U.S. patent application number 16/212374 was filed with the patent office on 2019-07-04 for 2'-chloro aminopyrimidinone and pyrimidine dione nucleosides.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Michael O' Neil Hanrahan Clarke, Richard L. Mackman, Dustin Siegel.
Application Number | 20190202852 16/212374 |
Document ID | / |
Family ID | 54066190 |
Filed Date | 2019-07-04 |
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United States Patent
Application |
20190202852 |
Kind Code |
A1 |
Clarke; Michael O' Neil Hanrahan ;
et al. |
July 4, 2019 |
2'-CHLORO AMINOPYRIMIDINONE AND PYRIMIDINE DIONE NUCLEOSIDES
Abstract
Provided herein are formulations, methods and substituted
2'-chloro aminopyrimidinone and pyrimidine dione compounds of
Formula (I) for treating Pneumovirinae virus infections, including
respiratory syncytial virus infections, as well as methods and
intermediates for synthesis of substituted 2'-chloro
aminopyrimidinone and pyrimidine dione compounds. ##STR00001##
Inventors: |
Clarke; Michael O' Neil
Hanrahan; (Redwood City, CA) ; Mackman; Richard
L.; (Millbrae, CA) ; Siegel; Dustin; (Half
Moon Bay, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
54066190 |
Appl. No.: |
16/212374 |
Filed: |
December 6, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15950442 |
Apr 11, 2018 |
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16212374 |
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15441561 |
Feb 24, 2017 |
9982006 |
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15950442 |
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14830121 |
Aug 19, 2015 |
9617295 |
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15441561 |
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62040349 |
Aug 21, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/00 20180101;
A61K 31/7072 20130101; C07H 19/06 20130101; A61K 31/7068 20130101;
C07H 19/073 20130101; C07H 19/10 20130101; A61P 31/12 20180101;
A61P 31/14 20180101 |
International
Class: |
C07H 19/06 20060101
C07H019/06; A61K 31/7072 20060101 A61K031/7072; C07H 19/073
20060101 C07H019/073; C07H 19/10 20060101 C07H019/10; A61K 31/7068
20060101 A61K031/7068 |
Claims
1. A compound of Formula I, or a pharmaceutically acceptable salt
thereof: ##STR00066## wherein R.sup.1 is selected from NH and N;
the dashed line (----), in conjunction with the solid line to which
it is parallel, represents an optional double bond; R.sup.2 is
selected from oxo or NH.sub.2, with the proviso that, when R.sup.2
is oxo, R.sup.1 is NH and the bond represented by the dashed line
(----), in conjunction with the solid line to which it is parallel,
is a single bond; and with the proviso that, when R.sup.2 is
NH.sub.2, R.sup.1 is N and the bond represented by the dashed line
(----), in conjunction with the solid line to which it is parallel,
is a double bond; R.sup.3 is selected from the group of H, F,
CH.sub.2F, CHF.sub.2, and CF.sub.3; R.sup.5 is selected from the
group of CN, unsubstituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with 1, 2, or 3 halogens, C.sub.1-C.sub.4 alkyl
substituted with 1 substituent selected from --S--CH.sub.3 and
--O--CH.sub.3, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
unsubstituted C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl substituted by 1, 2, or 3 substituents selected from F
and CH.sub.3; R.sup.4' is selected from the group of H,
--C(.dbd.O)R.sup.6, --C(.dbd.O)OR.sup.6, and
--C(.dbd.O)NR.sup.6R.sup.7; R.sup.4 is selected from the group of
H, --C(.dbd.O)R.sup.6, --C(.dbd.O)OR.sup.6, and
--C(.dbd.O)NR.sup.6R.sup.7; or a) R.sup.4 is a group of the
formula: ##STR00067## wherein: each Y is O, S, NR, .sup.+N(O)(R),
N(OR), .sup.+N(O)(OR), or N--NR.sub.2; and W.sup.1 and W.sup.2,
when taken together, are --Y.sup.3(C(R).sub.2).sub.3Y.sup.3--; or
one of W.sup.1 or W.sup.2 together with R.sup.4' is --Y.sup.3-- and
the other of W.sup.1 or W.sup.2 is Formula Ia; or W.sup.1 and
W.sup.2 are each, independently, a group of the Formula Ia:
##STR00068## wherein: each Y.sup.1 is, independently, O, S, NR,
.sup.+N(O)(R), N(OR), .sup.+N(O)(OR), or N--NR.sub.2; each Y.sup.2
is independently a bond, O, CR.sub.2, --O--CR.sub.2--, NR,
.sup.+N(O)(R), N(OR), .sup.+N(O)(OR), N--NR.sub.2, S, S--S, S(O),
or S(O).sub.2; each Y.sup.3 is a single bond; M1 is 0, 1,2, or 3;
each R.sup.x is independently R.sup.Y or the formula: ##STR00069##
wherein: each M2a, M2b, and M2c is independently 0 or 1; M2d is 0,
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; each R.sup.y is
independently H, F, Cl, Br, I, OH, R, --C(.dbd.Y.sup.1)R,
--C(.dbd.Y.sup.1)OR, --C(.dbd.Y.sup.1)N(R).sub.2, --N(R).sub.2,
--.sup.+N(R).sub.3, --SR, --S(O)R, --S(O).sub.2R, --S(O)(OR),
--S(O).sub.2(OR), --OC(.dbd.Y.sup.1)R, --OC(.dbd.Y.sup.1)OR,
--OC(.dbd.Y.sup.1)(N(R).sub.2), --SC(.dbd.Y.sup.1)R,
--SC(.dbd.Y.sup.1)OR, --SC(.dbd.Y.sup.1)(N(R).sub.2),
--N(R)C(.dbd.Y.sup.1)R, --N(R)C(.dbd.Y.sup.1)OR,
--N(R)C(.dbd.Y.sup.1)N(R).sub.2, --SO.sub.2NR.sub.2, --CN,
--N.sub.3, --NO.sub.2, --OR, or W.sup.3; or when taken together,
two R.sup.y on the same carbon atom form a carbocyclic ring having
3, 4, 5, 6, or 7 carbon ring atoms; or when taken together, two
R.sup.y on the same carbon atom form along with the carbon atom a
heterocycle having 3, 4, 5, 6, or 7 ring atoms wherein one ring
atom is selected from O or N and all other ring atoms are carbon;
each R is independently H, (C.sub.1-C.sub.8) alkyl,
(C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8) substituted alkenyl, (C.sub.2-C.sub.8) alkynyl,
(C.sub.2-C.sub.8) substituted alkynyl, C.sub.6-C.sub.10 aryl,
C.sub.6-C.sub.10 substituted aryl, a 3- to 10-membered heterocycle,
a substituted 3- to 10-membered heterocycle, a 5- to 12-membered
heteroaryl, a substituted 5- to 12-membered heteroaryl, arylalkyl,
substituted arylalkyl, heteroarylalkyl, or substituted
heteroarylalkyl; and W.sup.3 is W.sup.4 or W.sup.5; W.sup.4 is R,
--C(Y.sup.1)R.sup.y, --C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.y, or
--SO.sub.2W.sup.5; W.sup.5 is selected from phenyl, naphthyl, a
C.sub.3-C.sub.8 carbocycle, or a 3- to 10-membered heterocycle,
wherein W.sup.5 is independently substituted with 0, 1, 2, 3, 4, 5,
or 6 R.sup.y groups; each R.sup.6 and R.sup.7 is independently H,
(C.sub.1-C.sub.5)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.4-C.sub.5)carbocyclylalkyl,
C.sub.6-C.sub.10 aryl, C.sub.6-C.sub.10 substituted aryl, 5- to
10-membered heteroaryl, substituted 5- to 10-membered heteroaryl,
--C(.dbd.O)(C.sub.1-C.sub.5)alkyl,
--S(O).sub.n(C.sub.1-C.sub.5)alkyl or aryl(C.sub.1-C.sub.5)alkyl;
or R.sup.6 and R.sup.7 taken together with a nitrogen to which they
are both attached form a 3- to 7-membered heterocycle wherein any
one ring carbon atom of said heterocycle can optionally be replaced
with --O--, --S-- or --NR.sup.a--; and wherein each
(C.sub.1-C.sub.5)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl or aryl(C.sub.1-C.sub.5)alkyl of each
R.sup.6 or R.sup.7 is, independently, optionally substituted with
one, two, three, or four substituents selected from halo, hydroxy,
CN, N.sub.3, N(R.sup.a).sub.2 or OR.sup.a; and wherein one, two, or
three of the non-terminal carbon atoms of each said
(C.sub.1-C.sub.5)alkyl may be optionally replaced with --O--, --S--
or --NR.sup.a--; or b) R.sup.4 is a group selected from:
##STR00070## wherein: R.sup.8 is selected from phenyl, 1-naphthyl,
2-naphthyl, ##STR00071## R.sup.9 is selected from H and CH.sub.3;
R.sup.10 is selected from H or C.sub.1-C.sub.6 alkyl; R.sup.10' is
selected from H or C.sub.1-C.sub.6 alkyl; or R.sup.10 and
R.sup.10', together with the carbon atom to which they are bound,
form a 3-, 4-, 5-, or 6-membered spirocycle wherein all ring atoms
of the spirocycle are carbon; or R.sup.10 and R.sup.10', together
with the carbon atom to which they are bound, form a 3-, 4-, 5-, or
6-membered spirocycle wherein 1 or 2 of the ring atoms of the
spirocycle are selected from the group of O, S, and N, and all
other ring atoms of the spirocycle are carbon; R.sup.11 is selected
from H, C.sub.1-C.sub.5 alkyl, benzyl, C.sub.3-C.sub.6 cycloalkyl,
--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl,
--CH.sub.2CH.sub.2--S--C(O)--C.sub.3-C.sub.6 alkyl, ##STR00072##
R.sup.7' is selected from C.sub.1-C.sub.8 alkyl,
--O--C.sub.1-C.sub.8 alkyl, benzyl, --O-benzyl,
--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, and CF.sub.3; or c) R.sup.4
and R.sup.4' combine to form the structure selected from:
##STR00073##
2-21. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/040,349, filed on Aug. 21, 2014, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] Provided herein are substituted 2'-chloro aminopyrimidinone
and pyrimidine dione compounds, methods and pharmaceutical
formulations for treating Pneumovirinae virus infections,
particularly including respiratory syncytial virus infections, and
methods and intermediates useful for preparing the compounds.
BACKGROUND OF THE INVENTION
[0003] Pneumovirinae viruses are negative-sense, single-stranded,
RNA viruses that are responsible for many prevalent human and
animal diseases. The Pneumovirinae sub-family of viruses is a part
of the family Paramyxoviridae and includes human respiratory
syncytial virus (HRSV). Almost all children will have had an HRSV
infection by their second birthday. HRSV is the major cause of
lower respiratory tract infections in infancy and childhood with
0.5% to 2% of those infected requiring hospitalization. The elderly
and adults with chronic heart, lung disease or those that are
immunosuppressed also have a high risk for developing severe HRSV
disease (http://www.cdc.gov/rsv/index.html). No vaccine to prevent
HRSV infection is currently available. The monoclonal antibody
palivizumab is available for immunoprophylaxis, but its use is
restricted to infants at high risk, e.g., premature infants or
those with either congenital heart or lung disease, and the cost
for general use is often prohibitive. In addition, nucleoside
analog ribavirin has been approved as the only antiviral agent to
treat HRSV infections but has limited efficacy. Therefore, there is
a need for anti-Pneumovirinae therapeutics.
[0004] Examples of pyrrolo[2,3-d]pyrimidine compounds useful for
treating viral infections are described in U.S. 2012/0009147 A1
(Cho et al.), U.S. 2012/0020921 A1 (Cho et al.), WO 2008/089105 A2
(Babu et al.), WO 2008/141079 A1 (Babu et al.), WO 2009/132135 A1
(Butler et al.), WO 2010/002877 A2 (Francom), WO 2011/035231 A1
(Cho et al.), WO 2011/035250 A1 (Butler et al.), WO 2011/150288 A1
(Cho et al.), WO 2012/012465 (Cho et al.), WO 2012/012776 A1
(Mackman et al.), WO 2012/037038 (Clarke et al.), WO 2012/087596 A1
(Delaney et al.), and WO 2012/142075 A1 (Girijavallabhan et
al.).
[0005] There remains a need for new antiviral agents useful in
treating Paramyxoviridae viral infections, including Pneumovirinae
viral infections, such as HRSV infections, that are effective and
have acceptable toxicity profiles.
SUMMARY
[0006] Provided are compounds, methods, and pharmaceutical
formulations for the treatment of infections caused by the
Pneumovirinae virus family, including treatment of infections
caused by human respiratory syncytial virus.
[0007] Provided is a compound of Formula I, or a pharmaceutically
acceptable salt thereof:
##STR00002##
wherein: R.sup.1 is selected from NH and N; the dashed line (----),
in conjunction with the solid line to which it is parallel,
represents an optional double bond; R.sup.2 is selected from oxo or
NH.sub.2, with the proviso that, when R.sup.2 is oxo, R.sup.1 is NH
and the bond represented by the dashed line (----), in conjunction
with the solid line to which it is parallel, is a single bond; and
with the proviso that, when R.sup.2 is NH.sub.2, R.sup.1 is N and
the bond represented by the dashed line (----), in conjunction with
the solid line to which it is parallel, is a double bond; R.sup.3
is selected from the group of H, F, CH.sub.2F, CHF.sub.2, and
CF.sub.3; R.sup.5 is selected from the group of CN, unsubstituted
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with 1, 2,
or 3 halogens, C.sub.1-C.sub.4 alkyl substituted with 1 substituent
selected from --S--CH.sub.3 and --O--CH.sub.3, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, unsubstituted C.sub.3--C
cycloalkyl, C.sub.3--C cycloalkyl substituted by 1, 2, or 3
substituents selected from F and CH.sub.3; R.sup.4' is selected
from the group of H, --C(.dbd.O)R.sup.6, --C(.dbd.O)OR.sup.6, and
--C(.dbd.O)NR.sup.6R.sup.7;
[0008] R.sup.4 is selected from the group of H, --C(.dbd.O)R.sup.6,
--C(.dbd.O)OR.sup.6, and --C(.dbd.O)NR.sup.6R.sup.7;
[0009] or [0010] a) R.sup.4 is a group of the formula:
##STR00003##
[0011] wherein:
[0012] each Y is O, S, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), or
N--NR.sub.2; and
[0013] W.sup.1 and W.sup.2, when taken together, are
--Y.sup.3(C(R.sup.y).sub.2).sub.3Y.sup.3--;
[0014] or one of W.sup.1 or W.sup.2 together with R.sup.4' is
--Y.sup.3-- and the other of W.sup.1 or W.sup.2 is Formula Ia;
[0015] or W.sup.1 and W.sup.2 are each, independently, a group of
the Formula Ia:
##STR00004##
[0016] wherein:
[0017] each Y.sup.1 is, independently, O, S, NR, .sup.+N(O)(R),
N(OR), .sup.+N(O)(OR), or N--NR.sub.2;
[0018] each Y.sup.2 is independently a bond, O, CR.sub.2,
--O--CR.sub.2--, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR),
N--NR.sub.2, S, S--S, S(O), or S(O).sub.2;
[0019] each Y.sup.3 is a single bond;
[0020] M1 is 0, 1, 2, or 3;
[0021] each R.sup.x is independently R.sup.y or the formula:
##STR00005##
[0022] wherein:
[0023] each M2a, M2b, and M2c is independently 0 or 1;
[0024] M2d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0025] each R.sup.y is independently H, F, Cl, Br, I, OH, R,
--C(.dbd.Y.sup.1)R, --C(.dbd.Y.sup.1)OR,
--C(.dbd.Y.sup.1)N(R).sub.2, --N(R).sub.2, --.sup.+N(R).sub.3,
--SR, --S(O)R, --S(O).sub.2R, --S(O)(OR), --S(O).sub.2(OR),
--OC(.dbd.Y.sup.1)R, --OC(.dbd.Y.sup.1)OR,
--OC(.dbd.Y.sup.1)(N(R).sub.2), --SC(.dbd.Y.sup.1)R,
--SC(.dbd.Y.sup.1)OR, --SC(.dbd.Y.sup.1)(N(R).sub.2),
--N(R)C(.dbd.Y.sup.1)R, --N(R)C(.dbd.Y.sup.1)OR,
--N(R)C(.dbd.Y.sup.1)N(R).sub.2, --SO.sub.2NR.sub.2, --CN,
--N.sub.3, --NO.sub.2, --OR, or W.sup.3;
[0026] or when taken together, two R.sup.y on the same carbon atom
form a carbocyclic ring having 3, 4, 5, 6, or 7 carbon ring
atoms;
[0027] or when taken together, two R.sup.y on the same carbon atom
form along with the carbon atom a heterocycle having 3, 4, 5, 6, or
7 ring atoms wherein one ring atom is selected from O or N and all
other ring atoms are carbon;
[0028] each R is independently H, (C.sub.1-C.sub.8) alkyl,
(C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8) substituted alkenyl, (C.sub.2-C.sub.8) alkynyl,
(C.sub.2-C.sub.8) substituted alkynyl, C.sub.6-C.sub.10 aryl,
C.sub.6-C.sub.10 substituted aryl, a 3- to 10-membered heterocycle,
a substituted 3- to 10-membered heterocycle, a 5- to 12-membered
heteroaryl, a substituted 5- to 12-membered heteroaryl, arylalkyl,
substituted arylalkyl, heteroarylalkyl, or substituted
heteroarylalkyl; and
[0029] W.sup.3 is W.sup.4 or W.sup.5;
[0030] W.sup.4 is R, --C(Y.sup.1)R.sup.y, --C(Y.sup.1)W.sup.5,
--SO.sub.2R, or --SO.sub.2W.sup.5;
[0031] W.sup.5 is selected from phenyl, naphthyl, a C.sub.3-C.sub.8
carbocycle, or a 3- to 10-membered heterocycle, wherein W.sup.5 is
independently substituted with 0, 1, 2, 3, 4, 5, or 6 R.sup.y
groups;
[0032] each R.sup.6 and R.sup.7 is independently H,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.4-C.sub.8)carbocyclylalkyl,
C.sub.6-C.sub.10 aryl, C.sub.6-C.sub.10 substituted aryl, 5- to
10-membered heteroaryl, substituted 5- to 10-membered heteroaryl,
--C(.dbd.O)(C.sub.1-C.sub.8)alkyl,
--S(O).sub.n(C.sub.2-C.sub.8)alkyl or
aryl(C.sub.1-C.sub.8)alkyl;
[0033] or R.sup.6 and R.sup.7 taken together with a nitrogen to
which they are both attached form a 3- to 7-membered heterocycle
wherein any one ring carbon atom of said heterocycle can optionally
be replaced with --O--, --S-- or --NR.sup.a--;
[0034] and wherein each (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl or
aryl(C.sub.1-C.sub.5)alkyl of each R.sup.6 or R.sup.7 is,
independently, optionally substituted with one, two, three, or four
substituents selected from halo, hydroxy, CN, N.sub.3,
N(R.sup.a).sub.2 or OR.sup.a; and wherein one, two, or three of the
non-terminal carbon atoms of each said (C.sub.1-C.sub.8)alkyl may
be optionally replaced with --O--, --S-- or --NR.sup.a--; or [0035]
b) R.sup.4 is a group selected from:
##STR00006##
[0035] wherein:
[0036] R.sup.8 is selected from phenyl, 1-naphthyl, 2-naphthyl,
##STR00007##
[0037] R.sup.9 is selected from H and CH.sub.3;
[0038] R.sup.10 is selected from H or C.sub.1-C.sub.06 alkyl;
[0039] R.sup.10' is selected from H or C.sub.1-C.sub.6 alkyl;
[0040] or R.sup.10 and R.sup.10', together with the carbon atom to
which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle
wherein all ring atoms of the spirocycle are carbon;
[0041] or R.sup.10 and R.sup.10', together with the carbon atom to
which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle
wherein 1 or 2 of the ring atoms of the spirocycle are selected
from the group of O, S, and N, and all other ring atoms of the
spirocycle are carbon;
[0042] R.sup.11 is selected from H, C.sub.1-C.sub.8 alkyl, benzyl,
C.sub.3-C.sub.6 cycloalkyl, --CH.sub.2--C.sub.3-C.sub.6 cycloalkyl,
--CH.sub.2CH.sub.2--S--C(O)--C.sub.3-C.sub.6 alkyl,
##STR00008##
[0043] R.sup.7' is selected from C.sub.1-C.sub.8 alkyl,
--O--C.sub.1-C.sub.8 alkyl, benzyl, --O-benzyl,
--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, and CF.sub.3; or
[0044] c) R.sup.4 and R.sup.4' combine to form the structure
selected from:
##STR00009##
and R.sup.a in each appearance is independently selected from H and
C.sub.1-C.sub.6 alkyl, two adjacent R.sup.A in the group
--N(R.sub.a).sub.2 can together form a 4-, 5-, or 6-membered
heterocyclic ring containing 0 or 1 additional ring heteroatom
selected from O or N.
DETAILED DESCRIPTION
[0045] Provided is a compound of Formula I, or a pharmaceutically
acceptable salt thereof:
##STR00010##
wherein: R.sup.1 is selected from NH and N; the dashed line (----),
in conjunction with the solid line to which it is parallel,
represents an optional double bond; R.sup.2 is selected from oxo or
NH.sub.2, with the proviso that, when R.sup.2 is oxo, R.sup.1 is NH
and the bond represented by the dashed line (----), in conjunction
with the solid line to which it is parallel, is a single bond; and
with the proviso that, when R.sup.2 is NH.sub.2, R.sup.1 is N and
the bond represented by the dashed line (----), in conjunction with
the solid line to which it is parallel, is a double bond; R.sup.3
is selected from the group of H, F, CH.sub.2F, CHF.sub.2, and
CF.sub.3; R.sup.5 is selected from the group of CN, unsubstituted
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with 1, 2,
or 3 halogens, C.sub.1-C.sub.4 alkyl substituted with 1 substituent
selected from --S--CH.sub.3 and --O--CH.sub.3, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, unsubstituted C.sub.3-C.sub.6
cycloalkyl, C.sub.3-C.sub.6 cycloalkyl substituted by 1, 2, or 3
substituents selected from F and CH.sub.3; R.sup.4' is selected
from the group of H, --C(.dbd.O)R.sup.6, --C(.dbd.O)OR.sup.6, and
--C(.dbd.O)NR.sup.6R.sup.7;
[0046] R.sup.4 is selected from the group of H, --C(.dbd.O)R.sup.6,
--C(.dbd.O)OR.sup.6, and --C(.dbd.O)NR.sup.6R.sup.7;
[0047] or [0048] b) R.sup.4 is a group of the formula:
##STR00011##
[0049] wherein:
[0050] each Y is O, S, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), or
N--NR.sub.2; and
[0051] W.sup.1 and W.sup.2, when taken together, are
--Y.sup.3(C(R.sup.y).sub.2).sub.3Y.sup.3--;
[0052] or one of W.sup.1 or W.sup.2 together with R.sup.4' is
--Y.sup.3-- and the other of W.sup.1 or W.sup.2 is Formula Ia;
[0053] or W.sup.1 and W.sup.2 are each, independently, a group of
the Formula Ia:
##STR00012##
[0054] wherein:
[0055] each Y.sup.1 is, independently, O, S, NR, .sup.+N(O)(R),
N(OR), .sup.+N(O)(OR), or N--NR.sub.2;
[0056] each Y.sup.2 is independently a bond, 0, CR.sub.2,
--O--CR.sub.2--, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR),
N--NR.sub.2, S, S--S, S(O), or S(O).sub.2;
[0057] each Y.sup.3 is a single bond;
[0058] M1 is 0, 1, 2, or 3;
[0059] each R.sup.x is independently R.sup.y or the formula:
##STR00013##
[0060] wherein:
[0061] each M2a, M2b, and M2c is independently 0 or 1;
[0062] M2d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0063] each R.sup.y is independently H, F, Cl, Br, I, OH, R,
--C(.dbd.Y.sup.1)R, --C(.dbd.Y.sup.1)OR,
--C(.dbd.Y.sup.1)N(R).sub.2, --N(R).sub.2, --.sup.+N(R).sub.3,
--SR, --S(O)R, --S(O).sub.2R, --S(O)(OR), --S(O).sub.2(OR),
--OC(.dbd.Y.sup.1)R, --OC(.dbd.Y.sup.1)OR,
--OC(.dbd.Y.sup.1)(N(R).sub.2), --SC(.dbd.Y.sup.1)R,
--SC(.dbd.Y.sup.1)OR, --SC(.dbd.Y.sup.1)(N(R).sub.2),
--N(R)C(.dbd.Y.sup.1)R, --N(R)C(.dbd.Y.sup.1)OR,
--N(R)C(.dbd.Y.sup.1)N(R).sub.2, --SO.sub.2NR.sub.2, --CN,
--N.sub.3, --NO.sub.2, --OR, or W.sup.3;
[0064] or when taken together, two R.sup.y on the same carbon atom
form a carbocyclic ring having 3, 4, 5, 6, or 7 carbon ring
atoms;
[0065] or when taken together, two R.sup.y on the same carbon atom
form along with the carbon atom a heterocycle having 3, 4, 5, 6, or
7 ring atoms wherein one ring atom is selected from O or N and all
other ring atoms are carbon;
[0066] each R is independently H, (C.sub.1-C.sub.8) alkyl,
(C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.08) substituted alkenyl, (C.sub.2-C.sub.8) alkynyl,
(C.sub.2-C.sub.8) substituted alkynyl, C.sub.6-C.sub.10 aryl,
C.sub.6-C.sub.10 substituted aryl, a 3- to 10-membered heterocycle,
a substituted 3- to 10-membered heterocycle, a 5- to 12-membered
heteroaryl, a substituted 5- to 12-membered heteroaryl, arylalkyl,
substituted arylalkyl, heteroarylalkyl, or substituted
heteroarylalkyl; and
[0067] W.sup.3 is W.sup.4 or W.sup.5;
[0068] W.sup.4 is R, --C(Y.sup.1)R.sup.y, --C(Y.sup.1)W.sup.5,
--SO.sub.2R.sup.y, or --SO.sub.2W.sup.5;
[0069] W.sup.5 is selected from phenyl, naphthyl, a C.sub.3-C.sub.8
carbocycle, or a 3- to 10-membered heterocycle, wherein W.sup.5 is
independently substituted with 0, 1, 2, 3, 4, 5, or 6 R.sup.y
groups;
[0070] each R.sup.6 and R.sup.7 is independently H,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.4-C.sub.8)carbocyclylalkyl,
C.sub.6-C.sub.10 aryl, C.sub.6-C.sub.10 substituted aryl, 5- to
10-membered heteroaryl, substituted 5- to 10-membered heteroaryl,
--C(.dbd.O)(C.sub.1-C.sub.5)alkyl,
--S(O).sub.n(C.sub.1-C.sub.5)alkyl or
aryl(C.sub.1-C.sub.8)alkyl;
[0071] or R.sup.6 and R.sup.7 taken together with a nitrogen to
which they are both attached form a 3- to 7-membered heterocycle
wherein any one ring carbon atom of said heterocycle can optionally
be replaced with --O-- or --S--;
[0072] and wherein each (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl or
aryl(C.sub.1-C.sub.8)alkyl of each R.sup.6 or R.sup.7 is,
independently, optionally substituted with one, two, three, or four
substituents selected from halo, hydroxy, CN, or N.sub.3; and
wherein one, two, or three of the non-terminal carbon atoms of each
said (C.sub.1-C.sub.5)alkyl may be optionally replaced with --O--
or --S--; or [0073] b) R.sup.4 is a group selected from:
##STR00014##
[0073] wherein:
[0074] R.sup.8 is selected from phenyl, 1-naphthyl, 2-naphthyl,
##STR00015##
[0075] R.sup.9 is selected from H and CH.sub.3;
[0076] R.sup.10 is selected from H or C.sub.1-C.sub.6 alkyl;
[0077] R.sup.10' is selected from H or C.sub.1-C.sub.6 alkyl;
[0078] or R.sup.10 and R.sup.10', together with the carbon atom to
which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle
wherein all ring atoms of the spirocycle are carbon;
[0079] or R.sup.10 and R.sup.10', together with the carbon atom to
which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle
wherein 1 or 2 of the ring atoms of the spirocycle are selected
from the group of O, S, and N, and all other ring atoms of the
spirocycle are carbon;
[0080] R.sup.11 is selected from H, C.sub.1-C.sub.8 alkyl, benzyl,
C.sub.3-C.sub.6 cycloalkyl, --CH.sub.2--C.sub.3-C.sub.6 cycloalkyl,
--CH.sub.2CH.sub.2--S--C(O)--C.sub.3-C.sub.6 alkyl,
##STR00016##
[0081] R.sup.7' is selected from C.sub.1-C.sub.8 alkyl,
--O--C.sub.1-C.sub.8 alkyl, benzyl, --O-benzyl,
--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, and CF.sub.3; or [0082] d)
R.sup.4 and R.sup.4' combine to form the structure selected
from:
##STR00017##
[0083] Also provided are two separate embodiments comprising a
compound of Formula II, or a pharmaceutically acceptable salt
thereof, and a compound of Formula III, or a pharmaceutically
acceptable salt thereof:
##STR00018##
[0084] wherein, in each embodiment R.sup.3, R.sup.4, R.sup.4', and
R.sup.5 are as defined for Formula (I), above. Also provided are
two separate embodiments comprising a compound of Formula II, or a
pharmaceutically acceptable salt thereof, and a compound of Formula
III, or a pharmaceutically acceptable salt thereof, wherein, in
each embodiment R.sup.3, R.sup.4, and R.sup.5 are as defined for
Formula (I), above, and R.sup.4' is hydrogen.
[0085] Also provided are separate embodiments comprising a compound
of Formula I, or a pharmaceutically acceptable salt thereof,
Formula II, or a pharmaceutically acceptable salt thereof, and
Formula III, or a pharmaceutically acceptable salt thereof, wherein
in each embodiment R.sup.5 is selected from the group of CN,
unsubstituted C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkyl
substituted with 1, 2, or 3 halogens selected from F and Cl,
C.sub.1-C.sub.3 alkyl substituted with 1 substituent selected from
--S--CH.sub.3 and --O--CH.sub.3, C.sub.2-C.sub.3 alkenyl,
C.sub.2-C.sub.3 alkynyl, unsubstituted C.sub.3-C.sub.5 cycloalkyl,
C.sub.3-C.sub.5 cycloalkyl substituted by 1, 2, or 3 substituents
selected from F and CH.sub.3; and, when present, R.sup.a, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.4', R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y.sup.1, Y.sup.2, Y.sup.3,
W.sup.1, W.sup.2, W.sup.3, W.sup.4, W.sup.5, M1, M2a, M2b, M2c,
M2d, R.sup.x, and R.sup.y are as defined above for Formula (I).
Within each of these embodiments, there is a further embodiment
wherein R.sup.5 is as just defined, R.sup.3 is hydrogen, and,
R.sup.a, R.sup.1, R.sup.2, R.sup.4, R.sup.4', R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y.sup.1, Y.sup.2,
Y.sup.3, W.sup.1, W.sup.2, W.sup.3, W.sup.4, W.sup.5, M1, M2a, M2b,
M2c, M2d, R.sup.x, and R.sup.y are as defined above for Formula
(I). Within each of these embodiments, there is a further
embodiment wherein R.sup.5 is as just defined, R.sup.3 is F, and,
R.sup.a, R.sup.1, R.sup.2, R.sup.4, R.sup.4', R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y, Y.sup.1,
Y.sup.2, Y.sup.3, W, W.sup.2, W.sup.2, W.sup.4, W.sup.5, M1, M2a,
M2b, M2c, M2d, R.sup.x, and R.sup.y are as defined above for
Formula (I). Within each of these embodiments for a compound of
Formula II, or a pharmaceutically acceptable salt thereof, or of
Formula III, or a pharmaceutically acceptable salt thereof, there
is also a further embodiment wherein R.sup.4' and R.sup.5 are as
just defined, and R.sup.3 and R.sup.4 are each hydrogen. Within
each of these embodiments for a compound of Formula II, or a
pharmaceutically acceptable salt thereof, or of Formula III, or a
pharmaceutically acceptable salt thereof, there is also a further
embodiment wherein R.sup.5 are as just defined, and R.sup.3,
R.sup.4, and R.sup.4' are each hydrogen. Within each of these
embodiments for a compound of Formula II, or a pharmaceutically
acceptable salt thereof, or of Formula III, or a pharmaceutically
acceptable salt thereof, there is also a further embodiment wherein
R.sup.5 is as just defined, and R.sup.3 is F, and R.sup.4 is
hydrogen. Within each of these embodiments for a compound of
Formula II, or a pharmaceutically acceptable salt thereof, or of
Formula III, or a pharmaceutically acceptable salt thereof, there
is also a further embodiment wherein R.sup.5 is as just defined,
and R.sup.3 is F, R.sup.4 is hydrogen, and R.sup.4' is
hydrogen.
[0086] Also provided are separate embodiments comprising a compound
of Formula I, or a pharmaceutically acceptable salt thereof,
Formula II, or a pharmaceutically acceptable salt thereof, and
Formula III, or a pharmaceutically acceptable salt thereof, wherein
in each embodiment R.sup.5 is selected from the group of CN,
unsubstituted C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkyl
substituted with 1, 2, or 3 halogens selected from F and Cl,
C.sub.1-C.sub.3 alkyl substituted with 1 substituent selected from
--S--CH.sub.3 and --O--CH.sub.3, C.sub.2-C.sub.3 alkenyl,
C.sub.2-C.sub.3 alkynyl, unsubstituted C.sub.3-C.sub.4cycloalkyl,
C.sub.3-C.sub.4 cycloalkyl substituted by 1, 2, or 3 substituents
selected from F and CH.sub.3; and, when present, R.sup.a, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.4, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y, Y.sup.1, Y.sup.2,
Y.sup.3, W.sup.1, W.sup.2, W.sup.3, W.sup.4, W.sup.5, M1, M2a, M2b,
M2c, M2d, R.sup.x, and R.sup.y are as defined above for Formula
(I). Within each of these embodiments, there is a further
embodiment wherein R.sup.5 is as just defined, R.sup.3 is hydrogen,
and, R.sup.a, R.sup.1, R.sup.2, R.sup.4, R.sup.4, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y.sup.1, Y.sup.2,
Y.sup.3, W.sup.1, W.sup.2, W.sup.3, W.sup.4, W.sup.5, M1, M2a, M2b,
M2c, M2d, R.sup.x, and R.sup.y are as defined above for Formula
(I). Within each of these embodiments, there is a further
embodiment wherein R.sup.5 is as just defined, R.sup.3 is F, and,
R.sup.a, R.sup.1, R.sup.2, R.sup.4, R.sup.4, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y, Y.sup.1,
Y.sup.2, Y.sup.3, W.sup.1, W.sup.2, W.sup.3, W.sup.4, W.sup.5, M1,
M2a, M2b, M2c, M2d, R.sup.x, and R.sup.y are as defined above for
Formula (I). Within each of these embodiments for a compound of
Formula II, or a pharmaceutically acceptable salt thereof, or of
Formula III, or a pharmaceutically acceptable salt thereof, there
is also a further embodiment wherein R.sup.5 is as just defined,
and R.sup.3 and R.sup.4 are each hydrogen. Within each of these
embodiments for a compound of Formula II, or a pharmaceutically
acceptable salt thereof, or of Formula III, or a pharmaceutically
acceptable salt thereof, there is also a further embodiment wherein
R.sup.5 are as just defined, and R.sup.3, R.sup.4, and R.sup.4' are
each hydrogen. Within each of these embodiments for a compound of
Formula II, or a pharmaceutically acceptable salt thereof, or of
Formula III, or a pharmaceutically acceptable salt thereof, there
is also a further embodiment wherein R.sup.5 is as just defined,
and R.sup.3 is F, and R.sup.4 is hydrogen. Within each of these
embodiments for a compound of Formula II, or a pharmaceutically
acceptable salt thereof, or of Formula III, or a pharmaceutically
acceptable salt thereof, there is also a further embodiment wherein
R.sup.5 is as just defined, and R.sup.3 is F, R.sup.4 is hydrogen,
and R.sup.4' is hydrogen.
[0087] Also provided are separate embodiments comprising a compound
of Formula I, or a pharmaceutically acceptable salt thereof,
Formula II, or a pharmaceutically acceptable salt thereof, and
Formula III, or a pharmaceutically acceptable salt thereof, wherein
in each embodiment R.sup.5 is selected from the group of CN,
unsubstituted C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkyl
substituted with 1, 2, or 3 halogens selected from F and Cl,
C.sub.1-C.sub.3 alkyl substituted with 1 substituent selected from
--S--CH.sub.3 and --O--CH.sub.3, vinyl, ethynyl, unsubstituted
cyclopropyl, cyclopropyl substituted by 1 or 2 substituents
selected from F and CH.sub.3; and, when present, R.sup.a, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.4, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y, Y.sup.1, Y.sup.2,
Y.sup.3, W.sup.1, W.sup.2, W.sup.3, W.sup.4, W.sup.5, M1, M2a, M2b,
M2c, M2d, R.sup.x, and R.sup.y are as defined above for Formula
(I). Within each of these embodiments, there is a further
embodiment wherein R.sup.5 is as just defined, R.sup.3 is hydrogen,
and, R.sup.a, R.sup.1, R.sup.2, R.sup.4, R.sup.4, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y, Y.sup.1,
Y.sup.2, Y.sup.3, W.sup.1, W.sup.2, W.sup.3, W.sup.4, W.sup.5, M1,
M2a, M2b, M2c, M2d, R.sup.x, and R.sup.y are as defined above for
Formula (I). Within each of these embodiments, there is a further
embodiment wherein R.sup.5 is as just defined, R.sup.3 is F, and,
R.sup.a, R.sup.1, R.sup.2, R.sup.4, R.sup.4, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.10', R.sup.11, Y, Y.sup.1,
Y.sup.2, Y.sup.3, W.sup.1, W.sup.2, W.sup.3, W.sup.4, W.sup.5, M1,
M2a, M2b, M2c, M2d, R.sup.x, and R.sup.y are as defined above for
Formula (I). Within each of these embodiments for a compound of
Formula II, or a pharmaceutically acceptable salt thereof, or of
Formula III, or a pharmaceutically acceptable salt thereof, there
is also a further embodiment wherein R.sup.5 is as just defined,
and R.sup.3 and R.sup.4 are each hydrogen. Within each of these
embodiments for a compound of Formula II, or a pharmaceutically
acceptable salt thereof, or of Formula III, or a pharmaceutically
acceptable salt thereof, there is also a further embodiment wherein
R.sup.5 are as just defined, and R.sup.3, R.sup.4, and R.sup.4' are
each hydrogen. Within each of these embodiments for a compound of
Formula II, or a pharmaceutically acceptable salt thereof, or of
Formula III, or a pharmaceutically acceptable salt thereof, there
is also a further embodiment wherein R.sup.5 is as just defined,
and R.sup.3 is F, and R.sup.4 is hydrogen. Within each of these
embodiments for a compound of Formula II, or a pharmaceutically
acceptable salt thereof, or of Formula III, or a pharmaceutically
acceptable salt thereof, there is also a further embodiment wherein
R.sup.5 is as just defined, and R.sup.3 is F, R.sup.4 is hydrogen,
and R.sup.4' is hydrogen.
[0088] Also provided are two embodiments comprising, respectively,
a compound of Formula (II), or a pharmaceutically acceptable salt
thereof, and a compound of Formula (III), or a pharmaceutically
acceptable salt thereof, wherein, in each separate embodiment:
R.sup.3 is selected from the group of H and F; R.sup.5 is selected
from the group of CN, methyl, ethyl, propyl, vinyl, propenyl,
ethynyl, CH.sub.2F, CHF.sub.2, CH.sub.2Cl, CH.sub.2SMe,
--CH.sub.2OMe, and cyclopropyl; and R.sup.4 and R.sup.4' are as
defined above for Formula I.
[0089] Also provided are two embodiments comprising, respectively,
a compound of Formula (II), or a pharmaceutically acceptable salt
thereof, and a compound of Formula (III), or a pharmaceutically
acceptable salt thereof, wherein, in each separate embodiment:
R.sup.3 is selected from the group of H and F; R.sup.5 is selected
from the group of CN, methyl, ethyl, propyl, vinyl, propenyl,
ethynyl, CH.sub.2F, CHF.sub.2, CH.sub.2Cl, CH.sub.2SMe,
--CH.sub.2OMe, and cyclopropyl; R.sup.4 as defined above for
Formula I; and R.sup.4' is hydrogen.
[0090] Also provided are two embodiments comprising, respectively,
a compound of Formula (II), or a pharmaceutically acceptable salt
thereof, and a compound of Formula (III), or a pharmaceutically
acceptable salt thereof, wherein, in each separate embodiment:
R.sup.3 is selected from the group of H and F; R.sup.5 is selected
from the group of CN, methyl, ethyl, propyl, vinyl, propenyl,
ethynyl, CH.sub.2F, CHF.sub.2, CH.sub.2Cl, CH.sub.2SMe,
--CH.sub.2OMe, and cyclopropyl;
R.sup.4 is H; and
[0091] R.sup.4' is hydrogen.
[0092] Within each of the groups and embodiments described herein
for a compound of Formula I, Formula II, and Formula III, or a
pharmaceutically acceptable salt thereof, there is a further
embodiment wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4', and R.sup.5
are as defined for the individual group or embodiment and R.sup.4
is selected from:
##STR00019##
wherein:
[0093] n' is selected from 1, 2, 3, and 4;
[0094] R.sup.7 is selected from C.sub.1-C.sub.8 alkyl,
--O--C.sub.1-C.sub.8 alkyl, benzyl, --O-benzyl,
--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl,
--O--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, and CF.sub.3;
[0095] R.sup.7' is selected from C.sub.1-C.sub.8 alkyl,
--O--C.sub.2-C.sub.8 alkyl, benzyl, --O-benzyl,
--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, and CF.sub.3;
[0096] R.sup.8 is selected from phenyl, 1-naphthyl, 2-naphthyl,
##STR00020##
[0097] R.sup.9 is selected from H and CH.sub.3;
[0098] R.sup.10 is selected from H or C.sub.1-C.sub.6 alkyl;
[0099] R.sup.10' is selected from H or C.sub.1-C.sub.6 alkyl;
[0100] or R.sup.10 and R.sup.10', together with the carbon atom to
which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle
wherein all ring atoms of the spirocycle are carbon;
[0101] or R.sup.10 and R.sup.10', together with the carbon atom to
which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle
wherein 1 or 2 of the ring atoms of the spirocycle are selected
from the group of O, S, and N, and all other ring atoms of the
spirocycle are carbon; and
[0102] R.sup.11 is selected from H, C.sub.1-C.sub.8 alkyl, benzyl,
C.sub.3-C.sub.6 cycloalkyl, and --CH.sub.2--C.sub.3-C.sub.6
cycloalkyl.
[0103] Within each of the groups and embodiments described herein
for a compound of Formula I, Formula II, and Formula III, or a
pharmaceutically acceptable salt thereof, there is a further
embodiment wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4', and R.sup.5
are as defined for the individual group or embodiment and R.sup.4
is selected from:
##STR00021##
wherein:
[0104] R.sup.7 is selected from C.sub.1-C.sub.8 alkyl,
--O--C.sub.1-C.sub.8 alkyl, benzyl, and --CH.sub.2--C.sub.3-C.sub.6
cycloalkyl;
[0105] R.sup.7' is selected from C.sub.1-C.sub.8 alkyl,
--O--C.sub.1-C.sub.8 alkyl, benzyl, --O-benzyl,
--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, and CF.sub.3;
[0106] R.sup.10 is selected from H or C.sub.1-C.sub.6 alkyl;
[0107] R.sup.10' is selected from H or C.sub.1-C.sub.6 alkyl;
[0108] or R.sup.10 and R.sup.10', together with the carbon atom to
which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle
wherein all ring atoms of the spirocycle are carbon;
[0109] or R.sup.10 and R.sup.10', together with the carbon atom to
which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle
wherein 1 or 2 of the ring atoms of the spirocycle are selected
from the group of O, S, and N, and all other ring atoms of the
spirocycle are carbon; and
[0110] R.sup.11 is selected from C.sub.1-C.sub.8 alkyl, benzyl,
C.sub.3-C.sub.6 cycloalkyl, and --CH.sub.2--C.sub.3-C.sub.6
cycloalkyl.
[0111] Also provided are two embodiments comprising, respectively,
a compound of Formula (II), or a pharmaceutically acceptable salt
thereof, and a compound of Formula (III), or a pharmaceutically
acceptable salt thereof, wherein, in each separate embodiment:
R.sup.3 is selected from the group of H and F; R.sup.4' is
hydrogen; R.sup.5 is selected from the group of CN, methyl, ethyl,
propyl, vinyl, propenyl, ethynyl, CH.sub.2F, CHF.sub.2, CH.sub.2Cl,
CH.sub.2SMe, --CH.sub.2OMe, and cyclopropyl; and R.sup.4 is
selected from the group of:
##STR00022##
wherein:
[0112] R.sup.7 is selected from C.sub.1-C.sub.8 alkyl,
--O--C.sub.1-C.sub.8 alkyl, benzyl, and --CH.sub.2--C.sub.3-C.sub.6
cycloalkyl; and
[0113] R.sup.11 is selected from C.sub.1-C.sub.8 alkyl, benzyl,
C.sub.3-C.sub.6 cycloalkyl, and --CH.sub.2--C.sub.3-C.sub.6
cycloalkyl.
[0114] Within each of the groups and embodiments described herein
for a compound of Formula I, Formula II, and Formula III, or a
pharmaceutically acceptable salt thereof, there is a further
embodiment wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4', and R.sup.5
are as defined for the individual group or embodiment and R.sup.4
is selected from:
##STR00023##
[0115] Within each of the groups and embodiments described herein
for a compound of Formula I, Formula II, and Formula III, or a
pharmaceutically acceptable salt thereof, there is a further
embodiment wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4', and R.sup.5
are as defined for the individual group or embodiment and R.sup.4
is a group of the formula:
##STR00024##
[0116] Within each of the groups and embodiments described herein
for a compound of Formula I, Formula II, and Formula III, or a
pharmaceutically acceptable salt thereof, there is a further
embodiment wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4', and R.sup.5
are as defined for the individual group or embodiment and R.sup.4
is a group of the formula:
##STR00025##
[0117] Within each of the groups and embodiments described herein
for a compound of Formula I, Formula II, and Formula III, or a
pharmaceutically acceptable salt thereof, there is a further
embodiment wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4', and R.sup.5
are as defined for the individual group or embodiment and R.sup.4
is a group of the formula:
##STR00026##
[0118] Within each of the groups and embodiments described herein
for a compound of Formula I, Formula II, and Formula III, or a
pharmaceutically acceptable salt thereof, there is a further
embodiment wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are as
defined for the individual group or embodiment and R.sup.4 and
R.sup.4' combine to form the structure:
##STR00027##
and R.sup.11 is selected from H, C.sub.1-C.sub.8 alkyl, benzyl,
C.sub.3-C.sub.6 cycloalkyl, --CH.sub.2--C.sub.3-C.sub.6
cycloalkyl,
##STR00028##
[0119] Within each of the groups and embodiments described herein
for a compound of Formula I, Formula II, and Formula III, or a
pharmaceutically acceptable salt thereof, there is a further
embodiment wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are as
defined for the individual group or embodiment and R.sup.4 and
R.sup.4' combine to form the structure:
##STR00029##
[0120] wherein R.sup.9 is selected from H and CH.sub.3; R.sup.10 is
selected from H or C.sub.1-C.sub.6 alkyl; R.sup.10' is selected
from H or C.sub.1-C.sub.6 alkyl; and R.sup.11 is selected from H,
C.sub.1-C.sub.8 alkyl, benzyl, C.sub.3-C.sub.6 cycloalkyl, and
--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl.
DETAILED DESCRIPTION
[0121] The terms halo and halogen refer to halogen atoms selected
from F, Cl, Br, and I.
[0122] "Azido" refers to an azide group, i.e. the group --N.sub.3.
The term "n" as used herein refers to an integer selected from 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and
20.
[0123] The term "haloalkyl" as used herein refers to an alkyl as
defined herein, wherein one or more hydrogen atoms are each
replaced by a halo substituent. For example, a
(C.sub.1-C.sub.6)haloalkyl is a (C.sub.1-C.sub.6)alkyl wherein one
or more of the hydrogen atoms have been replaced by a halo
substituent. Such a range includes one halo substituent on the
alkyl group t to complete halogenation of the alkyl group.
[0124] The term "(C.sub.1-n)haloalkyl" as used herein, wherein n is
an integer, either alone or in combination with another radical, is
intended to mean an alkyl radical having 1 to n carbon atoms as
defined above wherein one or more hydrogen atoms are each replaced
by a halo substituent. Examples of (C.sub.1-n)haloalkyl, wherein n
is 2 include, but are not limited to, chloromethyl, chloroethyl,
dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.
Such groups may also be described based on the relevant halogen as
"(C.sub.1-n)chloroalkyl", "(C.sub.1-n)bromoalkyl", or
"(C.sub.1-n)fluoroalkyl groups".
[0125] The term "(C.sub.1-n)alkyl" as used herein, wherein n is an
integer, either alone or in combination with another radical, is
intended to mean acyclic, straight or branched chain alkyl radicals
containing from 1 to n carbon atoms. "(C.sub.1-8)alkyl" includes,
but is not limited to, methyl, ethyl, propyl (n-propyl), butyl
(n-butyl), 1-methylethyl (iso-propyl), 1-methylpropyl (sec-butyl),
2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), pentyl,
hexyl, heptyl, and octyl. The abbreviation Me denotes a methyl
group; Et denotes an ethyl group, Pr denotes a propyl group, iPr
denotes a 1-methylethyl group, Bu denotes a butyl group and tBu
denotes a 1,1-dimethylethyl group.
[0126] The term "alkyl" refers to a hydrocarbon containing normal,
secondary, or tertiary atoms. For example, an alkyl group can have
1 to 20 carbon atoms (i.e, (C.sub.1-C.sub.20)alkyl), 1 to 10 carbon
atoms (i.e., (C.sub.1-C.sub.10)alkyl), 1 to 8 carbon atoms (i.e.,
(C.sub.1-C.sub.8)alkyl) or 1 to 6 carbon atoms (i.e.,
(C.sub.1-C.sub.6 alkyl). Examples of suitable alkyl groups include,
but are not limited to, methyl (Me, --CH.sub.3), ethyl (Et,
--CH.sub.2CH.sub.3), 1-propyl (n--Pr, n-propyl,
--CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i--Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, and octyl
(--(CH.sub.2).sub.7CH.sub.3). "Alkyl" also refers to a saturated,
branched or straight chain hydrocarbon radical having two
monovalent radical centers derived by the removal of two hydrogen
atoms from the same or two different carbon atoms of a parent
alkane. For example, an alkyl group can have 1 to 10 carbon atoms
(i.e., (C.sub.1-C.sub.10)alkyl), or 1 to 6 carbon atoms (i.e.,
(C.sub.1-C.sub.6)alkyl) or 1-3 carbon atoms (i.e.,
(C.sub.1-C.sub.3)alkyl). Typical alkyl radicals include, but are
not limited to, methylene (--CH.sub.2--), 1,1-ethyl
(--CH(CH.sub.3)--), 1,2-ethyl (--CH.sub.2CH.sub.2--), 1,1-propyl
(--CH(CH.sub.2CH.sub.3)--), 1,2-propyl (--CH.sub.2CH(CH.sub.3)--),
1,3-propyl (--CH.sub.2CH.sub.2CH.sub.2--), 1,4-butyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0127] "Alkenyl" is a straight or branched hydrocarbon containing
normal, secondary or tertiary carbon atoms with at least one site
of unsaturation, i.e. a carbon-carbon, sp.sup.2 double bond. For
example, an alkenyl group can have 2 to 20 carbon atoms (i.e.,
C.sub.2-C.sub.20 alkenyl), 2 to 8 carbon atoms (i.e.,
C.sub.2-C.sub.8 alkenyl), or 2 to 6 carbon atoms (i.e.,
C.sub.2-C.sub.6 alkenyl). Examples of suitable alkenyl groups
include, but are not limited to, ethylene or vinyl
(--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
cyclopentenyl (--C.sub.5H.sub.7), and 5-hexenyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2).
[0128] The term "(C.sub.2-n)alkenyl", as used herein, wherein n is
an integer, either alone or in combination with another radical, is
intended to mean an unsaturated, acyclic straight or branched chain
radical containing two to n carbon atoms, at least two of which are
bonded to each other by a double bond. Examples of such radicals
include, but are not limited to, ethenyl (vinyl), 1-propenyl,
2-propenyl, and 1-butenyl. Unless specified otherwise, the term
"(C.sub.2-n)alkenyl" is understood to encompass individual
stereoisomers where possible, including but not limited to (E) and
(Z) isomers, and mixtures thereof. When a (C.sub.2-n)alkenyl group
is substituted, it is understood to be substituted on any carbon
atom thereof which would otherwise bear a hydrogen atom, unless
specified otherwise, such that the substitution would give rise to
a chemically stable compound, such as are recognized by those
skilled in the art.
[0129] "Alkynyl" is a straight or branched hydrocarbon containing
normal, secondary or tertiary carbon atoms with at least one site
of unsaturation, i.e. a carbon-carbon, sp triple bond. For example,
an alkynyl group can have 2 to 20 carbon atoms (i.e.,
C.sub.2-C.sub.20 alkynyl), 2 to 8 carbon atoms (i.e.,
C.sub.2-C.sub.8 alkyne,), or 2 to 6 carbon atoms (i e.,
C.sub.2-C.sub.6 alkynyl). Examples of suitable alkynyl groups
include, but are not limited to, acetylenic (--C.dbd.CH), propargyl
(--CH.sub.2C.dbd.CH), and the like.
[0130] The term "(C.sub.2-n)alkynyl", as used herein, wherein n is
an integer, either alone or in combination with another radical, is
intended to mean an unsaturated, acyclic straight or branched chain
radical containing two to n carbon atoms, at least two of which are
bonded to each other by a triple bond. Examples of such radicals in
which n is 4 include, but are not limited to, ethynyl, 1-propynyl,
2-propynyl, and 1-butynyl. When a (C.sub.2-n)alkynyl group is
substituted, it is understood to be substituted on any carbon atom
thereof which would otherwise bear a hydrogen atom, unless
specified otherwise, such that the substitution would give rise to
a chemically stable compound, such as are recognized by those
skilled in the art. The term "aryl" as used herein refers to a
single aromatic ring or a bicyclic or multicyclic ring. For
example, an aryl group can have 6 to 20 carbon atoms, 6 to 14
carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl
radical or an ortho-fused bicyclic or multicyclic radical having
about 9 to 14 atoms in which at least one ring is aromatic (e.g. an
aryl fused to one or more aryl or carbocycle). Such bicyclic or
multicyclic rings may be optionally substituted with one or more
(e.g. 1, 2 or 3) oxo groups on any carbocycle portion of the
bicyclic or multicyclic ring. It is to be understood that the point
of attachment of a bicyclic or multicyclic radical, as defined
above, can be at any position of the ring including an aryl or a
carbocycle portion of the ring. Typical aryl groups include, but
are not limited to, phenyl, indenyl, naphthyl,
1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.
[0131] Substituents on "substituted alkyl", "substituted alkenyl",
and "substituted alkynyl" groups includes those selected from the
group of halogens (F, Cl, Br, and I), OH, SH, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl).sub.2,
NO.sub.2, CN, --O--C.sub.1-C.sub.6 alkyl, and CF.sub.3. In one
embodiment, for "substituted alkyl" of from either 1 to 6 carbon
atoms or 1 to 8 carbon atoms and for "substituted alkenyl" and
"substituted alkynyl" groups of from 2 to 6 carbon atoms or from 2
to 8 carbon atoms, each may be substituted by 0, 1, 2, 3, or 4
substituents independently selected from F, Cl, Br, I, OH, SH,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6
alkyl).sub.2, NO.sub.2, CN, --O--C.sub.1-C.sub.6 alkyl, and
CF.sub.3. In another embodiment, for "substituted alkyl" of from
either 1 to 3 carbon atoms or 1 to 4 carbon atoms and for
"substituted alkenyl" and "substituted alkynyl" groups of from 2 to
3 carbon atoms or from 2 to 4 carbon atoms, each may be substituted
by 0, 1, 2, or 3 substituents independently selected from F, Cl,
Br, I, OH, SH, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl).sub.2, NO.sub.2, CN, --O--C.sub.1-C.sub.6
alkyl, and CF.sub.3.
[0132] "Aryl" includes an aromatic hydrocarbon monocyclic or
bicyclic ring having from six to 10 ring carbon atoms, including
phenyl and naphthyl rings. Substituted aryl groups include an
aromatic hydrocarbon monocyclic or bicyclic ring having from six to
10 ring carbon atoms, including phenyl and naphthyl rings,
including 1-naphthyl, 2-naphthyl rings, as well as a carbocyclic
aromatic monocyclic group containing 6 carbon atoms which may be
further fused to a second 5- or 6-membered carbocyclic group which
may be aromatic, saturated or unsaturated, including indanyl,
indenyl, tetrahydronaphthyl and dihydronaphthyl rings, with each of
the aryl rings being substituted by 0, 1, 2, or 3 substituents
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and
--CF.sub.3
[0133] "Arylalkyl" refers to an alkyl radical as defined herein in
which one of the hydrogen atoms bonded to a carbon atom is replaced
with an aryl radical as described herein (i.e., an
aryl-alkyl-moiety). The alkyl group of the "arylalkyl" is typically
1 to 6 carbon atoms (i.e. aryl(C.sub.1-C.sub.6)alkyl). Arylalkyl
groups include, but are not limited to, benzyl, 2-phenylethan-1-yl,
1-phenylpropan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl and the
like.
[0134] The term "aryl-(C.sub.1-n)alkyl-" as used herein, wherein n
is an integer, either alone or in combination with another radical,
is intended to mean an alkyl radical having 1 to n carbon atoms as
defined above which is itself substituted with an aryl radical as
defined above. Examples of aryl-(C.sub.1-n)alkyl-include, but are
not limited to, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl
and phenylpropyl. When an aryl-(C.sub.1-n)alkyl-group is
substituted, it is understood that substituents may be attached to
either the aryl or the alkyl portion thereof or both, unless
specified otherwise, such that the substitution would give rise to
a chemically stable compound, such as are recognized by those
skilled in the art.
[0135] Examples of "arylalkyl" used herein refer to a moiety of the
formula --(CH.sub.2).sub.q--Y, wherein q is an integer selected
independently in each instance from 1, 2, 3, 4, 5, or 6, and "Y" is
a phenyl or naphthyl ring, each substituted by 0, 1, 2, or 3
substituents independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, and --CF.sub.3.
[0136] The terms "heterocycle" and "heterocyclic" are synonymous
and refers to monocyclic and fused bicyclic, saturated or partially
unsaturated rings having, unless otherwise indicated, 3, 4, 5, 6,
7, 8, 9, or 10 ring atoms wherein 1, 2, 3, or 4 ring atoms is/are a
heteroatom independently selected from N, O and S and all remaining
ring atoms are C. In one embodiment, the heterocyclic group has 5,
6, 9 or 10 rings atoms wherein 1, 2 or 3 ring atoms is/are a
heteroatom independently selected from N, O and S. In all
embodiments wherein the heterocyclic group includes 2 or more
heteroatoms (N, O and S) the heteroatoms may be the same or
different. In all embodiments wherein the compound of Formula I
includes 2 or more heterocyclic groups, the heterocyclic groups may
be the same or different. Examples of heterocyclic groups include
but are not limited to oxiranyl, azetidinyl, oxetanyl, thietanyl,
furanyl, tetrahydrofuranyl, thiophenyl, tetrahydrothiophenyl,
sulfur oxidized tetrahydrothiophenyl, pyrrolyl, pyrrolinyl,
pyrrolidinyl, dioxolanyl, oxazolidinyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl,
pyranyl, dihydropyranyl, tetrahydropyranyl, pyridyl,
dihydropyridyl, piperidyl, dioxanyl, morpholinyl, dithianyl,
thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl,
triazinyl, indolizinyl, indolyl, isoindolyl, oxindolyl, indolinyl,
benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, benzothienyl,
indazolyl, benzimidazolyl, benzoxazolinyl, benzoxazolyl,
benzisoxazolyl, benzthiazolyl, benzotriazolyl, benzopyranyl,
purinyl, quinolizinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
octahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, pteridinyl, thianaphthalenyl and the
like. Heterocyclic groups may be bound through any available ring
carbon or ring heteroatom, such as N. Each "Heterocyclic group",
"heterocyclic ring" or "heterocycle" may be substituted by 0, 1, 2,
or 3 substituents independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1--C
alkoxy, and --CF.sub.3.
[0137] The term cycloalkyl refers to a cyclic aliphatic group. The
cycloallkyl groups herein may be referenced by the number of carbon
atoms in their ring, such as "C.sub.3-C.sub.4 cycloalkyl" referring
to a cycloalkyl ring with 3 or 4 carbon ring atoms or
"C.sub.3-C.sub.6 cycloalkyl" indicating a cycloalkyl ring with 3,
4, 5, or 6 carbon ring atoms, i.e. a cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl ring.
[0138] The term "carbocycle" or "carbocyclyl" refers to a saturated
(i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl,
cycloalkadienyl, etc.) ring having 3 to 8 carbon atoms as a
monocycle or a mutlicyclic ring system. In one embodiment the
carbocycle is a monocycle comprising 3-6 ring carbons (i.e.
(C.sub.3-C.sub.6)carbocycle). Carbocycle includes multicyclic
carbocyles having 7 to 12 carbon atoms as a bicycle, and up to
about 20 carbon atoms as a polycycle provided that the largest
single ring of a multicyclic carbocycle is 7 carbon atoms. The term
"spiro-bicyclic carbocycle" refers to a carbocycle bicyclic ring
system wherein the rings of the bicyclic ring system are connected
to a single carbon atom (e.g. spiropentane, spiro[4,5]decane,
spiro[4.5]decane, etc). The term "fused-bicyclic carbocycle" refers
to a carbocycle bicyclic ring system wherein the rings of the
bicyclic ring system are connected to two adjacent carbon atoms
such as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10
ring atoms arranged as a bicyclo [5,6] or [6,6] system (e.g.
decahydronaphthalene, norsabinane, norcarane). The term
"bridged-bicyclic carbocycle" refers to a carbocycle bicyclic ring
system wherein the rings of the bicyclic ring system are connected
to two non-adjacent carbon (e.g. norbornane, bicyclo[2.2.2]octane,
etc). The "carbocycle" or "carbocyclyl" may be optionally
substituted with one or more (e.g. 1, 2 or 3) oxo groups.
Non-limiting examples of monocyclic carbocycles include
cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,
1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,
1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,
cyclohexa-1,3-dienyl, cycloheptanyl, cycloheptenyl,
cyclohepta-1,3-dienyl, cyclohepta-1,4-dienyl, cyclooctyl, and
cyclooctenyl rings.
[0139] Each carbocyclyl group may be substituted by 0, 1, 2, or 3
substituents independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, and --CF.sub.3.
[0140] The term "heteroaryl" as used herein refers to a single
aromatic ring or a multiple condensed ring. The term includes
single aromatic rings of from about 1 to 6 carbon atoms and about
1-4 heteroatoms selected from the group consisting of oxygen,
nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may
also be present in an oxidized form provided the ring is aromatic.
Such rings include but are not limited to pyridyl, pyrimidinyl,
oxazolyl or furyl. The term also includes multiple condensed ring
systems (e.g. ring systems comprising 2 or 3 rings) wherein a
heteroaryl group, as defined above, can be fused with one or more
heteroaryls (e.g. naphthyridinyl), carbocycles (e.g.
5,6,7,8-tetrahydroquinolyl) or aryls (e.g. indazolyl) to form a
multiple condensed ring. Such multiple condensed rings may be
optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups
on the carbocycle portions of the condensed ring. It is to be
understood that the point of attachment of a heteroaryl multiple
condensed ring, as defined above, can be at any position of the
ring including a heteroaryl, aryl or a carbocycle portion of the
ring. Exemplary heteroaryls include but are not limited to pyridyl,
pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl,
indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl,
thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl,
indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl
benzofuranyl, benzimidazolyl and thianaphthenyl.
[0141] Each heteroaryl group may be substituted by 0, 1, 2, or 3
substituents independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, and --CF.sub.3.
[0142] "Heteroarylalkyl" refers to an alkyl radical as defined
herein in which one of the hydrogen atoms bonded to a carbon atom
is replaced with a heteroaryl radical as described herein (i.e., a
heteroaryl-alkyl-moiety). The alkyl group of the "heteroarylalkyl"
is typically 1 to 6 carbon atoms (i.e.
heteroaryl(C.sub.1-C.sub.6)alkyl). Heteroarylalkyl groups include,
but are not limited to heteroaryl-CH.sub.2--,
heteroaryl-CH(CH.sub.3)--, heteroaryl-CH.sub.2CH.sub.2--,
2-(heteroaryl)ethan-1-yl, and the like, wherein the "heteroaryl"
portion includes any of the heteroaryl groups described above. One
skilled in the art will also understand that the heteroaryl group
can be attached to the alkyl portion of the heteroarylalkyl by
means of a carbon-carbon bond or a carbon-heteroatom bond, with the
proviso that the resulting group is chemically stable. Examples of
heteroarylalkyls include by way of example and not limitation
5-membered sulfur, oxygen, and/or nitrogen containing heteroaryls
such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl,
oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur,
oxygen, and/or nitrogen containing heteroaryls such
pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl,
etc.
[0143] The heteroaryl ring of each of is the heteroarylalkyl group
may be substituted by 0, 1, 2, or 3 substituents independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.06 alkoxy, and --CF.sub.3.
Pharmaceutical Formulations
[0144] Also provided herein is a pharmaceutical formulation
comprising a pharmaceutically effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, and a pharmaceutically acceptable carrier or
excipient. Also provided are separate pharmaceutical formulations,
each comprising a pharmaceutically effective amount of a compound
of Formula (II), Formula (III), or a specific compounds of the
examples herein, or a pharmaceutically acceptable salt, solvate,
and/or ester thereof, and a pharmaceutically acceptable carrier or
excipient.
[0145] The compounds herein are formulated with conventional
carriers and excipients, which will be selected in accord with
ordinary practice. Tablets will contain excipients, glidants,
fillers, binders and the like. Aqueous formulations are prepared in
sterile form, and when intended for delivery by other than oral
administration generally will be isotonic. All formulations will
optionally contain excipients such as those set forth in the
"Handbook of Pharmaceutical Excipients" (1986). Excipients include
ascorbic acid and other antioxidants, chelating agents such as
EDTA, carbohydrates such as dextran, hydroxyalkylcellulose,
hydroxyalkylmethylcellulose, stearic acid and the like. The pH of
the formulations ranges from about 3 to about 11, but is ordinarily
about 7 to 10.
[0146] While it is possible for the active ingredients to be
administered alone it may be preferable to present them as
pharmaceutical formulations. The formulations, both for veterinary
and for human use, comprise at least one active ingredient, as
above defined, together with one or more acceptable carriers and
optionally other therapeutic ingredients, particularly those
additional therapeutic ingredients as discussed herein. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and physiologically
innocuous to the recipient thereof.
[0147] The formulations include those suitable for the foregoing
administration routes. The formulations may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. Techniques and
formulations generally are found in Remington's Pharmaceutical
Sciences (Mack Publishing Co., Easton, Pa.). Such methods include
the step of bringing into association the active ingredient with
the carrier which constitutes one or more accessory ingredients. In
general the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both, and then, if
necessary, shaping the product.
[0148] Formulations suitable for oral administration may be
presented as discrete units such as capsules, cachets or tablets
each containing a predetermined amount of the active ingredient; as
a powder or granules; as a solution or a suspension in an aqueous
or non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion. The active ingredient may also be
administered as a bolus, electuary or paste.
[0149] A tablet is made by compression or molding, optionally with
one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active or dispersing agent. Molded tablets may be made by
molding in a suitable machine a mixture of the powdered active
ingredient moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and optionally are formulated so as
to provide slow or controlled release of the active ingredient
therefrom.
[0150] For infections of the eye or other external tissues e.g.
mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w (including active
ingredient(s) in a range between 0.1% and 20% in increments of 0.1%
w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w
and most preferably 0.5 to 10% w/w. When formulated in an ointment,
the active ingredients may be employed with either a paraffinic or
a water-miscible ointment base. Alternatively, the active
ingredients may be formulated in a cream with an oil-in-water cream
base.
[0151] If desired, the aqueous phase of the cream base may include,
for example, at least 30% w/w of a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as propylene
glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG 400) and mixtures thereof. The
topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethyl sulphoxide and related
analogs.
[0152] The oily phase of the emulsions may be constituted from
known ingredients in a known manner. While the phase may comprise
merely an emulsifier (otherwise known as an emulgent), it desirably
comprises a mixture of at least one emulsifier with a fat or an oil
or with both a fat and an oil. Preferably, a hydrophilic emulsifier
is included together with a lipophilic emulsifier which acts as a
stabilizer. It is also preferred to include both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make up
the so-called emulsifying wax, and the wax together with the oil
and fat make up the so-called emulsifying ointment base which forms
the oily dispersed phase of the cream formulations.
[0153] Emulgents and emulsion stabilizers suitable for use in the
formulation include Tween.RTM. 60, Span.RTM. 80, cetostearyl
alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate
and sodium lauryl sulfate.
[0154] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties. The cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters known as Crodamol CAP may be
used, the last three being preferred esters. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils are used.
[0155] Pharmaceutical formulations herein comprise a combination
together with one or more pharmaceutically acceptable carriers or
excipients and optionally other therapeutic agents. Pharmaceutical
formulations containing the active ingredient may be in any form
suitable for the intended method of administration. When used for
oral use for example, tablets, troches, lozenges, aqueous or oil
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, solutions, syrups or elixirs may be prepared.
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
including sweetening agents, flavoring agents, coloring agents and
preserving agents, in order to provide a palatable preparation.
Tablets containing the active ingredient in admixture with
non-toxic pharmaceutically acceptable excipient which are suitable
for manufacture of tablets are acceptable. These excipients may be,
for example, inert diluents, such as calcium or sodium carbonate,
lactose, calcium or sodium phosphate; granulating and
disintegrating agents, such as maize starch, or alginic acid;
binding agents, such as starch, gelatin or acacia; and lubricating
agents, such as magnesium stearate, stearic acid or talc. Tablets
may be uncoated or may be coated by known techniques including
microencapsulation to delay disintegration and adsorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate alone or with a wax
may be employed.
[0156] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example calcium phosphate or kaolin, or as soft
gelatin capsules wherein the active ingredient is mixed with water
or an oil medium, such as peanut oil, liquid paraffin or olive
oil.
[0157] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients include a suspending agent, such as
sodium carboxymethylcellulose, methylcellulose, hydroxypropyl
methylcelluose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia, and dispersing or wetting agents such as
a naturally-occurring phosphatide (e.g., lecithin), a condensation
product of an alkylene oxide with a fatty acid (e.g.,
polyoxyethylene stearate), a condensation product of ethylene oxide
with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0158] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oral suspensions may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such
as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an antioxidant such as ascorbic
acid.
[0159] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent, a
suspending agent, and one or more preservatives. Suitable
dispersing or wetting agents and suspending agents are exemplified
by those disclosed above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0160] The pharmaceutical compositions may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil, such
as olive oil or arachis oil, a mineral oil, such as liquid
paraffin, or a mixture of these. Suitable emulsifying agents
include naturally-occurring gums, such as gum acacia and gum
tragacanth, naturally-occurring phosphatides, such as soybean
lecithin, esters or partial esters derived from fatty acids and
hexitol anhydrides, such as sorbitan monooleate, and condensation
products of these partial esters with ethylene oxide, such as
polyoxyethylene sorbitan monooleate. The emulsion may also contain
sweetening and flavoring agents. Syrups and elixirs may be
formulated with sweetening agents, such as glycerol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative, a flavoring or a coloring agent.
[0161] The pharmaceutical compositions may be in the form of a
sterile injectable or intravenous preparations, such as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable or intravenous preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally acceptable diluent or solvent, such as a
solution in 1,3-butane-diol or prepared as a lyophilized powder.
Among the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0162] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0163] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredient is dissolved
or suspended in a suitable carrier, especially an aqueous solvent
for the active ingredient. The active ingredient is preferably
present in such formulations in a concentration of 0.5 to 20%,
advantageously 0.5 to 10%, and particularly about 1.5% w/w.
[0164] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0165] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0166] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered
by rapid inhalation through the nasal passage or by inhalation
through the mouth so as to reach the alveolar sacs. Suitable
formulations include aqueous or oily solutions of the active
ingredient. Formulations suitable for aerosol or dry powder
administration may be prepared according to conventional methods
and may be delivered with other therapeutic agents such as
compounds heretofore used in the treatment or prophylaxis of
Pneumovirinae infections as described below.
[0167] Another embodiment provides a novel, efficacious, safe,
nonirritating and physiologically compatible inhalable composition
comprising a compound of Formulas I-Ill, or a pharmaceutically
acceptable salt thereof, suitable for treating Pneumovirinae
infections and potentially associated bronchiolitis. Preferred
pharmaceutically acceptable salts are inorganic acid salts
including hydrochloride, hydrobromide, sulfate or phosphate salts
as they may cause less pulmonary irritation. Preferably, the
inhalable formulation is delivered to the endobronchial space in an
aerosol comprising particles with a mass median aerodynamic
diameter (MMAD) between about 1 and about 5 .mu.m. Preferably, the
compound of Formulas I-Ill is formulated for aerosol delivery using
a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder
inhaler (DPI).
[0168] Non-limiting examples of nebulizers include atomizing, jet,
ultrasonic, pressurized, vibrating porous plate, or equivalent
nebulizers including those nebulizers utilizing adaptive aerosol
delivery technology (Denyer, J. Aerosol medicine Pulmonary Drug
Delivery 2010, 23 Supp 1, S1-S10). A jet nebulizer utilizes air
pressure to break a liquid solution into aerosol droplets. An
ultrasonic nebulizer works by a piezoelectric crystal that shears a
liquid into small aerosol droplets. A pressurized nebulization
system forces solution under pressure through small pores to
generate aerosol droplets. A vibrating porous plate device utilizes
rapid vibration to shear a stream of liquid into appropriate
droplet sizes.
[0169] In a preferred embodiment, the formulation for nebulization
is delivered to the endobronchial space in an aerosol comprising
particles with a MMAD predominantly between about 1 .mu.m and about
5 .mu.m using a nebulizer able to aerosolize the formulation of the
compound of Formulas I-Ill into particles of the required MMAD. To
be optimally therapeutically effective and to avoid upper
respiratory and systemic side effects, the majority of aerosolized
particles should not have a MMAD greater than about 5 .mu.m. If an
aerosol contains a large number of particles with a MMAD larger
than 5 .mu.m, the particles are deposited in the upper airways
decreasing the amount of drug delivered to the site of inflammation
and bronchoconstriction in the lower respiratory tract. If the MMAD
of the aerosol is smaller than about 1 .mu.m, then the particles
have a tendency to remain suspended in the inhaled air and are
subsequently exhaled during expiration.
[0170] When formulated and delivered according to the method
herein, the aerosol formulation for nebulization delivers a
therapeutically efficacious dose of the compound of Formulas I-Ill
to the site of Pneumovirinae infection sufficient to treat the
Pneumovirinae infection. The amount of drug administered must be
adjusted to reflect the efficiency of the delivery of a
therapeutically efficacious dose of the compound of Formulas I-Ill.
In a preferred embodiment, a combination of the aqueous aerosol
formulation with the atomizing, jet, pressurized, vibrating porous
plate, or ultrasonic nebulizer permits, depending on the nebulizer,
about, at least, 20, to about 90%, typically about 70% delivery of
the administered dose of the compound of Formulas I-Ill into the
airways. In a preferred embodiment, at least about 30 to about 50%
of the active compound is delivered. More preferably, about 70 to
about 90% of the active compound is delivered.
[0171] In another embodiment, a compound of Formulas I-Ill or a
pharmaceutically acceptable salt thereof, is delivered as a dry
inhalable powder. The compounds are administered endobronchially as
a dry powder formulation to efficacious deliver fine particles of
compound into the endobronchial space using dry powder or metered
dose inhalers. For delivery by DPI, the compound of Formulas I-Ill
is processed into particles with, predominantly, MMAD between about
1 .mu.m and about 5 .mu.m by milling spray drying, critical fluid
processing, or precipitation from solution. Media milling, jet
milling and spray-drying devices and procedures capable of
producing the particle sizes with a MMAD between about 1 .mu.m and
about 5 .mu.m are well known in the art. In one embodiment,
excipients are added to the compound of Formulas I-Ill before
processing into particles of the required sizes. In another
embodiment, excipients are blended with the particles of the
required size to aid in dispersion of the drug particles, for
example by using lactose as an excipient.
[0172] Particle size determinations are made using devices well
known in the art. For example a multi-stage Anderson cascade
impactor or other suitable method such as those specifically cited
within the US Pharmacopoeia Chapter 601 as characterizing devices
for aerosols within metered-dose and dry powder inhalers.
[0173] In another preferred embodiment, a compound of Formulas
I-Ill is delivered as a dry powder using a device such as a dry
powder inhaler or other dry powder dispersion devices. Non-limiting
examples of dry powder inhalers and devices include those disclosed
in U.S. Pat. Nos. 5,458,135; 5,740,794; 5,775,320; 5,785,049;
3,906,950; 4,013,075; 4,069,819; 4,995,385; 5,522,385; 4,668,218;
4,667,668; 4,805,811 and 5,388,572. There are two major designs of
dry powder inhalers. One design is a metering device in which a
reservoir for the drug is place within the device and the patient
adds a dose of the drug into the inhalation chamber. The second
design is a factory-metered device in which each individual dose
has been manufactured in a separate container. Both systems depend
on the formulation of the drug into small particles of MMAD from 1
.mu.m and about 5 .mu.m and often involve co-formulation with
larger excipient particles such as, but not limited to, lactose.
Drug powder is placed in the inhalation chamber (either by device
metering or by breakage of a factory-metered dosage) and the
inspiratory flow of the patient accelerates the powder out of the
device and into the oral cavity. Non-laminar flow characteristics
of the powder path cause the excipient-drug aggregates to
decompose, and the mass of the large excipient particles causes
their impaction at the back of the throat, while the smaller drug
particles are deposited deep in the lungs. In preferred
embodiments, a compound of Formulas I-Ill, or a pharmaceutically
acceptable salt thereof, is delivered as a dry powder using either
type of dry powder inhaler as described herein, wherein the MMAD of
the dry powder, exclusive of any excipients, is predominantly in
the range of 1 .mu.m to about 5 .mu.m.
[0174] In another embodiment, a compound of Formulas I-Ill is
delivered as a dry powder using a metered dose inhaler.
Non-limiting examples of metered dose inhalers and devices include
those disclosed in U.S. Pat. Nos. 5,261,538; 5,544,647; 5,622,163;
4,955,371; 3,565,070; 3,361,306 and 6,116,234. In preferred
embodiments, a compound of Formulas I-III, or a pharmaceutically
acceptable salt thereof, is delivered as a dry powder using a
metered dose inhaler wherein the MMAD of the dry powder, exclusive
of any excipients, is predominantly in the range of about 1-5
.mu.m.
[0175] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0176] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
[0177] The formulations are presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water for
injection, immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0178] It should be understood that in addition to the ingredients
particularly mentioned above the formulations may include other
agents conventional in the art having regard to the type of
formulation in question, for example those suitable for oral
administration may include flavoring agents.
[0179] Further provided are veterinary compositions comprising at
least one active ingredient as above defined together with a
veterinary carrier therefor.
[0180] Veterinary carriers are materials useful for the purpose of
administering the composition and may be solid, liquid or gaseous
materials which are otherwise inert or acceptable in the veterinary
art and are compatible with the active ingredient. These veterinary
compositions may be administered orally, parenterally or by any
other desired route.
[0181] Compounds herein are used to provide controlled release
pharmaceutical formulations containing as active ingredient one or
more of the compounds ("controlled release formulations") in which
the release of the active ingredient are controlled and regulated
to allow less frequency dosing or to improve the pharmacokinetic or
toxicity profile of a given active ingredient.
[0182] Effective dose of active ingredient depends at least on the
nature of the condition being treated, toxicity, whether the
compound is being used prophylactically (lower doses) or against an
active viral infection, the method of delivery, and the
pharmaceutical formulation, and will be determined by the clinician
using conventional dose escalation studies. It can be expected to
be from about 0.0001 to about 100 mg/kg body weight per day;
typically, from about 0.01 to about 10 mg/kg body weight per day;
more typically, from about 0.01 to about 5 mg/kg body weight per
day; most typically, from about 0.05 to about 0.5 mg/kg body weight
per day. For example, the daily candidate dose for an adult human
of approximately 70 kg body weight will range from 1 mg to 1000 mg,
preferably between 5 mg and 500 mg, and may take the form of single
or multiple doses.
Routes of Administration
[0183] One or more of the compounds (herein referred to as the
active ingredients) are administered by any route appropriate to
the condition to be treated. Suitable routes include oral, rectal,
nasal, pulmonary, topical (including buccal and sublingual),
vaginal and parenteral (including subcutaneous, intramuscular,
intravenous, intradermal, intrathecal and epidural), and the like.
It will be appreciated that the preferred route may vary with for
example the condition of the recipient. An advantage of the
compounds herein is that they are orally bioavailable and can be
dosed orally.
Combination Therapy
[0184] Compositions are also used in combination with other active
ingredients. For the treatment of Pneumovirinae virus infections,
preferably, the other active therapeutic agent is active against
Pneumovirinae virus infections, particularly respiratory syncytial
virus infections. Non-limiting examples of these other active
therapeutic agents are ribavirin, palivizumab, motavizumab,
RSV-IGIV (RespiGam.RTM.), MEDI-557, A-60444 (also known as RSV604),
MDT-637, BMS-433771, ALN-RSV0, ALX-0171 and mixtures thereof.
[0185] Many of the infections of the Pneumovirinae viruses are
respiratory infections. Therefore, additional active therapeutics
used to treat respiratory symptoms and sequelae of infection may be
used in combination with the compounds of Formulas I-Ill. The
additional agents are preferably administered orally or by direct
inhalation. For example, other preferred additional therapeutic
agents in combination with the compounds of Formulas I-Ill for the
treatment of viral respiratory infections include, but are not
limited to, bronchodilators and corticosteroids.
[0186] Glucocorticoids, which were first introduced as an asthma
therapy in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950),
remain the most potent and consistently effective therapy for this
disease, although their mechanism of action is not yet fully
understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13,
1985). Unfortunately, oral glucocorticoid therapies are associated
with profound undesirable side effects such as truncal obesity,
hypertension, glaucoma, glucose intolerance, acceleration of
cataract formation, bone mineral loss, and psychological effects,
all of which limit their use as long-term therapeutic agents
(Goodman and Gilman, 10th edition, 2001). A solution to systemic
side effects is to deliver steroid drugs directly to the site of
inflammation. Inhaled corticosteroids (ICS) have been developed to
mitigate the severe adverse effects of oral steroids. Non-limiting
examples of corticosteroids that may be used in combinations with
the compounds of Formulas I-Ill are dexamethasone, dexamethasone
sodium phosphate, fluorometholone, fluorometholone acetate,
loteprednol, loteprednol etabonate, hydrocortisone, prednisolone,
fludrocortisones, triamcinolone, triamcinolone acetonide,
betamethasone, beclomethasone diproprionate, methylprednisolone,
fluocinolone, fluocinolone acetonide, flunisolide,
fluocortin-21-butylate, flumethasone, flumetasone pivalate,
budesonide, halobetasol propionate, mometasone furoate, fluticasone
propionate, ciclesonide; or a pharmaceutically acceptable salts
thereof.
[0187] Other anti-inflammatory agents working through
anti-inflammatory cascade mechanisms are also useful as additional
therapeutic agents in combination with the compounds of Formulas
I-III for the treatment of viral respiratory infections. Applying
"anti-inflammatory signal transduction modulators" (referred to in
this text as AISTM), like phosphodiesterase inhibitors (e.g. PDE-4,
PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g.
blocking NF.kappa.B through IKK inhibition), or kinase inhibitors
(e.g. blocking P38 MAP, JNK, PI3K, EGFR or Syk) is a logical
approach to switching off inflammation as these small molecules
target a limited number of common intracellular pathways--those
signal transduction pathways that are critical points for the
anti-inflammatory therapeutic intervention (see review by P. J.
Barnes, 2006). These non-limiting additional therapeutic agents
include:
5-(2,4-Difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid
(2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRy-797);
3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluorormethoxy-ben-
zamide (PDE-4 inhibitor Roflumilast);
4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine
(PDE-4 inhibitor CDP-840);
N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino-
]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast);
N-(3,5-Dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3--
yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281);
8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid
(3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch
351591);
4-[5-(4-Fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyri-
dine (P38 inhibitor SB-203850);
4-[4-(4-Fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-y-
l]-but-3-yn-1-ol (P38 inhibitor RWJ-67657);
4-Cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic
acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of
Cilomilast, PDE-4 inhibitor);
(3-Chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazo-
lin-4-yl]-amine (Gefitinib, EGFR inhibitor); and
4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-
-2-ylamino)-phenyl]-benzamide (Imatinib, EGFR inhibitor).
[0188] Combinations comprising inhaled .beta.2-adrenoreceptor
agonist bronchodilators such as formoterol, albuterol or salmeterol
with the compounds of Formulas I-Ill are also suitable, but
non-limiting, combinations useful for the treatment of respiratory
viral infections.
[0189] Combinations of inhaled .beta.2-adrenoreceptor agonist
bronchodilators such as formoterol or salmeterol with ICS's are
also used to treat both the bronchoconstriction and the
inflammation (Symbicort.RTM. and Advair.RTM., respectively). The
combinations comprising these ICS and .beta.2-adrenoreceptor
agonist combinations along with the compounds of Formulas I-III are
also suitable, but non-limiting, combinations useful for the
treatment of respiratory viral infections.
[0190] For the treatment or prophylaxis of pulmonary
broncho-constriction, anticholinergics are of potential use and,
therefore, useful as an additional therapeutic agents in
combination with the compounds of Formulas I-Ill for the treatment
of viral respiratory infections. These anticholinergics include,
but are not limited to, antagonists of the muscarinic receptor
(particularly of the M3 subtype) which have shown therapeutic
efficacy in man for the control of cholinergic tone in COPD (Witek,
1999);
1-{4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-2-p-carbonyl}-pyr-
rolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide;
3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-
-8-azonia-bicyclo[3.2.1]octane (Ipratropium-N,N-diethylglycinate);
1-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid
1-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin);
2-Hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid
1-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate);
2-{1-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-dipheny-
l-acetamide (Darifenacin); 4-Azepan-1-yl-2,2-diphenyl-butyramide
(Buzepide);
7-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-o-
xa-9-azonia-tricyclo[3.3.1.02,4]nonane
(Oxitropium-N,N-diethylglycinate);
7-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl--
3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (Tiotropium-N,
N-diethylglycinate); Dimethylamino-acetic acid
2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester
(Tolterodine-N,N-dimethylglycinate);
3-[4,4-Bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-
-pyridin-2-yl-ethyl)-pyrrolidinium;
1-[1-(3-Fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazol-
idin-2-one;
1-Cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-y-
n-1-ol;
3-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-p-
henoxy-propyl)-1-azonia-bicyclo[2.2.2]octane
(Aclidinium-N,N-diethylglycinate); or
(2-Diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid
1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester.
[0191] The compounds of Formulas I-Ill may also be combined with
mucolytic agents to treat both the infection and symptoms of
respiratory infections. A non-limiting example of a mucolytic agent
is ambroxol. Similarly, the compounds of Formulas I-III may be
combined with expectorants to treat both the infection and symptoms
of respiratory infections. A non-limiting example of an expectorant
is guaifenesin.
[0192] Nebulized hypertonic saline is used to improve immediate and
long-term clearance of small airways in patients with lung diseases
(Kuzik, J. Pediatrics 2007, 266). The compounds of Formulas I-III
may also be combined with nebulized hypertonic saline particularly
when the Pneumovirinae virus infection is complicated with
bronchiolitis. The combination of the compounds of Formulas I-III
with hypertonic saline may also comprise any of the additional
agents discussed above. In one embodiment, nebulized about 3%
hypertonic saline is used.
[0193] It is also possible to combine any compound with one or more
additional active therapeutic agents in a unitary dosage form for
simultaneous or sequential administration to a patient. The
combination therapy may be administered as a simultaneous or
sequential regimen. When administered sequentially, the combination
may be administered in two or more administrations.
[0194] Co-administration of a compound herein with one or more
other active therapeutic agents generally refers to simultaneous or
sequential administration of a compound and one or more other
active therapeutic agents, such that therapeutically effective
amounts of the compound and one or more other active therapeutic
agents are both present in the body of the patient.
[0195] Co-administration includes administration of unit dosages of
the compounds before or after administration of unit dosages of one
or more other active therapeutic agents, for example,
administration of the compounds within seconds, minutes, or hours
of the administration of one or more other active therapeutic
agents. For example, a unit dose of a compound can be administered
first, followed within seconds or minutes by administration of a
unit dose of one or more other active therapeutic agents.
Alternatively, a unit dose of one or more other therapeutic agents
can be administered first, followed by administration of a unit
dose of a compound within seconds or minutes. In some cases, it may
be desirable to administer a unit dose of a compound first,
followed, after a period of hours (e.g., 1-12 hours), by
administration of a unit dose of one or more other active
therapeutic agents. In other cases, it may be desirable to
administer a unit dose of one or more other active therapeutic
agents first, followed, after a period of hours (e.g., 1-12 hours),
by administration of a unit dose of a compound herein.
[0196] The combination therapy may provide "synergy" and
"synergistic", i.e. the effect achieved when the active ingredients
used together is greater than the sum of the effects that results
from using the compounds separately. A synergistic effect may be
attained when the active ingredients are: (1) co-formulated and
administered or delivered simultaneously in a combined formulation;
(2) delivered by alternation or in parallel as separate
formulations; or (3) by some other regimen. When delivered in
alternation therapy, a synergistic effect may be attained when the
compounds are administered or delivered sequentially, e.g. in
separate tablets, pills or capsules, or by different injections in
separate syringes. In general, during alternation therapy, an
effective dosage of each active ingredient is administered
sequentially, i.e. serially, whereas in combination therapy,
effective dosages of two or more active ingredients are
administered together. A synergistic anti-viral effect denotes an
antiviral effect which is greater than the predicted purely
additive effects of the individual compounds of the
combination.
[0197] In still yet another embodiment, the present application
provides a method of treating Pneumovirinae virus infection in a
human, the method comprising administering to the human a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, and/or ester thereof.
Also provided are separate methods of treating Pneumovirinae virus
infection in a human, each comprising administering to the human a
therapeutically effective a pharmaceutically effective amount of a
compound of Formula (II), Formula (III), or one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, and a pharmaceutically
acceptable carrier or excipient.
[0198] In another embodiment, provided is a method of treating a
Pneumovirinae infection in a human by administering to the human a
therapeutically effective amount of a racemate, enantiomer,
diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form,
hydrate or solvate of a compound of a compound of Formula (I), or a
pharmaceutically acceptable salt or ester thereof.
[0199] Further provided are separate methods of treating a
Pneumovirinae infection in a human in need thereof, each method
comprising administering to the human a therapeutically effective
amount of a racemate, enantiomer, diastereomer, tautomer,
polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a
compound of Formula (II), Formula (III), or one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof.
[0200] In still yet another embodiment, the present application
provides for a method of treating human respiratory syncytial virus
infection in a human, the method comprising administering to the
human a therapeutically effective amount of a compound of Formula
(I), or a pharmaceutically acceptable salt, solvate, and/or ester
thereof.
[0201] In still yet another embodiment, the present application
provides for a method of treating human respiratory syncytial virus
infection in a human, the method comprising administering to the
human a therapeutically effective amount of a compound of Formula
(I), or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, and at least one additional active therapeutic agent.
[0202] Further provided are separate methods of treating a human
respiratory syncytial virus infection in a human in need thereof,
each method comprising administering to the human a therapeutically
effective amount of a compound of Formula (II), Formula (III), or
one of the specific compounds of the examples herein, or a
pharmaceutically acceptable salt, solvate, and/or ester
thereof.
[0203] Also provided are separate methods of treating a human
respiratory syncytial virus infection in a human in need thereof,
each method comprising administering to the human a therapeutically
effective amount of a compound of Formula (II), Formula (III), or
one of the specific compounds of the examples herein, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof,
and at least one additional active therapeutic agent.
[0204] Also provided are separate methods of treating a human
respiratory syncytial virus infection in a human in need thereof,
wherein the human is also experiencing bronchiolitis, each method
comprising administering to the human a therapeutically effective
amount of a compound of Formula (I), Formula (II), or one of the
specific compounds of the examples herein, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof.
[0205] Also provided are separate methods of treating a human
respiratory syncytial virus infection in a human in need thereof,
wherein the human is also experiencing pneumonia, each method
comprising administering to the human a therapeutically effective
amount of a compound of Formula (I), Formula (II), or one of the
specific compounds of the examples herein, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof.
[0206] Also provided are separate methods of improving respiratory
symptoms in a human experiencing a human respiratory syncytial
virus infection, each method comprising administering to the human
a therapeutically effective amount of a compound of Formula (I),
Formula (II), or one of the specific compounds of the examples
herein, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof.
[0207] Respiratory symptoms in a human experiencing a respiratory
syncytial virus infection may include congested or runny nose,
coughing, wheezing, sneezing, rapid breathing or difficulty
breathing, apnea, bronchiolitis, and pneumonia.
[0208] Also provided is an embodiment comprising the use of a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, for the manufacture of a medicament
for the treatment of a Pneumovirinae virus infection or a
respiratory syncytial virus infection in a human.
[0209] Also provided is an embodiment comprising the use of a
compound of Formula (II), Formula (III), one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, for the manufacture of a
medicament for the treatment of a Pneumovirinae virus infection or
a respiratory syncytial virus infection in a human.
[0210] Also provided is a pharmaceutical formulation comprising a
pharmaceutically effective amount of a compound of Formula (I), or
a pharmaceutically acceptable salt, solvate, and/or ester thereof,
and a pharmaceutically acceptable carrier or excipient. Further
provided is a pharmaceutical formulation comprising a
pharmaceutically effective amount of a compound of Formula (II),
Formula (III), or one of the specific compounds of the examples
herein, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, and a pharmaceutically acceptable carrier or
excipient.
[0211] Also provided is a pharmaceutical formulation comprising a
pharmaceutically effective amount of a compound of Formula (I), or
a pharmaceutically acceptable salt, solvate, and/or ester thereof,
and a pharmaceutically acceptable carrier or excipient and a
pharmaceutically effective amount of at least one additional active
therapeutic agent. Further provided is a pharmaceutical formulation
comprising a pharmaceutically effective amount of a compound of
Formula (II), Formula (III), or one of the specific compounds of
the examples herein, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, and a pharmaceutically acceptable
carrier or excipient and a pharmaceutically effective amount of at
least one additional active therapeutic agent.
[0212] Also provided are separate embodiments comprising a compound
of Formula (I), Formula (II), Formula (III), or one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, for use in the treatment of a
Pneumovirinae virus infection or a respiratory syncytial virus
infection in a human.
[0213] Also provided are separate embodiments comprising a compound
of Formula (I), Formula (II), Formula (III), or one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, for use as a medicament.
[0214] Also provided are separate embodiments comprising a method
for manufacturing a medicament intended for treatment of a
Pneumovirinae virus infection or a respiratory syncytial virus
infection in a human, characterised in that a compound of Formula
(I), Formula (II), Formula (III), or one of the specific compounds
of the examples herein, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, is used.
[0215] Also provided is a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, and/or ester thereof,
for the treatment of a Pneumovirinae virus infection or a
respiratory syncytial virus infection in a human.
[0216] Also provided are separate embodiments comprising that a
compound of Formula (II), Formula (III), or one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, for the treatment of a
Pneumovirinae virus infection or a respiratory syncytial virus
infection in a human.
[0217] Further provided is a compound as described in this
specification. Also provided is a pharmaceutical composition as
described in this specification. Also provided is a method of using
a compound of Formula (I), as described in this specification.
Further provided is a method of making a compound of Formula (I),
as described in this specification.
[0218] In still yet another embodiment, the present application
provides a compound of Formula (I), or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, and at least one
additional active therapeutic agent for use in a method of treating
human respiratory syncytial virus infection in a human.
[0219] In still yet another embodiment, the present application
provides a compound of Formula (I), or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, for use in a method
of treating human respiratory syncytial virus infection in a human,
wherein the method comprises administering a compound of Formula
(I), or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, and at least one additional active therapeutic agent, to
the human.
[0220] Also provided are separate embodiments comprising a compound
of Formula (II), Formula (III), or one of the specific compounds of
the examples herein, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, and at least one additional active
therapeutic agent for use in a method of treating a human
respiratory syncytial virus infection in a human.
[0221] Also provided are separate embodiments comprising a compound
of Formula (II), Formula (III), or one of the specific compounds of
the examples herein, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, for use in a method of treating
human respiratory syncytial virus infection in a human, wherein the
method comprises administering a compound of Formula (II), Formula
(III), or one of the specific compounds of the examples herein, or
a pharmaceutically acceptable salt, solvate, and/or ester thereof,
and at least one additional active therapeutic agent, to the
human.
[0222] Also provided are separate embodiments comprising a compound
of Formula (I), Formula (II), Formula (III), or one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof for use in a method of treating
a human respiratory syncytial virus infection in a human in need
thereof, wherein the human is also experiencing bronchiolitis.
[0223] Also provided are separate embodiments comprising a compound
of Formula (I), Formula (II), Formula (III), or one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof for use in a method of treating
a human respiratory syncytial virus infection in a human in need
thereof, wherein the human is also experiencing pneumonia.
[0224] Also provided are separate embodiments comprising a compound
of Formula (I), Formula (II), Formula (III), or one of the specific
compounds of the examples herein, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof for use in a method of
improving respiratory symptoms in a human experiencing a human
respiratory syncytial virus infection.
[0225] Also provided is a product comprising a compound of Formula
(I), Formula (II), Formula (III), or one of the specific compounds
of the examples herein, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, as a combined preparation for
simultaneous, separate, or sequential use in treating a human
respiratory syncytial virus infection in a human or a Pneumovirinae
virus infection in a human.
Metabolites of the Compounds
[0226] Also falling within the scope herein are the in vivo
metabolic products of the compounds described herein, to the extent
such products are novel and unobvious over the prior art. Such
products may result for example from the oxidation, reduction,
hydrolysis, amidation, esterification and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, included are novel and unobvious compounds produced by
a process comprising contacting a compound with a mammal for a
period of time sufficient to yield a metabolic product thereof.
Such products typically are identified by preparing a radiolabelled
(e.g. .sup.14C or .sup.3H) compound, administering it parenterally
in a detectable dose (e.g. greater than about 0.5 mg/kg) to an
animal such as rat, mouse, guinea pig, monkey, or to man, allowing
sufficient time for metabolism to occur (typically about 30 seconds
to 30 hours) and isolating its conversion products from the urine,
blood or other biological samples. These products are easily
isolated since they are labeled (others are isolated by the use of
antibodies capable of binding epitopes surviving in the
metabolite). The metabolite structures are determined in
conventional fashion, e.g. by MS or NMR analysis. In general,
analysis of metabolites is done in the same way as conventional
drug metabolism studies well-known to those skilled in the art. The
conversion products, so long as they are not otherwise found in
vivo, are useful in diagnostic assays for therapeutic dosing of the
compounds even if they possess no RSV antiviral activity of their
own.
[0227] Recipes and methods for determining stability of compounds
in surrogate gastrointestinal secretions are known. Compounds are
defined herein as stable in the gastrointestinal tract where less
than about 50 mole percent of the protected groups are deprotected
in surrogate intestinal or gastric juice upon incubation for 1 hour
at 37.degree. C. Simply because the compounds are stable to the
gastrointestinal tract does not mean that they cannot be hydrolyzed
in vivo. The prodrugs typically will be stable in the digestive
system but may be substantially hydrolyzed to the parental drug in
the digestive lumen, liver, lung or other metabolic organ, or
within cells in general. As used herein, a prodrug is understood to
be a compound that is chemically designed to efficiently liberate
the parent drug after overcoming biological barriers to oral
delivery.
[0228] Useful oxygen protecting groups include a silyl ether
protecting group or a benzyl-type protecting group, including
methoxybenzyl groups.
[0229] Useful silyl ether protecting groups include Trimethylsilyl
(TMS), Triethylsilyl (TES), Dimethylisopropylsilyl (IPDMS),
Diethylisopropylsilyl (DEIPS), Dimethylthexylsilyl (TDS),
t-Butyldimethylsilyl (TBS or TBDMS), t-Butyldiphenylsilyl (TBDPS),
Tribenzylsilyl, Tri-p-xylylxilyl, Triisopropylsilyl (TIPS),
Diphenylmethylsilyl (DPMS), Di-t-butylmethylsilyl (DTBMS),
Triphenylsilyl (TPS), Methyldiphenylsilyl (MDPS),
t-butylmethoxyphenylsilyl, Tris(trimethylsilyl)silyl (sisyl),
(2-Hydroxystyryl)dimethylsilyl (HSDMS),
(2-Hydroxystyryl)diisopropylsilyl (HSDIS).
t-Butylmethoxyphenylsilyl (TBMPS), and t-Butoxydiphenylsilyl
(DPTBOS) protecting groups.
[0230] Useful benzyl-type protecting groups include benzyl,
halogenated benzyl, p-methoxybenzyl, benzyloxymethyl,
2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl,
p-CF.sub.3-benzyl, p-methylbenzyl, p-methoxylbenzyl,
3,5-dimethylbenzyl, p-tert-butylbenzyl, o-nitrobenzyl,
p-nitrobenzyl, p-halobenzyl, including p-Br-benzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl,
2,6-difluorobenzyl, p-acylaminobenzyl (PAB), p-azidobenzyl (Azb),
4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl,
p-(methylsulfinyl)benzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl
N-oxido, 2-quinolinylmethyl, diphenylmethyl (DPM),
p,p'-dinitrobenzhydryl, triphenylmethyl,
alpha-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl, and 2-naphthylmethyl
protecting groups.
[0231] Useful amine protecting groups include p-methoxybenzyl
carbonyl (Moz or MeOZ), acetyl (Ac), benzoyl (Bz), p-methoxybenzyl
(PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts
or Tos), trifluoroacetamide, and trityl protecting groups.
[0232] Useful amine protecting groups also include carbamate and
amide protecting groups. Examples of carbamate protecting groups
include methyl and ethyl carbamates such as
9-fluorenylmethyloxycarbonyl (FMOC), 9-(2-sulfo)fluorenylmethyl,
9-(2,7-dibromo)fluorenylmethyl,
17-tetrabenzo[a,c,g,i]fluorenylmethyl (Tbfmoc),
2-chloro-3-indenylmethyl (Climoc), benz[f]inden-3-ylmethyl (Bimoc),
2,7-di-t-butyl[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanyl)]methyl
(DBD-Tmoc), [2-(1,3-dithianyl)methyl (Dmoc), and
1,1-dioxobenzo[b]thiophene-2-ylmethyl (Bsmoc) carbamates.
[0233] Examples of useful substituted ethyl carbamates include
1,1-dimethyl-2-cyanoethyl, 2-phosphonioethyl (Peoc),
2-methylthioethyl, 2-(p-toluenesulfonyl)ethyl,
2,2,2,-trichloroethyl (Troc), 2-(trimethylsilyl)ethyl (Teoc),
2-phenylethyl (hZ), 1-(1-adamantyl)-1-methylethyl (Adpoc),
1,1-dimethyl-2-bromoethyl, 1,1-dimethyl-2-chloroethyl,
1,1-dimethyl-2,2-dibromoethyl (DB-t-BOC),
1,1-dimethyl-2,2,2-trichloroethyl (TCBOC),
1-methyl-1-(4-biphenylyl)ethyl (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl (t-Bumeoc),
2-(2'pyridyl)ethyl, 2-(4'pyridyl)ethyl,
2,2-bis(4'-nitrophenyl)ethyl (Bnpeoc),
N-(2-pivaloylamino)-1,1,dimethylethyl,
2-[(2-nitrophenyl)dithio]-1-phenylethyl (NpSSPeoc),
2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl (Boc or BOC),
1-adamantyl (1-Adoc), 2-adamantyl (2-Adoc), vinyl (Voc), allyl
(Aloc or alloc), 1-isopropylallyl (Ipaoc), cinnamyl (Coc),
4-nitrocinnamyl (Noc), 3-(3'-pyridyl)prop-2-enyl (Paloc),
8-quinolyl, and N-hydroxypiperidinyl, carbamates, as well as
alkyldithio carbamates, including methyldithio, ethyldithio,
isopropyldithio, t-butyldithio, and phenyldithio carbamates.
[0234] Also useful are aryl-containing and substituted
aryl-containing carbamates such as benzyl, p-methoxybenzyl,
p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,
4-methylsulfinylbenzyl (Msz), 9-anthrylmethyl, 4-methylthiophenyl
(Mtpc), 1-methyl-1-(triphenylphosphonio)ethyl
(2-triphenylphosphonioisopropyl) (Ppoc), 2-dansylethyl (Dnseoc),
2-(4-nitrophenyl)ethyl (Npeoc), 4-phenylacetoxybenzyl (PhAcOZ),
4-azidobenzyl (ACBZ), 4-azidomethoxybenzyl,
m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, carbobenzyloxy
(Cbz), 4-benzisoxazolylmethyl (Bic),
2-(trifluoromethyl)-6-chromonylmethyl (Tcroc), phenyl, and
diphenylmethyl carbamates. Additional carbamates include butynyl,
cyclopentyl, cyclohexyl, cyclopropylmethyl, 1-methylcyclobutyl,
1-methylcyclohexyl, 1,1-dimethylpropynyl, and
1-methyl-1-cyclopropylmethyl carbamates.
[0235] Useful amide protecting groups for amines include N-formyl,
N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl
(TFA), N-phenylacetyl, N-3-phenylpropionyl, N-4-pentenoyl,
N-picolinoyl, N-3-pyridylcarboxamido, N-benzoylphenylalanyl,
N-benzoyl, and N-p-phenylbenzoyl amides.
TABLE-US-00001 TABLE 1 List of abbreviations and acronyms.
Abbreviation Meaning Ac acetate Ac.sub.2O acetic anhydride AcOH
acetic acid ACN acetonitrile Bn benzyl BOM benzyl chloromethyl
ether Bu butyl Bz benzoyl BzCl benzoyl chloride CAN ceric ammonium
nitrate CDI 1,1'-carbonyldiimidazole DAST diethylaminosulfur
trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA
N,N-diisopropylethylamine DCM dichloromethane DMAP
4-dimethylamiopyridine DMDO dimethydioxirane DMSO dimethylsulfoxide
DMF dimethylformamide DMTrCl 4,4'-dimethoxytritylchloride DMTr
4,4'-dimethoxytrityl EDCl
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride Et
ethyl EtOAc ethyl acetate hr hour Imid imidazole tBuOK potassium
tert-butoxide Me methyl MeOH methyl alcohol min minute MMTr
4-methoxytriphenylmethane MMTrCl 4-methoxytriphenylchloromethane
NBS N-bromosuccinimide NMP 1-methyl-2-pyrrolidinone Ph phenyl
Ph.sub.3P triphenylphosphine PMB para-methoxybenzyl PMBCl
para-methoxybenzyl chloride pTSA para-toluenesulfonic acid Pyr
pyridine RT room temperature TBAF tetrabutylammonium flouride TBS
tert-butyldimethylsilyl TBSCl tert-Butyldimethylsilyl chloride TEA
triethylamine TFA trifluoroacetic acid Tf.sub.2O
trifluoromethanesulfonic anhydride THF tetrahydrofuran TMS
trimethylsilyl TMSCl trimethylsilyl chloride TPSCl
2,4,6-triisopropylbenzenesulfonyl chloride
Species (Nucleosides)
[0236] Provided are the individual nucleoside compounds below, or a
pharmaceutically acceptable salt thereof.
##STR00030## ##STR00031## ##STR00032## ##STR00033##
Syntheses of Nucleoside Species
##STR00034##
[0237] Compound 2:
1-((2R,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-chloro-5,5-bis(hydroxyme-
thyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0238] Compound 1 (1 mmol) is dissolved in DMF (10 mL). To this
solution is added TBSCl (1.1 eq), followed by imidazole (1.5 eq).
The reaction is stirred until the reaction is complete. The
reaction is quenched by slowly adding a saturated aqueous solution
of NaHCO.sub.3. The mixture is diluted with DCM and water. The
layers are separated and the organic layer is extracted with a 5%
aqueous solution of LiCl twice. The organic phase is extracted with
brine and is then dried over Na.sub.2SO.sub.4. The drying agent is
removed by filtration and the filtrate is concentrated. The product
is isolated from the residue by silica gel column chromatography,
using a mixture of EtOAc and hexanes as the eluent.
[0239] The product from the TBS protection step described above is
dissolved in THF (10 mL) and MeOH (5 mL). This solution is cooled
in an ice bath and then a 1M solution of LiOH in water (20 eq of
LiOH) is added to the first solution. The ice bath is removed and
the reaction is stirred until the reaction is complete. The
reaction is cooled in an ice bath and brought to neutral pH by
slowly adding a 4N aqueous solution of HCl. The neutralized
reaction is concentrated and compound 2 is isolated from the
residue by silica gel column chromatography, using a mixture of
MeOH and DCM as the eluent.
Compound 3:
1-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((tert-
-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-chloro-
tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0240] Compound 2 (1 mmol) is dissolved in DCM (10 mL) and TEA is
added (2.5 eq). This solution is cooled to 00.degree. C. and then a
separate solution of DMTrCl (1.45 eq) in DCM (5 mL) is slowly
added. The reaction is stirred until the reaction is complete. The
reaction is quenched by adding MeOH (5 mL) and is then
concentrated. The residue is partitioned between DCM and sat.
NaHCO.sub.3. The layers are separated and the organic layer is
extracted with brine and is then dried over Na.sub.2SO.sub.4. The
drying agent is removed by filtration and the filtrate is
concentrated. The product is isolated from the residue by silica
gel column chromatography, using a mixture of EtOAc and hexanes as
the eluent.
[0241] The product from the DMTr protection step described above (1
mmol) is dissolved in DCM (10 mL). To this solution is added TBSCl
(1.1 eq), followed by imidazole (1.5 eq). The reaction is stirred
until the reaction is complete. The reaction is quenched by slowly
adding sat. NaHCO.sub.3. The mixture is diluted with DCM and water.
The layers are separated and the organic layer is extracted with
brine and is then dried over Na.sub.2SO.sub.4. The drying agent is
removed by filtration and the filtrate is concentrated. Compound 3
is isolated from the residue by silica gel column chromatography,
using a mixture of EtOAc and hexanes as the eluent.
Compound 4:
1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-3-chloro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-
e-2,4(1H,3H)-dione
[0242] Compound 3 (1 mmol) is dissolved in CHCl.sub.3 (10 mL). This
solution is cooled in an ice bath and a solution of pTSA (1.1 eq)
in MeOH (3 mL) is added in a drop-wise fashion. The reaction is
stirred until the reaction is complete. The reaction is quenched by
adding sat. NaHCO.sub.3 and is diluted with DCM. The layers are
separated and the organic phase is extracted with brine and is then
dried over Na.sub.2SO.sub.4. The drying agent is removed by
filtration and the filtrate is concentrated. Compound 4 is isolated
from the residue by silica gel column chromatography, using a
mixture of EtOAc and hexanes as the eluent.
Compound 5:
(2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsil-
yl)oxy)methyl)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahy-
drofuran-2-carbaldehyde
[0243] Compound 4 (1 mmol) is dissolved in toluene (8 mL) and DMSO
(2 mL). To this solution is added EDCl (3 eq). Pyridine (83
.quadrature.L) is then added followed by TFA (42 .quadrature.L).
The reaction is stirred until the reaction is complete. The
reaction is diluted with EtOAc, and the organic phase is washed
with water and then brine. The organic phase is dried over
Na.sub.2SO.sub.4 and the drying agent is removed by filtration. The
filtrate is concentrated to yield the crude compound 5, which is
used as is in subsequent reactions.
##STR00035##
Compound 6:
1-((2R,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-5-(hydroxym-
ethyl)tetrahydrofuran-2-yl)-3-(4-methoxybenzyl)pyrimidine-24(1H,3H)-dione
[0244] Compound 3 (1 mmol) is added as a solution in DMF (5 mL) to
an ice cold slurry of NaH (1.1 eq) in DMF (5 mL). This is allowed
to stir for 10 min and then PMBCl is added dropwise. The reaction
is allowed to stir until it is determined to be complete. The
reaction is quenched by the addition of water and then diluted with
EtOAc. The organic and aqueous phases are separated and the organic
phase is washed with 5% LiCl (twice), brine (once) and then dried
over Na.sub.2SO.sub.4. The filtrate is concentrated and the
PMB-protected compound is purified by silica gel column
chromatography, using a mixture of EtOAc and hexanes as the
eluent.
[0245] The PMB-protected compound (1 mmol) is dissolved in THF and
then a 1M solution of TBAF in THF is added. The reaction is stirred
until it is determined to be complete. The reaction is quenched
with a saturated solution of NH.sub.4Cl in water and diluted with
DCM. The layers are separated and the organic layer is extracted
with brine and dried over Na.sub.2SO.sub.4. The drying agent is
removed by filtration and the filtrate is concentrated. The
deprotected diol is isolated from the residue by silica gel column
chromatography, using a mixture of DCM and MeOH as the eluent.
[0246] The deprotected diol (1 mmol) is added as a solution in DMF
(5 mL) to an ice cold slurry of NaH 2.2 eq) in DMF (5 mL). This is
allowed to stir for 10 min. and then BnBr is added dropwise. The
reaction is allowed to stir until it is determined to be complete.
The reaction is quenched by the addition of water and then diluted
with EtOAc. The organic and aqueous phases are separated and the
organic phase is washed with 5% LiCl (twice), brine (once) and then
dried over Na.sub.2SO.sub.4. The filtrate is concentrated and the
Bn-protected compound is purified by silica gel column
chromatography, using a mixture of EtOAc and hexanes as the
eluent.
[0247] The Bn-protected compound (1 mmol) is dissolved in
CHCl.sub.3 (10 mL). This solution is cooled in an ice bath and a
solution of pTSA (1.1 eq) in MeOH (3 mL) is added in a drop-wise
fashion. The reaction is stirred until the reaction is complete.
The reaction is quenched by adding sat. NaHCO.sub.3 and is diluted
with DCM. The layers are separated and the organic phase is
extracted with brine and is then dried over Na.sub.2SO.sub.4. The
drying agent is removed by filtration and the filtrate is
concentrated. Compound 6 is isolated from the residue by silica gel
column chromatography, using a mixture of EtOAc and hexanes as the
eluent.
Compound 7:
1-((2R,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-5-(fluorome-
thyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0248] The compound 6 (1 mmol) is dissolved in toluene (10 mL).
This solution is cooled in an ice bath and then DAST (10 eq) is
added in a drop-wise fashion. The ice bath is removed and the
reaction is allowed to stir until it is determined to be complete.
The reaction is quenched by the addition of a saturated solution of
NaHCO.sub.3 in water and then diluted with EtOAc. The layers are
separated and the organic layer is extracted with brine and dried
over Na.sub.2SO.sub.4. The drying agent is removed by filtration
and the filtrate is concentrated. The product is isolated from the
residue by silica gel column chromatography, using a mixture of
EtOAc and hexanes as the eluent.
[0249] The product from the previous reaction (1 mmol) is dissolved
in a 3:1 mixture of ACN and water (10 mL). CAN (3 eq) is then added
in a single portion and the reaction is allowed to stir until it is
determined to be complete. The reaction is quenched by the addition
of brine and diluted with EtOAc. The layers are separated and the
organic layer is dried over Na.sub.2SO.sub.4. The drying agent is
removed by filtration and the filtrate is concentrated. Compound 7
is isolated from the residue by silica gel column chromatography,
using a mixture of EtOAc and hexanes as the eluent.
Compound 8:
4-amino-1-((2R,3R,4R,5R)-3-chloro-5-(fluoromethyl)-4-hydroxy-5-(hydroxyme-
thyl)tetrahydrofuran-2-yl)pyrimidin-2(H)-one
[0250] Compound 7 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at RT until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in THF (100 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
cytidine product is isolated by silica gel column chromatography,
eluting with a mixture of MeOH and DCM.
[0251] The cytidine product (1 mmol) from the previous reaction is
dissolved in DCM (10 mL). MMTrCl (3 eq) and AgNO.sub.3 (3 eq) are
added. The reaction is allowed to stir until it is determined to be
complete. The reaction is filtered, the filtrate is extracted with
brine and dried over Na.sub.2SO.sub.4. The drying agent is removed
by filtration and the filtrate is concentrated. The MMTr-protected
product is isolated from the residue by silica gel column
chromatography, using a mixture of EtOAc and hexanes as the
eluent.
[0252] The MMTr-protected product (1 mmol) from the previous
reaction is dissolved in acetone (10 mL). NH.sub.4HCO.sub.2 (45 eq)
and 10% Pd/C (1 g) are added and the reaction refluxed until it is
determined to be complete. The reaction is filtered through a pad
of Celite and the filtrate is concentrated. The deprotected diol
product is isolated from the residue by silica gel column
chromatography, using a mixture of DCM and MeOH as the eluent.
[0253] The deprotected diol product (1 mmol) from the previous
reaction is dissolved in CHCl.sub.3 (10 mL). This solution is
cooled in an ice bath and a solution of pTSA (1.1 eq) in MeOH (3
mL) is added in a drop-wise fashion. The reaction is stirred until
the reaction is complete. The reaction is quenched by adding sat.
NaHCO.sub.3. The mixture is concentrated, the residue is taken up
in MeOH and then filtered. The filtrate is concentrated and
compound 8 is isolated from the residue by silica gel column
chromatography, using a mixture of DCM and MeOH as the eluent.
Compound 9:
1-((2R,3R,4R,5R)-3-chloro-5-(fluoromethyl)-4-hydroxy-5-(hydroxymethyl)tet-
rahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0254] Compound 7 (1 mmol) is dissolved in acetone (10 mL).
NH.sub.4HCO.sub.2 (45 eq) and 10% Pd/C (1 g) are added and the
reaction refluxed until it is determined to be complete. The
reaction is filtered through a pad of Celite and the filtrate is
concentrated. Compound 9 is isolated from the residue by silica gel
column chromatography, using a mixture of DCM and MeOH as the
eluent.
##STR00036##
Compound 10:
1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-3-chloro-5-(chloromethyl)tetrahydrofuran-2-yl)pyrimidine-
-2,4(1H,3H)-dione
[0255] Compound 4 (1 mmol) is dissolved in DCE (10 mL). To this
solution is added Ph.sub.3P (2 eq) and CCl.sub.4 (2 eq). The
reaction is heated to 130.degree. C. using microwave irradiation
until the reaction is determined to be complete. The reaction is
concentrated and compound 10 is isolated from the residue by silica
gel column chromatography, using a mixture of EtOAc and hexanes as
the eluent.
Compound 11:
4-amino-1-((2R,3R,4R,5R)-3-chloro-5-(chloromethyl)-4-hydroxy-5-(hydroxyme-
thyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one
[0256] Compound 10 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in THF (100 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
product is isolated by silica gel column chromatography, eluting
with a mixture of MeOH and DCM.
[0257] The product from the above described reaction is dissolved
in THF (10 mL) and a solution of 1M TBAF in THF (3 eq) is added at
rt. The reaction is stirred until the reaction is determined to be
complete. The reaction is concentrated and compound 11 is isolated
from the residue by silica gel column chromatography using a
mixture of MeOH and DCM as the eluent.
Compound 12:
1-((2R,3R,4R,5R)-3-chloro-5-(chloromethyl)-4-hydroxy-5-(hydroxymethyl)tet-
rahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0258] Compound 10 (1 mmol) is dissolved in THF (10 mL) and a
solution of 1M TBAF in THF (3 eq) is added at rt. The reaction is
stirred until the reaction is determined to be complete. The
reaction is concentrated and compound 12 is isolated from the
residue by silica gel column chromatography using a mixture of MeOH
and DCM as the eluent.
##STR00037##
Compound 13:
(2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsil-
yl)oxy)methyl)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahy-
drofuran-2-carbonitrile
[0259] Compound 5 (1 mmol) is dissolved in pyridine (10 mL). To
this solution is added HONH.sub.2--HCl (1.5 eq). The reaction is
stirred until it is determined to be complete. The reaction is
quenched by the addition of water. The reaction is extracted with
EtOAc and the organic phase is dried over Na.sub.2SO.sub.4. The
drying agent is removed by filtration and the filtrate is
concentrated. The crude product is dissolved in ACN (10 mL) and CDl
(1.5 eq) is added. The reaction is stirred until it is determined
to be complete and is then quenched by adding water. The mixture is
extracted with DCM and the combined organics are dried over
Na.sub.2SO.sub.4. The drying agent is removed by filtration and the
filtrate is concentrated. Compound 13 is isolated from the residue
by silica gel column chromatography, using a mixture of EtOAc and
hexanes as the eluent.
Compound 14:
(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-chloro-3-hydroxy-2-(h-
ydroxymethyl)tetrahydrofuran-2-carbonitrile
[0260] Compound 13 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in THF (100 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
product is isolated by silica gel column chromatography, eluting
with a mixture of MeOH and DCM.
[0261] The product from the above described reaction is dissolved
in THF (10 mL) and a solution of 1M TBAF in THF (3 eq) is added at
rt. The reaction is stirred until the reaction is determined to be
complete. The reaction is concentrated and compound 14 is isolated
from the residue by silica gel column chromatography using a
mixture of MeOH and DCM as the eluent.
Compound 15:
(2R,3R,4R,5R)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydr-
oxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile
[0262] Compound 13 (1 mmol) is dissolved in THF (10 mL) and a
solution of 1M TBAF in THF (3 eq) is added at rt. The reaction is
stirred until the reaction is determined to be complete. The
reaction is concentrated and compound 15 is isolated from the
residue by silica gel column chromatography using a mixture of MeOH
and DCM as the eluent
##STR00038##
Compound 16:
1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-3-chloro-5-ethynyltetrahydrofuran-2-yl)pyrimidine-2,4(1H-
,3H)-dione
[0263] (Ph).sub.3PCH.sub.2Br--Br (2 mmol) is dissolved in THF (10
mL). This solution is cooled to -78.degree. C. and tBuOK (1M/THF, 3
mmol) is added in a drop-wise manner. This solution is stirred at
-78.degree. C. and then a solution of compound 5 in THF (5 mL) is
added in a drop-wise manner. The reaction is then allowed to warm
to room temperature and stirring is continued until it is
determined that the reaction is complete. The reaction is quenched
by the addition of saturated aqueous solution of NH.sub.4Cl. The
mixture is extracted with EtOAc and the combined organic extracts
are extracted with brine and dried over Na.sub.2SO.sub.4. The
drying agent is removed by filtration and the filtrate is
concentrated. The product is isolated from this residue by silica
gel column chromatography, using a mixture of EtOAc and hexanes as
the eluent.
[0264] The product from the previous reaction (1 mmol) is dissolved
in THF (10 mL). This solution is cooled to -78.degree. C. and then
tBuOK (1M/THF, 3 eq) is added in a drop-wise manner. The reaction
is allowed to stir until it is determined to be complete. The
reaction is quenched by the addition of sat. NH.sub.4Cl. The
mixture is extracted with EtOAc and the combined organic extracts
are extracted with brine and dried over Na.sub.2SO.sub.4. The
drying agent is removed by filtration and the filtrate is
concentrated. Compound 16 is isolated from this residue by silica
gel column chromatography, using a mixture of EtOAc and hexanes as
the eluent.
Compound 17:
4-amino-1-((2R,3R,4R,5R)-3-chloro-5-ethynyl-4-hydroxy-5-(hydroxymethyl)te-
trahydrofuran-2-yl)pyrimidin-2(1H)-one
[0265] Compound 16 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in THF (100 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
product is isolated by silica gel column chromatography, eluting
with a mixture of MeOH and DCM.
[0266] The product from the above described reaction is dissolved
in THF (10 mL) and a solution of 1M TBAF in THF (3 eq) is added at
rt. The reaction is stirred until the reaction is determined to be
complete. The reaction is concentrated and compound 17 is isolated
from the residue by silica gel column chromatography using a
mixture of MeOH and DCM as the eluent.
Compound 18:
1-((2R,3R,4R,5R)-3-chloro-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydro-
furan-2-yl)pyrimidine-2,4(1H,3H)-dione
[0267] Compound 16 (1 mmol) is dissolved in THF (10 mL) and a
solution of 1M TBAF in THF (3 eq) is added at rt. The reaction is
stirred until the reaction is determined to be complete. The
reaction is concentrated and compound 18 is isolated from the
residue by silica gel column chromatography using a mixture of MeOH
and DCM as the eluent.
##STR00039##
Compound 19:
1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-3-chloro-5-vinyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3-
H)-dione
[0268] (Ph).sub.3PCH.sub.3Br (4 mmol) is suspended in THF (10 mL)
and then nBuLi (2.5M/hexanes, 4 mmol) is added in a drop-wise
manner. The cold bath is replaced with an ice bath and the reaction
is stirred for 1 h. To this solution is added a solution of
compound 5 (1 mmol) in THF (5 mL). The ice bath is removed and the
reaction is allowed to stir at room temperature until it is
determined to be complete. The reaction is quenched by the addition
of sat. NH4Cl and the mixture is extracted with EtOAc. The organic
phase is extracted with brine and is then dried over
Na.sub.2SO.sub.4. The drying agent is removed by filtration and the
filtrate is concentrated. Compound 19 is isolated from this residue
by silica gel column chromatography, using a mixture of EtOAc and
hexanes as the eluent.
Compound 20:
4-amino-1-((2R,3R,4R,5R)-3-chloro-4-hydroxy-5-(hydroxymethyl)-5-vinyltetr-
ahydrofuran-2-yl)pyrimidin-2(1H)-one
[0269] Compound 19 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in THF (100 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
product is isolated by silica gel column chromatography, eluting
with a mixture of MeOH and DCM.
[0270] The product from the above described reaction is dissolved
in THF (10 mL) and a solution of 1M TBAF in THF (3 eq) is added at
rt. The reaction is stirred until the reaction is determined to be
complete. The reaction is concentrated and compound 20 is isolated
from the residue by silica gel column chromatography using a
mixture of MeOH and DCM as the eluent.
Compound 21:
1-((2R,3R,4R,5R)-3-chloro-4-hydroxy-5-(hydroxymethyl)-5-vinyltetrahydrofu-
ran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0271] Compound 19 (1 mmol) is dissolved in THF (10 mL) and a
solution of 1M TBAF in THF (3 eq) is added at rt. The reaction is
stirred until the reaction is determined to be complete. The
reaction is concentrated and compound 21 is isolated from the
residue by silica gel column chromatography using a mixture of MeOH
and DCM as the eluent.
##STR00040##
Compound 22:
1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-3-chloro-5-ethyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3-
H)-dione
[0272] Compound 19 (1 mmol) is dissolved in EtOAc (10 mL). 10% Pd/C
(1 g) is added and the reaction vessel atmosphere is evacuated and
refilled with H.sub.2. The reaction is stirred vigorously until it
is determined to be complete. The reaction is filtered through a
pad of Celite. The filtrate is concentrated and compound 22
isolated from this residue by silica gel column chromatography,
using a mixture of EtOAc and hexanes as the eluent.
Compound 23:
4-amino-1-((2R,3R,4R,5R)-3-chloro-5-ethyl-4-hydroxy-5-(hydroxymethyl)tetr-
ahydrofuran-2-yl)pyrimidin-2(1H)-one
[0273] Compound 22 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in THF (100 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
product is isolated by silica gel column chromatography, eluting
with a mixture of MeOH and DCM.
[0274] The product from the above described reaction is dissolved
in THF (10 mL) and a solution of 1M TBAF in THF (3 eq) is added at
rt. The reaction is stirred until the reaction is determined to be
complete. The reaction is concentrated and compound 23 is isolated
from the residue by silica gel column chromatography using a
mixture of MeOH and DCM as the eluent.
Compound 24:
1-((2R,3R,4R,5R)-3-chloro-5-ethyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofu-
ran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0275] Compound 22 (1 mmol) is dissolved in THF (10 mL) and a
solution of 1M TBAF in THF (3 eq) is added at rt. The reaction is
stirred until the reaction is determined to be complete. The
reaction is concentrated and compound 24 is isolated from the
residue by silica gel column chromatography using a mixture of MeOH
and DCM as the eluent.
##STR00041##
Compound 25:
1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-3-chloro-5-propyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,-
3H)-dione
[0276] Compound 5 is converted to compound 25 in a manner similar
to the conversion of compound 5 to compound 22 (a Wittig reaction
followed by a Pd/C catalyzed hydrogenation of the resulting
olefin).
Compound 26:
4-amino-1-((2R,3R,4R,5R)-3-chloro-4-hydroxy-5-(hydroxymethyl)-5-propyltet-
rahydrofuran-2-yl)pyrimidin-2(1H)-one
[0277] Compound 25 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in THF (100 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
product is isolated by silica gel column chromatography, eluting
with a mixture of MeOH and DCM.
[0278] The product from the above described reaction is dissolved
in THF (10 mL) and a solution of 1M TBAF in THF (3 eq) is added at
rt. The reaction is stirred until the reaction is determined to be
complete. The reaction is concentrated and compound 26 is isolated
from the residue by silica gel column chromatography using a
mixture of MeOH and DCM as the eluent.
Compound 27:
1-((2R,3R,4R,5R)-3-chloro-4-hydroxy-5-(hydroxymethyl)-5-propyltetrahydrof-
uran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0279] Compound 25 (1 mmol) is dissolved in THF (10 mL) and a
solution of 1M TBAF in THF (3 eq) is added at rt. The reaction is
stirred until the reaction is determined to be complete. The
reaction is concentrated and compound 27 is isolated from the
residue by silica gel column chromatography using a mixture of MeOH
and DCM as the eluent.
##STR00042##
Compound 28:
((2R,3R,4R,5R)-3-acetoxy-4-chloro-2-(chloromethyl)-5-(2,4-dioxo-3,4-dihyd-
ropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl acetate
[0280] Compound 12 (1 mmol) is dissolved in pyridine (10 mL) and
Ac.sub.2O (2.1 eq) is added. The reaction is stirred at rt until
the reaction is determined to be complete. The reaction is
concentrated and compound 28 is isolated from the residue by silica
gel column chromatography using a mixture of EtOAc and hexanes as
the eluent.
Compound 29:
((2R,3R,4R,5R)-3-acetoxy-5-(5-bromo-2,4-dioxo-3,4-dihydropyrimidin-1(2H)--
yl)-4-chloro-2-(chloromethyl)tetrahydrofuran-2-yl)methyl
acetate
[0281] Compound 28 (1 mmol) is dissolved in pyridine (10 mL) and
NBS (2 eq) is added. The reaction is stirred at rt until the
reaction is determined to be complete. The reaction is concentrated
and compound 29 is isolated from the residue by silica gel column
chromatography using a mixture of EtOAc and hexanes as the
eluent.
Compound 30:
((2R,3R,4R,5R)-3-acetoxy-4-chloro-2-(chloromethyl)-5-(5-fluoro-2,4-dioxo--
3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl
acetate
[0282] Compound 29 (1 mmol) is dissolved in dioxane (10 mL). To
this solution is added Sn.sub.2Me.sub.6 (2 eq) and
(Ph.sub.3P).sub.2PdCl.sub.2 (0.1 eq). The reaction is stirred at
80.degree. C. until the reaction is determined to be complete. The
reaction is concentrated and the stannylated product is isolated
from the residue by silica gel column chromatography using a
mixture of EtOAc and hexanes as the eluent. The stannane (1 mmol)
is dissolved in ACN (10 mL) and Selectfluor (2.2 eq) is added. The
reaction is stirred at rt until the reaction is determined to be
complete. The reaction is concentrated and compound 34 is isolated
from the residue by silica gel column chromatography using a
mixture of EtOAc and hexanes as the eluent.
Compound 31:
4-amino-1-((2R,3R,4R,5R)-3-chloro-5-(chloromethyl)-4-hydroxy-5-(hydroxyme-
thyl)tetrahydrofuran-2-yl)-5-fluoropyrimidin-2(1H)-one
[0283] Compound 30 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in water (50 mL) is then added to
the reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and
compound 35 is isolated by silica gel column chromatography,
eluting with a mixture of MeOH and DCM.
Compound 32:
1-((2R,3R,4R,5R)-3-chloro-5-(chloromethyl)-4-hydroxy-5-(hydroxymethyl)tet-
rahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione
[0284] Compound 30 (1 mmol) is dissolved in THF (10 mL) and a
saturated solution of NH.sub.3 in water (50 mL) is then added at
rt. The reaction is stirred until the reaction is determined to be
complete. The reaction is concentrated and compound 36 is isolated
from the residue by silica gel column chromatography using a
mixture of MeOH and DCM as the eluent.
##STR00043##
Compound 33:
1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-3-chloro-5-cyclopropyltetrahydrofuran-2-yl)pyrimidine-2,-
4(1H,3H)-dione
[0285] Compound 19 (1 mmol) is dissolved in DCM (10 mL). To this
solution is added BzCl (1 eq), Et.sub.3N (1.5 eq) and DMAP (0.1
eq). The reaction is stirred until the reaction is determined to be
complete. The reaction is quenched by the addition of a saturated
aqueous solution of NaHCO.sub.3. This mixture is diluted with DCM
and the layers are separated. The organic phase is extracted with
0.1N HCl, brine and then dried over Na.sub.2SO.sub.4. The drying
agent is removed by filtration and the filtrate is concentrated.
The benzoylated product is isolated from the residue by silica gel
column chromatography using a mixture of EtOAc and hexanes as the
eluent.
[0286] The benzoylated product (1 mmol) is combined with
Pd(OAc).sub.2 (0.1 eq) in ACN (10 mL) and this solution is added to
a solution of CH.sub.2N.sub.2 in Et.sub.2O (100 mL). The reaction
is stirred until the reaction is determined to be complete. The
reaction is quenched by the addition AcOH. The mixture is extracted
with a saturated aqueous solution of NaHCO.sub.3, brine and then
dried over Na.sub.2SO.sub.4. The drying agent is removed by
filtration and the filtrate is concentrated.
[0287] The crude cyclopropanated product (1 mmol) is taken up 7N
NH.sub.3 in MeOH. The reaction is stirred until the reaction is
determined to be complete. The reaction is concentrated and
compound 33 is isolated from the residue by silica gel column
chromatography using a mixture of EtOAc and hexanes as the
eluent.
Compound 34:
4-amino-1-((2R,3R,4R,5R)-3-chloro-5-cyclopropyl-4-hydroxy-5-(hydroxymethy-
l)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one
[0288] Compound 22 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete. A
saturated solution of NH.sub.3 in THF (100 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
product is isolated by silica gel column chromatography, eluting
with a mixture of MeOH and DCM.
[0289] The product from the above described reaction is dissolved
in THF (10 mL) and a solution of 1M TBAF in THF (3 eq) is added at
rt. The reaction is stirred until the reaction is determined to be
complete. The reaction is concentrated and compound 34 is isolated
from the residue by silica gel column chromatography using a
mixture of MeOH and DCM as the eluent.
Compound 35:
1-((2R,3R,4R,5R)-3-chloro-5-cyclopropyl-4-hydroxy-5-(hydroxymethyl)tetrah-
ydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0290] Compound 33 (1 mmol) is dissolved in THF (10 mL) and a
solution of 1M TBAF in THF (3 eq) is added at rt. The reaction is
stirred until the reaction is determined to be complete. The
reaction is concentrated and compound 35 is isolated from the
residue by silica gel column chromatography using a mixture of MeOH
and DCM as the eluent.
##STR00044##
Compound 36:
1-((2R,3R,4R)-4-(benzyloxy)-3-chloro-5,5-bis(hydroxymethyl)tetrahydrofura-
n-2-yl)-3-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione
[0291] Compound 1 (1 mmol) is dissolved in DMF (10 mL). To this
solution is added K.sub.2CO.sub.3 (5 eq) and then PMBCl (1.1 eq).
The reaction is stirred until the reaction is determined to be
complete. The reaction is diluted with EtOAc and water. The layers
are separated and the organic phase is washed with a 5% solution of
LiCl in water (twice) and brine. The organic phase is then dried
over Na.sub.2SO.sub.4. The drying agent is removed by filtration
and the filtrate is concentrated. The resulting residue is
dissolved in DMF (10 mL) and cooled to 0.degree. C. To this cooled
solution is added NaH (1.1 eq), followed by BnBr (1.2 eq). The
reaction is stirred until the reaction is determined to be
complete. The reaction is quenched by the addition of a saturated
solution of NH.sub.4Cl in water. The mixture is diluted with EtOAc.
The layers are separated and the organic phase is washed with a 5%
solution of LiCl in water (twice) and brine. The organic phase is
then dried over Na.sub.2SO.sub.4. The drying agent is removed by
filtration and the filtrate is concentrated. The Bn-protected
material is purified from this residue by silica gel column
chromatography using a mixture of EtOAc and hexanes as the
eluent.
[0292] The Bn-protected compound (1 mmol) is then dissolved in MeOH
(10 mL) and NaOMe (15 eq) is added. The reaction is stirred until
the reaction is determined to be complete. The reaction is quenched
by the addition of AcOH and the resulting mixture is concentrated.
Compound 36 is purified from this residue by silica gel column
chromatography using a mixture of EtOAc and hexanes as the
eluent.
Compound 37:
1-((2R,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-5-(hydroxym-
ethyl)tetrahydrofuran-2-yl)-3-(4-methoxybenzyl)pyrimidine--24(1H,3H)-dione
[0293] Compound 36 (1 mmol) is dissolved in pyridine (10 mL). To
this solution is added BzCl (1 eq). The reaction is stirred until
the reaction is determined to be complete. The reaction is diluted
with EtOAc and water. The layers are separated and the organic
phase is washed with water and brine. The organic phase is then
dried over Na.sub.2SO.sub.4. The drying agent is removed by
filtration and the filtrate is concentrated. The mono-Bz protected
material is purified from this residue by silica gel column
chromatography using a mixture of EtOAc and hexanes as the
eluent.
[0294] The above Bz-protected material (1 mmol) is dissolved in DMF
(10 mL). To this solution is added Cs.sub.2CO.sub.3 (5 eq) and then
BnBr (1.1 eq). The reaction is stirred until the reaction is
determined to be complete. The reaction is diluted with EtOAc and
water. The layers are separated and the organic phase is washed
with a 5% solution of LiCl in water (twice) and brine. The organic
phase is then dried over Na.sub.2SO.sub.4. The drying agent is
removed by filtration and the filtrate is concentrated. The
bisBn-protected material is purified from this residue by silica
gel column chromatography using a mixture of EtOAc and hexanes as
the eluent.
[0295] The bisBn-protected compound (1 mmol) is then dissolved in
MeOH (10 mL) and NaOMe (15 eq) is added. The reaction is stirred
until the reaction is determined to be complete. The reaction is
quenched by the addition of AcOH and the resulting mixture is
concentrated. Compound 37 is purified from this residue by silica
gel column chromatography using a mixture of EtOAc and hexanes as
the eluent.
Compound 38:
1-((2R,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-5-((R)-1-fl-
uoroethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0296] Compound 37 (1 mmol) is dissolved in DCM (10 mL). To this
solution is added Dess-Martin Periodinane (1.1 eq). The reaction is
stirred until the reaction is determined to be complete. The
reaction is concentrated and the product aldehyde is isolated from
the residue by silica gel column chromatography using a mixture of
EtOAc and hexanes as the eluent.
[0297] The aldehyde from above (1 mmol) is dissolved in THF (10 mL)
and the solution is cooled to -78.degree. C. To this cooled
solution is added MeMgBr (3 eq). The reaction is stirred until the
reaction is determined to be complete. The reaction is quenched by
the addition of a saturated aqueous solution of NH.sub.4Cl. The
resulting mixture is diluted with EtOAc and the layers are
separated. The organic phase is then dried over Na.sub.2SO.sub.4.
The drying agent is removed by filtration and the filtrate is
concentrated. The product alcohol is purified from this residue by
silica gel column chromatography using a mixture of EtOAc and
hexanes as the eluent.
[0298] The alcohol from above (1 mmol) is dissolved in toluene (10
mL). To this solution is added DAST (5 eq). The reaction is stirred
until the reaction is determined to be complete. The reaction is
quenched by the addition of a saturated aqueous solution of
Na.sub.2CO.sub.3. The resulting mixture is diluted with EtOAc and
the layers are separated. The organic phase is then dried over
Na.sub.2SO.sub.4. The drying agent is removed by filtration and the
filtrate is concentrated. The product fluoride is purified from
this residue by silica gel column chromatography using a mixture of
EtOAc and hexanes as the eluent.
[0299] The fluoride from above (1 mmol) is dissolved in a 3:1
mixture of ACN:H2O (10 mL). To this solution is added CAN (4 eq).
The reaction is stirred until the reaction is determined to be
complete. The reaction is diluted with brine and EtOAc. The layers
are separated and the organic phase is then dried over
Na.sub.2SO.sub.4. The drying agent is removed by filtration and the
filtrate is concentrated. Compound 38 is purified from this residue
by silica gel column chromatography using a mixture of EtOAc and
hexanes as the eluent.
Compound 39:
4-amino-1-((2R,3R,4R,5R)-3-chloro-5-((R)-1-fluoroethyl)-4-hydroxy-5-(hydr-
oxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(H)-one
[0300] Compound 38 (1 mmol) is dissolved in ACN (10 mL) and then
DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq) are added. The reaction
is stirred at rt until the reaction is determined to be complete.
Concentrated aqueous NH.sub.4OH (15 mL) is then added to the
reaction and stirring is continued at rt until the reaction is
determined to be complete. The reaction is concentrated and the
product is isolated by silica gel column chromatography, eluting
with a mixture of EtOAc and hexanes.
[0301] The aminated product from above (1 mmol) is dissolved in DCM
(10 mL). To this solution is added MMTrCl (2.1 eq) and AgNO.sub.3
(2.1 eq). The reaction is stirred until the reaction is determined
to be complete. The reaction is filtered and the filtrate is washed
with brine and then dried over Na.sub.2SO.sub.4. The drying agent
is removed by filtration and the filtrate is concentrated. The
MMTr-protected product is isolated from the residue by silica gel
column chromatography, eluting with a mixture of EtOAc and
hexanes.
[0302] The MMTr-protected product from above (1 mmol) is dissolved
in acetone (10 mL). To this solution is added HCO.sub.2NH.sub.4 (20
eq) and 10% Pd/C (2 g). The reaction is refluxed until the reaction
is determined to be complete. The reaction is cooled and the
filtered. The filtrate is concentrated and the residue is taken
back up in EtOAc. This solution is extracted with brine and dried
over Na.sub.2SO.sub.4. The drying agent is removed by filtration
and the filtrate is concentrated. The deprotected product is
purified from this residue by silica gel column chromatography
using a mixture of MeOH and DCM as the eluent.
[0303] The deprotected product from above (1 mmol) is dissolved in
an 80% aqueous solution of AcOH. The reaction is stirred until the
reaction is determined to be complete. The solvent is removed from
the reaction by evaporation and the residue is coevaped twice with
toluene. Compound 39 is purified from this residue by silica gel
column chromatography using a mixture of MeOH and DCM as the
eluent.
Compound 40:
1-((2R,3R,4R,5R)-3-chloro-5-((R)-1-fluoroethyl)-4-hydroxy-5-(hydroxymethy-
l)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0304] Compound 38 (1 mmol) is dissolved in acetone (10 mL). To
this solution is added HCO.sub.2NH.sub.4 (20 eq) and 10% Pd/C (2
g). The reaction is refluxed until the reaction is determined to be
complete. The reaction is cooled and the filtered. The filtrate is
concentrated and the residue is taken back up in DCM. This solution
is extracted with brine and dried over Na.sub.2SO.sub.4. The drying
agent is removed by filtration and the filtrate is concentrated.
The deprotected product is purified from this residue by silica gel
column chromatography using a mixture of MeOH and DCM as the
eluent.
##STR00045##
Compound 41:
1-((2R,3R,4R)-3-chloro-5,5-bis(hydroxymethyl)-4-((4-methoxyphenyl)dipheny-
lmethoxy)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0305] Compound 1 (1 mmol) is dissolved in DCM (10 mL). To this
solution is added AgNO.sub.3 (2 eq) and collidine (1 eq) and MMTrCl
(4 eq). The reaction stirred until the reaction is determined to be
complete. The reaction is filtered through celite, washing forward
with DCM. The filtrate is washed with 1M citric acid,
half-saturated brine and 5% NaHCO.sub.3. The organic phase is then
dried over Na.sub.2SO.sub.4. The drying agent is removed by
filtration and the filtrate is concentrated. The MMTr-protected
product is isolated from the residue by silica gel column
chromatography, eluting with a mixture of EtOAc and hexanes.
[0306] The MMTr-protected compound from above (1 mmol) is then
dissolved in MeOH (10 mL) and NaOMe (15 eq) is added. The reaction
is stirred until the reaction is determined to be complete. The
reaction is cooled to 0.degree. C. and quenched by the addition of
AcOH (15 eq) and the resulting mixture is concentrated. Compound 41
is purified from this residue by silica gel column chromatography
using a mixture of MeOH and DCM as the eluent.
Compound 42:
1-((2R,3R,4R,5R)-3-chloro-5-(hydroxymethyl)-4-((4-methoxyphenyl)diphenylm-
ethoxy)-5-((methylthio)methyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-d-
ione
[0307] Compound 41 is (1 mmol) dissolved in DCM (10 mL). To this
solution is added pyridine (10 mL) is added and the reaction is
cooled to -35.degree. C. Tf.sub.2O (2.1 eq) is added to the
reaction the reaction is stirred at -35.degree. C. until the
reaction is determined to be complete. The reaction is quenched by
the addition of water. The mixture is extracted with EtOAc and the
combined organic washes are dried over Na.sub.2SO.sub.4. The
filtering agent is removed by filtration and the filtrate is
concentrated. The bis-triflated product is isolated from the
residue by silica gel column chromatography, eluting with a mixture
of EtOAc and hexanes.
[0308] The bis-triflated product from above (1 mmol) is dissolved
in DMF (10 mL). This solution is cooled to 0.degree. C. and NaH
(1.1 eq) is added. The reaction is stirred until the reaction is
determined to be complete. To this mixture is added NaSMe (3 eq)
and 15-Crown-5 (0.1 eq). The reaction is stirred until the reaction
is determined to be complete. The reaction is diluted EtOAc and a
saturated aqueous solution of NH.sub.4Cl. The layers are separated
and the organic phase is extracted brine and dried over
Na.sub.2SO.sub.4. The filtering agent is removed by filtration and
the filtrate is concentrated. The anhydro product is isolated from
the residue by silica gel column chromatography, eluting with a
mixture of EtOAc and hexanes.
[0309] The anhydro product from above (1 mmol) is dissolved in THF
(10 mL). To this solution is added a 1N aqueous solution of NaOH
(1.1 eq). The reaction is stirred until the reaction is determined
to be complete. The reaction is diluted with EtOAc and a saturated
aqueous solution of NaHCO.sub.3. The layers are separated and the
organic phase is extracted with brine and dried over
Na.sub.2SO.sub.4. The drying agent is removed by filtration and the
filtrate is concentrated. Compound 42 is isolated from the residue
by silica gel column chromatography, eluting with a mixture of
EtOAc and hexanes.
Compound 43:
4-amino-1-((2R,3R,4R,5R)-3-chloro-4-hydroxy-5-(hydroxymethyl)-5-((methylt-
hio)methyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one
[0310] Compound 42 (1 mmol) is dissolved in DCM (10 mL). To this
solution is added AgNO.sub.3 (2 eq) and collidine (1 eq) and MMTrCl
(4 eq). The reaction stirred until the reaction is determined to be
complete. The reaction is filtered through celite, washing forward
with DCM. The filtrate is washed with 1M citric acid,
half-saturated brine and 5% NaHCO.sub.3. The organic phase is then
dried over Na.sub.2SO.sub.4. The drying agent is removed by
filtration and the filtrate is concentrated. The MMTr-protected
product is isolated from the residue by silica gel column
chromatography, eluting with a mixture of EtOAc and hexanes.
[0311] The MMTr-protected product from above (1 mmol) is dissolved
in ACN (10 mL) and then DMAP (2 eq), TPSCl (2 eq), and TEA (2 eq)
are added. The reaction is stirred at rt until the reaction is
determined to be complete. Concentrated aqueous NH.sub.4OH (15 mL)
is then added to the reaction and stirring is continued at rt until
the reaction is determined to be complete. The reaction is
concentrated and the product is isolated by silica gel column
chromatography, eluting with a mixture of EtOAc and hexanes.
[0312] The aminated product from above (1 mmol) is dissolved in an
80% aqueous solution of AcOH. The reaction is stirred until the
reaction is determined to be complete. The solvent is removed from
the reaction by evaporation and the residue is coevaped twice with
toluene. Compound 43 is purified from this residue by silica gel
column chromatography using a mixture of MeOH and DCM as the
eluent.
Compound 44:
1-((2R,3R,4R,5R)-3-chloro-4-hydroxy-5-(hydroxymethyl)-5-((methylthio)meth-
yl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0313] Compound 43 (1 mmol) is dissolved in an 80% aqueous solution
of AcOH. The reaction is stirred until the reaction is determined
to be complete. The solvent is removed from the reaction by
evaporation and the residue is coevaped twice with toluene.
Compound 44 is purified from this residue by silica gel column
chromatography using a mixture of MeOH and DCM as the eluent.
Nucleoside Triphosphates
##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050##
[0314] General Synthesis of Nucleoside Triphosphates
##STR00051##
[0315] General Procedure:
[0316] A nucleoside of the general formula GS-1 (1 mmol) is
dissolved in P(O)(OMe).sub.3 (10 mL) and cooled in an ice bath. To
this solution is added P(O)Cl.sub.3 (2 eq). The reaction is allowed
to stir in the ice bath until at least 50% conversion is determined
to have occurred. A solution of
[nBu.sub.3].sub.2P.sub.2O.sub.7H.sub.2 (10 eq) in ACN (10 mL) is
then added. The reaction is allowed to stir at 0.degree. C. until
the reaction is determined to have completed. The reaction is then
quenched by the addition of a 1M solution of triethylammonium
bicarbonate (5 mL). The reaction is concentrated and the residue is
semi-purified by ion exchange column chromatography. This
semi-purified material is further purified by reverse phase C18
column chromatography using 0.1% TEA as a modifier to yield the
nucleoside triphosphate of the general formula GS-2 as the
tetra-TEA salt.
General Synthesis of Acyclic Phosphoramidate Prodrugs
##STR00052##
[0317] General Procedure:
[0318] A nucleoside of the general formula GS-1 (1 mmol) is
dissolved in a 9:1 mixture of THF:NMP (10 mL). This solution is
cooled to -78.degree. C. and a 1M solution of tBuMgCl in THF (2 eq)
is added. This solution is stirred for 30 min at -78.degree. C. and
then at 00.degree. C. for 1 hr. To this solution is added a
solution of the para-nitrophenol phosphoramidate (1.1 eq) in THF (5
mL). The resulting reaction is allowed to stir until it is
determined to have completed. The reaction is quenched with a
saturated aqueous solution of NH.sub.4Cl and diluted with EtOAc.
The layers are separated and the organic phase is further extracted
with water and brine. The organic phase is dried over
Na.sub.2SO.sub.4, the drying agent is removed by vacuum filtration
and the filtrate is concentrated. Purification of this concentrate
by silica gel column chromatography yields the nucleoside prodrug
of the general formula GS-3.
General Synthesis of Acyclic Phosphate Prodrugs
##STR00053##
[0319] General Procedure:
[0320] A nucleoside of the general formula GS-1 (1 mmol) is
dissolved in a 9:1 mixture of THF:NMP (10 mL). This solution is
cooled to -78.degree. C. and a 1M solution of tBuMgCl in THF (2 eq)
is added. This solution is stirred for 30 min at -78.degree. C. and
then at 00.degree. C. for 1 hr. To this solution is added a
solution of the para-nitrophenol phosphate ester (1.1 eq) in THF (5
mL). The resulting reaction is allowed to stir until it is
determined to have completed. The reaction is quenched with a
saturated aqueous solution of NH.sub.4Cl and diluted with EtOAc.
The layers are separated and the organic phase is further extracted
with water and brine. The organic phase is dried over
Na.sub.2SO.sub.4, the drying agent is removed by vacuum filtration
and the filtrate is concentrated. Purification of this concentrate
by silica gel column chromatography yields the nucleoside prodrug
of the general formula GS-4.
General Synthesis of Cyclic Phosphoramidate Prodrugs
##STR00054##
[0321] General Procedure:
[0322] A nucleoside of the general formula GS-1 (1 mmol) is
dissolved in a 9:1 mixture of THF:NMP (10 mL). This solution is
cooled to -78.degree. C. and a 1M solution of tBuMgCl in THF (2 eq)
is added. This solution is stirred for 30 min at -78.degree. C. and
then at 0.degree. C. for 1 hr. To this solution is added a solution
of the chlorophosphoramidate (1.1 eq) in THF (5 mL). The resulting
reaction is allowed to stir until it is determined to have
completed. The reaction is quenched with a saturated aqueous
solution of NH.sub.4Cl and diluted with EtOAc. The layers are
separated and the organic phase is further extracted with water and
brine. The organic phase is dried over Na.sub.2SO.sub.4, the drying
agent is removed by vacuum filtration and the filtrate is
concentrated. Purification of this concentrate by silica gel column
chromatography yields the acyclic phosphoramidate intermediate.
[0323] The above acyclic phosphoramidate intermediate (1 mmol) is
dissolved in DMSO. To this solution is added tBuOK (1 eq). The
reaction is stirred until it is determined to be complete. The
reaction is cooled to 0.degree. C. and quenched by the addition of
1N HCl (1 eq of HCl). The resulting mixture is concentrated.
Purification of this concentrate by silica gel column
chromatography yields the nucleoside prodrug of the general formula
GS-5.
General Synthesis of Cyclic Phosphate Prodrugs
##STR00055##
[0324] General Procedure:
[0325] A nucleoside of the general formula GS-1 (1 mmol) is
dissolved in a 9:1 mixture of THF:NMP (10 mL). This solution is
cooled to -78.degree. C. and a 1M solution of tBuMgCl in THF (2 eq)
is added. This solution is stirred for 30 min at -78.degree. C. and
then at 00.degree. C. for 1 hr. To this solution is added a
solution of the bis para-nitrophenol phosphate ester (1.1 eq) in
THF (5 mL). The resulting reaction is allowed to stir until it is
determined to have completed. The reaction is quenched with a
saturated aqueous solution of NH.sub.4Cl and diluted with EtOAc.
The layers are separated and the organic phase is further extracted
with water and brine. The organic phase is dried over
Na.sub.2SO.sub.4, the drying agent is removed by vacuum filtration
and the filtrate is concentrated. Purification of this concentrate
by silica gel column chromatography yields the acyclic
para-nitrophenol phosphate ester intermediate.
[0326] The above acyclic para-nitrophenol phosphate ester
intermediate (1 mmol) is dissolved in DMSO. To this solution is
added tBuOK (1 eq). The reaction is stirred until it is determined
to be complete. The reaction is cooled to 0.degree. C. and quenched
by the addition of 1N HCl (1 eq of HCl). The resulting mixture is
concentrated. Purification of this concentrate by silica gel column
chromatography yields the nucleoside prodrug of the general formula
GS-5.
General Synthesis of Ester, Carbamate, Carbonate Prodrugs
(R.sup.2.dbd.NH.sub.2)
##STR00056##
General Procedure:
[0327] A nucleoside of the general formula GS-1 (1 mmol) is
dissolved in DMF (10 mL). To this solution is added
N',N'-dimethylformamide dimethyl acetal. The reaction is stirred
overnight. The reaction is concentrated and the resulting amidine
protected product is used as is in the next reaction.
[0328] To the above amidine protected product (1 mmol) is dissolved
in DCM (10 mL). To this solution is added DIPEA (2.2 eq). To this
solution is added either an acid chloride (2 eq), a chloroformate
(2 eq) or a carbamic chloride (2 eq), in order to access the
bis-ester, bis-carbonate, or the bis-carbamate, respectively. Once
the reaction is determined to have completed the reaction is
quenched by the addition of a saturated solution of NaHCO.sub.3.
The mixture is diluted with EtOAc and the layers are separated. The
organic layer is washed with water and brine and then dried over
Na.sub.2SO.sub.4. The drying agent is removed by filtration and the
filtrate is concentrated. The resulting crude product is taken on
into the next reaction.
[0329] The above described crude bis-ester, bis-carbonate, or
bis-carbamate (1 mmol) is dissolved in MeOH (10 mL). To this
solution is added hydrazine hydrate (10 eq). The reaction is
stirred until complete and the reaction is concentrated.
Purification of this concentrate by silica gel column
chromatography yields the nucleoside prodrug of the general formula
GS-7.
General Synthesis of Ester, Carbamate, Carbonate Prodrugs
(R.sup.2.dbd.OH)
##STR00057##
[0330] General Procedure:
[0331] A nucleoside of the general formula GS-1 (1 mmol) is
dissolved in DMF (10 mL). To this solution is added DBU (1.2 eq)
and BOMCl (1.1 eq). The reaction is stirred until complete. The
reaction is quenched by the addition of MeOH and resulting mixture
is concentrated. Purification of this concentrate by silica gel
column chromatography yields the BOM-protected nucleoside.
[0332] The above described BOM-protected nucleoside (1 mmol) is
dissolved in DCM (10 mL). To this solution is added DIPEA (2.2 eq).
To this solution is added either an acid chloride (2 eq), a
chloroformate (2 eq) or a carbamic chloride (2 eq), in order to
access the bis-ester, bis-carbonate, or the bis-carbamate,
respectively. Once the reaction is determined to have completed the
reaction is quenched by the addition of a saturated solution of
NaHCO.sub.3. The mixture is diluted with EtOAc and the layers are
separated. The organic layer is washed with water and brine and
then dried over Na.sub.2SO.sub.4. The drying agent is removed by
filtration and the filtrate is concentrated. Purification of this
concentrate by silica gel column chromatography yields the
BOM-protected bis-ester, bis-carbonate or bis-carbamate.
[0333] The above described BOM-protected bis-ester, bis-carbonate
or bis-carbamate (1 mmol) is dissolved in EtOH (10 mL). To this
solution is added 10% Pd(OH).sub.2/C. The atmosphere of the
reaction vessel is exchanged for H2 and the reaction is stirred
until it is complete. The reaction is filtered through Celite and
the filtrate is concentrated. Purification of this concentrate by
silica gel column chromatography yields the nucleoside prodrug of
the general formula GS-8.
Synthesis of Examples 1 and 2
##STR00058##
[0334] Intermediate
2-((3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-4-chloro-5-(2,4-dioxo-3,4--
dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2,2-diyl)bis(methylene)
dibenzoate
[0335] Intermediate 1 (Collect. Czech. Chem. Commun. 1997, 62, pp.
957-970) (590 mg, 1.18 mmol) was dissolved in anhydrous
N,N-dimethylformamide (5 mL). tert-Butyldimethylsilyl chloride (889
mg, 5.9 mmol) and imidazole (804 mg, 11.8 mmol) were added to the
reaction which was then stirred at 50.degree. C. for 16 hrs. HPLC
showed .about.16% conversion. The reaction was warmed to 65.degree.
C. and stirred for 3 hrs. HPLC showed .about.17% conversion. The
reaction was warmed to 80.degree. C. and stirred for 2 hrs. HPLC
showed .about.42% conversion. More tert-butyldimethylsilyl chloride
(889 mg, 5.9 mmol) and imidazole (804 mg, 11.8 mmol) were added.
The reaction was stirred at 80.degree. C. for 48 hrs.
[0336] HPLC showed .about.89% conversion. The reaction was cooled
to room temperature and diluted with ethyl acetate (40 mL). The
mixture was washed with saturated aqueous sodium bicarbonate
solution (20 mL) and then brine (20 mL). The organic was dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The crude residue was purified via SiO.sub.2 column chromatography
(40 g SiO.sub.2 Combiflash HP Gold Column 0-40% ethyl
acetate/hexanes) to yield a mixture of Intermediates 2 and 3 (655
mg mixture of isomers, 90%).
[0337] .sup.1H NMR (400 MHz, CDCl.sub.3) b 8.17-7.96 (m, 5H),
7.69-7.34 (m, 6H), 6.42-6.34 (m, 1H), 6.01 (m, 1H), 5.65 (m, 1H),
5.00 (dd, J=12.8 Hz, 1H), 4.85-4.71 (m, 2H), 4.65-4.47 (m, 3H),
4.05-3.97 (m, 1H), 3.90-3.80 (m, 1H), 0.97 (s, 9H), 0.78 (s, 9H),
0.19 (s, 3H), 0.13 (s, 3H), -0.01 (s, 3H), -0.15 (s, 3H).
[0338] MS m/z=614.9 [M+1]
##STR00059##
Intermediate
4-1-((2R,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-chloro-5,5-bis(hydroxy-
methyl) tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
[0339] A mixture of Intermediates 2 and 3 (655 mg, 1.06 mmol) was
dissolved in methanol (10 mL). Potassium carbonate (352 mg, 2.13
mmol) was added to the reaction and stirred for 12 hrs.
[0340] The reaction mixture was diluted with ethyl acetate (50 mL)
and washed with saturated aqueous sodium bicarbonate solution (20
mL) and then brine (20 mL). The organic was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The crude
residue was purified via SiO.sub.2 column chromatography (40 g
SiO.sub.2 Combiflash HP Gold Column 0-65-90% ethyl acetate/hexanes)
to afford Intermediates 4 and 5 (200 mg of Intermediate 4 (lower
spot) and 135 mg of Intermediate 5 (top spot), 78%).
Intermediate 4
[0341] .sup.1H NMR (400 MHz, CDCl.sub.3) b 8.32 (s, 1H), 7.33 (d,
J=8.1 Hz, 1H), 5.77 (dd, J=8.1, 2.3 Hz, 1H), 5.71 (d, J=7.4 Hz,
1H), 4.92 (dd, J=7.4, 6.5 Hz, 1H), 4.68 (d, J=6.5 Hz, 1H), 3.85
(ddd, J=29.3, 12.1, 2.7 Hz, 2H), 3.62 (ddd, J=12.3, 9.0, 5.6 Hz,
2H), 3.01 (dd, J=8.7, 3.0 Hz, 1H), 2.35 (dd, J=9.8, 3.8 Hz, 1H),
0.96 (s, 9H), 0.20 (s, 3H), 0.16 (s, 3H).
[0342] MS m/z=406.9 [M+1], 405.1 [M-1]
##STR00060##
Intermediate
6-1-((2R,3R,4R,5S)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((te-
rt-butyldimethylsilyl)oxy)-3-chloro-5-(hydroxymethyl)tetrahydrofuran-2-yl)-
pyrimidine-2,4(1H,3H)-dione
[0343] Intermediate 4 (120 mg, 0.29 mmol) was dissolved in
anhydrous dichloromethane (5 mL). Anhydrous pyridine (1 mL) was
added to the reaction which was then cooled in an ice bath and
stirred under atmosphere nitrogen. 4,4'-Dimethoxytrityl chloride
(120 mg, 0.35 mmol) was added to the reaction in one portion.
Reaction was stirred for 2 hrs. More 4,4'-dimethoxytrityl chloride
(120 mg, 0.35 mmol) was added and stirred for 2 hrs. Methanol (2
mL) was added to stop the reaction which was then concentrated
under reduced pressure. Residue was dissolved with ethyl acetate
(40 mL) and washed with saturated aqueous sodium bicarbonate
solution (20 mL) and then brine (20 mL). The organic was dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The crude was purified via SiO.sub.2 column chromatography (4 g
SiO.sub.2 Combiflash HP Gold Column 0-40% ethyl acetate/hexanes) to
afford Intermediate 6 (190 mg, 92%).
[0344] .sup.1H NMR (400 MHz, DMSO-d) b 11.49 (s, 1H), 7.86 (d,
J=8.2 Hz, 1H), 7.41-7.34 (m, 2H), 7.31-7.15 (m, 7H), 6.85 (dd,
J=9.0, 2.2 Hz, 4H), 6.04 (d, J=8.1 Hz, 1H), 5.77 (d, J=8.1 Hz, 1H),
5.29 (m, 1H), 4.72 (dd, J=8.1, 5.4 Hz, 1H), 4.42 (d, J=5.4 Hz, 1H),
3.88 (dd, J=11.5, 4.8 Hz, 1H), 3.71 (s, 6H), 3.52 (dd, J=11.4, 5.4
Hz, 1H), 3.44 (d, J=10.6 Hz, 1H), 2.83 (d, J=10.6 Hz, 1H), 0.68 (s,
9H), -0.01 (s, 3H), -0.29 (s, 3H).
[0345] MS m/z=707.4 [M-1], 731.2 [M+Na]
##STR00061##
Intermediate
7-1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldiphen-
ylsilyl)oxy)methyl)-3-chloro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimid-
ine-2,4(1H,3H)-dione
[0346] Intermediate 6 (180 mg, 0.254 mmol) was dissolved in
anhydrous N,N-dimethylformamide (5 mL). Imidazole (138 mg, 2.03
mmol) and tert-butyldiphenylsilyl chloride (260 uL, 1.02 mmol) were
added. Reaction was stirred at 50.degree. C. for 16 hrs.
[0347] More imidazole (140 mg, 2.03 mmol) and
tert-butyldiphenylsilyl chloride (260 uL, 1.02 mmol) were added.
Reaction was stirred at 50.degree. C. for 8 hrs. More imidazole
(140 mg, 2.03 mmol) and tert-butyldiphenylsilyl chloride (260 uL,
1.02 mmol) were added. Reaction was stirred at 50.degree. C. for 16
hrs.
[0348] HPLC showed .about.94% conversion. Reaction was cooled to
room temperature, diluted with ethyl acetate (40 mL) and washed
with brine (20 mL) three times. The organic was dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The crude was purified via SiO.sub.2 column chromatography (4 g
SiO.sub.2 Combiflash HP Gold Column 0-20-50% ethyl acetate/hexanes)
to afford title compound (205 mg, 85%) as colorless oil.
[0349] Material was dissolved in 80% v/v acetic acid aqueous
solution (10 mL) and stirred for 4 hrs. Reaction was diluted with
ethyl acetate (40 mL) and washed with brine (20 mL) three times.
Organic was then washed with saturated aqueous sodium bicarbonate
solution (20 mL) twice to give pH of 8. The organic was dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The crude was purified via SiO.sub.2 column chromatography (4 g
SiO.sub.2 Combiflash HP Gold Column 0-35% ethyl acetate/hexanes) to
afford Intermediate 7 (106 mg, 59% over 2 steps).
[0350] .sup.1H NMR (400 MHz, CDCl.sub.3) b 8.79 (s, 1H), 7.68-7.57
(m, 4H), 7.54-7.37 (m, 6H), 6.23 (d, J=7.9 Hz, 1H), 5.54-5.45 (m,
1H), 4.49-4.41 (m, 1H), 4.37 (dd, J=7.9, 5.8 Hz, 1H), 3.96 (d,
J=11.4 Hz, 1H), 3.86 (d, J=12.3 Hz, 1H), 3.74 (d, J=11.4 Hz, 1H),
3.56 (d, J=12.3 Hz, 1H), 1.11 (s, 9H), 0.93 (s, 9H), 0.16 (s, 3H),
0.03 (s, 3H).
[0351] MS m/z=643.5 [M-1], 667.4 [M+Na]
##STR00062##
Intermediate
8-1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldiphen-
ylsilyl)oxy)methyl)-3-chloro-5-(chloromethyl)tetrahydrofuran-2-yl)pyrimidi-
ne-2,4(1H,3H)-dione
[0352] Intermediate 7 (104 mg, 0.164 mmol) was dissolved in
1,2-dichloroethane (2 mL) and stirred under argon gas. Carbon
tetrachloride (32 uL, 0.328 mmol) and triphenylphosphine (86 mg,
0.328 mmol) were added to reaction which was then microwaved at
130.degree. C. for 40 mins. The reaction was concentrated under
reduced pressure. The crude was purified via SiO.sub.2 column
chromatography (4 g SiO.sub.2 Combiflash HP Gold Column 0-20% ethyl
acetate/hexanes) to afford Intermediate 8 (76 mg, 70%).
[0353] .sup.1H NMR (400 MHz, CDCl.sub.3) b 8.45 (d, J=2.4 Hz, 1H),
7.72-7.57 (m, 4H), 7.54-7.34 (m, 7H), 6.15 (d, J=7.6 Hz, 1H), 5.54
(dd, J=8.2, 2.2 Hz, 1H), 4.45-4.34 (m, 2H), 4.00 (d, J=11.2 Hz,
1H), 3.91-3.76 (m, 2H), 3.58 (d, J=12.1 Hz, 1H), 1.12 (s, 9H), 0.94
(s, 9H), 0.16 (s, 3H), 0.04 (s, 3H).
[0354] MS m/z=661.5 [M-1]
##STR00063##
Intermediate
9-4-amino-1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-but-
yldiphenyl
silyl)oxy)methyl)-3-chloro-5-(chloromethyl)tetrahydrofuran-2-yl-
)pyrimidin-2(1H)-one
[0355] Intermediate 8 (74 mg, 0.111 mmol) was dissolved in
anhydrous acetonitrile (5 mL). Triethylamine (31 uL, 0.223 mmol)
and 2,4,6-triisopropylbenzenesulfonyl chloride (68 mg, 0.223 mmol)
were added to the reaction. 4-(Dimethylamino)pyridine (27 mg, 0.223
mmol) was added to the reaction and stirred at room temperature for
16 hrs. 0.5M ammonia in 1,4-dioxane (5 mL) was added to the
reaction and stirred for 2 hrs.
[0356] The mixture was concentrated under reduced pressure. The
residue was dissolved in ethyl acetate (40 mL) and washed with
saturated aqueous sodium bicarbonate solution (10 mL) and brine (10
mL). The organic was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The crude was purified via
SiO.sub.2 column chromatography (4 g SiO.sub.2 Combiflash HP Gold
Column 0-80% ethyl acetate/hexanes) to afford Intermediate 9 (57
mg, 78%).
[0357] MS m/z=662.0 [M+1]
##STR00064##
Example
1-4-amino-1-((2R,3R,4R,5R)-3-chloro-5-(chloromethyl)-4-hydroxy-5--
(hydroxymethyl) tetrahydrofuran-2-yl)pyrimidin-2(1H)-one
[0358] Intermediate 9 (50 mg, 0.075 mmol) was dissolved in
anhydrous tetrahydrofuran (5 mL). Tetrabutylammonium fluoride
trihydrate (119 mg, 0.377 mmol) was added, and the reaction was
stirred at room temperature for 30 mins. HPLC showed reaction was
completed. Trifluoroacetic acid (29 uL, 0.377 mmol) was added to
give slightly acidic solution. The mixture was concentrated under
reduced pressure and purified with prep HPLC (Phenomenex Gemini C18
column, 0-100% acetonitrile/water). Fractions were combined and
concentrated under reduced pressure. Material was re-purified with
prep-HPLC (Phenomenex Gemini C18 column, 0-50% acetonitrile/water
with 0.1% trifluoroacetic acid as modifier). Fractions were
combined and concentrated under reduced pressure. Material was
dissolved in water (1 mL) and small amount of saturated aqueous
sodium bicarbonate solution was then added to give pH of 8.
Solution was loaded onto a pre-packed C18 column equilibrated with
water. Column was washed with water (5 column volumes) and then
eluted with 70% acetonitrile in water. Fractions were combined and
freeze-dried to afford Example 1 (9.4 mg, 40%).
[0359] .sup.1H NMR (400 MHz, D.sub.2O) .delta. 7.61 (d, J=7.7 Hz,
1H), 6.11 (d, J=8.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H), 4.72 (dd,
J=8.7, 5.3 Hz, 1H), 4.39 (d, J=5.2 Hz, 1H), 3.86-3.66 (m, 4H).
[0360] MS m/z=309.8 [M+1]
##STR00065##
Example
2-((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-chloro-2-(-
chloromethyl)-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate
[0361] To a solution of Example 1 (4.08 mg, 0.013 mmol) and
NaHCO.sub.3 (7 mg, 0.083 mmol) in PO(OMe).sub.3 (0.3 mL) at
0.degree. C. was added POCOl.sub.3 (31 mg, 0.202 mmol). The
reaction mixture was stirred at 0.degree. C. for 4 h, at which
point ion-exchange HPLC showed approximately 80% conversion. A
solution of pyrophosphate tributylamine salts (250 mg) in
CH.sub.3CN (0.5 mL) was added, followed by tributylamine (125 mg,
0.67 mmol). The reaction mixture was stirred at 0.degree. C. for
0.5 h, and ion-exchange HPLC showed the reaction was completed. The
reaction was quenched with triethylammonium bicarbonate buffer (1
M, 8 mL). The reaction mixture was stirred at RT for 0.5 h, then
concentrated and co-evaporated with water twice. The residue was
dissolved in H.sub.2O (5 mL) and loaded to a ion-exchange column,
eluted with H.sub.2O, then 5-35% triethylammonium bicarbonate
buffer (1M)-H.sub.2O. The product fractions were combined,
concentrated and co-evaporated with H.sub.2O to give about 28 mg of
material. The material was dissolved in 2 mL of H.sub.2O and
treated with NaHCO.sub.3 (40 mg). The resulting mixture was
purified with C-18 column, eluted with H.sub.2O, and the fractions
containing product were combined and concentrated under reduced
pressure to afford Example 2 as the tetra-sodium salt (3.0 mg,
35.7%).
[0362] .sup.1H NMR (400 MHz, D.sub.2O): .delta. 7.77 (d, J=7.6 Hz,
1H), 6.24 (d, J=6.8 Hz, 1H), 6.07 (d, J=7.6 Hz, 1H), 4.6-4.7 (m,
2H), 4.1-4.25 (m, 2H), 3.89 (d, J=12.8 Hz, 1H), 3.79 (d, J=12.0 Hz,
1H).
[0363] .sup.31P NMR (400 MHz, D.sub.2O): .delta.-8.10 (d, J=50.8
Hz), -13.76 (d, J=46 Hz), -23.97 (t, J=49.4 Hz).
[0364] MS m/z=548.4 [M-1], 549.9 [M+1]
Methods for Determining EC.sub.50's for the Inhibition of RSV in
Cells and IC.sub.50's for the Inhibition of RSV Viral
Polymerase
[0365] The following assays could be used to determine the
EC.sub.50 of the described nucleosides for the inhibition of RSV in
cell culture and to determine the IC50 of the described nucleoside
triphosphates for the inhibition of the RSV viral polymerase.
RSV Pol IC.sub.50 Determination
[0366] Transcription reactions contained 5 .mu.g of crude RSV RNP
complexes in 30 .mu.L of reaction buffer [50 mM TRIS-acetate (pH
8.0), 120 mM potassium acetate, 5% glycerol, 4.5 mM MgCl.sub.2, 3
mM DTT, 2 mM ethyleneglycol-bis(2-aminoethylether)-tetraacetic acid
(EGTA), 50 .mu.g/mL BSA, 2.5 U RNasin (Promega), ATP, GTP, UTP, CTP
and 1.5 uCi [.alpha.-.sup.32P] NTP (3000 Ci/mmol)]. The radiolabled
nucleotide used in the transcription assay was selected to match
the nucleotide analog being evaluated for inhibition of RSV RNP
transcription. Cold, competitive NTP was added at a final
concentration of one-half its K.sub.m (ATP=20 .mu.M, GTP=12.5
.mu.M, UTP=6 .mu.M and CTP=2 .mu.M). The three remaining
nucleotides were added at a final concentration of 100 .mu.M.
[0367] To determine whether nucleotide analogs inhibited RSV RNP
transcription, compounds were added using a 6 step serial dilution
in 5-fold increments. Following a 90 minute incubation at
30.degree. C., the RNP reactions were stopped with 350 .mu.L of
Qiagen RLT lysis buffer and the RNA was purified using a Qiagen
RNeasy 96 kit. Purified RNA was denatured in RNA sample loading
buffer (Sigma) at 65.degree. C. for 10 minutes and run on a 1.2%
agarose/MOPS gel containing 2M formaldehyde. The agarose gel was
dried and exposed to a Storm phosphorimager screen and developed
using a Storm phosphorimager (GE Healthcare). The concentration of
compound that reduced total radiolabled transcripts by 50%
(IC.sub.50) was calculated by non-linear regression analysis of two
replicates.
RSV Cell Culture EC.sub.50 Determination
[0368] Antiviral activity against RSV is determined using an
infectious cytopathic cell protection assay in HEp-2 cells. In this
assay, compounds inhibiting viral infection and/or replication
produce a cytoprotective effect against the virus-induced cell
killing that can be quantified using a cell viability reagent. The
techniques used here are novel adaptations of methods described in
published literature (Chapman et al., Antimicrob Agents Chemother.
2007, 51(9):3346-53.)
[0369] HEp-2 cells are obtained from ATCC (Manassas, Vir.) and
maintained in MEM media supplemented with 10% fetal bovine serum
and penicillin/streptomycin. Cells are passaged twice a week and
kept at subconfluent stage. Commercial stock of RSV strain A2
(Advanced Biotechnologies, Columbia, Md.) is titered before
compound testing to determine the appropriate dilution of the virus
stock that generates desirable cytopathic effect in HEp-2
cells.
[0370] For antiviral tests, HEp-2 cells are grown in large cell
culture flasks to near confluency but not fully so. The compounds
to be tested are prediluted in DMSO in 384-well compound dilution
plates, either in an 8 or 40 sample per plate standardized dose
response format. 3-fold serial dilution increments of each test
compound are prepared in the plates and test samples are
transferred via acoustic transfer apparatus (Echo, Labcyte) at 100
nl per well into cell culture assay 384-well plates. Each compound
dilution is transferred in single or quadruplicate samples into dry
assay plates, which are stored until assay is ready to go. The
positive and negative controls are laid out in opposite on ends of
the plate in vertical blocks (1 column).
[0371] Subsequently, an infectious mixture is prepared using an
appropriate dilution of virus stock previously determined by
titration with cells at a density of 50,000/ml and 20 uL/well is
added to test plates w/compounds via automation (uFlow, Biotek).
Each plate includes negative and positive controls (16 replicates
each) to create 0% and 100% virus inhibition standards,
respectively. Following the infection with RSV, testing plates are
incubated for 4 days in a 37.degree. C. cell culture incubator.
After the incubation, a cell viability reagent, Cell TiterGlo
(Promega, Madison, Wis.) is added to the assay plates, which are
incubated briefly, and a luminescent readout is measured (Envision,
Perkin Elmer) in all the assay plates. The RSV-induced cytopathic
effect, percentage inhibition, is determined from the levels of
remaining cell viability. These numbers are calculated for each
tested concentration relative to the 0% and 100% inhibition
controls, and the EC.sub.50 value for each compound is determined
by non-linear regression as a concentration inhibiting the
RSV-induced cytopathic effect by 50%. Various potent anti-RSV tool
compounds are used as positive controls for antiviral activity.
[0372] The EC.sub.50 for Example 1 is >50 .mu.M
* * * * *
References