally, the invention relates to the compounds of the formulas of
this invention being useful as agents having biological activity (particularly
antiviral activity) or as diagnostic agents.'Any of the uses mentioned with respect
to the present invention may be restricted to a non-medical use, a non-therapeutic
use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells
remote from an animal.
Salts and Solvates
The term "pharmaceutically acceptable salts" as used herein means the
therapeutically active non-toxic salt forms formed by the compounds of the
compounds of this invention. Such salts may include those derived by
combination of appropriate cations such as alkali and alkaline earth metal ions or
ammonium and quaternary amino ions with an acid anion moiety, typically a
carboxylic acid.
The compounds of the invention may bear multiple positive or negative
charges. The net charge of the compounds of the invention may be either positive
or negative. Any associated counter ions are typically dictated by the synthesis
and/or isolation methods by which the compounds are obtained. Typical counter
ions include, but are not limited to ammonium, sodium, potassium, lithium,
halides, acetate, trifh^roacetate, etc., and mixtures thereof. It will be understood
that the identity of any associated counter ion is not a critical feature of the
(*'
invention, and that the invention encompasses the compounds in association with
any type of couriter ion. Moreover, as the compounds can exist in a variety of
different forms, the invention is intended to encompass not only forms of the
compounds that are in association with counter ions (e.g., dry salts), but also
forms that are not in association with counter ions (e.g., aqueous or organic
solutions).
The compounds of this invention include the solvates formed with the
ccnripounds of this invention and their salts, such as for example hydrates,
alcoholates. The compositions herein comprise compounds of the invention in
their un-ionized, as well as zwitterionic form, and combinations with
stoichiometric amounts of water as in hydrates.
Also included within the scope of mis invention are the salts of the
compounds of this invention with one or more amino acids as described above.
The amino acid typically is one bearing a side chain with a basic or acidic group,
e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine,
threonine, alanine, isoleucine, or leucine.
Salts of Adds or bases which are not physiologically acceptable may also
find use, for example, in the preparation or purification of a compound of this
invention. All salts, whether or not derived form a physiologically acceptable
acid or base, are within the scope of the present invention.
The compounds of this invention optionally comprise salts of the
compounds herein, especially pharmaceutically acceptable non-toxic salts
containing, for example, Na+, Li+, K-t-, Ca+2 and Mg+2, Such salts may include
those derived by combination of appropriate cations such as alkali and alkaline
earth metal ions or ammonium and quaternary amino ions with an acid aruon
moiety, typically a carboxylic acid. The compounds of the invention may bear
multiple positive or negative charges. The net charge of the compounds of the
invention maybe either positive or negative. Any associated counter ions are
typically dictated by the synthesis and/or isolation methods by which the
compounds are obtained. Typical counter icx\s include, but are not limited to
ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, and
mixtures thereof. It wiU-beJuruiertitood that the identity of aiiy assocw-iad-couiUer
ion is not a critical feature of the invention, and that the invention encompasses
the compounds in association with any type of counter ioru Moreover, as the
compounds can exist in a variety of different forms, the invention is intended to
encompass not only forms of the compounds that are in
association with counter ions (e.g., dry salts), but also forms tfxat are not in
ij||ociation with counter ions (e.gv aqueous or organic solutions).
Metal salts typically are prepared by reacting the metal hydroxide with a
compound of this invention. Examples of metal salts which are prepared in this
way are salts containing Li+, Na+, Cat-2 and Mg-t-2 and K+. A less soluble metal,
salt can be precipitated from 'the solution of a more soluble salt by addition of the
suitable metal compound. In addition, salts may be formed from acid addition of
certain organic and inorganic acids to basic centers, typically amines, or to acidic
groups. Examples of. such appropriate acids include, for instance, inorganic acids
such as hydrohalogen acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid,
nitric add, phosphoric acid; or organic acids such as, for example, acetic,
propanoic> hydroxyacetic, benzojc, 2-hydroxypropanoic, 2-oxopropanoic, lactic,
furriaric, tartaric, pyruvic, maleic, malonic, malic, salicylic (La 2-hydroxybenzoic),
p-aminosalicylic, isemionic, lactobionic, succinic oxalic and citric acids; organic
sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and ptoluenesulfbnic
acids; and inorganic acids, such as hydrochloric, sulfuric,
phosphoric and sulfamic acids,. Cj-C^alkyisulfonic, benzenesulfonic, ptoluenesulfonic,
cyclohexariesulfamic. Exemplary salts include mesylate arid HCL
Also included within the scope of this invention are the salts of the parental
compounds with one or more amiao acids, especially the naturally-occurring
amino acids found as protein components. The amino acid typically is one
bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic
acid, or a neutral group such as glydne, serine, threonine, alanine, isoleucine, or
leucjne.
The compounds of the invention also include physiologically acceptable
salts thereofr-Examples-of-physiologically acceptable salts-of :the-cempQun.ds of
the invention include salts derived from an appropriate base, 9iich as an a&aU
inetai (for example, sodium), an alkaline earth (for example, magnesium),
ammonium and NX4+ (wherein. X is C^-C^ alkyl). Physiologically acceptable salts
of an hydrogen atom or an amino group include salts of organic carboxylic acids
such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,
lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic,
ethanesulfonic, benzenesulforiic and p-toluenesulfonic acids; and inorganic acids,
such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically
acceptable salts of a compound containing a hydroxy group include the anion of
said compound in combination with a suitable cation such as Na+ and NX4+
(wherein X typically is independently selected from H or a Cj-C4 alkyl group).
However, salts of acids or bases which are not physiologically acceptable may
also find use, for example, in the preparation or purification of a physiologically
acceptable compound. All salts, whether or not derived form a physiologically
acceptable acid or base, are within the scope of the present invention.
Isomers
The term "isomers" as used herein means all possible isomeric forms,
including tautomeric and stereochemical forms, which the compounds of the
formulas of this invention may possess, but not including position isomers.
Typically, the structures shown herein exemplify only one tautomeric or
resonance form of the compounds, but the corresponding alternative
configurations are contemplated as well. Unless otherwise stated, the chemical
designation of compounds denotes the mixture of all possible stereochemically
isomeric forms, said mixtures containing all diastereomers and enantiomers (since
the compounds of the formulas of this invention may have one or more chiral
centers), as well as the stereochemically pure or enriched isomers. More
particularly, stereogenic centers may have either the R- or S-configuration, and
double or triple bonds optionally are in either the cis- or trans-configuration.
Enriched isomeric forms of a compound of this invention are defined as a
single isomer substantially free of the compound's other enantiomers or
diastereomers. In particular, the term "stereoisomerically enriched" or "chirally
enriched" relates to compounds having a single stereoisomeric proportion of at
least about 80% (Le. at least 90% of one isomer and at most 10% of the other
ppsible isomers), preferably at least 90%, more preferably at least 94% and most
preferably at least 97%. The terms "enantiomerically pure" and
"diastereornerically pure" contain undetectable levels of any other isomer.
Separation of stereoisomers is accomplished by standard methods known
to those in the art One enantiomer of a compound of the Invention can be
separated substantially free of its opposing enantiomer by a method such as
formation of diastereomers using optically active resolving agents
("Stereochemistry of Carbon Compounds," (1962) by E. L. Eliel, McGraw Hill;
Lochmuller, C. H,, (1975) J- Chromatogr., 113:(3) 283-302). Separation of isomers
in ft mixture can be accomplished by any suitable method, including: (1)
formation of ionic, diastereomeric salts with chiral compounds and separation by
fractional crystallization or other methods, (2) formation of diastereomeric
compounds with chiral derivatizing reagents, separation of the diastereorrvers,
and conversion to the pure enantiomers, or (3) enantiomers can be separated
directly under chiral conditions. Under method (1), diastereomeric salts can be
formed by reaction of enantiomerically pure chiral bases such as brucine, quinine,
ephedrine, strychnine, a-methyi-b-phenylethylamine (amphetamine), with
asymmetric compounds bearing an acidic functionality, such as carboxylic acid
and sulfonic acid.
The diastereomeric salts optionally are induced to separate by fractional
crystallisation or ionic chromatography. For separation of the optical isomers of
amino compounds, addition of chiral carboxylic or sulfonic acids, such as
camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in
formation of the diastereomeric sa4ts. Alternatively, by method (2), the substrate
to-be-resolved may be reacted with one enantiomer-of-a-ehiral-compound to form
a diastereomeric pair (Eliel, E. and Wilen, S. (1994). Stereochemistry of Organic
Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be
formed by reacting asymmetric compounds with enantiomerically pure chiral
derivatizing reagents, such as menthyl derivatives, foEowed by separation of the
diastereomers and hydrolysis to yield the free, enantiomerically enriched
xanthene. A method of determining optical purity involves making chiral esters,
s2feh as a menthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl
acetete (Jacob ffi. (1982) J, Org. Chem. 47:4165), of the racemic mixture, and
analysing the NMR spectrum for the presence of the two atropisomeric
diastereomers. Stable diastereomers can be separated and isolated by normaland
reverse-phase chromatography following methods for separation of
atropisomeric ivaphthyl-isoquJnolines (Hoye, T., WO 96/15111). Under method
(3), a racerruc mixture of two asymmetric enantiorners is separated by
chromatography using a chiral stationary phase. Suitable chiral stationary phases
are, for example, polysaccharides, in particular cellulose or amylose derivatives.
CoxruxxerciaJly available pplysaccharide based chiral stationary phases are
OuralCel™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chkalpak™ AD,
AS, OP(-t-) and OT(+). Appropriate eluents or mobile phases for use in
combination with said polysaccharide chiral stationary phases are hexane,
modified with an alcohol such as ethanol, isopropanol. ("Chiral Liquid
Chromatography" (1989) W. J. Lough, Ed. Chapman and Hall, New York;
Okamoto, (1990). "Optical resolution of dihydropyridine enantiomers by Highperformance
liquid chromatography using phenylcarbamates of polysaccharides
as a chiral stationary phase", J. of Chromatogr. 513:375-378).
As used herein and unless otherwise stated, the term " enantiomer " means
each individual optically active form of a compound of the invention, having an
optical purity or enantiomeric excess (as determined by methods standard in the
art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the.
other enantiomer), preferably at least 90% and more preferably at least 98%.
The term, "isomers" as used herein means all possible isomeric forms,
_jncluding tautomeric and sterochemical forms, w^hich the compounds of the
formulas of this invention may possess, but not including position isomers.
Typically, the structures shown herein exemplify only one tautomeric or
resonance form of the compounds, but the corresponding alternative
configurations are contemplated as well. Unless otherwise stated, the chemical
designation of compounds denotes the mixture of all possible stareochemically
isomeric forms, said mixtures containing all diastereomers and enarvtiorners
fejyice the compounds of the formulas of this invention may have at least one
chiral center) of the basic molecule structure, as wel as the stereochemically pure
or enriched compounds. More pajticularly, stereogenic centers may have either
the R- or S-configuration, and multiple bonds may have either cis- or transconfiguration.
Pure isomeric forms of the said compounds are defined as isomers
substantially free of other enantiomeric or diastereomeric forms of the same basic
molecular structure. In particular, the term "stereoisomerically pure" or "chirally
pure" relates to compounds having a stereoisomeric excess of at least about 80%
(i.e. at least 90% of one isomer and at Baost 10% of the other possible Isomers),
preferably at least 90%, more preferably at least 94% and most preferably at least
97%. The terms "enantioiuerically pure" and "diastereomerically pure" should be
understood in a similar way, having regard to the enantiomeric excess,
respectively the diastereomeric excess, of the mixture in question.
Separation of stereoisomers is accomplished by standard methods known
to those in the art. One enantiorner of a compound of the invention can be
separated substantially free of its opposing enantiomer by a method such as
formation of diastereomers using optically active resolving agents
("Stereochemistry of Carbon Compounds," (1962) by E. L. Eliel, McGraw Hill;
Lochmuller, C. Hv (1975) J. Chromatogr., 113:(3) 283-302). Separation of isomers in
a mixture can be accomplished by any suitable method, including: (I) formation
of ionic, diastereomeric salts with chiral compounds and separation by fractional
crystallization or other methods, (2) formation of diastereomeric compounds with
chiral derivatmng reagents, separation of the diastereomers, and conversion to
the pure enantiomers^of-^J-enannomers can be separated directly under chiral
conditions. Under method (1), diastereomeric salts can be formed by reaction of
enantiornerically pure chiral bases such as brucine, quinine, ephedrine,
strychnine, a-methyl-b-phenylethylamine (amphetamine), with asymmetric
compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
The diastereomeric salts may be induced to separate by fractional
crystallization or ionic chromatography. For separation of the optical isomers of
amino compounds, addition of chiral carboxylic or sulfonic acids, such as
camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in
fonnation of the diastereomeric salts. Alternatively, by method (2), the substrate
to be resolved may be reacted with one enantiomer of a chiral compound to form,
a diastereomeric pair {Eliel, E. and Wilert, S. (1994) Stereochemistry of Organic
Compounds, John Wiley & Sons, Inc., p. 322), Diastereomeric compounds can be
formed by reacting asymmetric compounds with enantiomerically pure chiral
derivatizing reagents, such as menthyl derivatives, followed by separation of the
diastereomers and hydrolysis to yield the free, enantiomerically enriched
scamhene. A method of determining QpticzU. polity involves making crural esters,
jiuch as a menthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl
acetate (Jacob EL (1982) J. Org. Cham. 47:4165), of the racemic mixture, and
analyzing the NMR spectrum for the presence of the two atropisomeric
diastereomers- Stable diastereomers can be separated and isolated by normal- and
reverse-phase chromatography following methods for separation of atropisomeric
iiaphthyl-isoquinolines (Hoye, T., WO 96/15111). Under method (3), a racemic
mixture of two asymmetric enantiomers is separated by chromatography \ising a
dural stationary phase. Suitable chiral stationary phases are, for example,
polysaccharides, in particular cellulose or amylose derivatives. Commercially
available polysaccharide based chiral stationary phases are CruralCe!™ CA, OA,
OB5, OC5, OD, OF, OG, OJ and OK, and ChiralpaklM AD, AS, OP(-i-) and OT(+).
Appropriate eiuents or mobile phases for use in combination-with said
polysaccharide chiral stationary phases are hexane, modified with an alcohol such
as ethanol, isopropanol ("Chiral Liquid Chromatography" (1989) W. ]. Lough, Ed,
Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of
dihydropyridine enantiomers by High-performance liquid chromatography using
phenyicarbamates of poly saccharides as a chiral stationary phase", J. of
Chromatogr. 513:375-378).
The terms cis and trans are used herein in accordance with Chemical
Abstracts nomenclature and include reference to the position of the substituents
on a ring moiety, The absolute stereochemical configuration of the compounds of
f&mula (1) may easily be determined by those skilled in the art while using wellknown
methods such as, for example, X-ray diffraction.
Metabolites
The present invention also provides the in vivo metabolic products of the
compounds described herein, to the extent such products are novel and
unobvious over the prior art. Such products may result for example from the
oxidation, reduction, hydrolysis, amidation, esterification of the administered
compound, primarily due to enzymatic processes. Accordingly, the invention
includes novel and unob vious compounds produced by a process comprising
contacting a compound of this invention with a mammal for a period of time
sufficient to yield a metabolic product thereof.. Such products typically are
identified by preparing a radiolabelled (e.g. CH or H3) compound of the
invention, administering it parenterally in a detectable dose (e.g. greater than
about 0.5 mg/kg) to an anifnal such as rat, mouse, guinea pig, monkey, or to man,
allowing sufficient time for metabolism to occur (typically about 30 seconds to 30
hours) and isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they are labeled
(others are isolated by the use of antibodies capable of binding epitopes surviving
in the metabolite). The metabolite structures are determined in conventional
fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in
the same way as conventional drug metabolism studies well-known to those
skilled in the art. The conversion prodvirtq, so long w they ar found in vivo, are useful in diagnostic assays for therapeutic dosing of the
-compounds of the invention even if they_passessLno^tiyiral activity of their own.
Formulations
The compounds of the invention optionally are formulated with
conventional pharmaceutical carders and excipients, which will be selected in
accord with ordinary practice. Tablets will contain excipients, glidants, fillers,
binders. Aqueous formulations are prepared in sterile form, and when intended
AJK 'delivery by other than oral administration generally will be isotonic.
Formulations optionally contain excipients such as those set fonti in the
"Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and
other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin,
hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid.
Subsequently, the term "pharmaceutically acceptable carrier" as used
herein means any material or substance with which the active ingredient is
formulated in order to facilitate its application or dissemination to the locus to be
treated, for instance by dissolving, dispersing or diffusing the said composition,
and/or to facilitate its storage, transport en liandlirtg without Impairing its
effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid
or a gas which has been compressed to form a liquid, i.e. the compositions of this
invention can suitably be used as concentrates, emulsions, solutions, granulates,
dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or
powders.
Suitable pharmaceutical carriers for use in the said pharmaceutical
compositions and their formulation are well Icnown to those skilled in the art, and
there is no particular restriction to their selection within the present invention.
They may also include additives such as wetting agents, dispersing agents,
stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and
antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents
(such as sugars or sodium chloride), provided the same are consistent with
pharmaceutical practice, Le. carriers and additives which do not create permanent
damage to mammals. The pharmaceutical compositions of the present invention
may be prepared in any known-maimerr-f or- instance by homogeneously mixing;
coating and/or grinding the active ingredients, in a one-step or multi-steps
procedure, with the selected carrier material. Where appropriate, the other
additives such as surface-active agents are prepared by micronisation, for instance
in view to obtain them in the form of microspheres usually having a diameter of
about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or
sustained release of the active ingredients.
Suitable surface-active -igents, also known as emulgent or emulsifier, to be
used in the pharmaceutical compositions of the present invention are non-ionic,
cationic and/or anionic materials having good emulsifying, dispersing and/or
wetting properties. Suitable anionic surfactants include both water-soluble soaps
and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or
alkaline-earth, metal salts, unsubstituted or substituted ammonium salts of higher
fatty acids (C^C^), e.g. the sodium or potassium salts of oleic or stearic acid, or of
natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic
surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates
and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphbnates.
Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth
metal salts, unsubstituted ammonium salts or ammonium salts substituted with
an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or
calcium salt of lignosulphoriic acid or dodecylsulphonic acid or a mixture of fatty
alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth
metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate)
and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable
sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms.
Examples of alkylarylsulphonates are the sodium, calcium or alcoholamine salts
of dodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or a
naphthalene-sulphonic acid/formaldehyde condensation product. Also suitable
are the corresponding phosphates, e.g. salts of phosphoric acid ester and an
adduct of p-nonylphenol with ethylene and/or propylene oxide, or
phospholipids. Suitable phospholipids for this purpose are the natural
(originating from animal or plant cells) or synthetic phospholipids of the cephalin
or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine,
phosphatidylglycerine, lysolecitliin, cardiolipin, dioctanylphosphatidyl-choline,
dipalmitoylphoshatidyl -choline and their mixtures.
Suitable non-ionic surfactants include polyethoxylated and
f*blypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic
amines or amides containing at least 12 carbon atoms in the molecule,
aJkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether
derivatives of aliphatic and cydoaliphatic alcohols, saturated and unsaturated
fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol
ether groups and S to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6
to 18 carbon atoms in the alkyl moiety of the alkylphenpL Further suitable nonionic
surfactants are water-soluble adducts of polyethylene oxide with
poylypropylene glycol, ethylenediairunopolypropylene glycol containing 1 to 10
carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol
ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds
usually contain from I to 5 ethyleneglycol units per propyleneglycoi unit.
Representative examples of non-ionic surfactants are nonylphenol -
polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene
oxide adducts, uibutylphenoxypolyethoxyethanol, polyethyleneglycol and
octylphenoxypolyethoxyethanol. patty acid esters of polyethylene sorbitan (such
as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and
pentaerythritol are also suitable r.on-ionic surfactants.
Suitable cationic surfactants include quaternary ammonium salts,
particularly halides, having 4 hydrocarbon radicals optionally substituted with
halo, phenyi, substituted phenyl or hydroxy; for instance quaternary ammonium
salts containing as N-Subtftituent at least one CC alkyl radicaji (e-g- cetyl, laiyl,
palmityl, myristyl, oleyl) and, as further subsutuents, unsubstituted or
.halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl radicals.
A rh3re~cvetailea"cl:escription of surface-active agentsliTJitablenfoYttiis
purpose may be found for instance in "McCutcneon's Detergents and Emulsifiers
Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-
Taschenbucw', 2 4 ed. (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of
Surfactants, (Chemical Publishing Co.. New York, 1981).
Compounds of the invention and their physiologically acceptable salts
(hereafter collectively referred to as the active ingredients) may be administered
by any route appropriate to the condition to be treated, suitable routes including
oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and
parenteral (including subcutaneous, intramuscular, intravenous, intradermal,
intrathecal and epidural). The preferred route of administration may vary with
for example the condition of the recipient.
While it is possible for the active ingredients to be administered alone it is
preferable to present them as pharmaceutical formulations. The formulations,
both for veterinary and for human use, of the present invention comprise at least
one active ingredient, as above described, together with one or more
pharmaceutically acceptable carriers therefore and optionally other, therapeutic
ingredients. The carrier(s) optimally are "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not deleterious to
the recipient thereof. The formulations include those suitable for oral, rectal,
nasal, topical (including buccal and sublingual), vaginal or parenteral (including
subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural)
administration. The formulations may conveniently be presented in unit dosage
form and may be prepared by any of the methods well known in the art of
pharmacy. Such methods include the step of bringing into association the active
ingredient with the carrier which constitutes one or more accessory ingredients.
In general the formulations are prepared by uniformly and intimately bringing
into association the active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may
be presented as discrete units such as capsules, cachets or tablets each containing
a predetermined amount of the active ingredient; as a powder or granules; as
solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a. water-in-oil liquid emulsion. The active
ingredient may also be presented as a bolus, electuary or paste.
70
A tablet may be made by compression or molding, optionally with one or
more accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable maclune the active ingredient in a free-flowing form
such as a powder or granules, optionally mixed with a binder, lubricant, inert
diluent, preservative, surface active or dispersing agent. Molded tablets may be
made by molding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent. The tablets may optionally be coated or
scored and may be formulated so as to provide slow or controlled release of the
active ingredient therein. For infections of the eye or other external tissues e.g.
mouth and skin, the formulations are optionally applied as a topical ointment or
cream containing the active ingredient(s) in an amount of, for example, 0.075 to
20% w/w (including active ingredient(s) in a range between 0.1% and 20% in
increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15%
w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the
active ingredients may be employed with either a paraffinic or a water-miscible
ointment base. Alternatively, the active ingredients may be formulated in a cream
with an oil-in-water cream base. If desired, the aqueous phase of the cream base
may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as propylene glycol, butane
1,3-diol, rnannitol, sorbitol/ glycerol and polyethylene glycol (including PEG400)
and mixtures thereof. The topical formulations may desirably include a
compound which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal penetration
enhancers include dimethylsulfoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from
known ingredients in a known manner. While the phase may comprise merely an
emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of
at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally,
a hydrophilic emulsifier is included together with a lipophilic emulsifier which
acts as a stabilizer. It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying
wax/ and the wax together with the oil and fat make up the so-called emulsifying
ointment base which forms the oily dispersed phase of the cream formulations.
The choice of suitable oils or fats for the formulation is based on achieving
the desired cosmetic properties, since the solubility of the active compound in
most oils likely to be used in pharmaceutical emulsion formulations is very low.
Thus the cream should optionally be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or other containers.
Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate,
isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl
myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters known as Crodamol CAP may be used, the
last three being preferred esters. These may be used alone or in combination
depending on the properties required. Alternatively, high melting point lipids
such as white soft paraffin and/or liquid paraffin or other mineral oils can be
used.
Formulations suitable for topical administration to the eye also include eye
drops wherein the active ingredient is dissolved or suspended in a suitable
carrier, especially an aqueous solvent for the active ingredient. The active
ingredient is optionally present in such formulations in a concentration of 0.5 to
20%, advantageously 0.5 to 10% particularly about 1.5% w/w. Formulations
suitable for topical administration in the mouth include lozenges comprising the
active ingredient in a flavored basis, usually sucrose and acacia or tragacanth;
pastilles comprising the active ingredient in an inert basis such as gelatin and
glycerin, or sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository
with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for nasal administration wherein the carrier is a solid
include a coarse powder having a particle size for example in the range 20 to 500
microns (including particle sizes in a range between 20 and 500 microns in
increments of 5 microns such as 30 microns, 35 microns, etc), which is
administered in the manner in which snuff is taken, i.e. by rapid inhalation
through the nasal passage from a container of the powder held close up to the
nose. Suitable formulations wherein the carrier is a liquid, for administration as
for example a nasal spray or as nasal drops, include aqueous or oily solutions of
the active ingredient. Formulations suitable for aerosol administration may be
prepared according to conventional methods and may be delivered with other
therapeutic agents.
Formulations suitable for vaginal administration may be presented as
pessaries, tampons, creams, gels, pastes, foams or spray formulations containing
in addition to the active ingredient such carriers as are known in the art to be
appropriate.
Formulations suitable for parenteral administration include aqueous and
non-aqueous sterile injection solutions which may contain anti-oxidants, buffers,
bacteriostats and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents. The formulations may be
presented in unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in a freeze-dried (lyophilized) condition requiring only
the addition of the sterile liquid carrier, for example water for injections,
immediately prior to use. Extemporaneous injection solutions and suspensions
may be prepared from sterile powders, granules and tablets of the kind
previously described.
Preferred unit dosage formulations are those containing a daily dose or
unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of
an active ingredient.
It should be understood that in addition to the ingredients particularly
mentioned above the formulations of this invention may include other agents
conventional in the art having regard to the type of formulation in question, for
example those suitable for oral administration may include flavoring agents.
Compounds of the invention can be used to provide controlled release
pharmaceutical formulations containing as active ingredient one or more
compounds of the invention ("controlled release formulations") in which the
•^tlease of the active ingredient can be controlled and regulated to allow less
frequency dosing or to improve the pharmacokinetic or toxicity profile of a given
invention compound. Controlled release formulations adapted for oral
administration in which discrete units comprising one or more compounds of the
invention can be prepared according to conventional methods.
Additional ingredients may be included in order to control the duration of
action of the active ingredient in the composition. Control release compositions
may thus be achieved by selecting appropriate polymer carriers such as for
example polyesters, polyamino adds, polyvinyl pyrrolidone, ethylene-vinyl
acetate copolymers, mettvylceUulose, carboxymethylcelluJose, protomme stilfate.
The rate of drug release and duration of action may also be controlled by
incorporating the active ingredient into particles, e.g. microcapsules, of a
polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose,
polymethyl methacrylate and the other above-described polymers. Such methods
include colloid drug delivery systems like liposomes, microspheres,
microernulsions, nanoparticles, nanocapsules and so oru Depending on the route
of administration, the pharmaceutical composition may require protective
coatings. Pharmaceutical forms suitable for injectionable use include sterile
aqueous solutions or dispersions and sterile powders for the extemporaneous
preparation thereof. Typical carriers for this purpose therefore include
biocompatible aqueous buffers, etihanol, glycerol, propylene glycol, polyethylene
glycol and mixtures thereof.
m view of the fact that, when several active ingredients are used in
combination, they do not necessarily bring out their joint therapeutic effect
-jdirectly_atthe same time in me mammal to heLtreaied, Jaej:orresponding
• composition may also be in the form of a medical kit or package containing the
two ingredients in separate but adjacent repositories or compartments. In the
latter context, each active ingredient may therefore be formulated in a way
' suitable for an adcniriistration route different from that of the other ingredient,
e.g. one of them may be in the form of an oral or parenteral formulation, whereas
*Btt& other is in the form of an ampoule for intravenous injection or an aerosol.
Suitable methods for drug delivery include colloid drug delivery systems
like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and
so on. Depending on the route of administration, the pharmaceutical composition.
may require protective coatings, Pharmaceutical forms suitable for injectionable
use include sterile aqueous solutions or dispersions and sterile powders for the
extemporaneous preparation thereof. Typical carriers for this purpose therefore
include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol,
polyethylene glycol and mixtures thereof.
SeviSrral active ingredients used in combination may not necessarily bring
out their joint therapeutic effect directly at the same time in the mammal to be
treated. Thus, the corresponding composition may also be in the form of a
medical kit or package containing the two ingredients in separate but adjacent
repositories or compartments. In the latter context, each active ingredient may
therefore be formulated in a way suitable for an administration route different
from that of the other ingredient, e,g. one of them may be in the form of an oral
parenteral formulation whereas the other is in the form of an ampoule for
intravenous injection or an aerosol.
y Enumerated Compounds
Embodiments of the invention are named below in tabular format (Table
7). Each embodiment of Table 7 is depicted as a substituted nucleus (Sc) in which
the nucleus is designated by a number and each substituent is designated in. order
by further numbers. I is a schedule of nuclei used in forming the
embodiments of Table 7. Each nucleus.XSc)Js_gis£rLa.number designation from.
Table 1, and this' designation appears first in, each embodiment name. Similarly,
Tables 2, 3, 4, 5 and 6 list the selected substituents, again by number designation.
Accordingly, each named embodiment of Table 7 is depicted by a number
designating the nucleus from Table 1. If the nucleus is of formula 1 (from
1), then the letter and number substituents are in the order R1 (Table 2), R3 (Table
3), R4 (Table 4), and X (Table 6). If the nucleus is of formula 2 (from Table 1), then
the letter and number substituents are in the order R1 (Table 2), R3 (Table 3),4
(Table 4), R26 (Table 5), and X (Table 6). The same embodiments of the invention
exist for the nucleus of formula. 2 (Table 1) wherein the N at position 1 is
substituted by R25 (corresponding to the embodiments of R26 of Table 5) and the
single or double bonds in the irnidazo pyridine ring are adjusted accordingly.
Each group is shown having one or more tildas ("-")• The tildas are the
(Table Removed) The compounds of the formulas of this invention are prepared using
series of chemical reactions well known, to those skilled in the art, altogether
making up the process for preparing said compounds and exemplified further.
The processes described further are only meant as examples and by no means are
meant to limit the scope of the present invention.
The invention also relates to methods of making the compositions of the
invention. The compositions are prepared by any of the applicable techniques of
organic synthesis. Many such techniques are well known in the art. However,
many of the known techniques are elaborated in "Compendium of Organic
Synthetic Methods" (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and
Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3,
Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5,
Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J.,
"Advanced Organic Chemistry, Third Edition", (John Wiley & Sons, New York,
1985), "Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in
Modern Organic Chemistry. In 9 Volumes", Barry M. Trost, Editor-in-Chief
(Pergamon Press, New York, 1993 printing).
Exemplary methods tor the preparation of the compositions of the
yention are provided below. These methods are intended to illustrate the
nature of such preparations, and are not intended to limit the scope of applicable
methods.
Generally, the reaction conditions such as temperature, reaction time,
solvents., workup procedures, will be those common in the art for the particular
reaction to be performed. The cited reference material, together with material
cited therein, contains detailed descriptions of such conditions. Typically the
temperatures will be -10Q°C to 200*C, solvents will be aprotic or protic, and
reaction times will be 1.0 seconds to 10 days. Workup typically consists of
quenching any unreacted reagents followed by partition between a water/organic
layer system (extraction) and separating the layer containing the product.
Oxidation and reduction reactions are typically carried out at temperatures
near room temperature (about 20'C), although for metal hydride reductions
frequently the temperature is reduced to 0°C to -100°Q solvents are typically
aprotic for reductions and may be either protic or aprotic for oxidations. Reaction
times are adjusted to achieve desired conversions.
''' Condensation reactions are typically carried out at temperatures near room
temperature, although for non-equilibrating, kinetically controlled condensations
reduced temperatures (0°C to •WC) are also coenmon. Solvents can be either
protic (common in equilibrating reactions) or aprotic (common in kinetically
controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction byproducts
and use of anhydrous reaction conditions (e.g. inert gas environments)
are common in the art and will be applied when applicable.
General aspej5fjth£Sje_ex!amplary methods are described below.,_.£a.cii3f
the products of the following processes is optionally separated, isolated, and/or
purified prior to its. use in subsecquent processes.
The terms "treated", "treating", "treatment", mean contacting, mixing,
reacting, allowing to react, bringing into contact, and other terms common in the
art for Indicating that one or more chemical entities' is treated in
&4:
such a manner as to convert it to one or more other chemical entities. This means
igiat "treating compound one with compound two" is synonymous with "allowing
compound one to react with compound two", "contacting compound one with
compound two", "reacting compound one with compound two", and other
expressions common in the art of organic synthesis for reasonably indicating that
compound one was "treated", "reacted", "allowed to react", with compound two.
"Treating" indicates the reasonable and usual manner in which organic
chemicals are allowed to react. Normal concentrations (Q.01M to 10M, typically
0.1M to 1M), temperatures (-100°C to 250°C, typically -78PC to 150°C, more
typically -78°C to 10Q°C, still more typically 0°C to 100°Q, reaction vessels
(typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for
oxygen and water insensitive reactions or nitrogen or argon for oxygen or water
sensitive), are intended unless otherwise indicated. The knowledge of similar
reactions known in the art of organic synthesis is used in selecting the conditions
and apparatus for "treating" in a given process. In particular, one of ordinary skill
in the art of organic sysnthesis selects conditions and apparatus reasonably
expected to successfully carry out the chemical reactions of the described
processes based on the knowledge in the art.
Modification of the exemplified schemes and examples leads to various
analogs of the specific exemplary materials produced above. The above citations
describing suitable methods of organic synthesis are applicable to such
modifications.
In the exemplary schemes it may be advantageous to separate reaction
products from one another and/or from starting materials. The desired products
of each step or series of iteps is separated and/or purified (hereinafter separated)
to the. deskfid_degr.e&.of homogeneity by the techmqTjes_coriQriirL.the. art,
Typically such separations involve multiphase extraction, crystallization from a
solvent or solvent mixture, distillation, sublimation, or chromatography.
Gxrornatography can involve any number of methods including, for example, size
exclusion or ion exchange chromatography, high, medium, or low pressure liquid

qhromatography, small scale and preparative thin or thick layer
chromatography, as well as techniques of small scale thin layer and flash
chromatography. Such separations are desireable if addition reactions place
subsrituents at both of the pyrimidine nitrogen atoms. Separation of these
isomers is well within the skill of the artisan.
Another class of separation methods involves treatment of a mixture with a
reagent selected to bind to or render otherwise separable a desired product,
unreacted starting material, reaction by product, or the like. Such reagents
include adsorbents or absorbents such as activated carbon, molecular sieves, ion
exchange media, or the like. Alternatively, the reagents can be adds in the case of
a basic material, bases in the case of an. acidic material, binding reagents such as
antibodies, binding proteins, selective chelators such as crown ethers,
liquid/liquid ion extraction reagents (UX), or the like.
Selection of appropriate meichods of separation depends on the nature of
the materials involved. For example, boiling point, and molecular weight in
distillation and sublimation, presence or absence of polar functional groups in
chromatography, stability of materials in acidic and basic media in multiphase
extraction. One skilled Jn the art will apply techniques most likely to achieve the
desired Separation.
A synthetic route to 5-beTizyl-2-phenyl-5H-imidazo[4,5"d]pyrirnidin.e arid
Analogous compounds may be synthesized in the same fashion as in the
foregoing schemes by varying the starting materials, intermediates, solvents and
conditions as will be known by those skilled in the art.
An additional method for making the compounds of this invention
involves reacting a (substituted) 3,4-diaminopyrimidine (A) with B (Y-R1) to give
imidazo[4,5-d]pyrimidines (C); introducing further substituents (R2, R4 and/or R5
H) either a) by cylization of an appropriately substituted 3,4-
diaminopyrimidine (A) or b)) by introduction of the substituent(s) onto the
imidazo[4,5-d]pyrimidine (C); reacting the imidazo[4,5-c]pyrimidine (C) with an
alkylating agent (D) (R3-X-R6) in an appropriate solvent under addition of a base
at ambient temperature; and optionally, in the case of hydroxy, mercapto or
amino substituents in position 4 or 6 of the imidazopyrimidine (Z = O, S or NR);
introducing a further substituent (R25 or R26) at position 1 or 3 of the imidazo[4,5-
djpyrimidine.
Compounds of the invention also are conveniently prepared by a two step
^process. First, a (substituted) 3,4-diammopyrimidine (A) is reacted with B to give
imidaza[4,5-d3pyrimidines C (Scheme 1). If Y is COOH, then the cydization is
carried out under acidic catalysis (preferably in polyphosphoric acid at a
temperature between 90 and 200°C); other methods include reaction in 4N
hydrochloric acid at reflux temperature or neat at a temperature between 90 and
180°C (for aliphatic carboxylic acids). In the case of acid-sensitive groups like
aBcoxy or thiophene, the reaction can be carried out in phosphorus oxychloride at
a temperature between 70 and 120*0. Alternatively, reaction with aldehydes (Y =
CHO) or their bisulfite adducts under oxldative conditions (nitrobenzene, DDQ,
copper(H)a.cetate, Oy sulfur) gives umdazo[4,5-d]pyrimidirves C. Other metivods
are the reaction of (substituted) 3,4-diarninopyrimidines (A) with orthoesters (Y =
C(OR),), anhydrides (Y = OCOOR.) or acid halogenides (Y = COX).
Further methods for the preparation of the compounds of the invention are
set forth in Schemes 1-5 below.
The imidazo[4,5-d]pyrtoudines C are present in four tautomeric forms (1H, 3H,
4H,6H)
Substituents, for example R3 and R*, are introduced by two ways: i) by
cyEzation of an appropiately substituted 3,4-diaminopyrimidine or ii) by
introduction of the substituent(s) onto the imidazo[4,5-d]pyrimidine. Nitroamino
pyrimidines are commercially available. Reduction of the nitro group with iron in
a mixture of concentrated hydrochloric acid and ethanol gives the desired
substituted 3,4-diaminopyrimidine starting materials.
Scheme 2:
This reaction gives mixtures of four alkylation products. For example,
reaction of imidazo[4,5-d]pyrimidine C (R1 = 2,6-difluorophenyl, R2 = R4= H) with
2,6-difluorobenzyl bromide would be expected to give the following mixture.
This mixture can be separated by column chromatography (silica gel,
eluenfc mixture of dichloromethane and methanol). The structures of the isolated
components can then be assigned by NMR spectroseopy by single crystal x-ray
analysis. .
Alternatively, the crude reaction mixture can be recrystallized from an
appropiate solvent (mixture), e.g. from a mixture of diisopropyl ether and ethyl
acetate, to give the pure alkylated products.
Compounds of general structure E, F, G ajad H can be prepared by
alkylation (for example with (cyclo)alkylbromide or (cyclo)alkyliodide) of the
corresponding compounds where 2=Q, Z=S or Z=KTR or their isomers. TTn.
resulting mixtures can be separated by column chromatography. The required
starting materials are, for example, prepared from the corresponding chloroanalogues
by nuckophilic substitution, or by ether cleavage of the corresponding
ajkoxy analogues.
A mixture of 4,5-diaminopyrimidine (0.500 g), 2-fluorobenzoic acid (0.700 g) and
polyphosphoric acid (25 mL) was heated at 180°C for 3 hours. Then the reaction
mixture was cooled and poured into water (500 mL). The solution was adjusted
to pH = 8-9 by addition of solid NaOH and the resulting precipitate was collected
by filtration, washed with water and dried to give 8-(2-fluorophenyl)-purine (offwhite
powder, 88.5%).
!H NMR (200 MHz, DMSO-d6) 5 13.79 (br s, 1H, NH), 9.14 (s, 1H, purine-H), 8.95
(s, 1H, purine-H), 8.23 (m, 1H, phenyl-H), 7.73-7.41 (m, 3H, phenyl-H).
B.
8-(2-Fluorophenyl)-l-r(4-trifluoromethyl)phenylmethyn-lH-purine
8-(2-Fluorophenyl)-purine (430 mg) was dissolved in dry DMF (4 mL), aqueous
30% NaOH solution (400 mg) was added and the resulting mixture was stirred for
30 minutes. Then, 4-(trifluoromethyl)benzyl chloride (469 mg) was added and the
resulting mixture was stirred for 1 day at ambient temperature. Water (200 mL)
was and the resulting solution was extracted with ethyl acetate (3 x 70 mL). The
combined ethyl acetate phases were dried (Na2SO4) and evaporated. The residue
was recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate
1 '(30 mL) to give 8-(2-fluorophenyl)-l-[(4-trifluoromethyl)phenyhnethyl]-lH-purine
(GPJN-179) as an off-white powder (yield: 18.9 %, m.p.: 251-256°C).
'H NMR (200 MHz, DMSO-d6) 5 9.25 (d, 1H, purine-H, J=2.0 Hz), 9.14 (d, 1H,
purine-H, J=2.0 Hz), 8.33 (m, 1H, phenyl-H), 7.83-7.65 (AA'BB', 4H, benzyl-H),
7.53 (m, 1H, phenyl-H); 7.38-7.27 (m, 2H, phenyl- H), 5.78 (s, 2H, CHj.
8-(2,3-Difluorophenyl)-purine
Synthesized as described above for 8-(2-fluorophenyl)-purine, except that 2,3-
difluorobenzoic acid was used instead of 2-fluorobenzoic acid (white powder,
yield: 45.7%)
'H NMR (200 MHz, DMSO-d6) 8 13.70 (br s, 1H, NH), 9.18 (s, 1H, purine-H), 8.97
(s, 1H, purine-H), 8.04-7.96 (m, 1H, phenyl-H), 7.78-7.64 (m, 1 H, phenyl-H), 7.52-
7.40(01,1^ phenyl-H).
8-(23-Difluorophenyl)-l-f(4-trifluoromethyl)phenylrnethyl1-lH-purine
Synthesized as described above for Example 1, except that 8-(2,3-difluorophenyl)-
purine was used instead of 8-(2-fluorophenyl)-purine (white powder, yield: 9.4%,
m.p.: 267-271°C).
'H NMR (200 MHz, DMSO-d6) 8 9.33 (d, IH, purine-H, J=2.0 Hz), 9.17 (d, IH,
purine-H, J=2.0 Hz), 8.14 (m, IH, phenyl-H), 7.82-7.67 (AA'BB',4H, benzyl-H),
7.62-7.49 (m, IH, phenyl-H), 7.40-7.28 (m, IH, phenyl-H), 5.79 (s, 2H, CH,).
Synthesized as described above for Example 1, except that 4-
(trifluoromethoxy)benzyl bromide was used instead of 4-(trifluoromethyl)benzyl
chloride (white powder, yield: 11.2%, m.p.: 224-228°C).
'H NMR (200 MHz, DMSO-d6) 8 9.24 (d, IH, purine-H, J=2.0 Hz), 9.13 (d, IH,
purine-H, J=2.0 Hz), 8.31 (m, IH, phenyl-H), 7.66-7.26 (m, 6H, 4 benzyl-H, 2
phenyl-H), 5.69 (s, 2H, CH2).
Example 4
Synthesized as described above for Example 2, except that 4-
(trifluoromethoxy)benzyl bromide was used instead of 4-(trifluoromethyl)benzyl
chloride (gray powder, yield: 21.5%, m.p.: 254-258°C).
'H NMR (200 MHz, DMSO-d6) 8 9.34 (d, 1H, purine-H, J=2.0 Hz), 9.19 (d, 1H,
purine-H, J=2.0 Hz), 8.14 (m, 1H, phenyl-H), 7.68-7.41 (AA'BB', 4H, benzyl-H),
7.59-7.29 (m, 2H, phenyl-H), 5.72 (s, 2H, CH2).
Example 5
propoxyphenyl)-isoxazole was used instead of 4-(trifluoromethyl)benzyl chloride.
Purified by column chromatography (silica gel, eluent: dichloromethane:
methanol = 20:1), followed by recrystallization (diisopropyl ether/ethyl acetate).
Colourless crystals, yield: 7.4%, m.p.: 228-231°C).
'H NMR (200 MHz, DMSO-d6) 5 9.34 (d, 1H, purine-H, J=2.0 Hz), 9.15 (d, 1H,
purine-H, J=2.0 Hz), 8.17 (m, 1H, phenyl-H), 7.88-7.08 (AA'BB', 4H, benzyl-H),
7.63-7.48 (m, 1H, phenyl-H), 7.41-7.30 (m, 1H, phenyl- H), 7.01 (s, 1H, isoxazole-
H), 5.98 (s, 2H, CHJ, 3.98 (t, 2H, 00^,1=6.6 Hz), 1.73 (hex, 2H, CH2, J=6.6 Hz),
0.97(^3^0^,1=6.6 Hz).
4,5-Diaminopyrimidine (1) (4.5 g, 0.04 moles) and 2,3-difluorobenzoic acid (2)
(6.95 g, 0.044 moles) were suspended in 100 mL of Eaton's Acid. The reaction
mixture was heated in an oil bath at 190°C for 2 hours and then poured into
800mL ice/wafer. Solid sodium hydroxide was added (59g, 1.5 moles) to adjust to
pH 5, which resulted in the product precipitating from solution. The product was
filtered and washed twice with deionized water and air dried. The crude product
was recrystallized from water/ethanol resulting in 8 g of pure product (3) (M+l =
Purine (3) (500 mg, 2.15 mmoleu) was dissolved in lOmL of anhydrous DMF and
1.1 mL of sodium hydroxide solution (10% w/v) was added. 5-(Chloromethyl)-3-
(4-chlorophenyl)isoxazole (4) (587 mg, 2.6 mmoles) was added to the above
reaction mixture and the solution was stirred at room temperature overnight. The
crude product was triturated from water followed by recrystallization from hot
ethyl acetate. The precipitate was filtered to yield 30mg of the gold colored solid
l-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-8-(2/3-difluorophenyl)-lH-purine(5)
in high purity as determined by analytical LC/MS (M+l = 429) and JH NMR (400
MHz, DMSO-d6) 5 5.99 (s, 2H), 7.17 (s, IH), 7.34 (m, IH), 7.55 (s, 1H), 7.56 (d, 2H),
7.87 (d, 2H), 8.14 (m, IH), 9.14 (s, IH), 9.32 (s, IH).
Determination of antiviral (EC50) and cytpstatic activity (CC50)
Cells and viruses
Madin-Darbey Bovine Kidney (MDBK) cells were maintained in
Dulbecco's modified Eagle medium (DMEM) supplemented with BVDV-free 5%
fetal calf serum (DMEME-FCS) at 37°C in a humidified, 5% CO2 atmosphere.
Determination of cvtostatic effect on MDBK cells
The effect of the drugs on exponentially growing MDBK cells was assessed
as follows. Cells were seeded at a density of 5000 cell/well in 96 well plates in
MEM medium (Gibco) supplemented with 10% fetal calf serum, 2mM Lglutamine
(Life Technologies) and bicarbonate (Life Technologies). Cells were
cultured for 24 hr after which serial dilutions of the test compounds were added.
Cultures were then again further incubated for 3 days after which the effect on
cell growth was quantified by means of the MTS method (Promega). The
concentration that results in 50% inhibition of cell growth is defined as the 50 %
cytostatic concentration (CC50).
Anti-HCV assay/ Replicon assay
Huh-5-2 cells [a cell line with a persistent HCV replicon I3891uc-ubineo/
NS3-3'/5.1; replicon with firefly luciferase-ubiquitin-neomycin
phosphotransferase fusion protein and EMCV-IRES driven NS3-5B HCV
polyprotein] was cultured in RPMI medium (Gibco) supplemented with 10% fetal
calf serum, 2mM L-glutamine (Life Technologies), Ix non-essential amino acids
(Life Technologies); 100 HJ/ml penicillin and 100 ug/ml streptomycin and 250
ug/ml G418 (Geneticin, Life Technologies). Cells were seeded at a densitiy of
7000 cells per well in 96 well View Plate™ (Packard) in medium containing the
same components as described above, except for G418. Cells were allowed to
adhere and proliferate for 24 hr. At that time, culture medium was removed and
serial dilutions of the test compounds were added in culture medium lacking
G418. Interferon alfa 2a (500IU) was included as a positive control. Plates were
further incubated at 37°C and 5% CO2 for 72 hours. Replication of the HCV
replicon in Huh-5 cells results in luciferase activity in the cells. Luciferase activity
is measured by adding 50 ul of 1 x Glo-lysis buffer (Promega) for 15 minutes
followed by 50 ul of the Steady-Glo Luciferase assay reagent (Promega).
Luciferase activity is measured with a luminometer and the signal in each
individual well is expressed as a percentage of the untreated cultures. Parallel
cultures of Huh-5-2 cells, seeded at a density of 7000 cells/ well of classical 96-
well eel culture plates (Becton-Dickinson) are treated in a similar fashion except
that no Glo-lysis buffer or Steady-Glo Luciferase reagent is added. Instead the
density of the culture is measured by means of the MTS method (Promega).
Quantitative analysis of HCV RNA by Taqman real-time RT-FCR
Replicon cells were plated at 7.5 x 103 cells per well in a 96-well plate plates
at 37°C and 5% CO2 in Dulbecco's modified essential medium containing 10%
fetal calf serum, 1% nonessential amino acids and 1 mg/ml Geneticin. After
allowing 24 h for cell attachment/ different dilutions of compound were added to
the cultures. Plates were incubated for 5 days, at which time RNA was extracted
using the Qiamp Rneazyi Kit (Qiagen, Hilden, Germany). A 50 uL PCR reaction
contained TaqMan EZ buffer (50 mmol/L Bicine, 115 rnmol/L potassium acetate,
0.01 mmol/L EDTA, 60 nmol/L 6-carboxy-X-rhodamine, and 8% glycerol, pH 8.2;
Perkin Elmer Corp./Applied Biosystems), 300 umol/L deoxyadenosine
triphosphate, 300 ptmol/L deoxyguanosine triphosphate, 300 umol/L
deoxycytidine triphosphate, 600 umol/L deoxyuridine triphosphate, 200 umol/L
forward primer [5'-ccg gcT Ace Tgc ccA TTc], 200 umol/L reverse primer [ccA
GaT cAT ccT gAT cgA cAA G], 100 umol/L TaqMan probe [6-FAM-AcA Teg cAT
cgA gcg Age Acg TAc-TAMRA], 3 mmol/L manganese acetate, 0.5 U AmpErase
uracil-N-glycosylase, 7.5 U rTth DNA polymerase, and 10 ul of RNA elution.
After initial activation of uracil-N-glycosylase at 50°C for 2 minutes, RT was
performed at 60°C for 30 minutes, followed by inactivation of uraciJ-Nglycosylase
at 95°C for 5 minutes. Subsequent PCR amplification consisted of 40
cycles of denaturation at 94°C for 20 seconds and annealing and extension at 62°C
for 1 minute in an ABI7700 sequence detector. For each PCR run, negative
template and positive template samples were used. The cycle threshold value (Ctvalue)
is defined as the number of PCR cycles for which the signal exceeds the
baseline, which defines a positive value. The sample was considered to be positive
if the Ct-value was 50. Results are expressed as genomic equivalents (GE).
Example 8
Assay Results
All of the compounds of examples 1-6 exhibited excellent anti-HCV
antiviral activity and low toxicity.

We Claim:
the dotted lines represent optional double bonds, provided that no two
double bonds are adjacent to one another, and that the dotted lines represent at
least 3, optionally 4 double bonds;
UisN;
R1 is selected from hydrogen, aryl, heterocycle, CC,0 alkoxy,
C,C10 thioalkyl, C,.Ci0 alkyl-amino, C, C10 dialkyl-amino, Cj.,0 cycloalkyl, C.10
cycloalkenyl, and C4.,0 cycloalkynyl, wherein each are optionally substituted with
1 or more R';
Y is selected from a single bond, O, S(O)m (where m is an integer from 0 to
2), MR11, Cj.IO alkylene, C2.10 alkenylene, and C2.10 alkynylene, or C,.w alkylene,
alkenylene or C2.10 alkynylene, wherein 1 to 3 methylene groups optionally are
independently replaced by 1 to 3 heteroatoms selected from O, S or MR11;
R2 and R4 are independently selected from hydrogen, C,,lg aJkyl,
C2.18alkenyl, C2.18 alkynyl, C,.lg alkoxy, C,.18 alkylthio, halogen, -OH, -CN, -NO2,
-NR7RS, haloalkyloxy, haloalkyl, -C(=O)R9, -C(=S)R9, SH, aryl, aryloxy, arylthio,
arylalkyl, C,.18 hy4roxyaIkyl,..C3.10 cycloalkyl, Q,n cycloalkyloxy, Cvin
cycloalkylthio, Cj.,0 cycloalkenyl, C7.,0 cycloalkynyl, and heterocycle, provided that
when one of R25 or R24 is present, then either R2 or R" is selected from =O, =S, or
X is selected from C.CIO alkylene, C2.,0 alkenylene or C2.,0 alkynylene, where
(•ach may include one or more heteroatoms selected from O, S, or NR , provided
any such heteroatom is not adjacent to the N in the ring;
R3 is selected from aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl-N(R10)-/ or heterocycle, where each said substituent is
optionally substituted with at least one R", provided that for cycloalkenyl the
double bond is not adjacent to a nitrogen;
R5 independently is absent or is selected from hydrogen, C,.,8 alkyl, C2.,8
alkenyl, C2.I8 alkynyl, CM8 alkoxy, CM8 alkylthio, halogen, -OH, -CN, -NO2/ -NR7R8,
haloalkyloxy, haloalkyl, -C(=O)R9, -C(=O)OR9, -C(=S)R', SH, aryl, aryloxy,
arylthio, arylalkyl, C,.ia hydroxyalkyl, Cj.10 cycloalkyl, C3.10 cycloalkyloxy, Cj.,0
cycloalkylthio, C,.,0 cycloalkenyl, €,.,„ cycloalkynyl, and heterocycle;
R6 is selected from hydrogen/ G,.18 alkyl, C2.18 alkenyl, C2.18 alkynyl, C,.,8 .
alkoxy, CH8 alkylthio, C,.,8 alkylsulfoxide, C,.,8 alkylsulfone, C,.]8 halo-alkyl, C2.lt
halo-alkenyl, Cj.,, halo-alkynyl, CV18 halo-alkoxy, C,.,8 halo-alkylthio, Cwo
cycloalkyl, C3.10 cycloalkenyl, C7.w cycloalkynyl, halogen, OH, CN, cyanoalkyl,
-CO18, NO2, -NR7R", €,.„ haloalkyl, C(=O)R18, C(=S)R18, SH, aryl, aryloxy, arylthio,
arylsulfoxide, arylsulfone, arylsuLfonamide, aryl^.Jalkyl, aryKCj.jJalkyloxy,
arylCCj^^alkylthio, heterocycle, and C,.lg hydroxyalkyl, where each may be
optionally substituted with at least 1 R";
R7 and R8 are independently selected from hydrogen, GW8 alkyl, C,.18 alkenyl,
aryl, C^ cycloalkyl, C4.10 cycloalkenyl, heterocycle, -C(=O)R"; -C(=S) R", an amino
acid residue linked through a carboxyl group thereof, and the group formed
when;Rand'Rare taken together with the nitrogen to-form-a-heterocycle;
R9 and R18 are independently selected from hydrogen, OH, C,.,8 alkyl, C2.,8
alkenyl, Cj cycloalkyl, C4.10 cycloalkenyl, C,.lg alkoxy, -NR15R1&, aryl, ah amino acid
residue linked through an amino group of the amino acid, CH2OCH(=O)R9and
CH2OC(=O)OR" where R9' is C,-C,2 alkyl, Q-Q,, aryl, Q-C alkylaryl or C.-C,,,
ar alkyl;
R10 and R" are independently selected from the group consisting of
ydrogen, C^galkyl, Cj.,, alkenyl, C.w cycloalkyl, Cwo cycloalkenyl, aryl, -C(=O)R",
heterocyde, and an amino acid residue;
R12 is selected from the group consisting of hydrogen, C^w alkyl, C2.,8
alkenyl, aryl, C3.10 cycloalkyl, C4.IO cycloalkenyl, and an amino acid residue;
R15 and R14 are independently selected from hydrogen, C,.lg alkyl, C2.,g
alkenyl, C2.,, alkynyl, aryl, arylalkyl (unsubstituted, or substituted with C(O)OR18),
Q-io cycloalkyl, €„„ cycloalkenyl, and an amino acid residue;
R17 is independently selected from the group consisting of (a) hydrogen, C,.
]8 alkyl, C2.18 alkenyl, CM8 alkynyl, €,.,„ alkoxy, €„„ alkylthio, C,.tg alkylsulfoxide, C,.
18 alkylsulfone, C,.,8 halogenated alky!, C2.,8 halogenated alkenyl, C2.,8 halogenated
alkynyl, Q.,, halogenated alkoxy, C,.,s halogenated alkylthio, C3.]0 cycloalkyl, C^,,,
cycloalkenyl, Q.,,, cycloalkynyl, halogen, OH, CN, COZH, CO2R18, NO2, NR7R8,
haloalkyl, C(=O)R", C(=S)R", SH, aryl, heterocycle, aryloxy, arylthio,
arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthip,
heterocycle and C,.18 hydroxyalkyl, where each of said aryl, aryloxy, arylthio,
arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio,
heterocycle, or C,.,g hydroxyalkyl is optionally substituted with 1 or more R19, and
(b) M-Q- wherein M is a ring optionally substituted with 1 or more R19, and Q is a
bond or a linking group connecting M to R3 having 1 to 10 atoms selected from C
and optionally 1 or more O, N or S atoms and optionally substituted with 1 or
more R19;
R19 is selected from
(a)H;
—(b) NO2, SH, NR20R21, OH, halogen and-CN;
(c) Sulfone, sulfonamide and sulfoxide;
(d) Cj..,8alkyi, C2.]8 alkenyl and C2.18 alkynyl;
(e) Cj.jg alkyl, Cj.18 alkenyl and C2.18 alkynyl wherein 1 or more methylene are
replaced by 1 or more O, S, NR20, C(O)NR20Ra
/ OC(O)RU, C(O)OR12 or
N(R20)C(0);
(f) Substituents c), d) or e) substituted further by C^10 cycloalkyl, C4.w
cycloalkenyl, C4.i0 cycloalkj/nyl, aryl or heterocycle;
(g) €3. cycloalkyl, C4.w cycloalkenyl, C4.10 cycloalkynyl, aryl and heterocycle,
or said groups substituted with Cw alkyl, C(O)OR12 =O, halogen, CN,
CCONRV, C(O)R18 or OC(O)R18;
(h) C(O)R18, C(O)OR18, OC(O)R18, C(S)R18 and C(O)N(R12)2;
(i) Substituents d) or e) substituted with =O, CN, halogen, C(O)R18,
QOJNR^R21, OC(O)R", heterocycle, and heterocycle substituted with Q-C,.
. alkyl, C(O)OR12, =O, CN, halogen, OC(O)R18 or C(O)NR20R21;
(j) Substituents c) substituted further with Ca.i8 alkyl; and
(k) Substituents f) or g) substituted further with C alkyl, =O, NR^R21, CN,
Cj.18 alkoxy, heterocycle, CM8 haloalkyl, heterocyclealkyl or halogen;
R40 and R21 are independently selected from hydrogen, C,.1g alkyl, C
kenyl, Cj.,a alkynyl, aryl heterocycle, C cycloalkyl, C,,, cycloalkenyl,
-C(=O)R1Z, and -C(=S)R12;
R25 and R2are independently not present or are selected from hydrogen, C,.
lg alkyl, Co cycloalkyl, aryl and heterocycle, where each is optionally
independently substituted with 1 to 4 of Cw alkyl, CM alkoxy, halo, CHjOH,
benzyloxy, and OH;
R27 is selected from hydrogen, C,.18 alkyl, €,.,„ cycloalkyl, (Ccyc
alkyl, aryl, and arylC,.ls alkyl; and
salts, tautomers, polymorpte, isomers and solvates thereof,
2. Tne compound of claim 1 wherein R1 is haloaryl, X is methylene, R3 is
Keterocycle substituted with 1 or 2 R17.
3. The compound of claim 1 wherein R1 is an aryl or aromatic heterocycle
substituted with 1 or 2 R6.
:. The compound of claim 1 wherein R3 is heterocycle.
5. The compound of claim 1 wherein YR1 is haloaryl,
6. The compound of claim 5 wherein haloaryl is ortho-fluorophenyl.
7. The compound of claim 1 wherein R3is isoxazolyl substituted with 1 R17.
8. The compound of claim 2 wherein R17 is aryl or an aromatic heterocycle
which is substituted with 1,2 or 3 R".
9. The compound of claim 1 wherein YR' is none of hydrogen, C^0 cycloalkyl,
orCalkyl.
10. The compound of claim 9 wherein YR1 is not hydrogen or C, alkyl.
11. The compound of claim 1 wherein R19 is trihalomethyl, trihalomethoxy,
alkoxy or halogen.
12. The compound of claim 1 wherein R1 is aryl or aromatic heterocyle
substituted with 1,2 or 3 Rs wherein Ris halogen, C,.18 alkoxy; or C,.w haloalkyl.
13. The compound of claim 12 wherein R' is phenyl substituted with 1,2 or 3
halogen
14. The compound of claim 13 wherein halogen is fluoro.
15. The compound ot claim 1 wherein Y is a single bond, O, CH alkylene, C2 •Ikenylene, CM alkynylene or one of said groups containing 1 to 3 heteroatoms
selected from O, S or NR"
16. The compound of claim 15 wherein Y is -O(CHJ,.S-, -
-S-CCH (CHJS-(CHJ,s, -NR'HCH, -(CH-NR"-or C
1 7. The compound of claim 15 wherein Y is -OCH,-, -Clip-, C,.j alkylene, CM
alkenylene, C2.3 alkynylene, O or a bond.
18. The compound of claim 15 wherein Y is a bond.
19. The compound of claim 1 wherein YR1 is a single ring aromatic carbocycle
or a heterocycle containing 1 or 2 N, S or O atoms in the ring.
20. The compound of claim 19 wherein the carbocycle or heterocycle contains 4
to 6 ring atoms.
21. The compound of claim 1 wherein YR1 is halo- or halomethyl-substituted
phenyl.
22. The compound of claim 1 wherein aryl or heteroaryl are substituted ortho
or meta with halo- or halomethyl.
23. The compound of claim 1 wherein X is selected from the group consisting
of alkylene, alkynylene or alkenylene and said hydrocarbons having an intrachain
N, 0 or S heteroatom.
24. The compound of claim 1 wherein X is alkylene.
25. The compound of claim 23 wherein X is selected from the group consisting
5f -CH,., -CH(CH3)-, -CIVCH,-, -CHj-CHCH.,-, -CHCH-CHCH,, -(CH-O
(CH,), -(CH-S-CCH, -(CH-NRCH-, C3,0 cycloalkylidene, G2
alkenylene and C24 alkynylene.
26. The compound of claim 1 wherein X is methylene,
27. The compound of claim 1 wherein R3 is aryl or a heterocycle substituted
with 0 to 3 R'7.
28. The compound of claim 27 wherein the heterocycle is an aromatic
heterocycle.
29. The compound of claim 28 wherein the heterocycle contains 1,2 or 3 N, S
or O atoms in the ring, is linked to X through a ring carbon atom and contains 4 to
6 total ring atoms.
30. The compound of claim 29 wherein R3 is isoxazolyl substituted with 1 to 3
R17. .
31. The compound of claim 1 wherein R17 is aryl or a heterocycle further
substituted with 1 to 3 R19.
32. The compound of claim 1 wherein M is aryl or aromatic heterocycle.
33. The compound of claim 1 wherein Q contains 0 to 20 atoms selected from
C,O,S,NandH.
34. The compound of claim 1 wherein M is a cyclic group selected from R'\7.
35. The compound of claim 1 wherein R17 is selected from the group consisting
f Cj.10 cycloalkyl, C,.,0 cycloalkenyl, Q. cycloalkynyl, halogen, aryl, aryloxy,
arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl; arylalkyloxy;
arylalkylthio; heterocycle; C,.,, hydroxyalkyl, each of said C3.10 cycloalkyl, C3.IO
cycloalkenyl, C7.,0cycloalkynyl, halogen, aryl/ aryloxy, arylthio, arylsulfoxide,
arylsulfone, arylsulfonamide, arylalkyl; arylalkyloxy; arylalkylthio; heterocycle;
and C,.,, hydroxyalkyl is unsubstituted or is substituted 1 or more RWl
36. The compound of claim 1 wherein R17 is selected from the group
consisting of aryl and heterocycle, and where said aryl or heterocycle is optionally
substituted with 1 or more R19.
37. The compound of claim 1 wherein R9 and R'8 are H, OH or alkyl.
38. The compound of claim 1 wherein Rs is H.
39. The compound of claim 1 wherein R is halogen.
40. The compound of claim 1 wherein R7, R8, R10, R", R15, R16, R20, and R21 are
independently H or C,.18 alkyl.
41. The compound of claim 1 wherein R12is OH or alkyl.
42. The compound of claim 1 wherein R" is selected from the group consisting
of H; C,.18 alkyl; C,.,, alkenyl; C8 alkynyl; C^^alkoxy; alkenyloxy; alkyriyloxy; C10JL_.
alkylthio; Cwo cycloalkyl; C4.,0 cycloalkenyl; C4.,0 cycloalkynyl; halogen; OH; CN;
cyanoalkyl; NO2; NRR21; haloalkyl; haloalkyloxy; C(=O)R18; C(=O)QRtB;
OalkenylC(=O)OR18; -OalkylC(=O)NR20R21; aryl; heterocycle; -OalkylOC(=O)R18!
C(=O)N(CW alkyl), N(H)S(O)(O)(CW alkyl); arylalkyloxy; aryloxy; arylalkyloxy;
and arylalkyl.
43. The compound of claim 42 wherein R19 is independently selected from the
group consisting of halogen, N(Rm R21), alkoxy, halo-substituted alkyl and halosubstituted
alkoxy.
44. The compound of claim 1 wherein R25 and R26 are not present.
45. The compound of claim 1 which is not substituted at R25 but is substituted
at R26, and either R'or R4 is selected from (=O), (=S), and (=NR27).
46. The compound of claim 1 wherein haloalkyl or haloalkyloxy is -CF3 or -
OCF3.
47. The compound of claim 1 wherein R19 is any individual, combination or
subcornbination of substituents (a) - (k).
48. A Compound having the general formula (A),
wherein:
the dotted.lines.xepres.ent.optional double bonds, provided.thai.n.Q_lwjL.
double bonds are adjacent to one another, and that the dotted lines represent at
least 3, optionally 4 double bonds;
R1 is selected from hydrogen, aryl, heterocycle (other than piperazinyl,
piperidinyl, or either substituted with 1 or more Rsj, C, C10 alkoxy, Q.C,,, thioalkyl,
C, C10 alkyl-amino, C,.C10 dialkyl-amino, €,.,„ cycloalkyl, C4.10 cycloalkenyl, and
,.,0 cycloalkynyl, wherein each are optionally substituted with 1 or more R';
Y is selected from a single bond, O, S(O)m (where m is an integer from 0 to
2), NR", C,.10 alkylene, Q.w alkenylene, € alkynylene, or C,.10 alkylene, C^
alkenylene or C2.,0 alkynylene wherein 1 to 3 methylene groups optionally are
independently replaced by 1 to 3 heterbatoms selected from O, S or NR ;
provided, however, that YR1 is not H;
R2 and R4 are independently selected from hydrogen, CM8 alkyl,
Cz.lg alkenyl, Q.,, alkynyl, CMg alkoxy, C,.,g alkylthio, halogen, -OH, -CN, -NO2,
-NR7R8, haloalkyloxy, haloalkyl, -C(=O)R', -C(=S)R9, SH, aryl, aryloxy, arylthio,
arylalkyl, C,.lg hydroxyalkyl, CMO tycloalkyl, C3.10 cycloalkyloxy, Cj.,0
cycloalkylthio, €3.,,, cyclpalkenyl, C7.w cycloalkynyl, or heterocycle, provided that
when one of R25 or R26 is present, then either R2 or R4 is selected from (=O), (=S)7
and =NR27; and further provided that not both of R2 and R* is OH, SH, thio or oxo;
X is selected from C,.C10 alkylene, C alkenylene or C2.,0 alkynylene, where
each may include one or more heteroatoms selected from O, S, or NRU, provided
any such heteroatom is not adjacent to the NT in the ring;
R3 is selected from aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl-N(R10)-, or heterocycle, where each said substituent may be
optionally substituted with at least one R", provided that for cycloalkenyl the
double bond is not adjacent to a nitrogen;
R independently is absent or is selected from hydrogen, C,.lg alkyl, C2.,g
alkenyl, C2.I8 alkynyl, C,.1B alkoxy, C, alkylthio, halogen, -OH, CN, -NO2, -NR7R8,
haloalkyloxy, haloalkyl, -C(=O)R9, -C(=O)OR9, -C(=S)R9, SH, aryl, aryloxy,
arylthloTarylalkyrC;.,,, hydroxyalkyl, C cycloalkylTCeyctoalkylo-xy, 0,0
cycloalkylthio, Cwo cydoalkenyl, C7.,0 cycloalkynyl, or heterocycle;
R6 is selected from hydrogen, C,.,1, alkyl, Cw, alkenyl, Ca.,a alkynyl, C,.,8
alkoxy, C,.M alkylthio, C,.lg alkylsulfoxide, C,.,8 alkylsulfone, Ca halo-alkyl, C2.,g
halo-alkenyl, C2.lg halo-alkynyl, C,.,8 halo-alkoxy, C,.lg halo-alkylthio, Cwo
cycloalkyl, C3.10 cycloalkenyl, C7.,0 cycloalkynyl, halogen, OH, CN, cyanoalkyl,
", NO2, -NR7R8, CMg haloalkyl, C(=O)R", C(=S)R18
/ SH, aryl, aryloxy, arylthio,
arylsulfoxide, arylsulfone, arylsulfonamide, arylCCgJalkyl, aryl(C,.,8)alkyloxy,
aryl(C,.lfl)aIkylthio, heterocycle, C,.,8 hydroxyalkyl, where each may be optionally
substituted with at least 1 R";
R7 and R8 are independently selected from hydrogen, CM8 alkyl, C,..,, alkenyl,
aryl, C^0 cycloalkyl, C4.10 cycloalkenyl, heterocycle, -C(=O)R12; -C(=S) R12, an amino
acid residue linked through a carboxyl group thereof, or where R7 and R8 together
with the nitrogen form a heterocycle;
R9 and R18 are independently selected from hydrogen, OH, C,.,8 alkyl, C2.18
alkenyl, C3.10 cycloalkyl, C4.,0 cycloalkenyl, C,.]8 alkoxy, -NR1!R", aryl, an amino acid
residue linked through an amino group of the amino acid, CH2OCH(=O)Ror
CH,OC(=O)OR9" where R" is CrC12 alkyl, C^C* aryl, C6-CW alkylaryl or C^C^
aralkyl;
R10 and R" are independently selected from the group consisting of
hydrogen, C,.,8 alkyl, Q.,, alkenyl, Q,,, cycloalkyl, C4.10 cycloalkenyl, aryl, -C(=O)R12,
heterocycle, or an amino acid residue;
R1Z is selected from the group consisting of hydrogen, C,.1g alkyl, C2.18
alkenyl, aryl, C,.,,, cycloalkyl, C4.10 cycloalkenyl, or an amino acid residue;
R" and R16 are independently selected from hydrogen, C,.,8 alkyl, C2.18
alkenyl, C2.,g alkynyl, aryl, C cycloalkyl, C4.w cycloalkenyl, or an amino acid
residue; •
R17 is independently M-Q- wherein M is a ring optionally substituted with 1
or more R", and Q is a bond or a linking group connecting M to R3 having 1 to 10
atoms selected from C and optionally 1 or more O, N or S atoms and optionally
jubstituted with 1 or more R19-
R19is selected from
(b) NO2, SH, NR2^21, OH, halogen and CN;
(c) Sulfone, sulfonamide and sulfoxide;
(d) C,.18 alkyl, C2.18 alkenyl and C2.lg alkynyl;
(e) Cj.lg alkyl, C alkenyl and C2.18 alkynyl wherein 1 or more methylene are
replaced by 1 or more O, S, NR20, aCONR^R21, OC(O)R12, C(O)OR12 or
(f) Substituents c), d) or e) substituted further by C3.i0 cycloalkyl, C4.,0
cycloalkenyl, C4.10 cycloalkynyl, aryl or heterocycle;
(g) CjQ cycloalkyl, Ccycloalkenyl, C4.10 cycloalkynyl, aryl and heterocycle,
or said groups substituted with CM alkyl, C(O)OR12 =O, halogen, CN,
C(0)NR"Ra, C(0)R18 or OC(O)R18;
(h) C(O)R18, C(O)OR18, OC(O)R18, C(S)R18 and C(O)N(R12)2;
(i) Substituents d) or e) substituted with =O, GN, halogen, C(O)R18,
QCONR^R21, OC(O)R18, heterocycle and heterocycle substituted with CrC6
alkyl, C(O)OR" =O, CN, halogen, OC(O)R18 or QOJNR^R21;
(j) Substituents c) substituted further with C1-18 alkyl; and
(k) Substituents f) or g) substituted further with C148 alkyl, =O, NR^R21, CN,
Cwg alkoxy, heterocycle, Cj.18 haloalkyl, heterocyclealkyl or halogen;
R20 and Rzl are independently selected from hydrogen, C,;,, alkyl, C2.18
ilkenyl, C2.,8 alkynyl, aryl, heterocycle, Cj.10 cycloalkyl, C^10 cycloalkenyl,
C(=0)RU, or -C(=S)R";
R25 and R26 are independently not present or are selected from hydrogen, C,.
, alkyl, Ccycloalkyl, aryl and heterocycle, where each is optionally
ndependently substituted with 1 to 4 of C14 alkyl, C, alkoxy, halo, CHj,OH,
enzyloxy, and QH; and.
R27 is selected from hydrogen, C,.,8 alkyl, Cwo cycloalkyl, (C3.10 cycloalkyl)-Cw
ilkyl, aryl, and aryl C,.,8 alkyl, and
salts, tautomers, polymorphs, isomers and solvates thereof.
49. The compound of claim 48 wherein Y is a single bond, and R1 is aryl or
romatic heterocycle which is unsubstituted or substituted with one or more R6.
50. The compound of claim 48 wherein X is CC10 alkylene, Q. alkenylene or
C2.,0 alkynylene.
51. The compound of claim 48 wherein R3 is heterocyle.
52. The compound of claim 48 wherein RJ is heterocycle substituted with R17
where Q is a bond and M is aryl substituted with 1 or 2 R19.
53. The compound of claim 48 wherein Y is a single bond, and K' is pnenyi.
54. The compound of claim 48 wherein Rs is isoxazole substituted with R17
19 where Q is a bond and M is aryl substituted with 1 or 2 R .
55. The compound of claim 48 wherein Rs is isoxazole substituted with R17
1O where Q is a bond and M is phenyl substituted with 1 or 2 R .
56. A compound having the structure
and its salts, tautomers, polymorphs and solvates.
57. 8-(2-Fluorophenyl)-l-[(4-trifluoromethyl)phenylmethyl]-lH-purine and its
salts, tautomers, polymorphs and solvates.
58. l-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-8-(2,3-difluorophenyl)-lHpurine
and its salts, tautomers, polymorphs and solvates.
59. The compound
OCF3
and its salts, tautomers, polymorphs and solvates.
60, A compound of the structure
OCF3
md its salts, tautomers, polymorphs and solvates.
61. A composition comprising a pharmaceutically acceptable excipient and a
compound of claims 1,48, and 64-70.
62. A method comprising administering to a subject in need of treatment or
prophylaxis of a viral infection an antivirally effective amount of a composition of
claim 61.
63. The method of claim 62, wherein the viral infection is an HCV infection.
64. The method of claim 63 further comprising administering at least one
additional antiviral therapy to the subject.
65. The method of claim 64 wherein the additional therapy is is selected from
the group consisting of an interferon alpha and ribavirin.
66. A method of screening antiviral compounds which comprises providing a
compound of claims 1 or 48 and determining the anti-viral activity of said
compound.
67. ' The method of claim 66 wherein said anti- viral activity is determined by
the activity of said compound against one or more viruses belonging to the family
of the Flaviviridae and/or of the Picornaviridae.
68. A method for structure-activity determination of analogues of compounds
of WO 2004/005286 having the general structure
wherein the R, X and Y groups are defined in WO 2004/005286, comprising
(A) preparing an analoijue of a compound falling within the scope of
WO 2004/005286 wherein C7 is replaced by N; and
(B) determining the anti-HCV activity of the compound of step (A).
69. The method of claim 68 wherein the substituent is located at R3, R2, R4,



Documents:

1416-DELNP-2006-Correspondence-Others-(01-05-2006).pdf

1416-DELNP-2006-Correspondence-Others-(17-07-2006).pdf

1416-DELNP-2006-Correspondence-Others-(27-07-2006).pdf

1416-delnp-2007-1-Correspondence-Others-(31-10-2012).pdf

1416-delnp-2007-1416-delnp-2007-Correspondence Others-(03-01-2013).pdf

1416-delnp-2007-Abstract-(31-01-2014).pdf

1416-delnp-2007-Abstract-(31-10-2012).pdf

1416-delnp-2007-Abstract.pdf

1416-delnp-2007-Claims-(21-11-2013).pdf

1416-delnp-2007-Claims-(24-10-2013).pdf

1416-delnp-2007-Claims-(31-10-2012).pdf

1416-delnp-2007-claims.pdf

1416-delnp-2007-Correspondance Others-(06-05-2013).pdf

1416-delnp-2007-Correspondance Others-(16-04-2013).pdf

1416-delnp-2007-Correspondence Others-(08-02-2013).pdf

1416-delnp-2007-Correspondence Others-(09-10-2013).pdf

1416-delnp-2007-Correspondence Others-(10-05-2012).pdf

1416-delnp-2007-Correspondence Others-(16-06-2011).pdf

1416-delnp-2007-Correspondence Others-(17-09-2013).pdf

1416-delnp-2007-Correspondence Others-(19-12-2012).pdf

1416-delnp-2007-Correspondence Others-(21-10-2013).pdf

1416-delnp-2007-Correspondence Others-(24-10-2013).pdf

1416-delnp-2007-Correspondence Others-(30-10-2013).pdf

1416-delnp-2007-Correspondence Others-(31-01-2014).pdf

1416-delnp-2007-Correspondence-others (07-11-2012).pdf

1416-delnp-2007-Correspondence-others (27-05-2008).pdf

1416-DELNP-2007-Correspondence-Others-(09-11-2012).pdf

1416-delnp-2007-Correspondence-Others-(12-10-2012).pdf

1416-delnp-2007-Correspondence-Others-(20-12-2011).pdf

1416-delnp-2007-Correspondence-Others-(21-11-2013).pdf

1416-delnp-2007-Correspondence-Others-(31-10-2012).pdf

1416-DELNP-2007-Correspondence-Others.pdf

1416-delnp-2007-Description (Complete)-(31-10-2012).pdf

1416-delnp-2007-description (complete).pdf

1416-DELNP-2007-Form-1.pdf

1416-delnp-2007-Form-18 (27-05-2008).pdf

1416-delnp-2007-Form-2-(31-01-2014).pdf

1416-delnp-2007-Form-2-(31-10-2012).pdf

1416-delnp-2007-form-2.pdf

1416-delnp-2007-Form-3-(10-05-2012).pdf

1416-delnp-2007-Form-3-(12-10-2012).pdf

1416-delnp-2007-Form-3-(16-06-2011).pdf

1416-delnp-2007-Form-3-(19-12-2012).pdf

1416-delnp-2007-Form-3-(21-10-2013).pdf

1416-DELNP-2007-Form-3.pdf

1416-delnp-2007-form-5.pdf

1416-delnp-2007-GPA-(24-10-2013).pdf

1416-delnp-2007-GPA-(30-10-2013).pdf

1416-delnp-2007-pct-101.pdf

1416-delnp-2007-pct-102.pdf

1416-delnp-2007-pct-105.pdf

1416-delnp-2007-pct-210.pdf

1416-delnp-2007-pct-220.pdf

1416-delnp-2007-pct-237.pdf

1416-delnp-2007-pct-301.pdf

1416-delnp-2007-pct-306.pdf

1416-delnp-2007-pct-408.pdf

1416-delnp-2007-pct-409.pdf

1416-delnp-2007-pct-416.pdf

1416-delnp-2007-Petition-137-(21-10-2013).pdf

1416-delnp-2007-Petition-137-(31-10-2012).pdf

1416-delnp-2007-ur-Correspondence Others-(09-10-2013).pdf


Patent Number 259337
Indian Patent Application Number 1416/DELNP/2007
PG Journal Number 11/2014
Publication Date 14-Mar-2014
Grant Date 10-Mar-2014
Date of Filing 21-Feb-2007
Name of Patentee PUERSTINGER, GERHARD
Applicant Address BADHAUSSTRASSE 10/4, A-6080 IGLS, AUSTRIA
Inventors:
# Inventor's Name Inventor's Address
1 KIM, CHOUNG,U. 1750 ELIZABETH STREET, SAN CARLOS, CA 94070, USA
2 NEYTS, JOHAN HEIDEBERGSTRAAT 278, B-3010 KESSEL-LO, BELGIUM
3 OARE, DAVID,A. 1622 RALSTON AVENUE, BELMONT, CA 94002, USA
4 PUERSTINGER, GERHARD BADHAUSSTRASSE 10/4, A-6080 IGLS, AUSTRIA
PCT International Classification Number C07D 519/00
PCT International Application Number PCT/US2005/026606
PCT International Filing date 2005-07-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/591,726 2004-07-27 U.S.A.