NZ622331B2 - Quinazolinone analogs and use of quinazolinone analogs for treating or preventing certain viral infections - Google Patents
Quinazolinone analogs and use of quinazolinone analogs for treating or preventing certain viral infections Download PDFInfo
- Publication number
- NZ622331B2 NZ622331B2 NZ622331A NZ62233112A NZ622331B2 NZ 622331 B2 NZ622331 B2 NZ 622331B2 NZ 622331 A NZ622331 A NZ 622331A NZ 62233112 A NZ62233112 A NZ 62233112A NZ 622331 B2 NZ622331 B2 NZ 622331B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- hydroquinazolinylthio
- oxo
- alkyl
- indanylacetamide
- dichlorophenyl
- Prior art date
Links
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- 206010047461 Viral infection Diseases 0.000 title claims abstract description 28
- 230000017613 viral reproduction Effects 0.000 title claims abstract description 27
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- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological Effects 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Provided are quinazolinone analogue compounds and particularly their use in the prophylaxis or treatment of viral infections. The compounds may be particularly useful in the prophylaxis or treatment of Hepatitis C Virus, Japanese Encephalitis Virus and West Nile Virus infections.
Description
M-NZ
QUINAZOLINONE ANALOGS AND USE OF QUINAZOLINONE ANALOGS
FOR TREATING OR PREVENTING CERTAIN VIRAL INFECTIONS
DESCRIPTION
TECHNICAL FIELD
The present disclosure relates to treating or preventing viral infection from certain
flaviviruses and alphaviruses by administering a therapeutically effective amount of a
quinazolinone analog, pharmaceutically acceptable salt thereof or solvate thereof. The
flaviviruses treated according to this disclosure include Hepatitis C Virus (genotypes 1-7)
and Japanese Encephalitis Virus. Certain of the quinazolinone compounds of the present
disclosure can also be used to treat West Nile Virus. The present disclosure is also related
to certain novel quinazolinone compounds. The subjects treated include humans and
animals.
BACKGROUND OF DISCLOSURE
Flaviviruses and alphaviruses are positive sense RNA viruses and are important
human and/or animal pathogens that can cause acute virus infections with severe diseases
and/or death. Flaviviruses include members of families Flaviviridae including Dengue
Virus (DENV), Murray Valley Encephalitis Virus (MVEV), Saint Louis Encephalitis
Virus (SLEV), West Nile virus (WNV), Japanese Encephalitides Virus (JEV), Yellow
Fever Virus (YFV) and Tick-Borne Encephalitis Virus (TBEV) and Hepciviridae
including Hepatitis C Virus (HCV) and Pestiviruses including Bovine Diarrhea virus
(BVDV). Alphaviruses include Venezuela Equine Encephalitides Virus (VEEV), Eastern
Equine Encephalitis Virus (EEEV), Western Equine Encephalitides virus (WEEV) and
Ross River Virus (RRV). For most arbovirus listed above, there is no effective vaccine or
therapeutics currently available. There are no alphavirus vaccines currently available. The
need to develop antiviral drugs is urgent for developing control measures and treating
these diseases.
Vast amounts of research have accrued over the years related to developing
treatments against viral diseases to inhibit and kill viral infections. Some of this research
5184M-NZ
has resulted in agents approved for clinical use. Nevertheless, efforts continue at an ever-
increasing rate in view of the extreme difficulty in uncovering promising antiviral agents.
SUMMARY OF DISCLOSURE
According to a first aspect of the invention there is provided the use of at least one
compound selected from the group consisting of 2-[3-(3,4-dichlorophenyl)oxo(3-
hydroquinazolinylthio)]-N-(4-phenyl(1,3-thiazolyl))acetamide; N-benzothiazol
yl[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]acetamide; 2-[3-(3,4-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4-methyl(1,3-thiazol
yl))acetamide; N-(2,3-dihydro-1H-indenyl)(4-oxophenyl-3,4-dihydroquinazolin-
2-yl)thio) acetamide; 2-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-
N-indanylacetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-
N-indanylacetamide; 2-(5-fluorooxophenyl(3-hydroquinazolinylthio))-N-
indanylacetamide; N-indanyl(8-methyloxophenyl(3-hydroquinazolin
ylthio))acetamide; N-indanyl(8-methoxyoxophenyl(3-hydroquinazolin
ylthio))acetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; N-(2H-benzo[d]1,3-dioxolenyl)[3-(3,4-dichlorophenyl)
oxo(3-hydroquinazolinylthio)]acetamide; 3-[3-(3-chlorofluorophenyl)oxo(3-
hydroquinazolinylthio)]-N-indanylpropanamide; 2-[3-(3-chlorofluorophenyl)
oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; N-(2H-benzo[3,4-d]1,3-
dioxolanyl)[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolin
ylthio)]acetamide; 2-[3-(3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-(5-fluorooxophenyl(3-hydroquinazolinylthio))-N-
(1,2,3,4-tetrahydronaphthyl)acetamide; 2-[3-(4-chlorofluorophenyl)fluorooxo(3-
hydroquinazolinylthio)]-N-indanylacetamide; 2-[5-fluorooxo(3,4,5-
trifluorophenyl)(3-hydroquinazolinylthio)]-N-indanylacetamide; and 2-[3-(3,4-
dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indanylacetamide;
pharmaceutically acceptable salts thereof; solvates thereof and deuterated forms thereof
in the manufacture of a medicament for the treatment or prevention of a viral infection
from Hepatitis C virus.
5184M-NZ
According to preferred embodiments the present disclosure provides a
therapeutically effective amount of at least one compound represented by the formula:
R N X
wherein X is O, S or NR wherein R is H or C alkyl;
20 1-6
Y is (CR CR ) (CO) NR W;
11 12 n p 13
R and R are independently selected from the group consisting of H, halogen,
11 12
hydroxyl, C alkoxy, amino, nitro, cyano, CF and C alkyl;
1-6 3 1-4
R is H or C alkyl;
13 1-6
n is zero, one, two, three or four, five or six;
p is zero or one;
W is hydrogen, C alkoxy, halo C alkoxy, C alkyl, halo C alkyl, hydroxyC
1-6 1-6 1-6 1-6 1-
alkyl, amino C alkyl, carboxyC alkyl, C cycloalkyl, halo C cycloalkyl; or a
6 1-6 1-6 3-7 3-7
substituted or unsubstituted phenyl ring, a substituted or unsubstituted five-or 6-
membered saturated or unsaturated heterocyclic ring containing one, two, three or four
heteroatoms independently chosen from O, N and S, or a nine- or ten-or eleven -
membered fused bicyclic ring containing a phenyl ring or a six-membered heteroaromatic
ring as just defined, fused to either a saturated or unsaturated five- or six- or seven-
membered ring, which can be substituted or unsubstituted, when substituted any of the
above rings can be substituted by halogen, C alkyl, C alkenyl, C alkynyl, nitro,
1-6 2-6 2-6
cyano, C cycloalkyI, hydroxy, C alkoxy, haloC alkyl, halo C alkoxy, hydroxy C
3-7 1-6 1-6 1-6 1-
alkyl, hydroxy C alkoxy, phenyl, an unsubstituted five-membered heteroaromatic ring
6 1-6
as just described, a six-membered heteroaromatic ring as just described, a six-membered
saturated ring as just described or NR R ; each R and R is independently hydrogen
14 15 14 15
or C alkyl or R and R , together with the nitrogen atom to which they are attached,
1-6 14 15
may form a saturated 4-7 membered ring;
and each R , R , R , R , R , R , R , R and R is independently selected from the
2 3 4 5 6 7 8 9 10
group consisting of H, halogen, hydroxy, amino, nitro, cyano, formyl, CF , S(C alkyl),
3 1-4
5184M-NZ
S(O)C alkyl, S(O) C alkyl, C alkylcarbonyl, C alkyl, hydroxy C alkyl, C
1-4 2 1-4 1-4 1-6 1-6 1-
alkoxy, haloC alkoxy, hydroxy C alkoxy, C alkenyl, C alkynyl, C alkylamino,
6 1-6 1-6 2-6 2-6 1-6
di(C alkyl)amino; pharmaceutically acceptable salts thereof; solvates thereof and
deuterated forms thereof; is administered to a subject in need thereof.
Preferably, the present disclosure also relates to compounds represented by the
formula:
wherein W is a substituted or unsubstituted thiazoyl group and when substituted
W is substituted with a C alkyl, phenyl or benzoyl group, and each R , R , R , R , R ,
1-6 2 3 4 5 6
R , R , R and R is independently selected from the group consisting of H, halogen,
7 8 9 10
hydroxy, amino, nitro, cyano, CF , and C alkyl; R and R are independently selected
3 1-6 11 12
from the group consisting of H, halogen, hydroxyl, C alkoxy, amino, nitro, cyano, CF
1-6 3
and C alkyl; n is zero, one, two, three or four, five or six; pharmaceutically acceptable
salts thereof; solvates thereof and deuterated forms thereof in the manufacture of a
medicament for the treatment or prevention of a flavivirus selected from the group
consisting of Hepatitis C vicus (genotypes 1-7) and Japanese Encephalitides Virus.
A further preferred aspect of the present disclosure is concerned with a process
for treating or preventing a viral infection in a subject from Hepatitis C Virus, by
administering to the subject a therapeutically effective amount of at least one compound
selected from the group consisting of 2-[3-(3,4-dichlorophenyl)oxo(3-
hydroquinazolinylthio)]-N-(4-phenyl(1,3-thiazolyl))acetamide; N-benzothiazol
yl[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]acetamide; 2-[3-(3,4-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4-methyl(1,3-thiazol
yl))acetamide; N-(2,3-dihydro-1H-indenyl)(4-oxophenyl-3,4-dihydroquinazolin-
2-yl)thio) acetamide; 2-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-
N-indanylacetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-
5184M-NZ
N-indanylacetamide; 2-(5-fluorooxophenyl(3-hydroquinazolinylthio))-N-
indanylacetamide; N-indanyl(8-methyloxophenyl(3-hydroquinazolin
ylthio))acetamide; N-indanyl(8-methoxyoxophenyl(3-hydroquinazolin
ylthio))acetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; N-(2H-benzo[d]1,3-dioxolenyl)[3-(3,4-dichlorophenyl)
oxo(3-hydroquinazolinylthio)]acetamide; 3-[3-(3-chlorofluorophenyl)oxo(3-
hydroquinazolinylthio)]-N-indanylpropanamide; 2-[3-(3-chlorofluorophenyl)
oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; N-(2H-benzo[3,4-d]1,3-
dioxolanyl)[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolin
ylthio)]acetamide; 2-[3-(3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-(5-fluorooxophenyl(3-hydroquinazolinylthio))-N-
(1,2,3,4-tetrahydronaphthyl)acetamide; 2-[3-(4-chlorofluorophenyl)fluorooxo(3-
hydroquinazolinylthio)]-N-indanylacetamide; 2-[5-fluorooxo(3,4,5-
trifluorophenyl)(3-hydroquinazolinylthio)]-N-indanylacetamide; and 2-[3-(3,4-
dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indanylacetamide;
pharmaceutically acceptable salts thereof; solvates thereof and deuterated forms thereof.
A still further preferred aspect of the present disclosure relates to a process for
treating or preventing a viral infection in a subject from Japanese Encephalitis Virus by
administering to the subject a therapeutically effective amount of at least one compound
selected from the group consisting of 2-(5-fluorooxophenyl(3-hydroquinazolin
ylthio))-N-indanylacetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; 2-[3-(2,6-dichlorophenyl)oxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; and 2-(8-fluorooxophenyl(3-hydroquinazolin
ylthio))-N-indanylacetamide; pharmaceutically acceptable salts thereof; solvates
thereof and deuterated forms thereof.
Another aspect of the present disclosure is concerned with treating or preventing a
viral infection in a subject from West Nile Virus by administering to the subject a
therapeutically effective amount of at least one compound selected from the group
consisting of: 2-[3-(2-fluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide; 2-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
5184M-NZ
indanylacetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,5-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide, 2-[3-(3,4-dichlorophenyl)fluorooxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; N-indanyl(4-oxophenyl(3-hydroquinazolin
ylthio))acetamide; 2-[3-(4-chloromethylphenyl)oxo(3-hydroquinazolinylthio)]-
N-indanylacetamide; 2-[3-(4-fluoromethylphenyl)oxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; N-indanyl[4-oxo(3,4,5-trifluorophenyl)(3-
hydroquinazolinylthio)]acetamide; 2-[3-(3-bromomethylphenyl)oxo(3-
hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,4-dichlorophenyl)fluoro
oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,5-difluorophenyl)
oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,5-dichlorophenyl)
fluorooxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(2,6-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3-
bromochlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-
(8-fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide; and 2-[3-
(4,5-difluoro(2-pyridyl))oxo(3-hydroquinazolinylthio)]-N-indanylacetamide;
pharmaceutically acceptable salts thereof; solvates thereof and deuterated forms thereof.
Still other objects and advantages of the present disclosure will become readily
apparent by those skilled in the art from the following detailed description, wherein it is
shown and described only the preferred embodiments, simply by way of illustration of
the best mode. As will be realized, the disclosure is capable of other and different
embodiments, and its several details are capable of modifications in various obvious
respects, without departing from the disclosure. Accordingly, the description is to be
regarded as illustrative in nature and not as restrictive.
BEST AND VARIOUS MODES FOR CARRYING OUT DISCLOSURE
The present disclosure is concerned with a process for treating or preventing a
viral infection in a subject, wherein the viral infection is from a flavivirus selected from
the group consisting of Hepatitis C Virus (genotypes 1-7) and Japanese Encephalitis
5184M-NZ
Virus. The process comprises administering to the subject a therapeutically effective
amount of at least one compound represented by the formula:
R N X
wherein X is O, S or NR wherein R is H or C alkyl; X is more typically S;
20 1-6
Y is (CR CR ) (CO) NR W;
11 12 n p 13
R and R are independently selected from the group consisting of H, halogen,
11 12
hydroxyl, C alkoxy, amino, nitro, cyano, CF and C alkyl;
1-6 3 1-4
R is H or C alkyl;
13 1-6
n is zero, one, two, three, four, five or six; and more typically one, two or three;
p is zero or one; more typically p is one
W is hydrogen, C alkoxy, halo C alkoxy, C alkyl, halo C alkyl, hydroxyC
1-6 1-6 1-6 1-6 1-
alkyl, amino C alkyl, carboxyC alkyl, C cycloalkyl, halo C cycloalkyl; or a
6 1-6 1-6 3-7 3-7
substituted or unsubstituted phenyl ring, a substituted or unsubstituted five-or 6-
membered saturated or unsaturated heterocyclic ring containing one, two, three or four
heteroatoms independently chosen from O, N and S, or a nine- or ten-or eleven -
membered fused bicyclic ring containing a phenyl ring or a six-membered heteroaromatic
ring as just defined, fused to either a saturated or unsaturated five- or six- or seven-
membered ring, which can be substituted or unsubstitued, when substituted any of the
above rings can be substituted by halogen, C alkyl, C alkenyl, C alkynyl, nitro,
1-6 2-6 2-6
cyano, C cycloalkyI, hydroxy, C alkoxy, haloC alkyl, halo C alkoxy, hydroxy C
3-7 1-6 1-6 1-6 1-
alkyl, hydroxy C alkoxy, phenyl, an unsubstituted five-membered heteroaromatic ring
6 1-6
as just described, a six-membered heteroaromatic ring as just described, a six-membered
saturated ring as just described or NR R ; each R and R is independently hydrogen
14 15 14 15
or C alkyl or R and R , together with the nitrogen atom to which they are attached,
1-6 14 15
may form a saturated 4-7 membered ring;
5184M-NZ
and each R , R , R , R , R , R , R , R and R is independently selected from the
2 3 4 5 6 7 8 9 10
group consisting of H, halogen, hydroxy, amino, nitro, cyano, formyl, CF , S(C alkyl),
3 1-4
S(O)C alkyl, S(O) C alkyl, C alkylcarbonyl, C alkyl, hydroxy C alkyl, C
1-4 2 1-4 1-4 1-6 1-6 1-
alkoxy, haloC alkoxy, hydroxy C alkoxy, C alkenyl, C alkynyl, C alkylamino,
6 1-6 1-6 2-6 2-6 1-6
di(C alkyl)amino; pharmaceutically acceptable salts thereof; solvates thereof and
deuterated forms thereof.
According to more typical aspects of the present disclosure, Y in the above
formula is X(C H )C(=O)NH and W is a member selected from the group consisting of
wherein R and R each is independently selected from the group consisting of H,
16 17
halo, alkyl, alkoxy and aryl or R and R can be attached to form a five, six or seven
16 17
membered ring, that can be substituted or unsubstituted and wherein the ring can be a
hetero ring containing one or more of O, S and N hetero atoms in the ring. Examples of
some even more typical W members are represented by the following formulae:
Some even more typical compounds employed according to the present invention
can be represented by the following formula:
R N S
1
wherein R is represented by the formula:
5184M-NZ
and each R , R , R , R , R , R , R , R and R is independently selected from the
2 3 4 5 6 7 8 9 10
group consisting of H, halogen, hydroxy, amino, nitro, cyano, formyl, CF , S(C alkyl),
3 1-4
S(O)C alkyl, S(O) C alkyl, C alkylcarbonyl, C alkyl, hydroxy C alkyl, C
1-4 2 1-4 1-4 1-6 1-6 1-
alkoxy, haloC alkoxy, hydroxy C alkoxy, C alkenyl, C alkynyl, C alkylamino,
6 1-6 1-6 2-6 2-6 1-6
di(C alkyl)amino; R and R are independently selected from the group consisting of
1-6 11 12
H, halogen, hydroxyl, C alkoxy, amino, nitro, cyano, CF and C alkyl; n is zero, one,
1-6 3 1-4
two, three or four, five or six; pharmaceutically acceptable salts thereof; solvates thereof
and deuterated forms thereof.
The present disclosure is also directed to compounds represented by the formula:
wherein W is a substituted or unsubstituted thiazoyl group and when substituted
W is substituted with a C alkyl, phenyl or benzoyl group, and each R , R , R , R , R ,
1-6 2 3 4 5 6
R , R , R and R is independently selected from the group consisting of H, halogen,
7 8 9 10
hydroxy, amino, nitro, cyano, CF , and C alkyl; R and R are independently selected
3 1-6 11 12
from the group consisting of H, halogen, hydroxyl, C alkoxy, amino, nitro, cyano, CF
1-6 3
and C alkyl; n is zero, one, two, three or four, five or six; pharmaceutically acceptable
salts thereof ; solvates thereof and deuterated forms thereof. Some examples of
compounds according to this formula are 2-[3-(3,4-dichlorophenyl)oxo(3-
hydroquinazolinylthio)]-N-(4-phenyl(1,3-thiazolyl))acetamide; N-benzothiazol
yl[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]acetamide; and 2-[3-
(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4-methyl(1,3-thiazol
5184M-NZ
yl))acetamide; pharmaceutically acceptable salts thereof; solvates thereof and deuterated
forms thereof.
The present disclosure is also concerned with a process for treating or preventing
a viral infection in a subject from West Nile Virus by administering to the subject a
therapeutically effective amount of at least one compound selected from the group
consisting of: 2-[3-(2-fluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide; 2-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,5-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide, 2-[3-(3,4-dichlorophenyl)fluorooxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; N-indanyl(4-oxophenyl(3-hydroquinazolin
ylthio))acetamide; 2-[3-(4-chloromethylphenyl)oxo(3-hydroquinazolinylthio)]-
N-indanylacetamide; 2-[3-(4-fluoromethylphenyl)oxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; N-indanyl[4-oxo(3,4,5-trifluorophenyl)(3-
hydroquinazolinylthio)]acetamide; 2-[3-(3-bromomethylphenyl)oxo(3-
hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,4-dichlorophenyl)fluoro
oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,5-difluorophenyl)
oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,5-dichlorophenyl)
fluorooxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(2,6-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3-
bromochlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-
(8-fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide; and 2-[3-
(4,5-difluoro(2-pyridyl))oxo(3-hydroquinazolinylthio)]-N-indanylacetamide;
pharmaceutically acceptable salts thereof ; solvates thereof and deuterated forms thereof.
The term “alkyl” refers to straight or branched chain unsubstituted hydrocarbon
groups of typically 1 to 22 carbon atoms, more typically 1 to 8 carbon atoms, and even
more typically 1 to 4 carbon atoms.
Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of
branched alkyl groups include isopropyl and t-butyl.
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The alkoxy group typically contains 1 to 6 carbon atoms. Suitable alkoxy groups
typically contain 1-6 carbon atoms and include methoxy, ethoxy, propoxy and butoxy.
Examples of halo groups are Cl, F, Br and I.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups
having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl, and
diphenyl groups.
The term “cycloalkyl” refers to cyclic hydrocarbon ring systems typically
containing 3-6 carbon atoms, with typical examples being cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl.
Suitable alkenyl groups typically contain 2-6 carbon atoms and include ethenyl
and propenyl.
Suitable alkynyl groups typically contain 1-6 carbon atoms and include ethynyl
and propynyl.
The terms "heterocycle", "heterocyclic" and "heterocyclo" refer to an optionally
substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for
example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15
membered tricyclic ring system, which has at least one heteroatom and at least one
carbon atom in the ring. Each ring of the heterocyclic group containing a heteroatom may
have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms,
where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the
nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be
attached at any heteroatom or carbon atom. Examples of heterocycles and heteroaryls
include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,
pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine,
quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline,
quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,
imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2, 3,4-
tetrahydroisoquinoline, 4,5, 6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine,
thiophene, benzo [b] thiophene, morpholinyl, thiomorpholinyl (also referred to as
thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, furyl, furanyl, pyridyl,
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pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl,
benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,
isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-
thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl,
hypoxanthinyl, thiophene, furan, isopyrrole, 1,2,3-triazole, 1,2,4-triazole, oxazole,
thiazole, pyrimidine, aziridines, thiazole, 1,2,3-oxadiazole, thiazine, pyrrolidine,
oxaziranes, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl,
hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl,
imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N6-alkylpurines,
N6-benzylpurine, N6-halopurine, N6-vinypurine, N6-acetylenic purine, N6-acyl purine,
N6-hydroxyalkyl purine, N6-thioalkyl purine, thymine, cytosine, 6-azapyrimidine, 2-
mercaptopyrmidine, uracil, N5-alkyl-pyrimidines, N5-benzylpyrimidines, N5-
halopyrimidines, N5-vinyl-pyrimidine, N5-acetylenic pyrimidine, N5-acyl pyrimidine,
N5-hydroxyalkyl purine, and N6-thioalkyl purine, and isoxazolyl. The heteroaromatic
and heterocyclic moieties can be optionally substituted as described above for aryl,
including substituted with one or more substituents selected from hydroxyl, amino,
alkylamino, arylamino, alkoxy, aryloxy, alkyl, heterocycle, halo, carboxy, acyl, acyloxy,
amido, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,
either unprotected, or protected as necessary, as known to those skilled in the art, for
example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley
and Sons, Second Edition, 1991.
The term “cyclic group” is used herein to refer to either aryl groups, non-aryl
groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups),
or both. Cyclic groups have one or more ring systems that can be substituted or
unsubstituted. A cyclic group can contain one or more aryl groups, one or more non-aryl
groups, or one or more aryl groups and one or more non-aryl groups.
It is understood that the compounds of the present disclosure relate to all optical
isomers and stereo-isomers at the various possible atoms of the molecule, unless
specified otherwise. Compounds may be separated or prepare as their pure enantiomers
or diasteriomers by crystallization, chromatography or synthesis.
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The deuterated forms contain heavy hydrogen including deuterium. The carbon
labeled forms may contain carbon 13.
"Pharmaceutically acceptable salts" refer to derivatives of the disclosed
compounds wherein the parent compound is modified by making acid or base salts
thereof. The compounds of this disclosure form acid and base addition salts with a wide
variety of organic and inorganic acids and bases and includes the physiologically
acceptable salts which are often used in pharmaceutical chemistry. Such salts are also
part of this disclosure. Typical inorganic acids used to form such salts include
hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and
the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids,
phenyl substituted alkonic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic
acids, aliphatic and aromatic sulfonic acids may also be used. Such pharmaceutically
acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate,
benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
methylbenzoate, o-acetoxybenzoate, naphthalenebenzoate, bromide, isobutyrate,
phenylbutyrate, β-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, cabrate,
caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate,
hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate,
nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate,
propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate,
bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, p-
bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-
hydroxyethanesulfonate, methanesulfonate, naphthalenesulfonate, naphthalene
sulfonate, p-toleunesulfonate, xylenesulfonate, tartarate, and the like.
Bases commonly used for formation of salts include ammonium hydroxide and
alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary,
secondary and tertiary amines, aliphatic diamines. Bases especially useful in the
preparation of addition salts include sodium hydroxide, potassium hydroxide, ammonium
hydroxide, potassium carbonate, methylamine, diethylamine, and ethylene diamine.
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“Solvates” refers to the compound formed by the interaction of a solvent and a
solute and includes hydrates. Solvates are usually crystalline solid adducts containing
solvent molecules within the crystal structure, in either stoichiometric or non-
stoichiometric proportions.
The terms "effective amount" or “therapeutically effective amount” refer to an
amount of the compound of the invention sufficient to provide a benefit in the treatment
or prevention of viral disease, to delay or minimize symptoms associated with viral
infection or viral-induced disease, or to cure or ameliorate the disease or infection or
cause thereof. In particular, a therapeutically effective amount means an amount
sufficient to provide a therapeutic benefit in vivo. Used in connection with an amount of
a compound of the disclosure, the term preferably encompasses a non-toxic amount that
improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances
the therapeutic efficacy of or synergies with another therapeutic agent.
The term "treating" refers to relieving the disease, disorder, or condition, i.e.,
causing regression of the disease, disorder, and/or condition. The term “preventing”
refers to preventing a disease, disorder, or condition from occurring in a human or an
animal that may be predisposed to the disease, disorder and/or condition, but has not yet
been diagnosed as having it; and/or inhibiting the disease, disorder, or condition, i.e.,
arresting its development.
More typical compounds employed according to the present invention can be
synthesized according to the Scheme 1:
Scheme 1 R
R O R7 O
7 NCS
R R 8
8 6 2
acetone, reflux N R
R N S
R NH R R 9
9 2 5 3
R R 10
4
I II III
NH N
Cl CH Cl , Et N
2 2 3
+ Cl n
IV V VI
R R R R
2 4 2 4
R O R O
R NaOAc, R
N R N R
O 1,4-dioxane
R N SH R N S
R R N
10
III VI
VII O
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METHODS OF MAKING COMPOUNDS
According to Scheme 1, compounds of Formula III, Formula VI, or Formula VII,
can be prepared via the following reaction scheme:
Scheme 1 R
R O R7 O
7 NCS
R R 8
8 6 2
acetone, reflux N R
R N S
R NH R R 9
9 2 5 3
R R 10
4
I II III
NH N
Cl CH Cl , Et N Cl
2 2 3
+ Cl n
IV V VI
R R R R
2 4 2 4
R O R O
R NaOAc, R
N R N R
O 1,4-dioxane
R N SH R N S
R R N
10
III VI
VII O
Reaction of an anthranilic acid I with a thioisocyanate II in refluxing acetone or
similar inert organic solvents, gives rise to compounds of Formula III. Treatment of 2,3-
dihydro-1H-indenamine IV or any aromatic amine with chloroacetyl chloride or
similar acid chloride V in dichloromethane or similar organic solvent, containing an
amine base such as triethyl amine gives rise to compounds of Formula VI. When
Compound III and Compound VI are treated with sodium acetate or similar base, in 1,4-
doxane or a comparable organic solvent, compounds of type VIII are formed. This
reaction is preferably carried out at a temperature between 0 C and 50 C.
Examples
Preparation of 2-mercaptophenylquinazolin-4(3H)-ones
R N S
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General Procedure A: Example A1
2-mercaptophenylquinazolin-4(3H)-one
2-Amino benzoic acid (1 g, 7.29 mmol) and phenylthioisocyante (1.18 g, 8.75
mmol) were dissolved in 20 mL of acetone and the reaction mixture was refluxed and
checked by TLC. When the reaction was determined to be complete by TLC, the reaction
mixture was cooled to room temperature and filtered. The residue was crystallized from
ethanol to afford a white solid 465 mg (25 % yield) of the target compound 2-Mercapto-
3-phenylquinazolin-4(3H)-one. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (m, 1H), 7.38 -
7.45 (m, 4H), 7.55 - 7.64 (m, 3H), 8.03 (m, 1H), MS (EI) 255 [(M+1)+]*.
Example A2
3-(3,4-dichlorophenyl)mercaptoquinazolin-4(3H)-one
The title compound was prepared from the reaction of 2-amino benzoic acid with
3,4-dichlorophenylthioisocyante according to the general procedure A. Obtained as a
white solid MS (EI) 324 [(M+1)+].
Example A3
3-(3-chlorofluorophenyl)mercaptoquinazolin-4(3H)-one
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The title compound was prepared from the reaction of 2-amino benzoic acid with
3-chlorofluorophenylthioisocyante according to the general procedure A. Obtained as
a white solid MS (EI) 307 [(M+1)+].
Example A4
3-(3,4, 5-trifluorophenyl)mercaptoquinazolin-4(3H)-one
The title compound was prepared from the reaction of 2-amino benzoic acid with
3,4,5-trifluorofluorophenylthioisocyante according to the general procedure A. Obtained
as a white solid MS (EI) 309 [(M+1)+].
Example A5
3-(3,4-difluorophenyl)mercaptoquinazolin-4(3H)-one
The title compound was prepared from the reaction of 2-amino benzoic acid with
3,4-difluorofluorophenylthioisocyante according to the general procedure A. Obtained as
a white solid MS (EI) 291 [(M+1)+].
Example A6
3-(3-fluorochlorophenyl)mercaptoquinazolin-4(3H)-one
The title compound was prepared from the reaction of 2-amino benzoic acid with
3-fluorochlorofluorophenylthioisocyante according to the general procedure A.
Obtained as a white solid MS (EI) 307 [(M+1)+].
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Example A7
-fluoromercaptophenylquinazolin-4(3H)-one
The title compound was prepared from the reaction of 2-aminofluoro benzoic
acid with phenylthioisocyante according to the general procedure A. Obtained as a white
solid MS (EI) 273 [(M+1)+].
Example A8
3-(3-fluorochlorophenyl)fluoromercaptoquinazolin-4(3H)-one
The title compound was prepared from the reaction of 2-aminofluoro benzoic
acid with 3-fluorochlorophenylthioisocyante according to the general procedure A.
Obtained as a white solid MS (EI) 325[(M+1)+].
Example A9
3-(3,4-di chlorophenyl)fluoromercaptoquinazolin-4(3H)-one
The title compound was prepared from the reaction of 2-Aminofluoro benzoic
acid with 3,4-dichlorophenylthioisocyante according to the general procedure A.
Obtained as a white solid MS (EI) 340[(M+1)+].
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Example A10
3-(3-fluorobromophenyl)fluoromercaptoquinazolin-4(3H)-one
The title compound was prepared from the reaction of 2-aminofluoro benzoic
acid with 3-bromofluorophenylthioisocyante according to the general procedure A.
Obtained as a white solid MS (EI) 340[(M+1)+].
Examples B
N H R
Cl N
R Cl
16 and
General Procedure B: Example B1
2-chloro-N-(2, 3-Dihydro-1H-indenyl)acetamide
2,3-Dihydro-1H-inden amine (13.32 g, 0.01 mole), 15 mL of triethylamine
were added to 200 mL of dichloromethane in a 500 mL round bottom flask. The flask
was cooled to 0°C and chloroacetyl chloride (11.12 g, 0.01 mole) in 50 mL of
dichloromethane was slowly added. The reaction was warmed to room temperature and
stirred overnight. The mixture was evaporated under vacuum and the residue was
dissolved in 200 mL of ethyl acetate and 100 mL of water. The organic layer was washed
successively with NaHCO , 10 % citric acid, brine and dried over sodium sulfate and the
organic layer was evaporated under vacuum to afford as a white solid 2.1 g (98 % yield)
of the target compound 2-Chloro-N-(2, 3-dihydro-1H-indenyl) acetamide. 1H NMR
(400 MHz, DMSO-d6) δ 1.95 (m, 2H), 2.80 (m, 4H), 4.24 (s, 3H), 7.18 - 7.31 (m, 2H),
7.58 (m, 1H), MS (EI) 210[(M+1)+].
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Example B2
2-chloro-N-(2, 3-dihydro-1H-indenyl)acetamide
The title compound was prepared from the reaction of 2,3-dihydro-1H-inden
amine with chloroacetyl chloride according to the general procedure B . Obtained as a
white solid MS (EI) 210[(M+1)+].
Example B3
N-(benzo[d](1,3)dioxolylchloroacetamide
Cl H
The title compound was prepared from the reaction of benzo[d](1,3)dioxol
amine with chloroacetyl chloride according to the general procedure B . Obtained as a
white solid MS (EI) 214[(M+1)+].
Example B4
-chloro-N-(2,3-dihydro-1H-indenyl)pentanamide
Cl N
The title compound was prepared from the reaction of 2,3-dihydro-1H-inden
amine with 3-chloropropanoyl chloride according to the general procedure B . Obtained
as a white solid MS (EI) 224[(M+1)+].
Example B5
4-Chloro-N-(2, 3-dihydro-1H-indeneyl)butanamide
The title compound was prepared from the reaction of 2,3-dihydro-1H-inden
amine with 4-chlorobutanoyl chloride according to the general procedure B . Obtained as
a white solid MS (EI) 238[(M+1)+].
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Example B6
-chloro-N-(2, 3-dihydro-1H-indenyl)pentanamide
Cl N
The title compound was prepared from the reaction of 2,3-dihydro-1H-inden
amine with 4-chloropentanoyl chloride according to the general procedure B . Obtained
as a white solid MS (EI) 252[(M+1)+].
Example B7
2-Chloro-N-(5-chlor0benzo[d]oxazolyl)acetamide
Cl N
The title compound was prepared from the reaction of 5-chlorobenzo[d]oxazol
amine with chloroacetyl chloride according to the general procedure B . Obtained as a
white solid MS (EI) 245[(M+1)+].
Example B8
N-Benzoyl[d]thiazolyl)chloroacetamide
Cl H
The title compound was prepared from the reaction of benzo[d]thiazolamine
with chloroacetyl chloride according to the general procedure B. Obtained as a white
solid MS (EI) 228[(M+1)+].
Example B9
2-Chloro-N-(phenylthiazol-20yl)acetamide
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The title compound was prepared from the reaction of 4-phenylthiazolamine
with chloroacetyl chloride according to the general procedure B . Obtained as a white
solid MS (EI) 253[(M+1)+].
Example B10
2-Chloro-N-(methylthiazolyl)acetamide
The title compound was prepared from the reaction of 4-methylthiazolamine
with chloroacetyl chloride according to the general procedure B. Obtained as a white
solid MS (EI) 191[(M+1)+].
Examples C
R N S
General Procedure C: Example C1
N-(2,3-dihydro-1H-indenyl)(4-oxophenyl-3,4-dihydroquinazolinyl)thio)
acetamide
2-Mercaptophenylquinazolin-4(3H)-one (659.5 mg, 2.96 mmol), 2-chloro-N-(2,
3-dihydro-1H-indenyl) acetamide (620.6 mg, 2.96 mmol), sodium acetate (848.6 mg,
.36 mmol) and 6 mL of dioxane were placed in a 50 ml round bottom flask. The
reaction mixture was heated to reflux overnight. The solvent was removed under reduced
pressure and the residue was dissolved in 50 mL of dichloromethane and 50 mL of water.
The organic layers were separated and washed successively with 50 mL of saturated
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sodium bicarbonate, 1N hydrochloric acid and the organic layer was dried over sodium
sulfate, filtered and evaporated under reduced pressure. The residue was crystallized from
ethanol to afford fine brown needles 400 mg (30 % yield) of the target compound N-(2,3-
dihydro-1H-indenyl)(4-oxophenyl-3,4-dihydroquinazolinyl)thio)
acetamide1H NMR (400 MHz, DMSO-d6) δ 1.95 (m,2H), 2.80 (m, 4H), 4.04 (s, 3H),
7.09 (d, J = 7.1 Hz, 1H), 7.21 (d, 3 = 7.1 Hz, 1H), 7.40 - 7.62 (m, 7H), 7.78(d, 3 = 7.1 Hz,
1H), 8.06 (d, 3 = 7.1 Hz, 1H), 10.15 (s, 1H), MS (EI) 427 [(M+1)+].
Example C2
2-(3-(3,4-dichlorophenyl)oxo-3,4-dihydroquinazolinylthio)-N-(2,3-dihydro-1H-
indenyl)acetamide
The title compound was prepared from the reaction of 3-(3,4-dichlorophenyl)
mercaptoquinazolin-4(3H)-one with 2-chloro-N-(2,3-dihydro-1H-indenyl) acetamide
according to the general procedure C . Obtained as a white solid MS (EI) 497[(M+1)+].
Example C3
2-(3-(3-chlorofluorophenyl)oxo-3,4-dihydroquinazolinylthio)-N-(2,3-
dihydro-1H-indenyl)acetamide
The title compound was prepared from the reaction of 3-(3-chloro
fluorophenyl)mercaptoquinazolin-4(3H)-one with 2-chloro-N-(2,3-dihydro-1H-inden-
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-yl)acetamide according to the general procedure C . Obtained as a white solid MS (EI)
480[(M+1)+].
Example C4
-(3-(3-chlorofluorophenyl)oxo-3,4-dihydroquinazolinylthio)-N-(2,3-
dihydro-1H-indenyl)pentanamide
N S N
The title compound was prepared from the reaction of 3-(3-chloro
fluorophenyl)mercaptoquinazolin-4(3H)-one with 5-chloro-N-(2,3-dihydro-1H-inden-
-yl)pentanamide according to the general procedure C . Obtained as a white solid MS
(EI) 522[(M+1)+].
Example C5
N-(5-chlorobenzo[d]oxazolyl)(3-(3,4-dichlorophenyl)oxo-3,4-
dihydroquinazolinylthio)acetamide
The title compound was prepared from the reaction of 3-(3,4-dichlorophenyl)
mercaptoquinazolin-4(3H)-one with 3-chloro-N-(5-chlorobenzo[d]oxazol
yl)propanamide according to the general procedure C . Obtained as a white solid MS (EI)
531[(M+1)+].
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Example C6
N-(benzo[d]thiazolyl)(3-(3,4-dichlorophenyl)oxo-3,4-dihydroquinazolin
ylthio)acetamide
The title compound was prepared from the reaction of 3-(3,4-dichlorophenyl)
mercaptoquinazolin-4(3H)-one with N-(benzo[d]thiazolyl)chloroacetamide
according to the general procedure C . Obtained as a white solid MS (EI) 513[(M+1)+].
Example C7
2-(3-(3,4-dichlorophenyl)oxo-3,4-dihydroquinazolinylthio)-N-(4-phenylthiazol-
2-yl)acetamide compound with N-(benzo[d]thiazolyl)chloroacetamide (1:1)
The title compound was prepared from the reaction of 3-(3,4-dichlorophenyl)
mercaptoquinazolin-4(3H)-one with 2-chloro-N-(4-phenylthiazolyl)acetamide to the
general procedure C . Obtained as a white solid MS (EI) 513[(M+1)+].
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Example C8
2-(3-(3,4-dichlorophenyl)oxo-3,4-dihydroquinazolinylthio)-N-(4-methylthiazol-
2-yl)acetamide
The title compound was prepared from the reaction of 3-(3,4-dichlorophenyl)
mercaptoquinazolin-4(3H)-one with 2-chloro-N-(4-methylthiazolyl)acetamide to the
general procedure C . Obtained as a white solid MS (EI) 478[(M+1)+].
Example C9
N-(2,3-dihydro-1H-indenyl)(4-oxo(3,4,5-trifluorophenyl)-3,4-
dihydroquinazolinylthio)pentanamide
N F O
N S N
The title compound was prepared from the reaction of 3-(3,4,5-trifluorophenyl)
mercaptoquinazolin-4(3H)-one with 5-chloro-N-(2,3-dihydro-1H-inden
yl)pentanamide according to the general procedure C. Obtained as a white solid MS (EI)
524[(M+1)+].
Example C10
N-(2,3-dihydro-1H-indenyl)(5-fluorooxophenyl-3,4-dihydroquinazolin
ylthio)pentanamide
N S N
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The title compound was prepared from the reaction of 5-fluoromercapto
phenylquinazolin-4(3H)-one with 5-chloro-N-(2,3-dihydro-1H-indenyl)pentanamide
according to the general procedure C . Obtained as a white solid MS (EI) 524[(M+1)+].
The following compounds were synthesized using the procedures described above
in the general procedure A, B, and C sections.
Compound Name MS (EI) [(M+1)+]*
C11 2-[3-(2-fluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide
C12 2-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 481
C13 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 497
C14 2-(6-fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide
C15 2-(5-fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide
C16 N-indanyl(8-methyloxophenyl(3-hydroquinazolinylthio))acetamide
C17 N-indanyl(8-methoxyoxophenyl(3-hydroquinazolin
ylthio))acetamide 458
C18 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 497
C19 N-(2H-benzo[d]1,3-dioxolenyl)[3-(3,4-dichlorophenyl)oxo(3-
hydroquinazolinylthio)]acetamide 501
C20 2-[3-(3,5-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 497
C21 3-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylpropanamide 494
C22 2-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 481
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C23 N-(2H-benzo[3,4-d]1,3-dioxolanyl)[3-(3-chlorofluorophenyl)oxo(3-
hydroquinazolinylthio)]acetamide 485
C24 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4-methyl(1,3-
thiazolyl))acetamide 478
C25 N-indanyl[4-oxo(3,4,5-trifluorophenyl)(3-hydroquinazolin
ylthio)]propanamide 497
C26 2-[3-(3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 543
C27 2-[3-(3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 464
C28 2-(5-fluorooxophenyl(3-hydroquinazolinylthio))-N-(1,2,3,4-
tetrahydronaphthyl)acetamide 460
C29 2-[3-(4-chlorofluorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-
indanylacetamide 499
C30 2-[5-fluorooxo(3,4,5-trifluorophenyl)(3-hydroquinazolinylthio)]-N-
indanylacetamide 524
C31 2-[3-(3,4-dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indan-
-ylacetamide 515
C32 N-indanyl(4-oxophenyl(3-hydroquinazolinylthio))acetamide 428
C33 2-[3-(4-chloromethylphenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 477
C34 2-[3-(4-fluoromethylphenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 460
C35 N-indanyl[4-oxo(3,4,5-trifluorophenyl)(3-hydroquinazolin
ylthio)]acetamide 482
C36 2-[3-(3-bromomethylphenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 521
C37 2-[3-(3,4-dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 515
C38 2-[3-(3,5-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 464
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C39 2-[3-(3,5-dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 515
C40 2-[3-(2,6-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 497
C41 2-[3-(3-bromochlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 542
C42 2-(8-fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide
C43 2-[3-(4,5-difluoro(2-pyridyl))oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 465
C44 2-[3-(4-chlorofluoro(2-pyridyl))oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide 482
C45 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4-phenyl(1,3-
thiazolyl))acetamide 540
C46 N-benzothiazolyl[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolin
ylthio)]acetamide 514
*MS (E1) [(M+1)+]" is the molecular mass as determined by mass spectrometry used to
confirm the structure of each compound.
Other compounds employed according to the present invention can be prepared as
shown above by employing a corresponding substituted 2-amino benzoic acid and
corresponding substituted phenylthioisocynate. In addition, compounds employed
according to the present disclosure can be prepared using the methods disclosed in WO
2005/049613 to Bayliss et al., disclosure of which is incorporated herein by reference
using the appropriate reactants.
The following tables show results obtained from testing of compounds according
to the present disclosure.
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Table 1
HCV Con 1b (Replicon) RNA end-point
Example
IC ( M) TC ( M) TI
50 50 50
C1 C A C
C12 A B A
C15 B A B
C26 A B C
C45 A B B
IC : A <1.0 M; B 1-5 M; C >5 and < 25 M
TC : A ≥100.0 M; B <100 – ≥50 M; C <50 – ≥10 M; D <10 M
TI : A ≥50; B <50 – ≥10; C <10 – ≥5; D <5
Table 2
Example
IC ( M) TC ( M) TI
50 50 50
C8 C A C
C15 C A B
C17 C A C
C24 C A C
C25 C A C
IC : A <1.0 M; B 1-5 M; C >5 and < 25 M
TC : A ≥100.0 M; B <100 – ≥50 M; C <50 – ≥10 M; D <10 M
TI : A ≥50; B <50 – ≥10; C <10 – ≥5; D <5
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Table 3
HCV Con1b (Replicon) Luciferase end-point
Example
IC ( M) TC ( M) TI
50 50 50
C8 B A B
C12 B A A
C13 B B C
C16 B C B
C17 B A B
C18 C B B
C19 B A B
C21 C C C
C22 B C C
C23 C A C
C24 B A B
C26 A A A
C27 C A B
C28 C A C
C29 B A A
C30 B B B
C31 A C A
C45 A A A
C46 B A B
IC : A <1.0 M; B 1-5 M; C >5 and < 25 M
TC : A ≥100.0 M; B <100 – ≥50 M; C <50 – ≥10 M; D <10 M
TI : A ≥50; B <50 – ≥10; C <10 – ≥5; D <5
Table 4
Example
IC ( M) TC ( M)
50 50 50
C1 C A C
C11 C A C
C12 C A B
C13 C A B
C20 B A B
C27 C A B
C31 C A C
C32 C A B
C33 B B B
C34 C A B
C35 C A B
C36 C A B
C37 C C C
C38 C A C
C39 C B C
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Example
IC ( M) TC ( M)
50 50 50
C40 C A C
C41 C A C
C42 C A C
C43 C A C
IC : A <1.0 M; B 1-5 M; C >5 and < 25 M
TC : A ≥100.0 M; B <100 – ≥50 M; C <50 – ≥10 M; D <10 M
TI : A ≥50; B <50 – ≥10; C <10 – ≥5; D <5
The use of N-(2,3-dihydro-1H-indenyl)(4-oxophenyl-3,4-dihydro-
quinazolinyl)thio) acetamide, a compound employed according to the present
disclosure, for treating West Nile Virus has been disclosed. For example, please see
Chung et al. A Cell Based Assay for the Identification of Lead Compounds with Anti-
Viral Activity Against West Nile Virus, Probe Reports from the NIH Molecular Libraries
Program [Internet]. Bethesda (MD): National Center for Biotechnology Information
(US); 2010-2010 Feb 27 [updated 2010 Oct 4], PMID: 21433390 [PubMed]. When N-
(2,3-dihydro-1H-indenyl)(4-oxophenyl-3,4-dihydroquinazolinyl)thio)
acetamide was tested against Hepatitis C Virus, activity was observed (Table 1). Testing
analogs of N-(2,3-dihydro-1H-indenyl)(4-oxophenyl-3,4-dihydroquinazolin
yl)thio) acetamide in cell based virus CPE reduction assays showed Japanese
Encephalitis Virus replication was also inhibited by analogs of N-(2,3-dihydro-1H-inden-
-yl)(4-oxophenyl-3,4-dihydroquinazolinyl)thio) acetamide (Table 2).
Compounds according to the present disclosure can be used in treating Hepatitis C
Virus (genotypes 1-7) (Table 1 and Table 3) and Japanese Encephalitis Virus (Table 2).
In addition certain compounds according to the present disclosure can be used in treating
West Nile Virus (Table 4).
The reduction in HCV was determined with two assays using viral RNA
endpoints. A qPCR analysis and a blot hydridization method were used to show that the
activity is specific for HCV and not the luciferase end-point (Table 4). The data
demonstrated activity in a cell based HCV replicon assay (con 1b). This cell line
expresses a subgenomic section of the HCV genome containing NS2a, NS2b, NS3a,
NS3b, NS4a, NS4b, NS5a and NS5b. However, no activity was observed in biochemical
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assays: HCV protease (NS3b), HCV helicase, WNV protease (NS2bNS3), and HCV
polymerase (NS5b), these data exclude these proteins as targets of the quinazolinone
activity.
Exemplary embodiments of the present disclosure include:
Embodiment 1: A process for treating or preventing a viral infection in a subject,
wherein said viral infection is from a flavivirus selected from the group consisting of
Hepatitis C Virus (genotypes 1-7) and Japanese Encephalitis Virus, which comprises
administering to said subject a therapeutically effective amount of at least one compound
represented by the formula:
R N S
1
wherein R is represented by the formula:
each R , R , R , R , R , R , R , R and R is independently selected from the
2 3 4 5 6 7 8 9 10
group consisting of H, halogen, hydroxy, amino, nitro, cyano, formyl, CF , S(C alkyl),
3 1-4
S(O)C alkyl, S(O) C alkyl, C alkylcarbonyl, C alkyl, hydroxy C alkyl, C
1-4 2 1-4 1-4 1-6 1-6 1-
alkoxy, haloC alkoxy, hydroxy C alkoxy, C alkenyl, C alkynyl, C alkylamino,
6 1-6 1-6 2-6 2-6 1-6
di(C alkyl)amino; R and R are independently selected from the group consisting of
1-6 11 12
H, halogen, hydroxyl, C alkoxy, amino, nitro, cyano, CF and C alkyl; n is zero, one,
1-6 3 1-4
two, three or four, five or six; pharmaceutically acceptable salts thereof; solvates thereof
and deuterated forms thereof.
Embodiment 2: A process for treating or preventing a viral infection in a subject,
wherein said viral infection is from a flavivirus selected from the group consisting of
Hepatitis C Virus (genotypes 1-7) and Japanese Encephalitis Virus, which comprises
administering to said subject a therapeutically effective amount of at least one compound
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represented by the formula:
R N X
wherein X is O, S or NR wherein R is H or C alkyl;
20 1-6
Y is (CR CR ) (CO) NR W;
11 12 n p 13
R and R are independently selected from the group consisting of H, halogen,
11 12
hydroxyl, C alkoxy, amino, nitro, cyano, CF and C alkyl;
1-6 3 1-4
R is H or C alkyl;
13 1-6
n is zero, one, two, three, four, five or six;
p is zero or one;
W is hydrogen, C alkoxy, halo C alkoxy, C alkyl, halo C alkyl, hydroxyC
1-6 1-6 1-6 1-6 1-
alkyl, amino C alkyl, carboxyC alkyl, C cycloalkyl, halo C cycloalkyl; or a
6 1-6 1-6 3-7 3-7
substituted or unsubstituted phenyl ring, a substituted or unsubstituted five-or 6-
membered saturated or unsaturated heterocyclic ring containing one, two, three or four
heteroatoms independently chosen from O, N and S, or a nine- or ten-or eleven -
membered fused bicyclic ring containing a phenyl ring or a six-membered heteroaromatic
ring as just defined, fused to either a saturated or unsaturated five- or six- or seven-
membered ring, which can be substituted or unsubstitued, when substituted any of the
above rings can be substituted by halogen, C alkyl, C alkenyl, C alkynyl, nitro,
1-6 2-6 2-6
cyano, C cycloalkyI, hydroxy, C alkoxy, haloC alkyl, halo C alkoxy, hydroxy C
3-7 1-6 1-6 1-6 1-
alkyl, hydroxy C alkoxy, phenyl, an unsubstituted five-membered heteroaromatic ring
6 1-6
as just described, a six-membered heteroaromatic ring as just described, a six-membered
saturated ring as just described or NR R ; each R and R is independently hydrogen
14 15 14 15
or C alkyl or R and R , together with the nitrogen atom to which they are attached,
1-6 14 15
may form a saturated 4-7 membered ring; and each R , R , R , R , R , R , R , R and R
2 3 4 5 6 7 8 9 10
is independently selected from the group consisting of H, halogen, hydroxy, amino, nitro,
cyano, formyl, CF , S(C alkyl), S(O)C alkyl, S(O) C alkyl, C alkylcarbonyl, C
3 1-4 1-4 2 1-4 1-4 1-
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alkyl, hydroxy C alkyl, C alkoxy, haloC alkoxy, hydroxy C alkoxy, C alkenyl,
6 1-6 1-6 1-6 1-6 2-6
C alkynyl, C alkylamino, di(C alkyl)amino; pharmaceutically acceptable salts
2-6 1-6 1-6
thereof ; solvates thereof and deuterated forms thereof.
Embodiment 3: The process according to Embodiment 2 wherein Y in the above
formula is X(C H )C(=O)NH and W is a member selected from the group consisting of
wherein R and R each is independently selected from the group consisting of H,
16 17
halo, alkyl, alkoxy and aryl or R and R can be attached to form a five, six or seven
16 17
membered ring, that can be substituted or unsubstitued and wherein the ring can be a
hetero ring containing one or more O, S and/or N hetero atoms in the ring.
Embodiment 4: The process according to any one of embodiments 2 or 3 wherein
W is a member selected from the group consisting of :
Embodiment 5: The process according to any one of embodiments 1 to 4, wherein
said alkyl and said alkoxy contain 1 to 4 carbon atoms.
Embodiment 6: The process according to any one of embodiments 1 to 5, wherein
each of R , R , R , R , R , R , R and R is H and R is F.
2 4 5 6 7 8 9 10 3
Embodiment 7: The process according to any one of embodiments 1 to 5, wherein
each of R , R , R , R , R , R and R is H, R is Cl and R is F.
2 5 6 7 8 9 10 3 4
Embodiment 8: The process according to any one of embodiments 1 to 5, wherein
each of R , R , R , R , R , R and R is H and R and R are each Cl.
2 5 6 7 8 9 10 3 4
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Embodiment 9: The process according to any one of embodiments 1 to 5, wherein
each of R , R , R , R , R , R , R and R is H and R is F.
2 3 5 6 7 8 9 10 4
Embodiment 10: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R , R , R and R is H and R is F.
2 3 4 5 6 7 9 10 8
Embodiment 11: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R , R , R and R is H and R is CH .
2 3 4 5 6 7 9 10 8 3
Embodiment 12: The process according to any one of embodiments 1 to 5,
wherein each OF R , R , R , R , R , R , R and R is H and R is F.
2 3 4 5 6 8 9 10 7
Embodiment 13: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R , R , R and R is H and R is I.
2 3 4 5 6 8 9 10 7
Embodiment 14: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R , R , R and R is H and R is CH .
2 3 4 5 6 7 8 9 10 3
Embodiment 15: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R , R , R and R is H and R is OCH .
2 3 4 5 6 7 8 9 10 3
Embodiment 16: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R , R and R is H and each of R and R is Cl.
2 4 6 7 8 9 10 3 5
Embodiment 17: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R and R is H and each of R , R and R is F.
2 6 7 8 9 10 3 4 5
Embodiment 18: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R , R , R and R is H and R is F.
2 3 4 5 6 8 9 10 7
Embodiment 19: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R and R is H and each of R and R is F and R is Cl.
2 5 6 8 9 10 3 7 4
Embodiment 20: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R and R is H and each of R , R and R is F.
2 3 6 8 9 10 4 5 7
Embodiment 21: The process according to any one of embodiments 1 to 5,
wherein each of R , R , R , R , R and R is H and each of R R and R is F.
2 5 6 8 9 10 3, 4 7
Embodiment 22: The process according to any one of embodiments 1 to 5
wherein each of each R , R , R , R and R is H and each of R , R , R and R is F.
2 6 8 9 10 3 4 5 7
Embodiment 23: The process according to any one of embodiments 1 to 5,
wherein each R , R , R , R , R and R is H, each of R and R is Cl and R is F.
2 3 6 8 9 10 4 5 7
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Embodiment 24: The process according to any one of embodiments 1 to 5,
wherein each R , R , R , R , R and R is H, each of R and R is Cl and R is F.
2 5 6 8 9 10 3 4 7
Embodiment 25: The process according to any one of embodiments 1 to 5,
wherein each R , R , R , R , R and R is H, R is Br and each of R and R is F.
2 3 6 8 9 10 5 4 7
Embodiment 26: The process according to any one of embodiments 1 to 5,
wherein each R , R , R , R , R and R is H, R is Br and each of R and R is F.
2 4 6 8 9 10 3 4 7
Embodiment 27: A process for treating or preventing a viral infection in a subject
from Hepatitis C Virus, by administering to the subject a therapeutically effective
amount of at least one compound selected from the group consisting of N-(2,3-dihydro-
1H-indenyl)(4-oxophenyl-3,4-dihydroquinazolinyl)thio) acetamide; 2-[3-(3-
chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-
(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-(5-
fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide; N-indan
yl(8-methyloxophenyl(3-hydroquinazolinylthio))acetamide; N-indanyl
(8-methoxyoxophenyl(3-hydroquinazolinylthio))acetamide; 2-[3-(3,4-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; N-(2H-
benzo[d]1,3-dioxolenyl)[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolin
ylthio)]acetamide; 3-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylpropanamide; 2-[3-(3-chlorofluorophenyl)oxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; N-(2H-benzo[3,4-d]1,3-dioxolanyl)[3-(3-chloro
fluorophenyl)oxo(3-hydroquinazolinylthio)]acetamide; 2-[3-(3,4-dichlorophenyl)-
4-oxo(3-hydroquinazolinylthio)]-N-(4-methyl(1,3-thiazolyl))acetamide; 2-[3-(3,4-
difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,4-
difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-(5-fluoro-
4-oxophenyl(3-hydroquinazolinylthio))-N-(1,2,3,4-tetrahydronaphthyl)acetamide;
2-[3-(4-chlorofluorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide; 2-[5-fluorooxo(3,4,5-trifluorophenyl)(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,4-dichlorophenyl)fluorooxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolin
ylthio)]-N-(4-phenyl(1,3-thiazolyl))acetamide; and N-benzothiazolyl[3-(3,4-
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dichlorophenyl)oxo(3-hydroquinazolinylthio)]acetamide; pharmaceutically
acceptable salts thereof; solvates thereof and deuterated forms thereof.
Embodiment 28: A process for treating or preventing a viral infection in a subject
from West Nile Virus by administering to the subject a therapeutically effective amount
of at least one compound selected from the group consisting of: 2-[3-(2-fluorophenyl)
oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3-chloro
fluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,4-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,5-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,4-
difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide, 2-[3-(3,4-
dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indanylacetamide; N-
indanyl(4-oxophenyl(3-hydroquinazolinylthio))acetamide; 2-[3-(4-chloro
methylphenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(4-
fluoromethylphenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; N-
indanyl[4-oxo(3,4,5-trifluorophenyl)(3-hydroquinazolinylthio)]acetamide; 2-
[3-(3-bromomethylphenyl)oxo(3-hydroquinazolinylthio)]-N-indan
ylacetamide; 2-[3-(3,4-dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,5-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-
indanylacetamide; 2-[3-(3,5-dichlorophenyl)fluorooxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; 2-[3-(2,6-dichlorophenyl)oxo(3-hydroquinazolin
ylthio)]-N-indanylacetamide; 2-[3-(3-bromochlorophenyl)oxo(3-
hydroquinazolinylthio)]-N-indanylacetamide; 2-(8-fluorooxophenyl(3-
hydroquinazolinylthio))-N-indanylacetamide; and 2-[3-(4,5-difluoro(2-pyridyl))
oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; pharmaceutically acceptable
salts thereof ; solvates thereof and deuterated forms thereof.
Embodiment 29: A process for treating or preventing a viral infection in a subject
from Japanese Encephalitis Virus by administering to the subject a therapeutically
effective amount of at least one compound selected from the group consisting of 2-(5-
fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide; 2-[3-(3,4-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(2,6-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; and 2-(8-
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fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide;
pharmaceutically acceptable salts thereof; solvates thereof and deuterated forms thereof.
Embodiment 30: A compound represented by the formula:
wherein W is a substituted or unsubstituted thiazoyl group and when substituted
W is substituted with a C alkyl, phenyl or benzoyl group, and each R , R , R , R , R ,
1-6 2 3 4 5 6
R , R , R and R is independently selected from the group consisting of H, halogen,
7 8 9 10
hydroxy, amino, nitro, cyano, CF , and C alkyl; R and R are independently selected
3 1-6 11 12
from the group consisting of H, halogen, hydroxyl, C alkoxy, amino, nitro, cyano, CF
1-6 3
and C alkyl; n is zero, one, two, three or four, five or six; pharmaceutically acceptable
salts thereof; solvates thereof and deuterated forms thereof.
Embodiment 31: The compound according to Embodiment 30, wherein each of
R , R , R , R , R , R and R is hydrogen and each of R and R is chloro.
2 3 6 7 8 9 10 4 5
Embodiment 32: The compound according to Embodiment 30 being selected
from the group consisting of 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolin
ylthio)]-N-(4-phenyl(1,3-thiazolyl))acetamide; N-benzothiazolyl[3-(3,4-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]acetamide; and 2-[3-(3,4-
dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4-methyl(1,3-thiazol
yl))acetamide; pharmaceutically acceptable salts thereof and solvates thereof.
Embodiment 33: A process for treating or preventing a viral infection in a subject,
wherein said viral infection is from a flavivirus selected from the group consisting of
Hepatitis C Virus (genotypes 1-7) and Japanese Encephalitis Virus, which comprises
administering to said subject a therapeutically effective amount of at least one compound
according to any one of Embodiments 30-32, pharmaceutically acceptable salt thereof ;
solvate thereof or deuterated form thereof.
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Embodiment 34: A process for treating or preventing a viral infection in a subject,
wherein said viral infection is from Hepatitis C Virus, which comprises administering to
said subject a therapeutically effective amount of at least one compound according to any
one of Embodiments 30-32, pharmaceutically acceptable salt thereof or solvate thereof.
The compounds of the present disclosure can be administered by any
conventional means available for use in conjunction with pharmaceuticals, either as
individual therapeutic agents or in a combination of therapeutic agents. They can be
administered alone, but generally administered with a pharmaceutical carrier selected on
the basis of the chosen route of administration and standard pharmaceutical practice. The
compounds can also be administered in conjunction with other therapeutic agents.
The pharmaceutically acceptable carriers described herein, for example, vehicles,
adjuvants, excipients, or diluents, are well-known to those who are skilled in the art.
Typically, the pharmaceutically acceptable carrier is chemically inert to the active
compounds and has no detrimental side effects or toxicity under the conditions of use.
The pharmaceutically acceptable carriers can include polymers and polymer matrices.
The compounds of this disclosure can be administered by any conventional
method available for use in conjunction with pharmaceuticals, either as individual
therapeutic agents or in a combination of therapeutic agents.
The dosage administered will, of course, vary depending upon known factors,
such as the pharmacodynamic characteristics of the particular agent and its mode and
route of administration; the age, health and weight of the recipient; the nature and extent
of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the
effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to
1000 milligrams (mg) per kilogram (kg) of body weight, with the preferred dose being
0.1 to about 30 mg/kg.
Dosage forms (compositions suitable for administration) typically contain from
about 1 mg to about 500 mg of active ingredient per unit. In these pharmaceutical
compositions, the active ingredient will ordinarily be present in an amount of about 0.5-
95% weight based on the total weight of the composition.
5184M-NZ
The active ingredient can be administered orally in solid dosage forms, such as
capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups and
suspensions. It can also be administered parenterally, in sterile liquid dosage forms. The
active ingredient can also be administered intranasally (nose drops) or by inhalation of a
drug powder mist. Other dosage forms are potentially possible such as administration
transdermally, via patch mechanism or ointment.
Formulations suitable for oral administration can consist of (a) liquid solutions,
such as an effective amount of the compound dissolved in diluents, such as water, saline,
or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a
predetermined amount of the active ingredient, as solids or granules; (c) powders; (d)
suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may
include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol,
propylene glycol, glycerin, and the polyethylene alcohols, either with or without the
addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying
agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing,
for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium
phosphate, and corn starch. Tablet forms can include one or more of the following:
lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline
cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc,
magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients,
colorants, diluents, buffering agents, disintegrating agents, moistening agents,
preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge
forms can comprise the active ingredient in a flavor, usually sucrose and acacia or
tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as
gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to
the active ingredient, such carriers as are known in the art.
The compounds of the present disclosure, alone or in combination with other
suitable components, can be made into aerosol formulations to be administered via
inhalation. These aerosol formulations can be placed into pressurized acceptable
propellants, such as dichlorodifluoromethane, propane, and nitrogen. They also may be
5184M-NZ
formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or
an atomizer.
Formulations suitable for parenteral administration include aqueous and non-
aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers,
bacteriostats, and solutes that render the formulation isotonic with the blood of the
intended recipient, and aqueous and non-aqueous sterile suspensions that can include
suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The
compound can be administered in a physiologically acceptable diluent in a
pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water,
saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol,
isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene
glycol such as poly(ethyleneglycol) 400, glycerol ketals, such as 2,2-dimethyl-1,3-
dioxolanemethanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or an
acetylated fatty acid glyceride with or without the addition of a pharmaceutically
acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin,
carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose,
or emulsifying agents and other pharmaceutical adjuvants.
Oils, which can be used in parenteral formulations include petroleum, animal,
vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame,
cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral
formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl
myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral
formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable
detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium
halides, and alkylpyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl,
and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates,
(c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides,
and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for
example, alkyl ß-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts,
and (e) mixtures thereof.
5184M-NZ
The parenteral formulations typically contain from about 0.5% to about 25% by
weight of the active ingredient in solution. Suitable preservatives and buffers can be used
in such formulations. In order to minimize or eliminate irritation at the site of injection,
such compositions may contain one or more nonionic surfactants having a hydrophile-
lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such
formulations ranges from about 5% to about 15% by weight. Suitable surfactants include
polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high
molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol.
Pharmaceutically acceptable excipients are also well-known to those who are
skilled in the art. The choice of excipient will be determined in part by the particular
compound, as well as by the particular method used to administer the composition.
Accordingly, there is a wide variety of suitable formulations of the pharmaceutical
composition of the present disclosure. The following methods and excipients are merely
exemplary and are in no way limiting. The pharmaceutically acceptable excipients
preferably do not interfere with the action of the active ingredients and do not cause
adverse side-effects. Suitable carriers and excipients include solvents such as water,
alcohol, and propylene glycol, solid absorbents and diluents, surface active agents,
suspending agent, tableting binders, lubricants, flavors, and coloring agents.
The formulations can be presented in unit-dose or multi-dose sealed containers,
such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition
requiring only the addition of the sterile liquid excipient, for example, water, for
injections, immediately prior to use. Extemporaneous injection solutions and suspensions
can be prepared from sterile powders, granules, and tablets. The requirements for
effective pharmaceutical carriers for injectable compositions are well known to those of
ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co.,
Philadelphia, PA, Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on
Injectable Drugs, Toissel, 4th ed., 622-630 (1986).
Formulations suitable for topical administration include lozenges comprising the
active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles
5184M-NZ
comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose
and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier;
as well as creams, emulsions, and gels containing, in addition to the active ingredient,
such carriers as are known in the art.
Additionally, formulations suitable for rectal administration may be presented as
suppositories by mixing with a variety of bases such as emulsifying bases or water-
soluble bases. Formulations suitable for vaginal administration may be presented as
pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition
to the active ingredient, such carriers as are known in the art to be appropriate.
Suitable pharmaceutical carriers are described in Remington’s Pharmaceutical
Sciences, Mack Publishing Company, a standard reference text in this field.
The dose administered to an animal, particularly a human, in the context of the
present disclosure should be sufficient to affect a therapeutic response in the animal over
a reasonable time frame. One skilled in the art will recognize that dosage will depend
upon a variety of factors including a condition of the animal, the body weight of the
animal, as well as the severity and stage of the condition being treated.
A suitable dose is that which will result in a concentration of the active agent in a
patient which is known to affect the desired response. The preferred dosage is the
amount which results in maximum inhibition of the condition being treated, without
unmanageable side effects.
The size of the dose also will be determined by the route, timing and frequency of
administration as well as the existence, nature, and extend of any adverse side effects that
might accompany the administration of the compound and the desired physiological
effect.
Useful pharmaceutical dosage forms for administration of the compounds according
to the present disclosure can be illustrated as follows:
5184M-NZ
Hard Shell Capsules
A large number of unit capsules are prepared by filling standard two-piece hard
gelatine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg
of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil
or olive oil is prepared and injected by means of a positive displacement pump into molten
gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The
capsules are washed and dried. The active ingredient can be dissolved in a mixture of
polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets
A large number of tablets are prepared by conventional procedures so that the
dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of
magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of
lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase
palatability, improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules
These are solid oral dosage forms made by conventional and novel processes.
These units are taken orally without water for immediate dissolution and delivery of the
medication. The active ingredient is mixed in a liquid containing ingredient such as
sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or
caplets by freeze drying and solid state extraction techniques. The drug compounds may
be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent
components to produce porous matrices intended for immediate release, without the need
of water.
Moreover, the compounds of the present disclosure can be administered in the
form of nose drops, or metered dose and a nasal or buccal inhaler. The drug is delivered
from a nasal solution as a fine mist or from a powder as an aerosol.
5184M-NZ
The term “comprising” (and its grammatical variations) as used herein is used in
the inclusive sense of “having” or “including” and not in the exclusive sense of
“consisting only of.” The terms “a” and “the” as used herein are understood to
encompass the plural as well as the singular.
To the extent a term used in a claim is not defined above, it should be given its
broadest definition persons skilled in the art have given that term as reflected in at least
one printed publication or issued patent. All publications, patents and patent applications
cited in this specification are herein incorporated by reference, and for any and all
purpose, as if each individual publication, patent or patent application were specifically
and individually indicated to be incorporated by reference. In the case of inconsistencies,
the present disclosure will prevail.
The foregoing description of the disclosure illustrates and describes the present
disclosure. Additionally, the disclosure shows and describes only the preferred
embodiments but, as mentioned above, it is to be understood that the disclosure is capable
of use in various other combinations, modifications, and environments and is capable of
changes or modifications within the scope of the concept as expressed herein,
commensurate with the above teachings and/or the skill or knowledge of the relevant art.
The embodiments described hereinabove are further intended to explain best
modes known of practicing it and to enable others skilled in the art to utilize the
disclosure in such, or other, embodiments and with the various modifications required by
the particular applications or uses. Accordingly, the description is not intended to limit it
to the form disclosed herein. Also, it is intended that the appended claims be construed to
include alternative embodiments.
5184M-NZ
Claims (13)
1. Use of at least one compound selected from the group consisting of 2-[3-(3,4- dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4-phenyl(1,3-thiazol yl))acetamide; N-benzothiazolyl[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolin- 2-ylthio)]acetamide; 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4- methyl(1,3-thiazolyl))acetamide; N-(2,3-dihydro-1H-indenyl)(4-oxophenyl- 3,4-dihydroquinazolinyl)thio) acetamide; 2-[3-(3-chlorofluorophenyl)oxo(3- hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,4-dichlorophenyl)oxo(3- hydroquinazolinylthio)]-N-indanylacetamide; 2-(5-fluorooxophenyl(3- hydroquinazolinylthio))-N-indanylacetamide; N-indanyl(8-methyloxo phenyl(3-hydroquinazolinylthio))acetamide; N-indanyl(8-methoxyoxo phenyl(3-hydroquinazolinylthio))acetamide; 2-[3-(3,4-dichlorophenyl)oxo(3- hydroquinazolinylthio)]-N-indanylacetamide; N-(2H-benzo[d]1,3-dioxolenyl) [3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]acetamide; 3-[3-(3-chloro fluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylpropanamide; 2-[3-(3- chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; N- (2H-benzo[3,4-d]1,3-dioxolanyl)[3-(3-chlorofluorophenyl)oxo(3- hydroquinazolinylthio)]acetamide; 2-[3-(3,4-difluorophenyl)oxo(3- hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,4-difluorophenyl)oxo(3- hydroquinazolinylthio)]-N-indanylacetamide; 2-(5-fluorooxophenyl(3- hydroquinazolinylthio))-N-(1,2,3,4-tetrahydronaphthyl)acetamide; 2-[3-(4-chloro fluorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[5- fluorooxo(3,4,5-trifluorophenyl)(3-hydroquinazolinylthio)]-N-indan ylacetamide; and 2-[3-(3,4-dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]- N-indanylacetamide; pharmaceutically acceptable salts thereof; solvates thereof and deuterated forms thereof in the manufacture of a medicament for the treatment or prevention of a viral infection from Hepatitis C virus.
2. Use of at least one compound selected from the group consisting of 2-(5-fluoro oxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide; 2-[3-(3,4- 5184M-NZ dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(2,6- dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; and 2-(8- fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide; pharmaceutically acceptable salts thereof; solvates thereof and deuterated forms thereof in the manufacture of a medicament for the treatment or prevention of Japanese encephalitis viral infection.
3. Use of at least one compound selected from the group consisting of: 2-[3-(2- fluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3- chlorofluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3- (3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3- (3,5-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3- (3,4-difluorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide, 2-[3- (3,4-dichlorophenyl)fluorooxo(3-hydroquinazolinylthio)]-N-indan ylacetamide; N-indanyl(4-oxophenyl(3-hydroquinazolinylthio))acetamide; 2- [3-(4-chloromethylphenyl)oxo(3-hydroquinazolinylthio)]-N-indan ylacetamide; 2-[3-(4-fluoromethylphenyl)oxo(3-hydroquinazolinylthio)]-N- indanylacetamide; N-indanyl[4-oxo(3,4,5-trifluorophenyl)(3- hydroquinazolinylthio)]acetamide; 2-[3-(3-bromomethylphenyl)oxo(3- hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,4-dichlorophenyl)fluoro oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,5-difluorophenyl) oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3,5-dichlorophenyl) fluorooxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(2,6- dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2-[3-(3- bromochlorophenyl)oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; 2- (8-fluorooxophenyl(3-hydroquinazolinylthio))-N-indanylacetamide; and 2-[3- (4,5-difluoro(2-pyridyl))oxo(3-hydroquinazolinylthio)]-N-indanylacetamide; pharmaceutically acceptable salts thereof ; solvates thereof and deuterated forms thereof in the manufacture of a medicament for the treatment or prevention of a West Nile viral infection. 5184M-NZ
4. Use of a compound represented by the formula: wherein W is a substituted or unsubstituted thiazoyl group and when substituted W is substituted with a C alkyl, phenyl or benzoyl group, and each R , R , R , R , R , 1-6 2 3 4 5 6 R , R , R and R is independently selected from the group consisting of H, halogen, 7 8 9 10 hydroxy, amino, nitro, cyano, CF , and C alkyl; R and R are independently selected 3 1-6 11 12 from the group consisting of H, halogen, hydroxyl, C alkoxy, amino, nitro, cyano, CF 1-6 3 and C alkyl; n is zero, one, two, three or four, five or six; pharmaceutically acceptable salts thereof ; solvates thereof and deuterated forms thereof in the manufacture of a medicament for the treatment or prevention of a flavivirus selected from the group consisting of Hepatitis C vicus (genotypes 1-7) and Japanese Encephalitides Virus.
5. The use according to claim 4, wherein each of R , R , R , R , R , R and R is 2 3 6 7 8 9 10 hydrogen and each of R and R is chloro.
6. The use according to claim 4 being selected from the group consisting of 2-[3- (3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]-N-(4-phenyl(1,3-thiazol yl))acetamide; N-benzothiazolyl[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolin- 2-ylthio)]acetamide; and 2-[3-(3,4-dichlorophenyl)oxo(3-hydroquinazolinylthio)]- N-(4-methyl(1,3-thiazolyl))acetamide; pharmaceutically acceptable salts thereof ; solvates thereof and deuterated forms thereof.
7. The use according to any one of claims 4 to 6 wherein said viral infection is a flavivirus selected from the group consisting of Hepatitis C Virus (genotypes 1-7) and Japanese Encephalitis Virus. 5184M-NZ
8. Use of a compound represented by the formula: R N S 10 1 wherein R is represented by the formula: each R , R , R , R , R , R , R , R and R is independently selected from the 2 3 4 5 6 7 8 9 10 group consisting of H, halogen, hydroxy, amino, nitro, cyano, formyl, CF , S(C alkyl), 3 1-4 S(O)C alkyl, S(O) C alkyl, C alkylcarbonyl, C alkyl, hydroxy C alkyl, C 1-4 2 1-4 1-4 1-6 1-6 1- alkoxy, haloC alkoxy, hydroxy C alkoxy, C alkenyl, C alkynyl, C alkylamino, 6 1-6 1-6 2-6 2-6 1-6 di(C alkyl)amino; R and R are independently selected from the group consisting of 1-6 11 12 H, halogen, hydroxyl, C alkoxy, amino, nitro, cyano, CF and C alkyl; n is zero, one, 1-6 3 1-4 two, three or four, five or six; pharmaceutically acceptable salts thereof ; solvates thereof and deuterated forms thereof in the manufacture of a medicament for the treatment or prevention of a flavivirus viral infection selected form the group consisting of Hepatitis C Virus (genotypes 1-7) and Japanese Encephalitis Virus..
9. Use of a compound represented by the formula: R N X wherein X is O, S or NR wherein R is H or C alkyl; 20 20 1-6 Y is (CR CR ) (CO) NR W; 11 12 n p 13 5184M-NZ R and R are independently selected from the group consisting of H, halogen, 11 12 hydroxyl, C alkoxy, amino, nitro, cyano, CF and C alkyl; 1-6 3 1-4 R is H or C alkyl; 13 1-6 n is zero, one, two, three, four, five or six; p is zero or one; W is hydrogen, C alkoxy, halo C alkoxy, C alkyl, halo C alkyl, 1-6 1-6 1-6 1-6 hydroxyC alkyl, amino C alkyl, carboxyC alkyl, C cycloalkyl, halo C 1-6 1-6 1-6 3-7 3-7 cycloalkyl; or a substituted or unsubstituted phenyl ring, a substituted or unsubstituted five-or 6-membered saturated or unsaturated heterocyclic ring containing one, two, three or four heteroatoms independently chosen from O, N and S, or a nine- or ten-or eleven - membered fused bicyclic ring containing a phenyl ring or a six-membered heteroaromatic ring as just defined, fused to either a saturated or unsaturated five- or six- or seven- membered ring, which can be substituted or unsubstitued, when substituted any of the above rings can be substituted by halogen, C alkyl, C alkenyl, C alkynyl, nitro, 1-6 2-6 2-6 cyano, C cycloalkyI, hydroxy, C alkoxy, haloC alkyl, halo C alkoxy, hydroxy C 3-7 1-6 1-6 1-6 1- alkyl, hydroxy C alkoxy, phenyl, an unsubstituted five-membered heteroaromatic ring 6 1-6 as just described, a six-membered heteroaromatic ring as just described, a six-membered saturated ring as just described or NR R ; each R and R is independently hydrogen 14 15 14 15 or C alkyl or R and R , together with the nitrogen atom to which they are attached, 1-6 14 15 may form a saturated 4-7 membered ring; and each R , R , R , R , R , R , R , R and R 2 3 4 5 6 7 8 9 10 is independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, formyl, CF , S(C alkyl), S(O)C alkyl, S(O) C alkyl, C alkylcarbonyl, C 3 1-4 1-4 2 1-4 1-4 1- alkyl, hydroxy C alkyl, C alkoxy, haloC alkoxy, hydroxy C alkoxy, C alkenyl, 6 1-6 1-6 1-6 1-6 2-6 C alkynyl, C alkylamino, di(C alkyl)amino; pharmaceutically acceptable salts 2-6 1-6 1-6 thereof ; solvates thereof and deuterated forms thereof in the manufacture of a medicament for the treatment or prevention of a flavivirus selected from the group consisting of Hepatitis C Virus (genotypes 1-7) and Japanese Encephalitis Virus.
10. The use according to claim 9 wherein Y in the above formula is X(C H )C(=O)NH and W is a member selected from the group consisting of 5184M-NZ 17 O wherein R and R each is independently selected from the group consisting of H, 16 17 halo, alkyl, alkoxy and aryl or R and R can be attached to form a five, six or seven 16 17 membered ring, that can be substituted by halogen, C alkyl, C alkenyl, C a1kynyl, 1-6 2-6 2-6 nitro, cyano, C cycloalkyl, hydroxy, C alkoxy, haloC alkyl, halo C alkoxy, hydroxy 3-7 1-6 1-6 1-6 C a1kyl, hydroxy C a1koxy, phenyl, an unsubstituted five-membered heteroaromatic 1-6 1-6 ring, a six-membered heteroaromatic ring, or a six-membered saturated ring.
11. Use according to claim 9 or 10 wherein W is a member selected from the group consisting of:
12. The use according to any one of claims 7 -11 wherein said alkyl and said alkoxy contain 1 to 4 carbon atoms.
13. The use according to claim 7, wherein each of R , R , R , R , R , R , R and R is 2 4 5 6 7 8 9 10 H and R is F; or of R , R , R , R , R , R and R is H, R is Cl and R is F; or 2 5 6 7 8 9 10 3 4 of R , R , R , R , R , R and R is H and R and R are each Cl; or 2 5 6 7 8 9 10 3 4 of R , R , R , R , R , R , R and R H and R is F; or 2 3 5 6 7 8 9 10 is 4 of R , R , R , R , R , R , R and R is H and R is F; or 2 3 4 5 6 7 9 10 8 of R , R , R , R , R , R , R and R is H and R is CH ; or 2 3 4 5 6 7 9 10 8 3 5184M-NZ of R , R , R , R , R , R , R and R is H and R is F; or 2 3 4 5 6 8 9 10 7 of R , R , R , R , R , R , R and R is H and R is I; or 2 3 4 5 6 8 9 10 7 of R , R , R , R , R , R , R and R is H and R is CH ; or 2 3 4 5 6 7 8 9 10 3 of R , R , R , R , R , R , R and R is H and R is OCH ; or 2 3 4 5 6 7 8 9 10 3 of R , R , R , R , R , R and R is H and each of R and R is Cl’ or 2 4 6 7 8 9 10 3 5 of R , R , R , R , R and R H and each of R , R and R is F; or 2 6 7 8 9 10 is 3 4 5 of R , R , R , R , R , R , R and R is H and R is F; or 2 3 4 5 6 8 9 10 7 of R , R , R , R , R and R is H and each of R and R is F and R is Cl; or 2 5 6 8 9 10 3 7 4 of R , R , R , R , R and R is H and each of R , R and R is F; or 2 3 6 8 9 10 4 5 7 of R , R , R , R , R and R is H and each of R R and R is F; or 2 5 6 8 9 10 3, 4 7 of each R , R , R , R and R is H and each of R , R , R and R is F; or 2 6 8 9 10 3 4 5 7 each R , R , R , R , R and R is H, each of R and R is Cl and R is F or 2 3 6 8 9 10 4 5 7 each R , R , R , R , R and R is H, each of R and R is Cl and R is F; or 2 5 6 8 9 10 3 4 7 each R , R , R , R , R and R is H, R is Br and each of R and R is F; or 2 3 6 8 9 10 5 4 7 each R , R , R , R , R and R is H, R is Br and each of R and R is F. 2 4 6 8 9 10 3 4 7 Dated this 6th day of November 2015 SOUTHERN RESEARCH INSTITUTE AND SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE FRASER OLD & SOHN Patent Attorneys for the Applicant
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201161522859P | 2011-08-12 | 2011-08-12 | |
US61/522,859 | 2011-08-12 | ||
PCT/US2012/050347 WO2013025508A1 (en) | 2011-08-12 | 2012-08-10 | Quinazolinone analogs and use of quinazolinone analogs for treating or preventing certain viral infections |
Publications (2)
Publication Number | Publication Date |
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NZ622331A NZ622331A (en) | 2015-11-27 |
NZ622331B2 true NZ622331B2 (en) | 2016-03-01 |
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