U.S. patent application number 17/370586 was filed with the patent office on 2021-12-30 for heterocyclic derivatives for the treatment of rsv.
The applicant listed for this patent is GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.. Invention is credited to Elyse BOURQUE, Eddy LEE, Richard K. PLEMPER, John VERNACHIO.
Application Number | 20210403444 17/370586 |
Document ID | / |
Family ID | 1000005839740 |
Filed Date | 2021-12-30 |
United States Patent
Application |
20210403444 |
Kind Code |
A1 |
PLEMPER; Richard K. ; et
al. |
December 30, 2021 |
HETEROCYCLIC DERIVATIVES FOR THE TREATMENT OF RSV
Abstract
Disclosed herein are compounds and compositions for treating or
inhibiting RSV and related members of the pneumovirus and
paramyxovirus families such as human metapneumovirus, mumps virus,
human parainfluenzaviruses, and Nipah and hendra virus, and methods
of treatment or prevention thereof.
Inventors: |
PLEMPER; Richard K.;
(Decatur, GA) ; LEE; Eddy; (Alpharetta, GA)
; VERNACHIO; John; (Alpharetta, GA) ; BOURQUE;
Elyse; (L'etang-du Nord, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC. |
Atlanta |
GA |
US |
|
|
Family ID: |
1000005839740 |
Appl. No.: |
17/370586 |
Filed: |
July 8, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16099957 |
Nov 8, 2018 |
11084796 |
|
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PCT/US2017/031945 |
May 10, 2017 |
|
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17370586 |
|
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62333996 |
May 10, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 279/16 20130101;
C07D 417/12 20130101; A61K 31/542 20130101; C07D 417/06 20130101;
A61K 31/5415 20130101; A61P 31/14 20180101; C12N 2760/18511
20130101 |
International
Class: |
C07D 279/16 20060101
C07D279/16; A61P 31/14 20060101 A61P031/14; A61K 31/542 20060101
A61K031/542; A61K 31/5415 20060101 A61K031/5415; C07D 417/06
20060101 C07D417/06; C07D 417/12 20060101 C07D417/12 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND
DEVELOPMENT
[0002] This invention was made with government support under grants
HD079327 and AI071002 awarded by the National Institutes of Health
(NIH). The government has certain rights in the invention.
Claims
1. A method of inhibiting RSV, comprising administering to a
patient in need thereof, an effective amount of a compound of
Formula 1: ##STR00147## or a pharmaceutically acceptable salt
thereof, wherein X is selected from O, S, or NR.sup.7; z is
selected from 0, 1, 2, 3, 4, 5, and 6; y is selected from 0, 1, 2,
3, 4, 5, and 6; R.sup.1 and R.sup.2 are independently selected from
R.sup.a, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, C(.dbd.O)R.sup.a,
C(.dbd.O)OR.sup.a, C(.dbd.O)N(R.sup.a).sub.2, C(.dbd.O)SR.sup.a;
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are independently selected
from independently selected from --R.sup.a, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2; wherein when multiple R.sup.a groups
are present, said R.sup.a groups may together form a ring; R.sup.7,
when present, is R.sup.a, C(O)R.sup.a, SO.sub.2R.sup.a, COOR.sup.a,
C(O)N(R.sup.a).sub.2, wherein either of R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 may together form a double bond wherein either
of R.sup.4 and R.sup.6 or R.sup.3 and R.sup.5 may together form a
carbonyl, imine or olefin; and wherein any of two or more of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 or R.sup.7, or
R.sup.a groups may together form a ring; and wherein R.sup.a is in
each case independently selected from hydrogen, C.sub.1-8 alkyl,
C.sub.3-8 cycloalkyl, C.sub.2-8 heterocyclyl, C.sub.6-12 aryl,
C.sub.3-12 heteroaryl, C.sub.1-8 alkyl-C.sub.3-8 cycloalkyl,
C.sub.1-8 alkyl-C.sub.2-8 heterocyclyl, C.sub.1-8 alkyl-C.sub.6-12
aryl, and C.sub.1-8 alkyl-C.sub.3-12 heteroaryl.
2. The method according to claim 1, wherein X is S.
3. The method according to claim 1, wherein R.sup.3 and R.sup.4
together form a ring.
4. The method according to claim 1, wherein R.sup.3 and R.sup.4
together form an aryl or heteroaryl ring.
5. The method according to claim 1, wherein R.sup.3 and R.sup.4 can
together form a phenyl ring, to give a compound of Formula 1b or
1b-i: ##STR00148## wherein a is selected from 0, 1, 2, 3 and 4; and
R.sup.8 is independently selected from --R.sup.a, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, wherein R.sup.a has the meanings as
set forth in claim 1.
6. The method according to claim 1, wherein z is 0.
7. The method according to claim 1, wherein y is 1.
8. The method according to claim 1, wherein R.sup.1 is
N(R.sup.a).sub.2.
9. The method according to claim 1, wherein R.sup.1 is selected
from ##STR00149## b is selected from 0, 1, 2, 3 and 4. R.sup.9 is
independently selected from --R.sup.a, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, wherein R.sup.a has the meanings given
above, and any two or more R.sup.9 groups may together form a ring;
wherein R.sup.10 when present, is independently selected from
R.sup.a, C(O)R.sup.a, SO.sub.2R.sup.a, COOR.sup.a,
C(O)N(R.sup.a).sub.2, wherein R.sup.10 may, with any one or more of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 or R.sup.7,
R.sup.8, or R.sup.a groups, together form a ring.
10. The method according to claim 1, wherein R.sup.1 is a group of
the formula: ##STR00150##
11. The method according to claim 1, wherein R.sup.2 is
C(.dbd.O)NHR.sup.a1, wherein said R.sup.a1 is selected from
C.sub.3-8 cycloalkyl, C.sub.2-8 heterocyclyl, C.sub.6-12 aryl, and
C.sub.3-12 heteroaryl.
12. The method according to claim 1, wherein R.sup.2 is
C(.dbd.O)NH--C.sub.3-8 cycloalkyl.
13. The method according to claim 1, wherein R.sup.2 is
C(.dbd.O)NHcyclohexyl.
14. The method according to claim 1 wherein the compound of formula
1 is: ##STR00151##
15. A method of treating or preventing an RSV infection, comprising
administering to a patient in need thereof, an effective amount of
a compound of Formula 1: ##STR00152## or a pharmaceutically
acceptable salt thereof, wherein X is selected from O, S, or
NR.sup.7; z is selected from 0, 1, 2, 3, 4, 5, and 6; y is selected
from 0, 1, 2, 3, 4, 5, and 6; R.sup.1 and R.sup.2 are independently
selected from R.sup.a, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a,
C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a, C(.dbd.O)N(R.sup.a).sub.2,
C(.dbd.O)SR.sup.a; R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are
independently selected from independently selected from --R.sup.a,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2; wherein when multiple R.sup.a groups
are present, said R.sup.a groups may together form a ring; R.sup.7,
when present, is R.sup.a, C(O)R.sup.a, SO.sub.2R.sup.a, COOR.sup.a,
C(O)N(R.sup.a).sub.2, wherein either of R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 may together form a double bond wherein either
of R.sup.4 and R.sup.6 or R.sup.3 and R.sup.5 may together form a
carbonyl, imine or olefin; and wherein any of two or more of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 or R.sup.7, or
R.sup.a groups may together form a ring; and wherein R.sup.a is in
each case independently selected from hydrogen, C.sub.1-8 alkyl,
C.sub.3-8 cycloalkyl, C.sub.2-8 heterocyclyl, C.sub.6-12 aryl,
C.sub.3-12 heteroaryl, C.sub.1-8 alkyl-C.sub.3-8 cycloalkyl,
C.sub.1-8 alkyl-C.sub.2-8 heterocyclyl, C.sub.1-8 alkyl-C.sub.6-12
aryl, and C.sub.1-8 alkyl-C.sub.3-12 heteroaryl.
16. The method of treating or preventing an RSV infection according
to claim 15 wherein the compound is administered via a route of
administration selected from the group consisting of buccal, oral,
intravenous, inhalation, intradermal, intramuscular, topical,
subcutaneous, rectal, vaginal, parenteral, pulmonary, intranasal,
and ophthalmic.
17. The method of treating or preventing an RSV infection according
to claim 15 wherein the compound of Formula 1 is selected from the
group consisting of: ##STR00153##
18. The method of treating or preventing an RSV infection according
to claim 15 wherein the compound of Formula 1 is: ##STR00154##
19. A compound of Formula 1: ##STR00155## or a pharmaceutically
acceptable salt thereof, wherein X is selected from O, S, or
NR.sup.7; z is selected from 0, 1, 2, 3, 4, 5, and 6; y is selected
from 0, 1, 2, 3, 4, 5, and 6; R.sup.1 and R.sup.2 are independently
selected from R.sup.a, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a,
C(.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a, C(.dbd.O)N(R.sup.a).sub.2,
C(.dbd.O)SR.sup.a; R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are
independently selected from independently selected from --R.sup.a,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2; wherein when multiple R.sup.a groups
are present, said R.sup.a groups may together form a ring; R.sup.7,
when present, is R.sup.a, C(O)R.sup.a, SO.sub.2R.sup.a, COOR.sup.a,
C(O)N(R.sup.a).sub.2, wherein either of R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 may together form a double bond wherein either
of R.sup.4 and R.sup.6 or R.sup.3 and R.sup.5 may together form a
carbonyl, imine or olefin; and wherein any of two or more of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 or R.sup.7, or
R.sup.a groups may together form a ring; and wherein R.sup.a is in
each case independently selected from hydrogen, C.sub.1-8 alkyl,
C.sub.3-8 cycloalkyl, C.sub.2-8 heterocyclyl, C.sub.6-12 aryl,
C.sub.3-12 heteroaryl, C.sub.1-8 alkyl-C.sub.3-8 cycloalkyl,
C.sub.1-8 alkyl-C.sub.2-8 heterocyclyl, C.sub.1-8 alkyl-C.sub.6-12
aryl, and C.sub.1-8 alkyl-C.sub.3-12 heteroaryl.
20. The compound according to claim 19 wherein the compound is
selected from the group consisting of: ##STR00156##
21. A pharmaceutical composition comprising the compound of claim
19 and a pharmaceutically acceptable carrier, vehicle, or
excipient.
22. A pharmaceutical composition comprising a compound of Formula
1: ##STR00157## or a pharmaceutically acceptable salt thereof,
wherein X is selected from O, S, or NR.sup.7; z is selected from 0,
1, 2, 3, 4, 5, and 6; y is selected from 0, 1, 2, 3, 4, 5, and 6;
R.sup.1 and R.sup.2 are independently selected from R.sup.a,
OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, C(.dbd.O)R.sup.a,
C(.dbd.O)OR.sup.a, C(.dbd.O)N(R.sup.a).sub.2, C(.dbd.O)SR.sup.a;
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are independently selected
from independently selected from --R.sup.a, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2; wherein when multiple R.sup.a groups
are present, said R.sup.a groups may together form a ring; R.sup.7,
when present, is R.sup.a, C(O)R.sup.a, SO.sub.2R.sup.a, COOR.sup.a,
C(O)N(R.sup.a).sub.2, wherein either of R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 may together form a double bond wherein either
of R.sup.4 and R.sup.6 or R.sup.3 and R.sup.5 may together form a
carbonyl, imine or olefin; and wherein any of two or more of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 or R.sup.7, or
R.sup.a groups may together form a ring; and wherein R.sup.a is in
each case independently selected from hydrogen, C.sub.1-8 alkyl,
C.sub.3-8 cycloalkyl, C.sub.2-8 heterocyclyl, C.sub.6-12 aryl,
C.sub.3-12 heteroaryl, C.sub.1-8 alkyl-C.sub.3-8 cycloalkyl,
C.sub.1-8 alkyl-C.sub.2-8 heterocyclyl, C.sub.1-8 alkyl-C.sub.6-12
aryl, and C.sub.1-8 alkyl-C.sub.3-12 heteroaryl; and a
pharmaceutically acceptable carrier, vehicle, or excipient.
23. The pharmaceutical composition according to claim 22 wherein
the compound is selected from the group consisting of:
##STR00158##
24. The pharmaceutical composition according to claim 22 wherein
the compound is: ##STR00159##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. Ser.
No. 16/099,957 having a filing date of Nov. 8, 2018, which was a
371 application of International application PCT/US2017/031945
filed on May 10, 2017, which claimed the benefit of U.S.
Provisional Application Ser. No. 62/333,996, filed May 10, 2016,
the disclosures of all said applications being incorporated herein
in their entirety.
FIELD OF THE INVENTION
[0003] The invention relates to the use of small molecule
therapeutics for the treatment of respiratory syncytial virus (RSV)
and related members of the pneumovirus and paramyxovirus family
such as human metapneumovirus, mumps virus, human
parainfluenzaviruses, and Nipah and hendra virus.
BACKGROUND
[0004] Respiratory syncytial virus (RSV) is a member of the
paramyxovirus family, which consists of mostly highly contagious
nonsegmented, negative polarity RNA viruses that spread through the
respiratory route. Specifically, RSV is a member of the order
Mononegavirales, which consists of the non-segmented negative
strand RNA viruses in the Families Paramyxoviridae, Pneumoviridae;
Bunyaviridae, Rhabdoviridae and Filoviridae. RSV of humans (often
also termed RSV or HRSV) is a member of the Pneumoviridae. Based on
genetic and antigenic variations in the structural proteins, RSV is
classified into two subgroups, A and B (Mufson, M. et al., J. Gen.
Virol. 66:2111-2124). Other members of the Pneumovirus family
include viruses such as bovine RSV (BRSV), ovine RSV (ORSV),
pneumonia virus of mice (PVM), and the human metapneumoviruses
amongst others.
[0005] In addition to the genome features described above, family
characteristics include a lipid envelope containing one or more
glycoprotein species considered to be associated with attachment
and entry of the host cell. Entry is considered to require a
process by which the viral envelope fuses with the membrane of the
host cell. Fusion of infected cells with, for example, their
neighbors, can also result in the formation of fused multinucleate
cells known as syncytia in some cases. The fusion process is
believed to be glycoprotein mediated and is a feature shared with
diverse enveloped viruses in other taxonomic groups. In the case of
the pneumo- and paramyxoviruses, virions characteristically express
a fusion glycoprotein (F), which mediates membrane fusion.
[0006] Respiratory syncytial virus (RSV) is the leading cause of
acute upper and lower respiratory tract infections (LRTI) in
adults, young children and infants. Although at risk populations
include the hospitalized, elderly and high-risk adults, RSV is
primarily considered to be a pediatric disease due to the
prevalence and severity of unfavorable outcomes in infants. Acute
LRTI infections are a leading cause of global childhood mortality
and morbidity. Serological evidence indicates that in the western
world approximately 95% of all children have been infected with RSV
by the age of two and 100% of children have been exposed by the
time they reach adulthood.
[0007] RSV disease is thus the leading cause of virus
infection-induced death among children less than 1 year of age and
can be life-threatening to the elderly and the immunocompromised.
Reinfection with RSV can occur throughout life, but infants born
prematurely, or with bronchopulmonary dysplasia or a congenital
heart defect, are at highest risk of developing severe disease. In
a typical case, initial RSV infection of airway epithelia cells is
followed by rapid spread from the nasopharynx to the lower airways
that can affect respiratory function through excessive mucus,
necrotic epithelial debris, and inflammatory cells obstructing the
airways.
[0008] RSV is a seasonal infectious disease that generally runs
from November to March/April in the Northern Hemisphere. In more
tropical climates, the annual epidemics are more variable, often
coinciding with the wet season. In most cases the RSV infections
will only cause minor upper respiratory illness with symptoms
resembling that of the common cold. However, severe infection with
the virus may result in bronchiolitis or pneumonia, which may
result in hospitalization or death. Further, since the immune
response to RSV infection is not protective, RSV infections reoccur
throughout adulthood. Annual re-infection rates in adults of 3-6%
have been observed.
[0009] RSV infections place a significant burden on the healthcare
system. This is particularly so in the case of infants such as, for
example, immunodeficient infants, which on average spend twice as
long in hospital as other patients with an RSV infection (7-8 days
compared to 3-4 days). Hospitalization of infants with acute
RSV-related bronchiolitis or RSV-related pneumonia involves
supportive care management with oxygen therapy, fluids to prevent
dehydration, nasal suctioning and respiratory support. There is
also an economic impact associated with parents taking time away
from work to care for their child.
[0010] Attempts to develop an effective RSV vaccine have been
fruitless thus far, because the virus is poorly immunogenic overall
and neutralizing antibody titers wane quickly after infection.
Although ribavirin has been approved for RSV treatment, it has not
been widely adopted in clinical use due to efficacy and toxicity
issues. The humanized neutralizing antibody palivizumab is used for
immunoprophylaxis of high-risk pediatric patients, but high costs
prohibit broad-scale implementation.
[0011] Accordingly, there remains an urgent and unmet need for new
compounds that are useful in the treatment and prevention of RSV
infections. Small-molecule drug-like therapeutics have high promise
to provide a novel avenue towards RSV disease management and
prevention. It is therefore an object of the present invention to
provide new small-molecule therapeutics classes for the treatment
of human patients and other hosts infected with RSV.
SUMMARY
[0012] Disclosed herein are compounds, compositions, and methods of
inhibiting RSV, or treating or preventing RSV infection in a
patient in need thereof. RSV can be inhibited, and RSV infection
can be treated or prevented by administering to a patient in need
thereof a composition containing an anti-RSV compound of Formula
1:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein [0013] X is
selected from O, S, or NR.sup.7; [0014] z and y are independently
selected from an integer from 0-6; [0015] R.sup.1 and R.sup.2 are
independently selected from R.sup.a, OR.sup.a, N(R.sup.a).sub.2,
SR.sup.a, wherein R.sup.a is in each case independently selected
hydrogen, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, C.sub.2-8
heterocyclyl, C.sub.6-12 aryl, C.sub.3-12 heteroaryl, C.sub.1-8
alkyl-C.sub.3-8 cycloalkyl, C.sub.1-8 alkyl-C.sub.2-8 heterocyclyl,
C.sub.1-8 alkyl-C.sub.6-12 aryl, and C.sub.1-8 alkyl-C.sub.3-12
heteroaryl; and when N(R.sup.a).sub.2 is present, [0016] R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 are independently selected from
independently selected from --R.sup.a, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2; wherein R.sup.a is independently
selected from the definitions given above, [0017] R.sup.7, when
present, is R.sup.a, C(O)R.sup.a, SO.sub.2R.sup.a, COOR.sup.a,
C(O)N(R.sup.a).sub.2, wherein either of R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 may together form a double bond wherein either
of R.sup.4 and R.sup.6 or R.sup.3 and R.sup.5 may together form a
carbonyl, imine or olefin; wherein any of two or more of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 or R.sup.7, or R.sup.a
groups may together form a ring.
[0018] The details of one or more embodiments are set forth in the
descriptions below. Other features, objects, and advantages will be
apparent from the description and from the claims.
BRIEF DESCRIPTION OF THE FIGURES
[0019] FIG. 1 includes a depiction of the virus yield of an RSV
inhibitor in accordance with the invention [RSVP-172944] as a
function of concentration.
[0020] FIG. 2 includes a depiction of the RdRp activity of an RSV
inhibitor in accordance with the invention [RSVP-172944] as a
function of concentration.
[0021] FIG. 3 includes a depiction of the activity of an RSV
inhibitor in accordance with the invention [RSVP-172944] in tabular
format.
DETAILED DESCRIPTION
[0022] Before the present compounds, compositions, methods and
systems are disclosed and described, it is to be understood that
the methods and systems are not limited to specific synthetic
methods, specific compounds, specific components, or to particular
compositions. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments only
and is not intended to be limiting.
[0023] As used in the specification and the appended claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise. Ranges may be expressed
herein as from "about" one particular value, and/or to "about"
another particular value. When such a range is expressed, another
embodiment includes, from the one particular value and/or to the
other particular value. Similarly, when values are expressed as
approximations, by use of the antecedent "about," it will be
understood that the particular value forms another embodiment. It
will be further understood that the endpoints of each of the ranges
are significant both in relation to the other endpoint, and
independently of the other endpoint.
[0024] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances where it does not.
[0025] Throughout the description and claims of this specification,
the word "comprise" and variations of the word, such as
"comprising" and "comprises," means "including but not limited to,"
and is not intended to exclude, for example, other additives,
components, integers or steps. "Exemplary" means "an example of"
and is not intended to convey an indication of a preferred or ideal
embodiment. "Such as" is not used in a restrictive sense, but for
explanatory purposes.
[0026] Disclosed are components that can be used to perform the
disclosed methods and systems. These and other components are
disclosed herein, and it is understood that when combinations,
subsets, interactions, groups, etc. of these components are
disclosed that while specific reference of each various individual
and collective combinations and permutation of these may not be
explicitly disclosed, each is specifically contemplated and
described herein, for all methods and systems. This applies to all
aspects of this application including, but not limited to, steps in
disclosed methods. Thus, if there are a variety of additional steps
that can be performed it is understood that each of these
additional steps can be performed with any specific embodiment or
combination of embodiments of the disclosed methods.
[0027] Unless stated to the contrary, a formula with chemical bonds
shown only as solid lines and not as wedges or dashed lines
contemplates each possible isomer, e.g., each enantiomer,
diastereomer, and meso compound, and a mixture of isomers, such as
a racemic or scalemic mixture.
[0028] The term "alkyl" as used herein is a branched or unbranched
hydrocarbon group such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl,
decyl, dodecyl, and the like. The alkyl group can also be
substituted or unsubstituted. Unless stated otherwise, the term
"alkyl" contemplates both substituted and unsubstituted alkyl
groups. The alkyl group can be substituted with one or more groups
including, but not limited to, alkoxy, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino,
carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro,
silyl, sulfo-oxo, or thiol as described herein. An alkyl group
which contains no double or triple carbon-carbon bonds is
designated a saturated alkyl group, whereas an alkyl group having
one or more such bonds is designated an unsaturated alkyl
group.
[0029] Unsaturated alkyl groups having a double bond can be
designated alkenyl groups, and unsaturated alkyl groups having a
triple bond can be designated alkynyl groups. Unless specified to
the contrary, the term alkyl embraces both saturated and
unsaturated groups.
[0030] The term "cycloalkyl" as used herein is a non-aromatic
carbon-based ring composed of at least three carbon atoms. Examples
of cycloalkyl groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, etc. The term
"heterocycloalkyl" is a cycloalkyl group as defined above where at
least one of the carbon atoms of the ring is replaced with a
heteroatom such as, but not limited to, nitrogen, oxygen, sulfur,
selenium or phosphorus. The cycloalkyl group and heterocycloalkyl
group can be substituted or unsubstituted. Unless stated otherwise,
the terms "cycloalkyl" and "heterocycloalkyl" contemplate both
substituted and unsubstituted cyloalkyl and heterocycloalkyl
groups. The cycloalkyl group and heterocycloalkyl group can be
substituted with one or more groups including, but not limited to,
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,
halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol as
described herein. A cycloalkyl group which contains no double or
triple carbon-carbon bonds is designated a saturated cycloalkyl
group, whereas an cycloalkyl group having one or more such bonds
(yet is still not aromatic) is designated an unsaturated cycloalkyl
group. Unless specified to the contrary, the term alkyl embraces
both saturated and unsaturated groups.
[0031] The term "aryl" as used herein is an aromatic ring composed
of carbon atoms. Examples of aryl groups include, but are not
limited to, phenyl and naphthyl, etc. The term "heteroaryl" is an
aryl group as defined above where at least one of the carbon atoms
of the ring is replaced with a heteroatom such as, but not limited
to, nitrogen, oxygen, sulfur, selenium or phosphorus. The aryl
group and heteroaryl group can be substituted or unsubstituted.
Unless stated otherwise, the terms "aryl" and "heteroaryl"
contemplate both substituted and unsubstituted aryl and heteroaryl
groups. The aryl group and heteroaryl group can be substituted with
one or more groups including, but not limited to, alkyl, alkoxy,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy,
ketone, nitro, silyl, sulfo-oxo, or thiol as described herein.
[0032] Exemplary heteroaryl and heterocyclyl rings include:
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,
carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyL
cirrnolinyl, decahydroquinolinyl, 2H,6H.about.1,5,2-dithiazinyl,
dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,
methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,
quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl, and xanthenyl.
[0033] The terms "alkoxy," "cycloalkoxy," "heterocycloalkoxy,"
"cycloalkoxy," "aryloxy," and "heteroaryloxy" have the
aforementioned meanings for alkyl, cycloalkyl, heterocycloalkyl,
aryl and heteroaryl, further providing said group is connected via
an oxygen atom.
[0034] As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a
broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic, and
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
below. The permissible substituents can be one or more and the same
or different for appropriate organic compounds. For purposes of
this disclosure, the heteroatoms, such as nitrogen, can have
hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valencies of
the heteroatoms. This disclosure is not intended to be limited in
any manner by the permissible substituents of organic compounds.
Also, the terms "substitution" or "substituted with" include the
implicit proviso that such substitution is in accordance with
permitted valence of the substituted atom and the substituent, and
that the substitution results in a stable compound, e.g., a
compound that does not spontaneously undergo transformation such as
by rearrangement, cyclization, elimination, etc. Unless
specifically stated, a substituent that is said to be "substituted"
is meant that the substituent is substituted with one or more of
the following: alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, aldehyde, amino, carboxylic
acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,
sulfo-oxo, or thiol as described herein. In a specific example,
groups that are said to be substituted are substituted with a
protic group, which is a group that can be protonated or
deprotonated, depending on the pH.
[0035] Unless specified otherwise, the term "patient" refers to any
mammalian organism, including but not limited to, humans.
[0036] Pharmaceutically acceptable salts are salts that retain the
desired biological activity of the parent compound and do not
impart undesirable toxicological effects. Examples of such salts
are acid addition salts formed with inorganic acids, for example,
hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids
and the like; salts formed with organic acids such as acetic,
oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric,
malic, methanesulfonic, p-toluenesulfonic, napthalenesulfonic, and
polygalacturonic acids, and the like; salts formed from elemental
anions such as chloride, bromide, and iodide; salts formed from
metal hydroxides, for example, sodium hydroxide, potassium
hydroxide, calcium hydroxide, lithium hydroxide, and magnesium
hydroxide; salts formed from metal carbonates, for example, sodium
carbonate, potassium carbonate, calcium carbonate, and magnesium
carbonate; salts formed from metal bicarbonates, for example,
sodium bicarbonate and potassium bicarbonate; salts formed from
metal sulfates, for example, sodium sulfate and potassium sulfate;
and salts formed from metal nitrates, for example, sodium nitrate
and potassium nitrate. Pharmaceutically acceptable and
non-pharmaceutically acceptable salts may be prepared using
procedures well known in the art, for example, by reacting a
sufficiently basic compound such as an amine with a suitable acid
comprising a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium, or lithium) or alkaline earth metal
(for example, calcium) salts of carboxylic acids can also be
made.
[0037] Disclosed herein are compounds, compositions and methods of
inhibiting RSV or treating or preventing RSV infection in a patient
in need thereof by administering to the patient an effective amount
of at least one RSV inhibiting compound. In certain embodiments,
the RSV inhibiting compound has the structure of Formula I:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein [0038] X is
selected from O, S, or NR.sup.7; [0039] z and y are independently
selected from an integer from 0-6; [0040] R.sup.1 and R.sup.2 are
independently selected from R.sup.a, OR.sup.a, N(R.sup.a).sub.2,
SR.sup.a, C(.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a,
C(.dbd.O)N(R.sup.a).sub.2, C(.dbd.O)SR.sup.a, [0041] wherein
R.sup.a is in each case independently selected hydrogen, C.sub.1-8
alkyl, C.sub.3-8 cycloalkyl, C.sub.2-8 heterocyclyl, C.sub.6-12
aryl, C.sub.3-12 heteroaryl, C.sub.1-8 alkyl-C.sub.3-8 cycloalkyl,
C.sub.1-8 alkyl-C.sub.2-8 heterocyclyl, C.sub.1-8 alkyl-C.sub.6-12
aryl, and C.sub.1-8 alkyl-C.sub.3-12 heteroaryl; and when
N(R.sup.a).sub.2 is present, said two R.sup.a groups may together
form a ring; [0042] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are
independently selected from independently selected from --R.sup.a,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2; wherein R.sup.a is independently
selected from the definitions given above, [0043] R.sup.7, when
present, is R.sup.a, C(O)R.sup.a, SO.sub.2R.sup.a, COOR.sup.a,
C(O)N(R.sup.a).sub.2, wherein either of R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 may together form a double bond wherein either
of R.sup.4 and R.sup.6 or R.sup.3 and R.sup.5 may together form a
carbonyl, imine or olefin; wherein any of two or more of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 or R.sup.7, or R.sup.a
groups may together form a ring.
[0044] As used herein, the term olefin includes unsubstituted
methylene (e.g., .dbd.CH.sub.2), as well as substituted groups
including the functional groups falling with the definitions of
R.sup.3, R.sup.4, R.sup.5, or R.sup.6. The term imine includes the
primary imine (e.g., .dbd.NH) as well as substituted imines
including the functional groups falling with the definitions of
R.sup.7.
[0045] In certain embodiments, X is S. The RSV inhibiting compound
can have the structure of Formula 1a
##STR00003##
wherein R.sup.1-R.sup.6, y, and z have the meanings given for the
compound of Formula 1.
[0046] In some cases, the R.sup.3 and R.sup.4 together form a ring,
preferably an aryl or heteroaryl ring. In some instance, the
R.sup.3 and R.sup.4 can together form a phenyl ring, e.g., the RSV
inhibiting compound can have the structure of Formula 1 b or 1
b-i:
##STR00004##
wherein R.sup.1, R.sup.2, X, y and z are as defined above, a is
selected from 0, 1, 2, 3 and 4, and R.sup.8 includes --R.sup.a,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --SO.sub.2R.sup.a,
--SO.sub.2N(R.sup.a).sub.2; --C(O)R.sup.a, OC(O)R.sup.a,
--COOR.sup.a, --C(O)N(R.sup.a).sub.2, --OC(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O), --N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl,
--Br, --I, --CN, --NO.sub.2. When multiple R.sup.8 groups are
present, each R.sup.8 group is selected independently from the list
provided above. In some embodiments, it is preferred that a is
0.
[0047] In certain embodiments, it is preferred that z is 0 and y is
1:
##STR00005##
wherein R.sup.1-R.sup.8, X, and a have the meanings given
above.
[0048] In certain preferred embodiments of the above compounds
(e.g., Formula 1, Formula 1a, Formula 1b, Formula 1b-I, Formula
1-xy, Formula 1a-xy, Formula 1b-xy, and Formula 1 b-i-xy), R.sup.1
is defined as N(R.sup.a).sub.2. In especially preferred
embodiments, N(R.sup.a).sub.2 is a group selected from:
##STR00006##
Wherein R.sup.7 is as defined above, R.sup.9 is independently
selected from --R.sup.a, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --SO.sub.2R.sup.a, --SO.sub.2N(R.sup.a).sub.2,
--C(O)R.sup.a, OC(O)R.sup.a, --COOR.sup.a, --C(O)N(R.sup.a).sub.2,
--OC(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O),
--N(R.sup.a)C(O)N(R.sup.a).sub.2, --F, --Cl, --Br, --I, --CN,
--NO.sub.2, wherein R.sup.a has the meanings given above, and any
two or more R.sup.9 groups may together form a ring, and b is
selected from 0, 1, 2, 3 and 4. In certain preferred embodiments,
R.sup.1 is a group of the formula:
##STR00007##
[0049] In certain preferred embodiments of the above compounds
(e.g., Formula 1, Formula 1a, Formula 1b, Formula 1b-I, Formula
1-xy, Formula 1a-xy, Formula 1b-xy, and Formula 1 b-i-xy), R.sup.2
is defined as C(.dbd.O)N(R.sup.a).sub.2. For instance, R.sup.2 can
be C(.dbd.O)NHR.sup.a, wherein the R.sup.a group present in R.sup.2
is C.sub.3-8 cycloalkyl, C.sub.2-8 heterocyclyl, C.sub.6-12 aryl,
or C.sub.3-12 heteroaryl. Preferred groups include C.sub.5-6
cycloalkyl and C.sub.6 aryl.
[0050] The following compounds in accordance with the present
invention and also known as the "C" series are shown in Table 1
below:
TABLE-US-00001 TABLE 1 Compounds of the Invention AVG-044 (172944)
C ##STR00008## AVG-045 C ##STR00009## AVG-046 C ##STR00010##
AVG-047 C ##STR00011## AVG-048 C ##STR00012## AVG-049 C
##STR00013## AVG-050 C ##STR00014## AVG-051 C ##STR00015## AVG-052
C ##STR00016## AVG-053 C ##STR00017## AVG-054 C ##STR00018##
AVG-055 C ##STR00019## AVG-056 C ##STR00020## AVG-057 C
##STR00021## AVG-058 C ##STR00022## AVG-059 C ##STR00023## AVG-060
C ##STR00024## AVG-061 C ##STR00025## AVG-062 C ##STR00026##
AVG-063 C ##STR00027## AVG-064 C ##STR00028## AVG-083 C
##STR00029## AVG-084 C ##STR00030## AVG-085 C ##STR00031## AVG-086
C ##STR00032## AVG-087 (purity <90%) C ##STR00033## AVG-111 C
##STR00034## AVG-112 C ##STR00035## AVG-113 C ##STR00036## AVG-114
C ##STR00037## AVG-137 C ##STR00038## AVG-138 C ##STR00039##
AVG-139 C ##STR00040## AVG-140 C ##STR00041## AVG-141 C
##STR00042## AVG-142 C ##STR00043## AVG-143 C ##STR00044## AVG-144
C ##STR00045## AVG-145 C ##STR00046## AVG-146 C ##STR00047##
AVG-147 C ##STR00048## AVG-148 C ##STR00049## AVG-149 C
##STR00050## AVG-150 C ##STR00051## AVG-151 C ##STR00052## AVG-152
C ##STR00053## AVG-153 C ##STR00054## AVG-154 C ##STR00055##
AVG-155 C ##STR00056## AVG-156 C ##STR00057## AVG-182 C
##STR00058## AVG-215 C ##STR00059## AVG-216 C ##STR00060## AVG-217
C ##STR00061## AVG-218 C ##STR00062## AVG-219 C ##STR00063##
AVG-220 C ##STR00064## AVG-221 C ##STR00065## AVG-222 C
##STR00066## AVG-223 C ##STR00067## AVG-224 C ##STR00068## AVG-235
C ##STR00069## AVG-236 C ##STR00070## AVG-237 C ##STR00071##
AVG-238 C ##STR00072##
[0051] The compounds defined in the above aspects are RSV antiviral
agents and are useful in the treatment of RSV infections.
Accordingly, these compounds of the invention are useful in the
treatment of RSV disease, such as bronchiolitis or pneumonia, or in
reducing exacerbation of underlying or pre-existing respiratory
diseases or conditions wherein RSV infection is a cause of said
exacerbation. The underlying or pre-existing respiratory diseases
or conditions may include asthma, chronic obstructive pulmonary
disease (COPD) and immunosuppression such as immunosuppression
experienced by bone marrow transplant recipients. The compounds
above may also be combined with one or more other RSV antiviral
agents.
[0052] The compounds of the invention may be formulated as
pharmaceutical compositions and administered to a human patient as
set forth in more detail below. The compounds can be delivered in a
number of suitable ways including orally, intravenously, topically,
parentally, subcutaneously, intradermally, or by inhalation.
Exemplary routes of administration include buccal, oral,
intravenous, intramuscular, topical, subcutaneous, rectal, vaginal,
parenteral, pulmonary, intranasal, ophthalmic, and the like, as set
forth in more detail below.
[0053] Useful dosages of the compounds of the invention for
inclusion in the pharmaceutical compositions of the invention can
be determined by comparing in vitro activity and in vivo activity
of the compounds in appropriate animal models. Generally, the
concentration of the compound(s) of the invention in a liquid
composition will range from about 0.1% to about 95% by weight,
preferably from about 0.5% to about 25% by weight. The
concentration in a semi-solid or solid composition will range from
about 0.1% to 100% by weight, preferably about 0.5% to about 5% by
weight. Single doses for intravenous injection, subcutaneous,
intramuscular or topical administration, infusion, ingestion or
suppository will generally be from about 0.001 to about 5000 mg,
and be administered from about 1 to about 3 times daily, to yield
levels of about 0.01 to about 500 mg/kg, for adults.
[0054] The compounds can be co-administered with one or more other
agents for the treatment or prevention of RSV infection. The other
agents can be formulated separately, and administered either at the
same or different time as the compounds of the instant invention.
The other agents can be co-formulated with the compounds of the
instant invention to give a combination dosage form.
Pharmaceutical Compositions and Modes of Administration
[0055] The invention also provides a pharmaceutical composition
comprising a compound of formula (I) and a pharmaceutically
acceptable vehicle, excipient or carrier, and the form of this
composition can be suitable for a number of different modes of
administration to a patient as set forth below.
[0056] The pharmaceutical composition may further comprise or be
administered in combination with one or more other RSV antiviral
agents such as Virazole.RTM., BMS-4337715, TMC3531216, MDT-637
(formerly VP-14637), GS-5806, RSV604, ALNRSV01, AL-8176 (or
ALS-8176) and/or other agents that may be developed as inhibitors
of viral entry, assembly, replication, egress or host-virus
interactions
[0057] The term "composition" is intended to include the
formulation of an active ingredient with conventional vehicles,
carriers and excipients, and also with encapsulating materials as
the carrier, to give a capsule in which the active ingredient (with
or without other carriers) is surrounded by the encapsulation
carrier. Any carrier must be "pharmaceutically acceptable" meaning
that it is compatible with the other ingredients of the composition
and is not deleterious to a subject. The compositions of the
present invention may contain other therapeutic agents as described
above, and may be formulated, for example, by employing
conventional solid or liquid vehicles or diluents, as well as
pharmaceutical additives of a type appropriate to the mode of
desired administration (for example, excipients, binders,
preservatives, stabilizers, flavours and the like) according to
techniques such as those well known in the art of pharmaceutical
formulation (see, for example, Remington: The Science and Practice
of Pharmacy, 21st Ed., 2005, Lippincott Williams &
Wilkins).
[0058] The pharmaceutical composition includes those suitable for
oral, rectal, nasal, topical (including buccal and sub-lingual),
vaginal or parenteral (including intramuscular, sub-cutaneous and
intravenous) administration or in a form suitable for
administration by inhalation or insufflation.
[0059] The compounds of the invention, together with a conventional
adjuvant, carrier, or diluent, may thus be placed into the form of
pharmaceutical compositions and unit dosages thereof, and in such
form may be employed as solids, such as tablets or filled capsules,
or liquids such as solutions, suspensions, emulsions, elixirs, or
capsules filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile
injectable solutions for parenteral (including subcutaneous)
use.
[0060] Such pharmaceutical compositions and unit dosage forms
thereof may comprise conventional ingredients in conventional
proportions, with or without additional active compounds or
principles, and such unit dosage forms may contain any suitable
effective amount of the active ingredient commensurate with the
intended daily dosage range to be employed.
[0061] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispensable
granules. A solid carrier can be one or more substances which may
also act as diluents, flavouring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0062] Suitable vehicles, carriers or excipients include magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter and the
like. The term "preparation" is intended to include the formulation
of the active compound with an encapsulating material as the
carrier by providing a capsule in which the active component, with
or without carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid forms suitable for oral administration.
[0063] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water-propylene glycol solutions.
For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol
solution.
[0064] Sterile liquid form compositions include sterile solutions,
suspensions, emulsions, syrups and elixirs. The active ingredient
can be dissolved or suspended in a pharmaceutically acceptable
carrier, such as sterile water, sterile organic solvent or a
mixture of both.
[0065] The compositions according to the present invention may thus
be formulated for parenteral administration (for example, by
injection, for example bolus injection or continuous infusion) and
may be presented in unit dose form in ampoules, pre-filled
syringes, small volume infusion or in multi-dose containers with an
added preservative. The compositions may take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles,
and may contain formulation agents such as suspending, stabilising
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form, obtained by aseptic isolation of sterile solid
or by lyophilisation from solution, for constitution with a
suitable vehicle, for example, sterile, pyrogen-free water, before
use.
[0066] Pharmaceutical forms suitable for injectable use include
sterile injectable solutions or dispersions, and sterile powders
for the extemporaneous preparation of sterile injectable solutions.
They should be stable under the conditions of manufacture and
storage and may be preserved against oxidation and the
contaminating action of microorganisms such as bacteria or
fungi.
[0067] The solvent or dispersion medium for the injectable solution
or dispersion may contain any of the conventional solvent or
carrier systems for the compounds, and may contain, for example,
water, ethanol, polyol (for example, glycerol, propylene glycol and
liquid polyethylene glycol and the like), suitable mixtures
thereof, and vegetable oils.
[0068] Pharmaceutical forms suitable for injectable use may be
delivered by any appropriate route including intravenous,
intramuscular, intracerebral, intrathecal, epidural injection or
infusion.
[0069] Sterile injectable solutions are prepared by incorporating
the active compounds in the required amount in the appropriate
solvent with various other ingredients such as these enumerated
above, as required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilised
active ingredient into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, preferred methods of
preparation are vacuum drying or freeze-drying of a previously
sterile-filtered solution of the active ingredient plus any
additional desired ingredients.
[0070] When the active ingredients are suitably protected they may
be orally administered, for example, with an inert diluent or with
an assimilable edible carrier, or they may be enclosed in hard or
soft shell gelatin capsule, or they may be compressed into tablets,
or they may be incorporated directly with the food of the diet. For
oral therapeutic administration, the active compound may be
incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions,
syrups, wafers and the like.
[0071] The amount of active compound in therapeutically useful
compositions should be sufficient that a suitable dosage will be
obtained.
[0072] The tablets, troches, pills, capsules and the like may also
contain the components as listed hereafter: a binder such as gum,
acacia, corn starch or gelatin; excipients such as dicalcium
phosphate; a disintegrating agent such as corn starch, potato
starch, alginic acid and the like; a lubricant such as magnesium
stearate; and a sweetening agent such a sucrose, lactose or
saccharin; or a flavouring agent such as peppermint, oil of
wintergreen, or cherry flavouring. When the dosage unit form is a
capsule, it may contain, in addition to materials of the above
type, a liquid carrier.
[0073] Various other materials may be present as coatings or to
otherwise modify the physical form of the dosage unit. For
instance, tablets, pills, or capsules may be coated with shellac,
sugar or both. A syrup or elixir may contain the active compound,
sucrose as a sweetening agent, methyl and propylparabens as
preservatives, a dye and flavouring such as cherry or orange
flavour. Of course, any material used in preparing any dosage unit
form should be pharmaceutically pure and substantially non-toxic in
the amounts employed. In addition, the active compound(s) may be
incorporated into sustained-release preparations and formulations,
including those that allow specific delivery of the active peptide
to specific regions of the gut.
[0074] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavours, stabilising and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing
the finely divided active component in water with viscous material,
such as natural or synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, or other well-known suspending agents.
[0075] Pharmaceutically acceptable carriers and/or diluents include
any and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents and the
like.
[0076] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavours, stabilisers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilising agents and the like.
[0077] For topical administration to the epidermis the compounds
according to the invention may be formulated as ointments, creams
or lotions, or as a transdermal patch. Ointments and creams may,
for example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
contain one or more emulsifying agents, stabilising agents,
dispersing agents, suspending agents, thickening agents, or
colouring agents.
[0078] Formulations suitable for topical administration in the
mouth include lozenges comprising active agent in a flavoured base,
usually sucrose and acacia or tragacanth; pastilles 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.
[0079] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The formulations may be provided in single or multidose
form. In the latter case of a dropper or pipette, this may be
achieved by the patient administering an appropriate, predetermined
volume of the solution or suspension.
[0080] In the case of a spray, this may be achieved for example by
means of a metering atomising spray pump. To improve nasal delivery
and retention the compounds according to the invention may be
encapsulated with cyclodextrins, or formulated with other agents
expected to enhance delivery and retention in the nasal mucosa.
[0081] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurised pack with a suitable propellant such
as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, a
hydrofluorocarbon (HFC) for example hydrofluoroalkanes (HFA),
carbon dioxide, or other suitable gas.
[0082] The aerosol may conveniently also contain a surfactant such
as lecithin. The dose of drug may be controlled by provision of a
metered valve.
[0083] Alternatively the active ingredients may be provided in the
form of a dry powder, for example a powder mix of the compound in a
suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP). Conveniently the powder carrier will form a gel in the nasal
cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of, for example gelatin, or
blister packs from which the powder may be administered by means of
an inhaler.
[0084] In formulations intended for administration to the
respiratory tract, including intranasal formulations, the compound
will generally have a small particle size for example of the order
of 5 to 10 microns or less. Such a particle size may be obtained by
means known in the art, for example by micronization.
[0085] When desired, formulations adapted to give sustained release
of the active ingredient may be employed.
[0086] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0087] It is especially advantageous to formulate parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used herein refers to
physically discrete units suited as unitary dosages for the
subjects to be treated; each unit containing a predetermined
quantity of active material calculated to produce the desired
therapeutic effect in association with the required pharmaceutical
carrier. The specification for the novel dosage unit forms of the
invention are dictated by and directly dependent on (a) the unique
characteristics of the active material and the particular
therapeutic effect to be achieved, and (b) the limitations inherent
in the art of compounding such an active material for the treatment
of viral infection in living subjects having a diseased condition
in which bodily health is impaired as herein disclosed in
detail.
[0088] The invention also includes the compounds in the absence of
carrier where the compounds are in unit dosage form.
[0089] Liquids or powders for intranasal administration, tablets or
capsules for oral administration and liquids for intravenous
administration are the preferred compositions.
[0090] The compounds as set forth above can be useful in a method
of inhibiting RSV or in treating or preventing an RSV infection of
other infections caused by related members of the paramyxovirus
family such as mumps virus, human parainfluenzaviruses, and Nipah
and hendra virus. The reference to RSV as used hereinbelow also
include these related members or the paramyxovirus family compounds
can also be used to treat an RSV disease or reduce exacerbation of
an underlying or pre-existing respiratory disease wherein RSV
infection is a cause of said exacerbation. The RSV disease may
include bronchiolitis or pneumonia. The underlying or pre-existing
respiratory diseases or conditions may include asthma, chronic
obstructive pulmonary disease (COPD) and immunosuppression such as
immunosuppression experienced by bone marrow transplant
recipients.
[0091] Treatment may be therapeutic treatment or prophylactic
treatment or prevention. Generally, the term "treating" means
affecting a subject, tissue or cell to obtain a desired
pharmacological and/or physiological effect and includes: (a)
inhibiting the viral infection or RSV disease, such as by arresting
its development or further development; (b) relieving or
ameliorating the effects of the viral infection or RSV disease,
such as by causing regression of the effects of the viral infection
or RSV disease; (c) reducing the incidence of the viral infection
or RSV disease or (d) preventing the viral infection or RSV disease
from occurring in a subject, tissue or cell predisposed to the
viral infection or RSV disease or at risk thereof, but has not yet
been diagnosed with a protective pharmacological and/or
physiological effect so that the viral infection or RSV disease
does not develop or occur in the subject, tissue or cell.
[0092] The term "subject" refers to any animal, in particular
mammals such as humans, having a disease which requires treatment
with the compound of formula (I). Particularly preferred treatment
groups include at risk populations such as hospitalised subjects,
the elderly, high-risk adults and infants. In one embodiment of the
invention, an effective amount of the above compounds, or
pharmaceutical compositions thereof, is administered to a patient
or subject in need thereof.
[0093] The term "administering" or "administered" should be
understood to mean providing a compound or pharmaceutical
composition of the invention to a subject suffering from or at risk
of the disease or condition to be treated or prevented.
[0094] As indicated above, although the invention has been
described with particular reference to treating RSV infections and
diseases, more particularly human and animal RSV infections or
diseases, it will be appreciated that the invention may also be
useful in the treatment of other viruses of the sub-family
Pneumovirinae, more particularly, the genera Pneumovirus and
Metapneumovirus.
Dosages
[0095] The term "therapeutically effective amount" refers to the
amount of the compound of formula (I) that will elicit the
biological or medical response of a subject, tissue or cell that is
being sought by the researcher, veterinarian, medical doctor or
other clinician.
[0096] By "effective amount" is generally considered that amount
that will be effective to treat the condition sought to be treated,
or to inhibit RSV, and this effective amount is variable based on a
variety of factors including age, size and condition of the patient
being treated. Accordingly, one skilled in the art would be readily
able to determine the specific effective amount for each patient
being treated for RSV, an RSV-related condition, or to inhibit RSV
in a given case.
[0097] In the treatment of RSV infections or diseases, an
appropriate dosage level will generally be about 0.01 to about 500
mg per kg subject body weight per day which can be administered in
single or multiple doses. The dosage may be selected, for example,
to any dose within any of these ranges, for therapeutic efficacy
and/or symptomatic adjustment of the dosage to the subject to be
treated.
[0098] As indicated above, it will be understood that the specific
dose level and frequency of dosage for any particular subject may
be varied and will depend upon a variety of factors including the
activity of the specific compound employed, the metabolic stability
and length of action of that compound, the age, body weight,
general health, sex, diet, mode and time of administration, rate of
excretion, drug combination, the severity of the particular
condition, and the subject undergoing therapy.
[0099] Methods of Preparation
[0100] The compounds of the invention may generally be prepared by
the following methods. Unless otherwise stated, the groups of each
of the compounds are as previously defined.
[0101] General information regarding method of preparation: In the
syntheses of the present invention, all evaporations were carried
out in vacuo with a rotary evaporator. Analytical samples were
dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC)
was performed on silica gel plates, spots were visualized by UV
light (214 and 254 nm). Purification by column and flash
chromatography was carried out using silica gel (200-300 mesh).
Solvent systems are reported as mixtures by volume. All NMR spectra
were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical
shifts are reported in 5 values in ppm with the deuterated solvent
as the internal standard. Data are reported as follows: chemical
shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,
br=broad, m=multiplet), coupling constant (Hz), integration.
[0102] As described further below, the general method for producing
compounds in accordance with the invention is shown schematically
as follows:
##STR00073## ##STR00074##
[0103] Additional information regarding this general method is
included in the Examples below.
Examples
[0104] The following examples are set forth below to illustrate the
methods and results according to the disclosed subject matter.
These examples are not intended to be inclusive of all aspects of
the subject matter disclosed herein, but rather to illustrate
representative methods, compositions, and results. These examples
are not intended to exclude equivalents and variations of the
present invention, which are apparent to one skilled in the
art.
[0105] Efforts have been made to ensure accuracy with respect to
numbers (e.g., amounts, temperature, etc.) but some errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, temperature is in .degree. C. or is at
ambient temperature, and pressure is at or near atmospheric. There
are numerous variations and combinations of reaction conditions,
e.g., component concentrations, temperatures, pressures, and other
reaction ranges and conditions that can be used to optimize the
product purity and yield obtained from the described process. Only
reasonable and routine experimentation will be required to optimize
such process conditions.
Example 1
[0106] General Method of Preparation of the Compounds of the
Invention
[0107] In all of the experimental data as reported below, the
following abbreviations are used:
[0108] rt: room temperature
[0109] UV: ultra violet
[0110] HPLC: high pressure liquid chromatography
[0111] Rt: retention time
[0112] LCMS: Liquid chromatography mass spectroscopy
[0113] NMR: Nuclear magnetic resonance spectroscopy
[0114] CC: column chromatography
[0115] TLC: thin layer chromatography
[0116] sat: saturated
[0117] aq: aqueous
[0118] DCM: dichloromethane
[0119] DCE: dichloroethane
[0120] DMF: dimethylformamide
[0121] DIPEA: diisopropylethylamine
[0122] EtOAc: ethyl acetate
[0123] TEA: triethylamine
[0124] THF: tetrahydrofurane
[0125] TFA: trifluoroacetic acid
[0126] t-BuOK: Potassium tert-butoxide
[0127] n-BuOH: n-Butanol
[0128] EtOH: Ethanol
[0129] HOAc: acetic acid
[0130] o/n: overnight
[0131] h: hour(s)
[0132] min: minutes
[0133] HATU:
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
[0134] LiHMDS: Lithium bis(trimethylsilyl)amide
[0135] General information: All evaporations were carried out in
vacuo with a rotary evaporator. Analytical samples were dried in
vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was
performed on silica gel plates, spots were visualized by UV light
(214 and 254 nm). Purification by column and flash chromatography
was carried out using silica gel (200-300 mesh). Solvent systems
are reported as mixtures by volume. All NMR spectra were recorded
on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are
reported in 5 values in ppm with the deuterated solvent as the
internal standard. Data are reported as follows: chemical shift,
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad,
m=multiplet), coupling constant (Hz), integration.
General Synthetic Method
[0136] The general synthetic method for producing the compounds of
the invention is set forth below:
##STR00075## ##STR00076##
Exemplary Experimental Procedures for the General Method
[0137] 1. The synthesis of 2H-benzo[b][1,4]thiazin-3(4H)-one (C-2)
is shown as follows:
##STR00077##
[0138] A mixture of C-1 (20.0 g, 159.8 mmol), methyl
2-chloroacetate (20.8 g, 191.7 mmol) and KOH (17.9 g, 319.5 mmol)
in water (80 mL) and EtOH (400 mL) was stirred at 80.degree. C. for
20 h. The mixture was concentrated in vacuo. The residue was
diluted with water (150 mL) and stirred for several minutes. The
resulting solid was collected by filtration, washed with water (100
mL.times.3) and dried in vacuo to get the desired compound C-2
(14.5 g, 55% yield) as a light brown solid.
[0139] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow Rate:
1.5 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 1.5 min, then under this condition for
0.5 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.1 min and under this condition for 0.1
min. Purity is 98.7% (in 254 nm). Rt=0.870 min; MS Calcd.: 165.1;
MS Found: 166.3 [M+H].sup.+.
2. The synthesis of tert-butyl
2-(3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)acetate (C-3) is shown as
follows:
##STR00078##
[0140] To a solution of C-2 (20.0 g, 121.1 mmol) in DMF (150 mL)
was added NaH (60%, 5.3 g, 133.2 mmol) in portions and the
temperature was maintained at 0.degree. C. After being stirred for
10 min, tert-butyl 2-bromoacetate (28.3 g, 145.3 mmol) was added
dropwise over 5 min. After the addition, the reaction mixture was
stirred at room temperature for 2 h. The mixture was diluted with
water (200 mL) and extracted with ethyl acetate (100 mL.times.3).
The combined organic layers were washed with brine (100
mL.times.2), dried over sodium sulfate, and concentrated to
dryness. The residue was purified by column chromatography on
silica gel (petrol ether/EtOAc=5/1) to give C-3 (18.0 g, 53% yield)
as yellow oil.
[0141] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow Rate:
2.0 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 1.6 min, then under this condition for
1.4 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.05 min and under this condition for 0.7
min. Rt=1.874 min; MS Calcd.: 279.1; MS Found: 302.2
[M+Na].sup.+.
3. The synthesis of ethyl
4-(2-tert-butoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-2-
-carboxylate (C-4d) is shown as follows:
##STR00079##
[0142] To a solution of C-3 (10.0 g, 35.8 mmol) in THF (150 mL) at
-78.degree. C. was added LiHMDS (1 M in THF, 71.6 mL, 71.6 mmol)
dropwise. After being stirred for 10 min at this temperature, ethyl
carbonochloridate (3.9 g, 35.8 mmol) was added dropwise over 5 min
and the reaction mixture was stirred at -78.degree. C. for 2 h. The
mixture was diluted with sat. NH.sub.4Cl solution (100 mL) and
extracted with ethyl acetate (80 mL.times.3). The combined organic
layers were washed with brine (100 mL.times.2), dried over sodium
sulfate, and concentrated to dryness. The residue was purified by
column chromatography on silica gel (petrol ether/EtOAc=4/1) to
give C-4d (8.0 g, 64% yield) as brown oil.
[0143] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow Rate:
2.0 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 1.6 min, then under this condition for
1.4 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.05 min and under this condition for 0.7
min. Purity is 74.7%. Rt=1.923 min; MS Calcd.: 351.1; MS Found:
374.0 [M+Na].sup.+.
4. The synthesis of
2-(2-(ethoxycarbonyl)-3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)acetic
acid (C-5f) is shown as follows:
##STR00080##
[0144] A mixture of C-4d (150 mg, 0.43 mmol) in TFA (2 mL) was
stirred at room temperature for 1 h. The solvent was removed by
concentration to give C-5f (120 mg, 95% yield) as yellow oil, which
was used for next step directly.
[0145] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow Rate:
2.0 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 1.6 min, then under this condition for
1.4 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.05 min and under this condition for 0.7
min. Purity is 72.1%. Rt=1.526 min; MS Calcd.: 295.0; MS Found:
296.0 [M+H].sup.+.
5. The synthesis of ethyl
4-(2-(cyclohexylamino)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thia-
zine-2-carboxylate (C-6f) is shown as follows:
##STR00081##
[0146] A mixture of C-5f (120 mg, 0.41 mmol), HATU (311 mg, 0.82
mmol), DIPEA (210 mg, 1.63 mmol) and cyclohexanamine (40 mg, 0.41
mmol) in THF (5 mL) was stirred at room temperature under nitrogen
for 16 h. The mixture was diluted with water (30 mL) and extracted
with ethyl acetate (20 mL.times.3). The combined organic layers
were washed with brine (20 mL.times.2), dried over sodium sulfate,
and concentrated to dryness. The residue was purified by column
chromatography on silica gel (petrol ether/EtOAc=2/1) to give C-6f
(110 mg, 72% yield) as brown oil.
[0147] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm*4.6 mm*3.5 um); Column Temperature: 40.degree. C.; Flow Rate:
1.5 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 1.5 min, then under this condition for
0.5 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.1 min and under this condition for 0.1
min. Purity is >95% (in 254 nm). Rt=1.280 min; MS Calcd.: 376.1;
MS Found: 377.4 [M+H].sup.+.
6. The synthesis of
4-(2-(cyclohexylamino)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thia-
zine-2-carboxylic acid (C-7f) is shown as follows:
##STR00082##
[0148] To a solution of C-6f (100 mg, 0.27 mmol) in MeOH (6 mL) was
added 2 N NaOH (0.27 mL, 0.54 mmol). The reaction mixture was
stirred at room temperature for 1 h. The mixture was diluted with
water (20 mL), then adjusted to pH=2-3 with diluted hydrochloric
acid and extracted with ethyl acetate (20 mL.times.3). The combined
organic layers were washed with brine (20 mL.times.2), dried over
sodium sulfate, and concentrated to dryness to give C-7f (90 mg,
97% yield) as a white solid.
[0149] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm*4.6 mm*3.5 um); Column Temperature: 40.degree. C.; Flow Rate:
1.5 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 1.5 min, then under this condition for
0.5 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.1 min and under this condition for 0.1
min. Purity is >99% (in 254 nm). Rt=1.096 min; MS Calcd.: 348.1;
MS Found: 349.3 [M+H].sup.+.
7. The synthesis of
N-cyclohexyl-2-(3-oxo-2-(piperidine-1-carbonyl)-2H-benzo[b][1,4]thiazin-4-
(3H)-yl) acetamide (AVG-044) is shown as follows:
##STR00083##
[0150] A mixture of C-7f (90 mg, 0.26 mmol), HATU (160 mg, 0.42
mmol), DIPEA (134 mg, 1.03 mmol) and piperidine (22 mg, 0.26 mmol)
in THF (4 mL) was stirred at room temperature under nitrogen for 16
h. The mixture was diluted with water (20 mL) and extracted with
ethyl acetate (20 mL.times.3). The combined organic layers were
washed with brine (20 mL.times.2), dried over sodium sulfate, and
concentrated to dryness. The residue was purified by Prep-TLC
(petrol ether/EtOAc=1/1) to give AVG-044 (23 mg, 21% yield) as a
white solid.
[0151] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow Rate:
2.0 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 3.0 min, then under this condition for
1.0 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.05 min and under this condition for 0.7
min. Purity is 97.3%. Rt=2.684 min; MS Calcd.: 415.2; MS Found:
416.1 [M+H].sup.+.
[0152] Agilent HPLC 1200; Column: L-column2 ODS (150 mm*4.6 mm*5.0
.mu.m); Column Temperature: 40.degree. C.; Flow Rate: 1.0 mL/min;
Mobile Phase: from 95% [water+0.1% TFA] and 5% [CH.sub.3CN+0.1%
TFA] to 0% [water+0.1% TFA] and 100% [CH.sub.3CN+0.1% TFA] in 10
min, then under this condition for 5 min, finally changed to 95%
[water+0.1% TFA] and 5% [CH.sub.3CN+0.1% TFA] in 0.1 min and under
this condition for 5 min. Purity is 97.3%. Rt=9.907 min.
[0153] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.03 (d, J=7.6 Hz,
1H), 7.33 (dd, J=7.8, 1.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.06 (ddd,
J=7.6, 7.6, 0.8 Hz, 1H), 6.94 (dd, J=8.4, 0.8 Hz, 1H), 5.39 (d,
J=17.2 Hz, 1H), 4.41 (s, 1H), 3.86 (d, J=17.2 Hz, 1H), 3.83-3.76
(m, 1H), 3.57-3.51 (m, 2H), 3.41-3.16 (m, 2H), 1.84-1.81 (m, 2H),
1.69-1.65 (m, 6H), 1.58-1.55 (m, 2H), 1.43-1.35 (m, 1H), 1.33-1.25
(m, 2H), 1.20-1.03 (m, 3H).
7. The synthesis of
N-cyclohexyl-2-(2-(morpholine-4-carbonyl)-3-oxo-2H-benzo[b][1,4]thiazin-4-
(3H)-yl) acetamide (AVG-054) is shown as follows:
##STR00084##
[0154] A mixture of C-7f (90 mg, 0.26 mmol), HATU (160 mg, 0.42
mmol), DIPEA (134 mg, 1.03 mmol) and morpholine (23 mg, 0.26 mmol)
in THF (4 mL) was stirred at room temperature under nitrogen for 16
h. The mixture was diluted with water (20 mL) and extracted with
ethyl acetate (20 mL.times.3). The combined organic layers were
washed with brine (20 mL.times.2), dried over sodium sulfate, and
concentrated to dryness. The residue was purified by Prep-HPLC to
give AVG-054 (24 mg, 22% yield) as a white solid.
[0155] Prep-HPLC Condition:
[0156] 1.1 Chromatographic Equipment [0157] Gilson Prep-HPLC
system: GX-281 sample manager, 306 pump, 806 Manometric module, 811
D DYNAMIC Mixer, UVNIS-156
[0158] 1.2 Chromatographic Condition [0159] Column: Waters
X-Bridge.TM. Prep C18 5 .mu.m OBD.TM., 30.times.100 mm [0160]
Flowrate: 20 mL/min [0161] Gradient:
TABLE-US-00002 [0161] Water (0.04% Time(min) MeOH
NH.sub.4HCO.sub.3) 0 55 45 8.0 80 20 9 95 5 13.5 95 5 13.6 55 45
17.6 55 45
[0162] Wavelength: 214 nm and 254 nm.
[0163] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow Rate:
2.0 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 3.0 min, then under this condition for
1.0 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.05 min and under this condition for 0.7
min. Purity is >99%. Rt=2.268 min; MS Calcd.: 417.2; MS Found:
418.0 [M+H].sup.+.
[0164] Agilent HPLC 1200; Column: L-column2 ODS (150 mm*4.6 mm*5.0
.mu.m); Column Temperature: 40.degree. C.; Flow Rate: 1.0 mL/min;
Mobile Phase: from 95% [water+0.1% TFA] and 5% [CH.sub.3CN+0.1%
TFA] to 0% [water+0.1% TFA] and 100% [CH.sub.3CN+0.1% TFA] in 10
min, then under this condition for 5 min, finally changed to 95%
[water+0.1% TFA] and 5% [CH.sub.3CN+0.1% TFA] in 0.1 min and under
this condition for 5 min. Purity is >99%. Rt=8.103 min.
[0165] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (d, J=8.0 Hz,
1H), 7.34 (dd, J=7.6, 1.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.08 (ddd,
J=7.6, 7.4, 0.8 Hz, 1H), 6.96 (dd, J=8.2, 1.0 Hz, 1H), 5.39 (d,
J=17.2 Hz, 1H), 4.39 (s, 1H), 3.90 (d, J=17.2 Hz, 1H), 3.84-3.74
(m, 3H), 3.71-3.62 (m, 2H), 3.59-3.49 (m, 2H), 3.47-3.37 (m, 2H),
1.85-1.81 (m, 2H), 1.72-1.60 (m, 2H), 1.48-1.22 (m, 3H), 1.19-1.01
(m, 3H).
Example 2
[0166] Cell Lines and Transfections
[0167] Human carcinoma (HEp-2, ATCC CCL-23), human lung carcinoma
(A549, ATCC CCL-185), human bronchial epithelial (BEAS-2B, ATCC
CRL-9609), human embryonic kidney (293T, ATCC CRL-3216), and Madin
Darby canine kidney (MDCK, ATCC CCL-34) cells were maintained at
37.degree. C. and 5% CO2 in Dulbecco's modified Eagle's medium
(DMEM) supplemented with 7.5% fetal bovine serum. Lipofectamine
2000 or GeneJuice were used for all transient transfection
reactions.
[0168] RSV Amplification and Virion Purification
[0169] recRSV stocks were grown on HEp-2 cells inoculated at a
multiplicity of infection (MOI) of 0.01 pfu/cell. Infected cells
were kept for 16 hours at 37.degree. C., followed by incubation at
32.degree. C. for five to seven days. Cell-associated progeny virus
was released through one freeze/thaw cycle and titers determined by
TCID.sub.50 titration on HEp-2 cells. Two alternative strategies
were explored to remove contaminating luciferase proteins from
virus stocks. Progeny virions in culture supernatants (IAV stocks)
or released through one freeze/thaw cycle from infected cells (RSV
stocks) were cleared (4,000.times.g for 20 minutes at 4.degree.
C.), then pelleted (60,000.times.g for 30 minutes at 4.degree. C.).
Pelleted material was resuspended in TNE buffer (50 mM Tris/Cl pH
7.2, 10 mM EDTA) and purified through a 20/60% one-step sucrose
gradient in TNE buffer (100,000.times.g for 90 minutes at 4.degree.
C.). Virions were harvested from the gradient intersection.
[0170] Automated HTS Protocol in 384-Well Plate Format
[0171] BEAS-2B cells (8.times.10.sup.3/well) were injected in 30
.mu.l/well into barcoded white wall/clear bottom 384-well plates
using a MultiFlo automated dispenser (BioTek) equipped with dual
10-.mu.l peristaltic pump manifolds, collected (150.times.g for 90
seconds at 25.degree. C.), and incubated for five hours at
37.degree. C. and 5% CO.sub.2. Compound was added to a final
concentration of 5 .mu.M (20 nl/well) using a high-density pin tool
(V&P Scientific) attached to the pipetting head of Hamilton
Nimbus liquid handler, followed by infection in 10 .mu.l/well using
the MultiFlo dispenser unit, spin collection (150.times.g for 90
seconds at 25.degree. C.), and incubation for 40 hours at
37.degree. C. and 5% CO.sub.2. Final vehicle (DMSO) concentration
was 0.05%. Barcodes of source and assay plates were automatically
detected and recorded by the Nimbus unit at the time of stamping.
Using a stacker unit with integrated barcode reader (Biotek)
attached to an H1 Biotek synergy plate reader, plates were
automatically loaded, luciferase substrates (15 .mu.l/well)
injected, and bioluminescence recorded after a three minute lag
time. Readouts were automatically saved by plate barcode. For
analysis of primary screen raw data, normalized relative inhibition
values were calculated for each compound by subtracting each value
from the average of the plate vehicle controls, followed by
dividing the results by the difference between the means of plate
vehicle and positive controls. Hits candidates were defined as
compounds showing .gtoreq.75% inhibition of normalized signal
intensity against either or both viral targets.
[0172] Dose-Response Counterscreens
[0173] Two-fold serial dilutions of hit candidates were prepared in
384-well plates in three replicates each using the Nimbus liquid
handler. BEAS-2B cells (8.times.10.sup.3/well) were then plated as
before, serial dilutions transferred using the pin-tool, and cells
infected with recombinant virus strains expressing distinct
luciferase reporter proteins or left uninfected for cell viability
assessment. Reporter signals were recorded as outlined above. To
determine cell viability, PrestoBlue substrate (life technologies)
was added after 40-hour incubation of cells at 37.degree. C. (5
.mu.l/well) and top-read fluorescence (excitation 560 nm; emission
590 nm; instrument gain 85) recorded after 45 minutes of incubation
at 37.degree. C. using the H1 synergy plate reader. Four-parameter
variable slope regression modeling was applied to determine 50%
active (EC.sub.50) and toxic (CC.sub.50) concentrations.
[0174] RSV Minigenome Reporter Assays
[0175] An RSV minigenome reporter plasmid (pHH-RSV-repl-firefly)
was constructed under the control of the constitutive RNA pol I
promoter by generating a firefly luciferase open reading frame
flanked by the 5'- and 3'-non-coding regions and transfer into a
pHH plasmid backbone harboring an RNA pol I promoter. Huh-7 cells
were co-transfected with this plasmid and expression plasmids
pRSV-L, pRSV-M2-1, pRSV-N and pRSV-P, which encode the RSV
polymerase protein subunits. Test compounds were added in serial
dilutions, luciferase reporter activities determined 40 hours
post-transfection, and EC.sub.50 concentrations calculated if
possible.
[0176] Virus Yield Reduction Assay
[0177] Hep2 cells were seeded in a 12-well plate format and exposed
to serial dilutions of compound (3-fold, 20 .mu.M highest),
followed by infection with recombinant RSV-A2 harboring the fusion
protein of the L19F isolate at a multiplicity of infection (MOI) of
0.1. Cell-associated progeny virions were harvested after 48-hour
incubation at 37.degree. C. and subjected to TCID.sub.50 titration
on Hep2 cells. Viral titers were calculated based on the Spearman
Karber method and inhibitory concentrations based on virus yields
determined through four-parameter variable slope regression
modeling.
[0178] Statistical Analysis
[0179] The Excel and Prism 6 (GraphPad) software packages were used
for data analysis. Statistical significance of differences between
sample groups were assessed by unpaired two-tailed t tests or
one-way analysis of variance (ANOVA) in combination with Tukey's
multiple comparison post-tests, respectively.
[0180] Assay results for RSV-172944 are presented in FIGS. 1-2.
##STR00085##
[0181] The compositions and methods of the appended claims are not
limited in scope by the specific compositions and methods described
herein, which are intended as illustrations of a few aspects of the
claims and any compositions and methods that are functionally
equivalent are intended to fall within the scope of the claims.
Various modifications of the compositions and methods in addition
to those shown and described herein are intended to fall within the
scope of the appended claims. Further, while only certain
representative compositions and method steps disclosed herein are
specifically described, other combinations of the compositions and
method steps also are intended to fall within the scope of the
appended claims, even if not specifically recited. Thus, a
combination of steps, elements, components, or constituents may be
explicitly mentioned herein or less, however, other combinations of
steps, elements, components, and constituents are included, even
though not explicitly stated. The term "comprising" and variations
thereof as used herein is used synonymously with the term
"including" and variations thereof and are open, non-limiting
terms. Although the terms "comprising" and "including" have been
used herein to describe various embodiments, the terms "consisting
essentially of" and "consisting of" can be used in place of
"comprising" and "including" to provide for more specific
embodiments of the invention and are also disclosed. Other than in
the examples, or where otherwise noted, all numbers expressing
quantities of ingredients, reaction conditions, and so forth used
in the specification and claims are to be understood at the very
least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, to be construed
in light of the number of significant digits and ordinary rounding
approaches.
Example 3: Additional Testing of the C Series Compounds
[0182] Additional testing was conducted to determine additional
parameters of the compounds of the invention. In the following
Table, a group of selected C series compounds was analyzed with
regard to MS, LC, and NMR, and the results are provided below.
TABLE-US-00003 Compound Rt(min) Rt(Min) ID Structure M + 1 (LCMS)
(HPLC) Method 1HNMR (400 MHz) AVG-044 ##STR00086## 416.1 2.68 9.91
C (CDCl.sub.3) .delta. 8.03 (d, J = 7.6 Hz, 1H), 7.33 (dd, J = 7.8,
1.4 Hz, 1H), 7.26- 7.24 (m, 1H), 7.06 (ddd, J = 7.6, 7.6, 0.8 Hz,
1H), 6.94 (dd, J = 8.4, 0.8 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H),
4.41 (s, 1H), 3.86 (d, J = 17.2 Hz, 1H), 3.83-3.76 (m, 1H),
3.57-3.51 (m, 2H), 3.41-3.16 (m, 2H), 1.84- 1.81 (m, 2H), 1.69-1.65
(m, 6H), 1.58-1.55 (m, 2H), 1.43-1.35 (m, 1H), 1.33-1.25 (m, 2H),
1.20- 1.03 (m, 3H). AVG-045 ##STR00087## 418.3 2.23 8.00 C
(CDCl.sub.3) .delta. 8.32 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.6 Hz,
1H), 7.29-7.28 (m, 1H), 7.08 (dd, J = 7.6, 7.2 Hz, 1H), 6.92 (d, J
= 8.4 Hz, 1H), 5.43 (d, J = 17.2 Hz, 1H), 4.42 (s, 1H), 4.06-4.04
(m, 1H), 3.92-3.88 (m, 3H), 3.57-3.54 (m, 2H), 3.47-3.42 (m, 2H),
3.37- 3.35 (m, 1H), 3.26-3.25 (m, 1H), 1.78-1.71 (m, 3H), 1.69-1.64
(m, 3H), 1.52-1.48 (m, 2H), 1.40- 1.38 (m, 2H) AVG-046 ##STR00088##
417.3 1.84 6.43 C (CDCl.sub.3) .delta. 8.25 (d, J = 7.6 Hz, 1H),
7.34 (dd, J = 7.8, 1.4 Hz, 1H), 7.29- 7.24 (m, 1H), 7.06 (ddd, J =
7.8, 7.4, 1.2 Hz, 1H), 6.92 (dd, J = 8.4, 0.8 Hz, 1H), 5.41 (d, J =
17.2 Hz, 1H), 4.41 (s, 1H), 4.0-3.90 (m, 1H), 3.90 (d, J = 17.2 Hz,
1H), 3.60-3.53 (m, 2H), 3.38-3.30 (m, 1H), 3.26- 3.19 (m, 1H),
3.10-3.02 (m, 2H), 2.73-2.65 (m, 2H), 1.86-1.85 (m, 2H), 1.77-1.60
(m, 4H), 1.53- 1.50 (m, 2H), 1.45-1.35 (m, 3H). AVG-047
##STR00089## 431.3 1.97 7.07 C (CDCl.sub.3) .delta. 8.27 (d, J =
6.8 Hz, 1H), 7.34 (dd, J = 8.0, 1.2 Hz, 1H), 7.28- 7.24 (m, 1H),
7.6 (ddd, J = 7.8, 7.4, 1.2 Hz, 1H), 6.91 (dd, J = 8.4, 0.8 Hz,
1H), 5.42 (d, J = 17.6 Hz, 1H), 4.40 (s, 1H), 3.92-3.86 (m, 2H),
3.58-3.53 (m, 2H), 3.34- 3.33 (m, 1H), 3.26-3.21 (m, 1H), 2.86-2.83
(m, 2H), 2.31 (s, 3H), 2.18- 2.15 (m, 2H), 1.86-1.84 (m, 2H),
1.77-1.70 (m, 3H), 1.54-1.50 (m, 4H), 1.40-1.32 (m, 1H) AVG-048
##STR00090## 376.2 2.47 8.83 C (CDCl.sub.3) .delta. 8.10 (d, J =
6.8 Hz, 1H), .delta. 7.33 (dd, J = 7.8, 1.4 Hz, 1H), 7.26-7.24 (m,
1H), 7.06 (ddd, J = 7.6, 7.2, 1.2 Hz, 1H), 6.93 (dd, J = 8.4, 0.8
Hz, 1H), 5.38 (d, J = 17.2 Hz, 1H), 4.41 (s, 1H), 4.12-4.10 (m,
1H), 3.88 (d, J = 17.2 Hz, 1H), 3.57-3.53 (m, 2H), 3.29-3.21 (m,
2H), 1.70-1.64 (m, 4H), 1.53-1.39 (m, 1H), 1.11- 1.09 (m, 1H), 1.10
(dd, J = 6.4, 0.8 Hz, 6H). AVG-049 ##STR00091## 430.3 2.89, 2.91
10.28, 10.36 C (CDCl.sub.3) .delta. 8.04-7.96 (m, 1H), 7.37-7.30
(m, 1H), 7.29-7.25 (m, 1H), 7.08- 7.05 (m, 1H), 6.98-6.96 (m, 1H),
5.41-5.36 (m, 1H), 4.43-4.41 (m, 1H), 4.06-3.73 (m, 2H), 3.61- 3.44
(m, 2H), 3.42-3.18 (m, 2H), 1.89-1.75 (m, 1H), 1.69-1.64 (m, 4H),
1.54-1.50 (m,4H), 1.48- 1.32 (m, 3H), 1.32-1.22 (m, 2H), 1.26-1.14
(m, 1H), 1.09-0.88 (m, 1H), 0.88-0.84 (m, 1H), 0.83- 0.78 (m, 2H).
AVG-050 ##STR00092## 444.3 2.99 10.62 C (CDCl.sub.3) .delta. 8.10
(d, J = 8.4 Hz, 1H), 7.33 (dd, J = 7.8, 1.4 Hz, 1H), 7.26- 7.21 (m,
1H), 7.06 (dd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.95 (dd, J = 8.2, 1.0
Hz, 1H), 5.39 (d, J = 17.6 Hz, 1H), 4.42 (s, 1H), 3.89 (d, J = 17.2
Hz, 1H), 3.77 (m, 1H), 3.55 (m, 2H), 3.39-3.30 (m, 1H), 3.30-3.18
(m, 1H), 1.69-1.67 (m, 3H), 1.66-1.65 (m, 3H), 1.53- 1.46 (m, 1H),
1.45-1.36 (m, 2H), 1.36-1.32 (m 3H), 1.29-1.25 (m, 1H), 1.26-1.24
(m, 1H) , 0.87 (s, 3H), 0.82 (s, 3H). AVG-051 ##STR00093## 402.3
2.6 9.25 C (CDCl.sub.3) .delta. 8.16 (d, J = 6.8 Hz, 1H), 7.33 (dd,
J = 7.6, 1.6 Hz, 1H), 7.26- 7.20 (m, 1H), 7.06 (ddd, J = 7.6, 7.6,
1.2 Hz, 1H), 6.93 (dd, J = 8.2, 0.6 Hz, 1H), 5.40 (d, J = 17.2 Hz,
1H), 4.41 (s, 1H), 4.26-4.25 (m, 1H), 3.88 (d, J = 17.2 Hz, 1H),
3.59-3.46 (m, 2H), 3.37-3.34 (m, 1H), 3.26- 3.24 (m, 1H), 1.87 (m,
2H), 1.77-1.59 (m, 5H), 1.55-1.44 (m, 5H), 1.44- 1.24 (m, 2H).
AVG-052 ##STR00094## 424.2 2.71 9.66 C (CDCl.sub.3) .delta. 9.58
(s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 7.6, 1.6 Hz, 1H),
7.35-7.26 (m, 1H), 7.20-7.12 (m, 3H), 7.13-7.07 (m, 2H), 5.63 (d, J
= 17.2 Hz, 1H), 4.47 (s, 1H), 4.09 (d, J = 17.6 Hz, 1H), 3.57-3.54
(m, 1H), 3.50-3.41 (m, 1H), 3.40-3.30 (m, 1H), 3.28-3.13 (m, 1H),
2.15 (s, 3H), 1.81-1.71 (m, 1H), 1.70-1.59 (m, 3H), 1.48-1.45 (m,
1H), 1.37- 1.32 (m, 1H). AVG-053 ##STR00095## 424.1 2.78 10.32 C
(CDCl.sub.3) .delta. 9.85 (s, 1H), 7.60 (s, 1H), 7.52 (d, J = 8.8
Hz, 1H), 7.36 (dd, J = 7.6, 1.6 Hz, 1H), 7.26- 7.22 (m, 1H), 7.15
(dd, J = 8.0, 7.6 Hz, 1H), 7.06 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H),
7.01 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.61 (d, J =
17.2 Hz, 1H), 4.48 (s, 1H), 4.01 (d, J = 17.2 Hz, 1H), 3.70-3.57
(m, 2H), 3.36-3.26 (m, 2H), 2.30 (s, 3H), 2.01-1.71 (m, 3H),
1.71-1.63 (m, 1H), 1.53-1.29 (m, 2H). AVG-054 ##STR00096## 418 2.27
8.1 C (CDCl.sub.3) .delta. 7.86 (d. J = 8.0 Hz, 1H), 7.34 (dd, J =
7.6, 1.2 Hz, 1H), 7.31- 7.27 (m, 1H), 7.08 (ddd, J = 7.6, 7.4, 0.8
Hz, 1H), 6.96 (dd, J = 8.2, 1.0 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H),
4.39 (s, 1H), 3.90 (d, J = 17.2 Hz, 1H), 3.84-3.74 (m, 3H),
3.71-3.62 (m, 2H), 3.59-3.49 (m, 2H), 3.47- 3.37 (m, 2H), 1.85-1.81
(m, 2H), 1.72-1.60 (m, 2H), 1.48-1.22 (m, 3H), 1.19-1.01 (m, 3H).
AVG-055 ##STR00097## 417.3 1.99 7.04 C (CDCl.sub.3) .delta. 7.93
(d, J = 7.2 Hz, 1H), 7.34 (dd, J = 7.8, 1.4 Hz, 1H), 7.31- 7.27 (m,
1H), 7.07 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.95 (dd, J = 8.2, 1.0
Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 4.41 (s, 1H), 3.89 (d, J = 17.2
Hz, 1H), 3.84-3.75 (m, 1H), 3.66-3.54 (m, 2H), 3.48-3.29 (m, 2H),
3.10- 2.94 (m, 2H), 2.87-2.83 (m, 1H), 2.76-2.67 (m, 1H), 1.88-1.80
(m, 3H), 1.61-1.53 (m, 2H), 1.37- 1.24 (m, 2H), 1.19-1.01 (m, 3H).
AVG-056 ##STR00098## 431.1 1.77 6.44 C (DMSO-d.sub.6) .delta. 7.96
(d, J = 8.0 Hz, 1H), 7.44 (dd, J = 7.8, 1.4 Hz, 1H), 7.31 (ddd, J =
8.8, 8.4, 1.4 Hz, 1H), 7.08 (dd, J = 7.2, 6.8 Hz, 1H), 6.93 (d, J =
7.6 Hz, 1H), 5.14 (s, 1H), 4.69 (d, J = 16.8 Hz, 1H), 4.28 (d, J =
17.2 Hz, 1H), 3.63-3.52 (m, 2H), 3.48-3.38 (m, 2H), 3.30 (s, 2H),
2.39- 2.28 (m, 3H), 2.18 (s, 3H), 1.72-1.61 (m, 4H), 1.55-1.48 (m,
1H), 1.31- 1.17 (m, 2H), 1.13-1.01 (m, 3H). AVG-057 ##STR00099##
376.3 2.43 8.67 C (CDCl.sub.3) .delta. 7.98 (d, J = 7.2 Hz, 1H),
7.31 (dd, J = 7.7, 1.4 Hz, 1H), 7.25- 7.23 (m, 1H), 7.06 (ddd, J =
7.6, 7.6, 1.2 Hz, 1H), 6.95 (dd, J = 8.4, 0.8 Hz, 1H), 5.40 (d, J =
17.2 Hz, 1H), 4.40 (s, 1H), 3.90 (d, J = 17.2 Hz, 1H), 3.83-3.75
(m, 1H), 3.14 (s, 3H), 2.88 (s, 3H), 1.88-1.78 (m, 2H), 1.72-1.61
(m, 2H), 1.34-1.25 (m, 3H), 1.21- 1.12 (m, 2H), 1.10-0.98 (m, 1H).
AVG-058 ##STR00100## 430.2 2.8 10.4 C (CDCl.sub.3) .delta. 7.45 (d,
J = 8.0 Hz, 1H), 7.35 (dd, J = 7.8, 1.4 Hz, 1H), 7.25- 7.22 (m,
1H), 7.06 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.94 (dd, J = 8.4, 0.8
Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 4.25
(s, 1H), 3.82-.378 (m, 2H), 3.55-3.53 (m, 1H), 1.92- 1.90 (m, 1H),
1.78-1.64 (m, 5H), 1.52-1.48 (m, 2H), 1.34-1.28 (m, 5H), 1.15-1.11
(m, 6H), 0.81- 0.77 (m, 1H). AVG-059 ##STR00101## 430.3 2.62 9.42 C
(CDCl.sub.3) .delta. 7.24 (dd, J = 7.8, 1.4 Hz, 1H), 7.24- 7.19 (m,
1H), 7.06 (ddd, J = 7.6, 7.2, 0.8 Hz, 1H), 6.88 (ddd, J = 7.6, 6.8,
0.8 Hz, 1H), 5.35-5.20 (m, 1H), 4.64-4.62 (m, 1H), 4.41-4.34 (m,
0.5H), 4.25-4.18 (m, 1H), 3.85-3.69 (m, 1H), 3.56-3.47 (m, 1H),
3.45- 3.28 (m, 2.5H), 2.94- 2.87 (m, 3H), 1.91-1.75 (m, 3H),
1.71-1.64 (m, 5H), 1.55-1.50 (m, 4H), 1.43-1.32 (m, 3H), 1.14- 1.07
(m, 1H). AVG-060 ##STR00102## 402.1 2.27 8.65 C (CDCl.sub.3)
.delta. 7.42 (dd, J = 7.8, 1.4 Hz, 1H), 7.30 (ddd, J = 7.8, 7.4,
1.2 Hz, 1H), 7.07-6.97 (m, 1H), 6.89 (dd, J = 8.2, 1.0 Hz, 1H),
5.26 (d, J = 16.2 Hz, 1H), 4.64 (s, 1H), 4.22 (d, J = 16.2 Hz, 1H),
3.77-3.75 (m, 1H), 3.59-3.56 (m, 2H), 3.45-3.44 (m, 3H), 3.44- 3.34
(m, 1H), 3.34-3.26 (m, 1H), 1.68-1.67 (m, 3H), 1.67-1.62 (m, 4H),
1.59-1.51 (m, 4H), 1.26 (s, 1H). AVG-061 ##STR00103## 450.2 2.94
10.52 C (CDCl.sub.3) .delta. 8.04 (d, J = 8.0 Hz, 1H), 7.23-7.14
(m, 2H), 6.87 (dd, J = 8.0, 1.6 Hz, 1H), 5.38 (d, J = 17.2 Hz, 1H),
4.49 (s, 1H), 3.86 (d, J = 17.2 Hz, 1H), 3.82-3.74 (m, 1H),
3.72-3.59 (m, 2H), 3.39-3.24 (m, 1H), 3.21-3.07 (m, 1H), 1.91- 1.80
(m, 3H), 1.77-1.60 (m, 5H), 1.56-1.48 (m, 2H), 1.43-1.26 (m, 3H),
1.20-1.04 (m, 3H). AVG-062 ##STR00104## 450.2 3 10.75 C
(CDCl.sub.3) .delta. 8.00 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 2.0 Hz,
1H), 7.22 (dd, J = 8.8, 2.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.40
(d, J = 17.6 Hz, 1H), 4.43 (s, 1H), 3.89-3.75 (m, 2H), 3.61-3.48
(m, 2H), 3.39-3.24 (m, 2H), 1.84-1.79 (m, 2H), 1.76- 1.61 (m, 6H),
1.56-1.40 (m, 3H), 1.33-1.22 (m, 2H), 1.19-1.03 (m, 3H). AVG-063
##STR00105## 450.2 2.86 10.29 C (CDCl.sub.3) .delta. 7.98 (d, J =
7.6 Hz, 1H), 7.25 (s, 1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 6.94 (d,
J = 2.0 Hz, 1H), 5.37 (d, J = 17.6 Hz, 1H), 4.42 (s, 1H), 3.91-3.75
(m, 2H), 3.63-3.50 (m, 2H), 3.37- 3.20 (m, 2H), 1.98-1.78 (m, 2H),
1.78-1.58 (m, 7H), 1.55-1.49 (m, 1H), 1.47-1.38 (m, 1H), 1.36- 1.24
(m, 2H), 1.21-1.04 (m, 3H). AVG-064 ##STR00106## 450.2 2.59 9.31 C
(CDCl.sub.3) .delta. 7.37 (d, J = 7.2 Hz, 1H), 7.34 (dd, J = 8.0,
1.6 Hz, 1H), 7.05 (dd, J = 8.0, 7.6 Hz, 1H), 4.79 (d, J = 16.8 Hz,
1H), 4.53-4.42 (m, 2H), 3.85-3.71 (m, 1H), 3.67- 3.21 (m, 4H),
1.94-1.75 (m, 2H), 1.72-1.61 (m, 5H), 1.60-1.49 (m, 3H), 1.43-1.24
(m, 3H), 1.21- 1.08 (m, 3H). AVG-083 ##STR00107## 432.3 2.2 8.32 C
(CDCl.sub.3) .delta. 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.30- 7.27 (m,
1H), 7.15 (d, J = 7.6 Hz, 1H), 7.07 (ddd, J = 7.6, 7.6, 0.8 Hz,
1H), 6.94 (dd, J = 8.0, 0.8 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.37
(d, J = 16.8 Hz, 1H), 4.26 (s, 1H), 3.90-3.74 (m, 5H), 3.46-3.22
(m, 2H), 1.94-1.91 (m, 1H), 1.84-1.81 (m, 1H), 1.77- 1.64 (m, 3H),
1.63-1.58 (m, 1H), 1.42-1.33 (m, 3H), 1.32-1.19 (m, 2H), 1.19-1.02
(m, 3H). AVG-084 ##STR00108## 431.3 1.80 6.30 C (CDCl.sub.3)
.delta. 7.37 (d, J = 7.6 Hz, 1H), 7.30-7.24 (m, 1H), 7.11 (d, J =
7.6 Hz, 1H), 7.07 (dd, J = 7.6 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H),
6.80 (d, J = 8.0 Hz, 1H), 5.36 (d, J = 16.8 Hz, 1H), 4.26 (s, 1H),
3.86 (d, J = 16.8 Hz, 1H), 3.86-3.66 (m, 2H), 3.07-2.96 (m, 2H),
2.73-2.58 (m, 2H), 1.95- 1.56 (m, 5H), 1.52-1.07 (m, 9H). AVG-085
##STR00109## 445.3 2.07 7.40 C (CDCl.sub.3) .delta. 7.36 (d, J =
7.6 Hz, 1H), 7.30-7.26 (m, 1H), 7.26-7.23 (m, 1H), 7.06 (dd, J =
7.6, 7.2 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.0 Hz,
1H), 5.38 (d, J = 16.8 Hz, 1H), 4.26 (s, 1H), 3.88-3.76 (m, 2H),
3.62-3.50 (m, 1H), 2.74- 2.65 (m, 1H), 2.61-2.50 (m, 1H), 2.23 (s,
3H), 2.10-2.00 (m, 1H), 1.98- 1.88 (m, 2H), 1.84-1.64 (m, 4H),
1.47-1.05 (m, 9H). AVG-086 ##STR00110## 404.3 2.69 9.63 C
(CDCl.sub.3) .delta. 7.45 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 7.8,
1.4 Hz, 1H), 7.26- 7.23 (m, 1H), 7.06 (ddd, J = 7.6, 7.2, 0.8 Hz,
1H), 6.94 (d, J = 8.4 Hz, 1H), 6.52 (s, 1H), 5.42 (d, J = 17.2 Hz,
1H), 4.27 (s, 1H), 3.88-3.75 (m, 2H), 3.28-3.24 (m, 1H), 3.03- 2.9
(m, 1H), 1.94-1.91 (m, 1H), 1.82-1.78 (m, 1H), 1.75-1.65 (m, 2H),
1.38-1.27 (m, 4H), 1.19- 1.04 (m, 3H), 1.02-0.79 (m, 3H), 0.73 (t,
J = 7.2 Hz, 3H). AVG-087 ##STR00111## 390.3 2.56 9.19 C
(CDCl.sub.3) .delta. 7.48 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 7.6,
1.2 Hz, 1H), 7.26- 7.22 (m, 1H), 7.06 (ddd, J = 8.0, 7.6, 0.6 Hz,
1H), 6.94 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 8.0 Hz, 1H), 5.40 (d, J
= 17.2 Hz, 1H), 4.24 (s, 1H), 3.90- 3.74 (m, 3H), 1.96-1.88 (m,
1H), 1.84-1.76 (m, 1H), 1.75-1.65 (m, 2H), 1.43-1.27 (m, 4H), 1.19-
1.10 (m, 2H), 1.09-1.07 (m, 3H), 0.76 (d, J = 6.4 Hz, 3H). AVG-111
##STR00112## 408.2 2.60 9.24 C (CDCl.sub.3) .delta. 7.71-7.67 (m,
1H), 7.53-7.49 (m, 1H), 4.42 (dd, J = 7.6 Hz, 0.8 Hz, 1H),
7.36-7.31 (m, 2H), 7.26-7.23 (m, 2H), 7.07-7.03 (m, 1H), 5.72 (d, J
= 16.8 Hz, 1H), 5.21 (d, J = 17.2 Hz, 1H), 4.66 (s, 1H), 3.66- 3.58
(m, 1H), 3.54-3.34 (m, 3H), 1.71-1.58 (m, 4H), 1.58-1.43 (m, 2H).
AVG-112 ##STR00113## 407.2 2.53 9.00 C (CDCl.sub.3) .delta. 11.73
(brs, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.36
(dd, J = 7.8, 1.4 Hz, 1H), 7.26-7.17 (m, 2H), 7.13 (ddd, J = 8.2,
7.6, 1.6 Hz, 1H), 7.03 (ddd, J = 8.0, 7.6, 0.8 Hz, 1H), 6.87 (dd, J
= 8.0, 0.8 Hz, 1H), 6.30 (d, J = 17.2 Hz, 1H), 4.85 (d, J = 17.2
Hz, 1H), 4.54 (s, 1H), 3.72- 3.57 (m, 2H), 3.46-3.33 (m, 2H),
1.87-1.60 (m, 5H), 1.49-1.38 (m, 1H). AVG-113 ##STR00114## 334.2
1.96 7.38 C (CDCl.sub.3) .delta. 8.29 (s, 1H), 7.38-7.32 (m, 1H),
7.29- 7.27 (m, 1H), 7.08 (dd, J = 7.6, 7.6 Hz, 1H), 7.01 (d, J =
8.4 Hz, 1H), 5.51-5.24 (m, 2H), 4.44 (s, 1H), 3.91 (d, J = 17.5 Hz,
1H), 3.60-3.47 (m, 2H), 3.41-3.32 (m, 1H), 3.29-3.20 (m, 1H), 1.87-
1.72 (m, 1H), 1.72-1.62 (m, 3H), 1.53-1.45 (m, 1H), 1.42-1.30 (m,
1H). AVG-114 ##STR00115## 374.2 2.34 8.4 C (CDCl.sub.3) .delta.
8.32 (s, 1H), 7.33 (dd, J = 7.8, 1.4 Hz, 1H), 7.30-7.27 (m, 1H),
7.06 (ddd, J = 7.6, 7.4, 1.0 Hz, 1H), 6.92 (dd, J = 8.4, 0.8 Hz,
1H), 5.42 (d, J = 17.6 Hz, 1H), 4.40 (s, 1H), 3.90 (d, J = 17.6 Hz,
1H), 3.64-3.47 (m, 2H), 3.42- 3.16 (m, 2H), 2.91-2.77 (m, 1H),
1.81-1.72 (m, 1H), 1.72-1.61 (m, 3H), 1.56-1.47 (m, 1H), 1.43- 1.32
(m, 1H), 0.76-0.60 (m, 2H), 0.60-0.37 (m, 2H). AVG-137 ##STR00116##
424.3 2.62 9.31 C (DMSO-d.sub.6) .delta. 8.72 (t, J = 5.8 Hz, 1H),
7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.33- 7.27 (m, 3H), 7.23-7.20 (m,
3H), 7.09 (dd, J = 7.6, 7.2 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.14
(s, 1H), 4.68 (d, J = 17.2 Hz, 1H), 4.51 (d, J = 16.8 Hz, 2H), 4.32
(d, J = 6.0 Hz, 2H), 3.51- 3.41 (m, 2H), 3.26-3.20 (m, 2H),
1.55-1.52 (m, 4H), 1.44-1.42 (m, 1H), 1.30-1.28 (m, 1H) AVG-138
##STR00117## 438.2 2.76 9.75 C (DMSO-d.sub.6) .delta. 8.75-8.55 (m,
1H), 7.31-7.23 (m, 1.5H), 7.23-7.19 (m, 2H), 7.16-7.08 (m, 3H),
7.06-6.92 (m, 2H), 6.65- 6.62 (m, 0.5H), 5.41- 5.34 (m, 1H),
5.11-5.02 (m, 1H), 4.38 (s, 1H), 3.89-3.76 (m, 1H), 3.54- 3.40 (m,
2H), 3.35-3.12 (m, 2H), 1.75-1.53 (m, 4H), 1.45-1.25 (m, 5H)
AVG-139 ##STR00118## 452.3 2.90 10.15 C (DMSO-d.sub.6) .delta. 8.35
(s, 1H), 7.45 (dd, J = 7.8, 1.2 Hz, 1H), 7.36 (dd, J = 7.8, 1.2 Hz,
1H), 7.31- 7.24 (m, 4H), 7.18-7.17 (m, 1H), 7.10 (dd, J = 7.6, 7.2
Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 5.14 (s, 1H), 4.74 (d, J = 17.2
Hz, 1H), 4.30 (d, J = 16.8 Hz, 1H), 3.55-3.51 (m, 1H), 3.44-3.39
(m, 2H), 3.26-3.21 (m, 1H), 1.58-1.52 (m, 6H), 148- 1.42 (m, 4H),
1.28-1.26 (m, 2H) AVG-140 ##STR00119## 390.3 2.66 9.48 C
(CDCl.sub.3) .delta. 7.68 (s, 1H), 7.32 (dd, J = 7.8, 1.4 Hz, 1H),
7.31-7.27 (m, 1H), 7.06 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.96 (dd,
J = 8.4, 0.8 Hz, 1H), 5.34 (d, J = 17.2 Hz, 1H), 4.41 (s, 1H), 3.80
(d, J = 17.2 Hz, 1H), 3.58-3.48 (m, 2H),
3.38- 3.18 (m, 2H), 1.86-1.61 (m, 4H), 1.59 (s, 9H), 1.54-1.46 (m,
1H), 1.43- 1.37 (m, 1H). AVG-141 ##STR00120## 404.2 2.69 9.97 C
(CDCl.sub.3) .delta. 7.70 (d, J = 7.2 Hz, 1H), 7.37 (dd, J = 7.6,
1.2 Hz, 1H), 7.30- 7.28 (m, 1H), 7.07 (ddd, J = 7.6, 7.6, 0.8 Hz,
1H), 6.94 (dd, J = 8.4, 0.8 Hz, 1H), 6.28 (s, 1H), 5.42 (d, J =
17.2 Hz, 1H), 4.22 (s, 1H), 3.88- 3.73 (m, 2H), 2.01-1.86 (m, 1H),
1.80-1.65 (m, 3H), 1.41-1.18 (m, 4H), 1.17-1.09 (m, 2H), 1.09 (s,
9H). AVG-142 ##STR00121## 438.3 2.66 9.35 C (DMSO-d.sub.6) .delta.
8.98 (t, J = 5.8 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.45 (dd, J =
7.6, 1.2 Hz, 1H), 7.33 (ddd, J = 8.4, 8.4, 1.2 Hz, 1H), 7.17 (m,
3H), 7.12 (dd, J = 8.0, 7.2 Hz, 1H), 6.94-6.90 (m, 3H), 4.85 (d, J
= 17.2 Hz, 1H), 4.58 (s, 1H), 4.24-4.20 (m, 3H), 3.55- 3.52 (m,
1H), 1.64-1.57 (m, 3H), 1.51-1.48 (m, 2H), 1.22-1.15 (m, 2H),
1.09-0.99 (m, 3H) AVG-143 ##STR00122## 452.3 2.79, 2.86 9.68, 9.88
C (DMSO-d.sub.6) .delta. 7.40-7.26 (m, 4H), 7.17-6.95 (m, 4H),
6.90-6.78 (m, 2H), 6.67(d, J = 7.6 Hz, 1H), 5.46-5.38 (m, 1H),
4.92- 4.84 (m, 1H), 4.34-4.26 (m, 1H), 3.87-3.65 (m, 2H), 1.92-1.62
(m, 3H), 1.58-1.40 (m, 4H), 1.36- 1.05 (m, 5H), 0.75-0.60 (m, 1H).
AVG-144 ##STR00123## 466.2 2.79 10.31 C (CDCl.sub.3) .delta. 7.51
(dd, J = 7.6, 1.6 Hz, 1H), 7.43- 7.31 (m, 2H), 7.20 (ddd, J = 7.6,
7.6, 1.0 Hz, 1H), 7.11-6.96 (m, 3H), 6.89 (dd, J = 8.4, 0.8 Hz,
1H), 6.85 (s, 1H), 6.76-6.72 (m, 2H), 5.42 (d, J = 16.8 Hz, 1H),
4.29 (s, 1H), 3.72 (d, J = 16.8 Hz, 1H), 3.67-3.52 (m, 1H),
1.80-1.68 (m, 1H), 1.63 (s, 3H), 1.57-1.53 (m, 1H), 1.52-1.42 (m,
2H), 1.41 (s, 3H), 1.34- 1.26 (m, 1H), 1.25-1.08 (m, 2H), 1.01-0.80
(m, 2H), 0.51-0.32 (m, 1H). AVG-145 ##STR00124## 446.3 2.79 9.88 C
(CDCl.sub.3) .delta. 8.10 (d, J = 7.6 Hz, 1H), 7.20 (dd, J = 8.4,
8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H),
5.39 (d, J = 17.2 Hz, 1H), 4.43 (s, 1H), 3.94-3.84 (m, 4H),
3.83-3.73 (m, 1H), 3.67-3.45 (m, 2H), 3.45-3.20 (m, 2H), 1.90- 1.74
(m, 3H), 1.72-1.61 (m, 5H), 1.55-1.48 (m, 2H), 1.48-1.38 (m, 1H),
1.37-1.25 (m, 2H), 1.22- 1.12 (m, 2H), 1.11-1.03 (m, 1H). AVG-146
##STR00125## 446.3 2.78 9.67 C (CDCl.sub.3) .delta. 8.00 (d, J =
8.0 Hz, 1H), 6.88-6.84 (m, 2H), 6.78 (dd, J = 8.8, 2.8 Hz, 1H),
5.37 (d, J = 17.2 Hz, 1H), 4.40 (s, 1H), 3.86-3.76 (m, 5H),
3.60-3.49 (m, 2H), 3.38-3.25 (m, 2H), 1.87-1.80 (m, 2H), 1.76- 1.61
(m, 6H), 1.57-1.38 (m, 2H), 1.37-1.25 (m, 3H), 1.20-1.03 (m, 3H).
AVG-147 ##STR00126## 446.2 2.87 10.12 C (CDCl.sub.3) .delta. 7.94
(d, J = 7.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.54 (dd, J = 8.4,
2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 5.29 (d, J = 17.2 Hz, 1H),
4.29 (s, 1H), 3.81 (d, J = 17.2 Hz, 1H), 3.77-3.67 (m, 1H), 3.70
(s, 3H), 3.57-3.44 (m, 2H), 3.29- 3.21 (m, 1H), 3.19-3.11 (m, 1H),
1.84-1.70 (m, 2H), 1.68-1.54 (m, 5H), 1.51-1.42 (m, 2H), 1.37- 1.16
(m, 4H), 1.15-0.95 (m, 3H). AVG-148 ##STR00127## 446.3 2.61 9.29 C
(CDCl.sub.3) .delta. 7.07-6.95 (m, 3H), 6.84 (dd, J = 8.0, 1.2 Hz,
1H), 4.83 (d, J = 16.4 Hz, 1H), 4.39 (s, 1H), 4.16 (d, J = 17.6 Hz,
1H), 3.82 (s, 3H), 3.82-3.74 (m, 1H), 3.66- 3.50 (m, 2H), 3.34-3.17
(m, 2H), 1.93-1.80 (m, 2H), 1.72-1.63 (m, 5H), 1.60-1.49 (m, 2H),
1.38- 1.24 (m, 4H), 1.23-1.09 (m, 3H). AVG-149 ##STR00128## 494.2
3.133 10.91 C (CDCl.sub.3) .delta. 7.99 (d, J = 8.0 Hz, 1H), 7.46
(d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.8, 2.0 Hz, 1H), 6.80 (d, J =
8.8 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 4.42 (s, 1H), 3.83 (d, J =
17.2 Hz, 1H), 3.79-3.74 (m, 1H), 3.59-3.49 (m, 2H), 3.38-3.27 (m,
2H), 1.83-1.80 (m, 2H), 1.76- 1.62 (m, 6H), 1.56-1.55 (m, 2H),
1.49-1.43 (m, 1H), 1.36-1.25 (m, 2H), 1.19-1.06 (m, 3H). AVG-150
##STR00129## 434.3 2.90 10.18 C (CDCl.sub.3) .delta. 7.99 (d, J =
7.6 Hz, 1H), 7.07 (dd, J = 7.8, 3.0 Hz, 1H), 6.97 (ddd, J = 8.8,
8.0, 2.8 Hz, 1H), 6.90 (dd, J = 9.2, 4.4 Hz, 1H), 5.39 (d, J = 17.2
Hz, 1H), 4.43 (s, 1H), 3.84 (d, J = 17.2 Hz, 1H), 3.83-3.74 (m,
1H), 3.61-3.50 (m, 2H), 3.37-3.24 (m, 2H), 1.87-1.78 (m, 2H), 1.76-
1.63 (m, 6H), 1.60-1.51 (m, 2H), 1.48-1.38 (m, 1H), 1.37-1.24 (m,
2H), 1.20-1.03 (m, 3H). AVG-151 ##STR00130## 430.3 2.92 10.38 C
(CDCl.sub.3) .delta. 8.01 (d, J = 7.2 Hz, 1H), 7.12 (s, 1H), 7.05
(d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.38 (d, J = 17.2
Hz, 1H), 4.40 (s, 1H), 3.85 (d, J = 17.2 Hz, 1H), 3.83-3.78 (m,
1H), 3.60-3.48 (m, 2H), 3.39- 3.23(m, 2H), 2.29 (s, 3H), 1.87-1.78
(m, 2H), 1.77-1.61 (m, 6H), 1.57- 1.49 (m, 2H), 1.48-1.37 (m, 1H),
1.36-1.23 (m, 2H), 1.20-1.01 (m, 3H). AVG-152 ##STR00131## 444.3
3.05 10.69 C (CDCl.sub.3) .delta. 8.02 (d, J = 7.6 Hz, 1H), 7.13
(d, J = 2.0 Hz, 1H), 7.07 (dd, J = 8.4, 2.0 Hz, 1H), 6.85 (d, J =
8.4 Hz, 1H), 5.37 (d, J = 17.2 Hz, 1H), 4.40 (s, 1H), 3.87 (d, J =
17.2 Hz, 1H), 3.83-3.72 (m, 1H), 3.63-3.42 (m, 2H), 3.42-3.20 (m,
2H), 2.62-2.57 (m, 2H), 1.88- 1.80 (m, 2H), 1.79-1.71 (m, 1H),
1.71-1.62 (m, 5H), 1.57-1.49 (m, 2H), 1.47-1.38 (m, 1H), 1.37- 1.25
(m, 2H), 1.22 (t, J = 7.6 Hz, 3H), 1.19-1.01 (m, 3H). AVG-153
##STR00132## 458.3 3.19 10.95 C (CDCl.sub.3) .delta. 8.01 (d, J =
7.6 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.6, 1.8 Hz,
1H), 6.86 (d, J = 8.4 Hz, 1H), 5.36 (d, J = 17.2 Hz, 1H), 4.40 (s,
1H), 3.87 (d, J = 17.2 Hz, 1H), 3.83-3.72 (m, 1H), 3.63-3.45 (m,
2H), 3.43-3.21 (m, 2H), 2.91-2.77 (m, 1H), 1.91- 1.79 (m, 2H),
1.78-1.71 (m, 1H), 1.71-1.59 (m, 5H), 1.57-1.47 (m, 2H), 1.45-1.36
(m, 1H), 1.35- 1.25 (m, 2H), 1.23 (d, J = 7.2 Hz, 6H), 1.18-1.10
(m, 2H), 1.10-0.99 (m, 1H). AVG-154 ##STR00133## 492.3 3.15 11.08 C
(CDCl.sub.3) .delta. 8.07 (d, J = 7.6 Hz, 1H), 7.60-7.52 (m, 3H),
7.51-7.41 (m, 3H), 7.39-7.33 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H),
5.42 (d, J = 17.6 Hz, 1H), 4.46 (s, 1H), 3.93 (d, J = 17.6 Hz, 1H),
3.86-3.73 (m, 1H), 3.60- 3.49 (m, 2H), 3.41-3.24 (m, 2H), 1.91-1.78
(m, 2H), 1.77-1.61 (m, 6H), 1.53-1.42 (m, 2H), 1.40- 1.22 (m, 3H),
1.22-1.01 (m, 3H). AVG-155 ##STR00134## 417.3 2.39 8.59 C
(CDCl.sub.3) .delta. 8.50 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.05
(d, J = 7.2 Hz, 1H), 6.82 (d, J = 6.0 Hz, 1H), 5.43 (d, J = 17.6
Hz, 1H), 4.49 (s, 1H), 3.87 (d, J = 17.6 Hz, 1H), 3.81-3.72 (m,
1H), 3.61- 3.50 (m, 2H), 3.41-3.23 (m, 2H), 1.88-1.74 (m, 3H),
1.74-1.60 (m, 6H), 1.54-1.37 (m, 2H), 1.35- 1.26 (m, 2H), 1.18-1.02
(m, 3H). AVG-156 ##STR00135## 484.2 2.94 10.77 C (CDCl.sub.3)
.delta. 8.00 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.51
(dd, J = 8.8, 1.6 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 5.43 (d, J =
17.6 Hz, 1H), 4.48 (s, 1H), 3.89 (d, J = 17.6 Hz, 1H), 3.84-3.73
(m, 1H), 3.61-3.48 (m, 2H), 3.41-3.25 (m, 2H), 1.83 (d, J = 12.1
Hz, 2H), 1.78-1.61 (m, 6H), 1.56-1.47 (m, 2H), 1.47- 1.39 (m, 1H),
1.37-1.26 (m, 2H), 1.19-1.03 (m, 3H). AVG-182 ##STR00136## 423.2
2.52 8.82 C (CDCl.sub.3) .delta.11.65 (brs, 1H), 7.76 (d, J = 6.8
Hz, 1H), 7.45-7.34 (m, 2H), 7.26-7.14 (m, 3H), 7.08 (dd, J = 7.6,
7.2 Hz, 1H), 7.00-6.91 (m, 1H), 6.26- 6.08 (m, 1H), 5.65 (brs, 1H),
5.03 (d, J = 16.4 Hz, 1H), 4.06-3.97 (m, 1H), 3.83-3.75 (m, 1H),
3.59-3.51 (m, 1H), 3.43- 3.34 (m, 1H), 1.82-1.60 (m, 4H), 1.60-1.52
(m, 1H), 1.44-1.34 (m, 1H). AVG-215 ##STR00137## 456.3 3.15 10.82 C
(CDCl.sub.3) .delta. 8.03 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 1.6 Hz,
1H), 7.35 (dd, J = 8.8, 1.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H),
5.46-5.35 (m, 2H), 5.10 (s, 1H), 4.42 (s, 1H), 3.88 (d, J = 16.8
Hz, 1H), 3.83-3.75 (m, 1H), 3.57-3.50 (m, 2H), 3.39- 3.29 (m, 2H),
2.12 (s, 3H), 1.93-1.80 (m, 2H), 1.78-1.62 (m, 6H), 1.61- 1.58 (m,
1H), 1.51-1.39 (m, 2H), 1.34-1.26 (m, 2H), 1.20-1.04 (m, 3H).
AVG-216 ##STR00138## 430.3 2.83 10.421 C (CDCl.sub.3) .delta. 8.19
(brs, 1H), 7.33 (dd, J = 8.0, 1.6 Hz, 1H), 7.29-7.25 (m, 1H), 7.06
(ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.42 (d,
J = 17.6 Hz, 1H), 4.42 (s, 1H), 3.92 (d, J = 17.2 Hz, 2H),
3.56-3.49 (m, 2H), 3.39- 3.33 (m, 1H), 3.30-3.24 (m, 1H), 3.22-3.16
(m, 1H), 3.06-3.00 (m, 1H), 1.78-1.62 (m, 9H), 1.55- 1.35 (m, 3H),
1.17-1.08 (m, 3H), 0.89-0.80 (m, 2H). AVG-217 ##STR00139## 464.3
3.21 11.23 C (DMSO-d.sub.6) .delta. 8.11 (t, J = 5.6 Hz, 1H), 7.57
(d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.6, 2.2 Hz, 1H), 6.97 (d, J =
8.8 Hz, 1H), 5.19 (s, 1H), 4.65 (d, J = 17.2 Hz, 1H), 4.36 (d, J =
17.2 Hz, 1H), 3.54-3.26 (m, 4H), 2.99-2.87(m, 2H), 1.66-1.49 (m,
9H), 1.48-1.26 (m, 3H), 1.18- 1.01 (m, 3H), 0.88-0.72 (m, 2H).
AVG-218 ##STR00140## 464.2 3.18 11.10 C (CDCl.sub.3) .delta. 7.43
(d, J = 7.6 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 9.2,
2.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H),
5.40 (d, J = 17.2 Hz, 1H), 4.25 (s, 1H), 3.85-3.74 (m, 2H),
3.63-3.52 (m, 1H), 1.94-1.87 (m, 1H), 1.82-1.63 (m, 5H), 1.62- 1.51
(m, 2H), 1.44-1.05 (m, 11H), 0.95-0.84 (m, 1H). AVG-219
##STR00141## 458.2 3.01 10.55 C (CDCl.sub.3) .delta. 9.53 (s, 1H),
7.40 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.31-7.27 (m,
1H), 7.22- 7.14 (m, 2H), 7.13-7.09 (m, 1H), 7.06 (d, J = 8.4 Hz,
1H), 5.63 (d, J = 17.2 Hz, 1H), 4.49 (s, 1H), 4.04 (d, J = 17.2 Hz,
1H), 3.56-3.36 (m, 3H), 3.33-3.20 (m, 1H), 2.14 (s, 3H), 1.79-1.60
(m, 4H), 1.52-1.46 (m, 1H), 1.45-1.33 (m, 1H). AVG-220 ##STR00142##
444.2 2.82 9.86 C (CDCl.sub.3) .delta. 9.64 (s, 1H), 7.69 (d, J =
8.0 Hz, 1H), 7.40-7.34 (m, 2H), 7.33- 7.30 (m, 1H), 7.25-7.21 (m,
2H), 7.14-7.07 (m, 2H), 5.51 (d, J = 17.2 Hz, 1H), 4.49 (s, 1H),
4.23 (d, J = 17.6 Hz, 1H), 3.59-3.45 (m, 2H), 3.39-3.28 (m, 1H),
3.28- 3.14 (m, 1H), 1.78-1.59 (m, 5H), 1.39-1.25 (m, 1H). AVG-221
##STR00143## 440.3 2.67 9.46 C (CDCl.sub.3) .delta. 9.06 (s, 1H),
7.99 (d, J = 6.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.32-7.27 (m,
1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12-7.04 (m, 2H), 6.93 (dd, J =
7.6, 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.28 (d, J = 18.0 Hz,
1H), 4.53 (s, 1H), 4.38 (d, J = 16.4 Hz, 1H), 3.75 (s, 3H),
3.57-3.48 (m, 2H), 3.38-3.29 (m, 2H), 1.73-1.60 (m, 4H), 1.52-1.47
(m, 1H), 1.45- 1.35 (m, 1H). AVG-222 ##STR00144## 441.2 2.46 8.71 C
(CDCl.sub.3) .delta. 10.08 (s, 1H), 8.31 (dd, J = 4.6, 1.0 Hz, 1H),
8.21 (d, J = 8.4 Hz, 1H), 7.68 (ddd, J = 8.8, 8.8, 1.8 Hz, 1H),
7.35 (dd, J = 7.6, 1.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.10-6.96 (m,
3H), 5.59 (d, J = 17.6 Hz, 1H), 4.51 (s, 1H), 4.12 (d, J = 17.6 Hz,
1H), 3.80-3.73 (m, 1H), 3.65- 3.58 (m, 1H), 3.36-3.21 (m, 2H),
1.79-1.65 (m, 2H), 1.63-1.60 (m, 2H), 1.46-1.24 (m, 2H). AVG-223
##STR00145## 411.2 2.45 8.57 C (DMSO-d.sub.6) .delta. 10.35 (s,
1H), 8.75 (d, J = 2.4 Hz, 1H), 8.28 (m, J = 3.2 Hz, 1H), 8.06 (dd,
J = 6.8, 1.6 Hz, 1H), 7.48 (dd, J = 7.6, 1.2 Hz, 1H), 7.38- 7.29
(m, 2H), 7.14-7.08 (m, 2H), 5.22 (s, 1H), 4.91 (d, J = 17.6 Hz,
1H), 4.66 (d, J = 17.6 Hz, 1H), 3.56-3.49 (m, 2H), 3.39-3.38 (m,
2H), 1.57-1.47 (m, 4H), 1.32- 1.29 (m, 2H) AVG-224 ##STR00146##
441.2 2.37 8.47 C (CDCl.sub.3) .delta. 10.24 (s, 1H), 8.45 (s, 2H),
7.72 (d, J = 4.8 Hz, 2H), 7.38 (dd, J = 7.8, 1.4 Hz, 1H), 7.32-
7.28 (m, 1H), 7.09 (dd, J = 7.6, 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz,
1H), 5.63 (d, J = 18.0 Hz, 1H), 4.50 (s, 1H), 4.03 (d, J = 17.6 Hz,
1H), 3.80-3.60 (m, 2H), 3.48-3.23 (m, 2H), 1.85-1.64 (m, 4H),
1.56-1.21 (m, 2H).
Example 4: Potency Range of Certain Compounds (EC50 Values)
[0183] The potency range of selected compounds (EC50 values) was
tested and the results are provided below:
TABLE-US-00004 Potency Compound # Range* AVG-044 B AVG-045 D
AVG-046 D AVG-047 D AVG-048 D AVG-049 B AVG-050 B AVG-051 B AVG-052
B AVG-053 D AVG-054 B AVG-055 D AVG-056 C AVG-057 B AVG-058 B
AVG-059 D AVG-060 D AVG-061 B AVG-062 A AVG-063 B AVG-064 C AVG-083
D AVG-084 D AVG-085 D AVG-086 C AVG-087 C AVG-111 D AVG-112 C
AVG-113 D AVG-114 D AVG-137 B AVG-138 B AVG-139 B AVG-140 B AVG-141
B AVG-142 C AVG-143 D AVG-144 B AVG-145 B AVG-146 B AVG-147 C
AVG-148 C AVG-149 B AVG-150 B AVG-151 C AVG-152 B AVG-153 B AVG-154
D AVG-155 B AVG-156 B AVG-182 D AVG-215 B AVG-216 B AVG-217 B
AVG-218 B AVG-219 A AVG-220 B AVG-221 B AVG-223 C AVG-224 C
*Potency Range (EC50 values) A >0.1-1.0 .mu.M B >1.0-10.0
.mu.M C >10.0-20.0 .mu.M D >20.0 .mu.M
* * * * *