U.S. patent application number 15/000821 was filed with the patent office on 2016-08-18 for pyrazolo[1,5-a]pyrimidines as antiviral agents.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Constantine G. Boojamra, Hon Chung Hui, Petr Jansa, Richard L. Mackman, Jay P. Parrish, Michael Sangi, Dustin Siegel, David Sperandio, Hai Yang.
Application Number | 20160235748 15/000821 |
Document ID | / |
Family ID | 47557523 |
Filed Date | 2016-08-18 |
United States Patent
Application |
20160235748 |
Kind Code |
A1 |
Boojamra; Constantine G. ;
et al. |
August 18, 2016 |
PYRAZOLO[1,5-A]PYRIMIDINES AS ANTIVIRAL AGENTS
Abstract
The invention provides compounds and pharmaceutically acceptable
salts and esters and compositions thereof, for treating viral
infections. The compounds and compositions are useful for treating
Pneumovirinae virus infection including Human respiratory syncytial
virus infections.
Inventors: |
Boojamra; Constantine G.;
(San Francisco, CA) ; Hui; Hon Chung; (Foster
City, CA) ; Jansa; Petr; (San Mateo, CA) ;
Mackman; Richard L.; (Millbrae, CA) ; Parrish; Jay
P.; (El Dorado Hills, CA) ; Sangi; Michael;
(San Mateo, CA) ; Siegel; Dustin; (San Carlos,
CA) ; Sperandio; David; (Palo Alto, CA) ;
Yang; Hai; (San Mateo, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
47557523 |
Appl. No.: |
15/000821 |
Filed: |
January 19, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14566340 |
Dec 10, 2014 |
9278975 |
|
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15000821 |
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13722962 |
Dec 20, 2012 |
8946238 |
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14566340 |
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61618510 |
Mar 30, 2012 |
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61579625 |
Dec 22, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 519/00 20130101;
A61P 11/00 20180101; A61P 31/12 20180101; A61K 31/519 20130101;
A61K 45/06 20130101; A61K 31/675 20130101; A61K 31/5377 20130101;
A61K 31/538 20130101; C07F 9/6561 20130101; C07D 487/08 20130101;
A61K 31/5025 20130101; C07D 487/04 20130101 |
International
Class: |
A61K 31/5025 20060101
A61K031/5025; C07D 487/04 20060101 C07D487/04; A61K 31/5377
20060101 A61K031/5377; C07F 9/6561 20060101 C07F009/6561; A61K
31/675 20060101 A61K031/675; A61K 45/06 20060101 A61K045/06; C07D
519/00 20060101 C07D519/00 |
Claims
1. A compound of formula I: ##STR00360## or a salt or ester,
thereof; wherein: A is --(C(R.sup.4).sub.2).sub.n-- wherein any one
C(R.sup.4).sub.2 of said --(C(R.sup.4).sub.2).sub.n-- may be
optionally replaced with --O--, --S--, --S(O).sub.p--, NH or
NR.sup.a; n is 3, 4, 5 or 6; each p is 1 or 2; Ar is a
C.sub.2-C.sub.20 heterocyclyl group or a C.sub.6-C.sub.20 aryl
group, wherein the C.sub.2-C.sub.20 heterocyclyl group or the
C.sub.6-C.sub.20 aryl group is optionally substituted with 1, 2, 3,
4 or 5 R.sup.6; each R.sup.3, R.sup.4 or R.sup.6 is independently
H, oxo, OR.sup.11, NR.sup.11R.sup.12, NR.sup.11C(O)R.sup.11,
NR.sup.aC(O)OR.sup.11, NR.sup.11C(O)NR.sup.11R.sup.12, N.sub.3, CN,
NO.sub.2, SR.sup.11, S(O).sub.pR.sup.a, NR.sup.11S(O).sub.pR.sup.a,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11,
--C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)SR.sup.11,
--S(O).sub.p(OR.sup.11), --SO.sub.2NR.sup.11R.sup.12,
--NR.sup.11S(O).sub.p(OR.sup.11),
--NR.sup.11SO.sub.pNR.sup.11R.sup.12,
NR.sup.aC(.dbd.NR.sup.11)NR.sup.11R.sup.12, halogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl;
or two R.sup.4 on adjacent carbon atoms, when taken together, may
optionally form a double bond between the two carbons to which they
are attached or may form a (C.sub.3-C.sub.7)cycloalkyl ring wherein
one carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be
optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or
--NR.sup.a--; or four R.sup.4 on adjacent carbon atoms, when taken
together, may optionally form an optionally substituted C.sub.6
aryl ring; or two R.sup.4 on the same carbon atom, when taken
together, may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring
wherein one carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring
may be optionally replaced by --O--, --S--, --S(O).sub.p--, --NH--
or --NR.sup.a--; or two R.sup.6 on adjacent carbon atoms, when
taken together, may optionally form a (C.sub.3-C.sub.7)cycloalkyl
ring wherein one carbon atom of said (C.sub.3-C.sub.7)cycloalkyl
ring may be optionally replaced by --O--, --S--, --S(O).sub.p--,
--NH-- or --NR.sup.a--; each R.sup.a is independently
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl wherein any
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)alkenyl or (C.sub.2-C.sub.8)alkynyl of R.sup.a is
optionally substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl, and wherein any
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of R.sup.a is optionally
substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl or (C.sub.1-C.sub.8)alkyl; each
R.sup.11 or R.sup.12 is independently H, (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.4-C.sub.8)carbocyclylalkyl, --C(.dbd.O)R.sup.a,
--S(O).sub.pR.sup.a or aryl(C.sub.1-C.sub.8)alkyl; or R.sup.11 and
R.sup.12 taken together with a nitrogen to which they are both
attached form a 3 to 7 membered heterocyclic ring wherein any one
carbon atom of said heterocyclic ring can optionally be replaced
with --O--, --S--, --S(O).sub.p--, --NH--, --NR.sup.a-- or
--C(O)--; and wherein each (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of each R.sup.6, R.sup.11 or
R.sup.12 is, independently, optionally substituted with one or more
oxo, halogen, hydroxy, NH.sub.2, CN, N.sub.3, N(R.sup.a).sub.2,
NHR.sup.a, SH, SR.sup.a, S(O).sub.pR.sup.a, OR.sup.a,
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a,
--C(O)H, --C(.dbd.O)OR.sup.a, --C(.dbd.O)OH,
--C(.dbd.O)N(R.sup.a).sub.2, --C(.dbd.O)NHR.sup.a,
--C(.dbd.O)NH.sub.2, NHS(O)R.sup.a, NR.sup.aS(O).sub.pR.sup.a,
NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a, NHC(O)OR.sup.a,
NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a; provided the compound is not: ##STR00361##
2. The compound of claim 1 wherein each R.sup.3 is H.
3. The compound of claim 1 wherein n is 3.
4. The compound of claim 1 wherein each R.sup.4 is H.
5. The compound of claim 1 wherein A is --(CH.sub.2).sub.3--.
6. The compound of claim 1 wherein the compound of formula I is a
compound of formula Ia: ##STR00362## or a salt or ester,
thereof.
7. The compound of claim 1 wherein Ar is phenyl, pyridyl,
1,2,3,4-tetrahydronaphthyl, indazolyl, 1,6-naphthyridyl,
2,3,-dihydroindanyl, quinolyl, indolyl, 4H-benzo][d][1,3]dioxanyl,
pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,
1,2,3,4-tetrahydroquinolyl, benzo[d][1,3]dioxolyl, quinoxalyl,
isoquinolyl, naphthyl, thiophenyl, pyrazolyl,
4,5,6,7-tetrahydrobenzothiophenyl or pyrazolo[3,4,b]pyridinyl,
wherein any phenyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, indazolyl,
1,6-naphthyridyl, 2,3,-dihydroindanyl, quinolyl, indolyl,
4H-benzo][d][1,3]dioxanyl, pyrazolo[1,5-a]pyridinyl,
imidazo[1,2-a]pyridinyl, 1,2,3,4-tetrahydroquinolyl,
benzo[d][1,3]dioxolyl, quinoxalyl, isoquinolyl, naphthyl,
thiophenyl, pyrazolyl, 4,5,6,7-tetrahydrobenzothiophenyl or
pyrazolo[3,4,b]pyridinyl of Ar is optionally substituted with 1 to
5 R.sup.6.
8. The compound of claim 1 wherein each R.sup.6 is independently
OR.sup.11, CN, S(O).sub.pR.sup.a, halogen, (C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.4-C.sub.8)carbocyclylalkyl,
NR.sup.11C(O)R.sup.11 or NR.sup.11S(O).sub.pR.sup.a, wherein any
(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of R.sup.6 is optionally
substituted with one or more oxo, halogen, hydroxy, NH.sub.2, CN,
N.sub.3, N(R.sup.a).sub.2, NHR.sup.a, SH, SR.sup.a,
S(O).sub.pR.sup.a, OR.sup.a, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2,
--C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a.
9. The compound of claim 1 wherein each R.sup.6 is independently
OR.sup.11, CN, S(O).sub.pR.sup.a, halogen, (C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl,
wherein any (C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl,
C.sub.2-C.sub.20 heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of R.sup.6 is optionally
substituted with one or more oxo, halogen, hydroxy, NH.sub.2, CN,
N.sub.3, N(R.sup.a).sub.2, NHR.sup.a, SH, SR.sup.a,
S(O).sub.pR.sup.a, OR.sup.a, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2,
--C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a.
10. The compound of claim 1 selected from: ##STR00363##
##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368##
##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373##
##STR00374## ##STR00375## ##STR00376## and salts and esters,
thereof.
11. The compound of claim 1 selected from: ##STR00377##
##STR00378## ##STR00379## and salts and esters, thereof.
12. A compound of formula: ##STR00380## wherein W is: ##STR00381##
##STR00382## or a salt, or stereoisomer thereof.
13. The compound of claim 12 selected from: ##STR00383##
##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388##
##STR00389## and salts thereof.
14. A compound of formula: ##STR00390## wherein Y is: ##STR00391##
##STR00392## ##STR00393## ##STR00394## ##STR00395## or a salt, or
stereoisomer thereof.
15. The compound of claim 14 selected from: ##STR00396##
##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401##
##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406##
##STR00407## ##STR00408## ##STR00409## ##STR00410## and salts
thereof.
16. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt or ester thereof and a pharmaceutically acceptable
carrier.
17. The pharmaceutical composition of claim 16 further comprising a
therapeutic agent selected from ribavirin, palivizumab,
motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771,
ALN-RSV0 and ALX-0171 and mixtures thereof.
18. A method of treating a Pneumovirinae virus infection in a
mammal in need thereof comprising administering to the mammal a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt or ester thereof.
19. The method of claim 18 wherein the Pneumovirinae virus
infection is caused by a respiratory syncytial virus.
20. The method of claim 18 further comprising administering a
therapeutically effective amount of a therapeutic agent or
composition thereof selected from the group consisting of
ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444,
MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures
thereof.
21. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 12, or a pharmaceutically
acceptable salt or ester thereof and a pharmaceutically acceptable
carrier.
22. The pharmaceutical composition of claim 21 further comprising a
therapeutic agent selected from ribavirin, palivizumab,
motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771,
ALN-RSV0 and ALX-0171 and mixtures thereof.
23. A method of treating a Pneumovirinae virus infection in a
mammal in need thereof comprising administering to the mammal a
therapeutically effective amount of a compound of claim 12, or a
pharmaceutically acceptable salt or ester thereof.
24. The method of claim 23 wherein the Pneumovirinae virus
infection is caused by a respiratory syncytial virus.
25. The method of claim 24 further comprising administering a
therapeutically effective amount of a therapeutic agent or
composition thereof selected from the group consisting of
ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444,
MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures
thereof.
26. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 14, or a pharmaceutically
acceptable salt or ester thereof and a pharmaceutically acceptable
carrier.
27. The pharmaceutical composition of claim 26 further comprising a
therapeutic agent selected from ribavirin, palivizumab,
motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771,
ALN-RSV0 and ALX-0171 and mixtures thereof.
28. A method of treating a Pneumovirinae virus infection in a
mammal in need thereof comprising administering to the mammal a
therapeutically effective amount of a compound of claim 14, or a
pharmaceutically acceptable salt or ester thereof.
29. The method of claim 23 wherein the Pneumovirinae virus
infection is caused by a respiratory syncytial virus.
30. The method of claim 24 further comprising administering a
therapeutically effective amount of a therapeutic agent or
composition thereof selected from the group consisting of
ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444,
MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/722,962, filed Dec. 20, 2012, which claims the benefit
under 35 U.S.C. .sctn.119(e) of U.S. Provisional Application No.
61/579,625, filed Dec. 22, 2011, and U.S. Provisional Application
No. 61/618,510, filed Mar. 30, 2012. The foregoing applications are
incorporated herein by reference in their entireties.
BACKGROUND
[0002] 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.
SUMMARY
[0003] Provided herein are methods and compounds for the treatment
of infections caused by the Pneumovirinae virus family.
[0004] Accordingly, one embodiment provides a compound of formula
I:
##STR00001##
[0005] or a salt or ester, thereof;
wherein:
[0006] A is --(C(R.sup.4).sub.2).sub.n-- wherein any one
C(R.sup.4).sub.2 of said --(C(R.sup.4).sub.2).sub.n-- may be
optionally replaced with --O--, --S--, --S(O).sub.p--, NH or
NR.sup.a;
[0007] n is 3, 4, 5 or 6;
[0008] each p is 1 or 2;
[0009] Ar is a C.sub.2-C.sub.20 heterocyclyl group or a
C.sub.6-C.sub.20 aryl group, wherein the C.sub.2-C.sub.20
heterocyclyl group or the C.sub.6-C.sub.20 aryl group is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.6;
[0010] each R.sup.3, R.sup.4 and R.sup.6 is independently H, oxo,
OR.sup.11, NR.sup.11R.sup.12, NR.sup.11C(O)R.sup.11,
NR.sup.11C(O)OR.sup.11, NR.sup.11C(O)NR.sup.11R.sup.12, N.sub.3,
CN, NO.sub.2, SR.sup.11, S(O).sub.pR.sup.a,
NR.sup.11S(O).sub.pR.sup.a, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)SR.sup.11, --S(O).sub.p(OR.sup.11),
--SO.sub.2NR.sup.11R.sup.12, --NR.sup.11S(O).sub.p(OR.sup.11),
NR.sup.11SO.sub.pNR.sup.11R.sup.12,
NR.sup.11C(.dbd.NR.sup.11)NR.sup.11R.sup.12, halogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl;
[0011] or two R.sup.4 on adjacent carbon atoms, when taken
together, may optionally form a double bond between the two carbons
to which they are attached or may form a
(C.sub.3-C.sub.7)cycloalkyl ring wherein one carbon atom of said
(C.sub.3-C.sub.7)cycloalkyl ring may be optionally replaced by
--O--, --S--, --S(O).sub.p--, --NH-- or --NR.sup.a--;
[0012] or four R.sup.4 on adjacent carbon atoms, when taken
together, may optionally form an optionally substituted C.sub.6
aryl ring;
[0013] or two R.sup.4 on the same carbon atom, when taken together,
may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring wherein one
carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be
optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or
--NR.sup.a--;
[0014] or two R.sup.6 on adjacent carbon atoms, when taken
together, may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring
wherein one carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring
may be optionally replaced by --O--, --S--, --S(O).sub.p--, --NH--
or --NR.sup.a--;
[0015] each R.sup.a is independently (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl
wherein any (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)alkenyl or (C.sub.2-C.sub.8)alkynyl of R.sup.a is
optionally substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl, and wherein any
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of R.sup.a is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) OH, NH.sub.2,
CO.sub.2H, C.sub.2-C.sub.20 heterocyclyl or
(C.sub.1-C.sub.8)alkyl;
[0016] each R.sup.11 or R.sup.12 is independently H,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.4-C.sub.8)carbocyclylalkyl,
--C(.dbd.O)R.sup.a, --S(O).sub.pR.sup.a or
aryl(C.sub.1-C.sub.8)alkyl; or R.sup.11 and R.sup.12 taken together
with a nitrogen to which they are both attached form a 3 to 7
membered heterocyclic ring wherein any one carbon atom of said
heterocyclic ring can optionally be replaced with --O--, --S--,
--S(O).sub.p--, --NH--, --NR.sup.a-- or --C(O)--; and
[0017] wherein each (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of each R.sup.6, R.sup.11 or
R.sup.12 is, independently, optionally substituted with one or more
(e.g. 1, 2, 3, 4 or 5) oxo, halogen, hydroxy, NH.sub.2, CN,
N.sub.3, N(R.sup.a).sub.2, NHR.sup.a, SH, SR.sup.a,
S(O).sub.pR.sup.a, OR.sup.a, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2,
--C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a;
[0018] provided the compound is not:
##STR00002##
[0019] Another embodiment provides a compound of formulas 1-111
(i.e., compounds 1-111), as described in examples 1 and 2, or a
salt or ester thereof.
[0020] Another embodiment provides a compound of formula I (e.g.,
compounds 112-209) or a stereoisomer (e.g. enantiomer, diasteromer,
atropisomer) or a salt or ester thereof.
[0021] Another embodiment provides a compound of formulas 1-111 or
a stereoisomer (e.g., enantiomer, diasteromer, atropisomer) or a
salt or ester thereof.
[0022] Another embodiment provides a pharmaceutical composition
comprising a compound of formula I or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
[0023] Another embodiment provides a pharmaceutical composition
comprising a compound of formulas 1-111 or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
[0024] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g., a human) in need thereof
comprising administering a therapeutically effective amount of a
compound of formula I or a pharmaceutically acceptable salt or
ester thereof.
[0025] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g., a human) in need thereof
comprising administering a therapeutically effective amount of a
compound of formulas 1-111, or a pharmaceutically acceptable salt
or ester thereof.
[0026] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g., a human) in need thereof
comprising administering a therapeutically effective amount of a,
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.
[0027] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g., a human) in need thereof
comprising administering a therapeutically effective amount of a,
tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or
solvate of a compound of formulas 1-111, or a pharmaceutically
acceptable salt or ester thereof.
[0028] Another embodiment provides a method of treating a
respiratory syncytial virus infection in a mammal (e.g., a human)
in need thereof comprising administering a therapeutically
effective amount of a compound of formula I, or a pharmaceutically
acceptable salt or ester thereof.
[0029] Another embodiment provides a method of treating a
respiratory syncytial virus infection in a mammal (e.g., a human)
in need thereof comprising administering a therapeutically
effective amount of a compound of formulas 1-111, or a
pharmaceutically acceptable salt or ester thereof.
[0030] Another embodiment provides a method of treating a
respiratory syncytial virus infection in a mammal (e.g., a human)
in need thereof comprising administering a therapeutically
effective amount of a tautomer, polymorph, pseudopolymorph,
amorphous form, hydrate or solvate of a compound of formula 1, or a
pharmaceutically acceptable salt or ester thereof.
[0031] Another embodiment provides a method of treating a
respiratory syncytial virus infection in a mammal (e.g. a human) in
need thereof comprising administering a therapeutically effective
amount of a tautomer, polymorph, pseudopolymorph, amorphous form,
hydrate or solvate of a compound of formulas 1-111, or a
pharmaceutically acceptable salt or ester thereof.
[0032] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g. a human) in need thereof
comprising administering a therapeutically effective amount of a
compound of formula I or a pharmaceutically acceptable salt or
ester thereof, and a pharmaceutically acceptable diluent or
carrier.
[0033] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g. a human) in need thereof
comprising administering a therapeutically effective amount of a
compound of formulas 1-111 or a pharmaceutically acceptable salt or
ester thereof, and a pharmaceutically acceptable diluent or
carrier.
[0034] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g. a human) in need thereof
comprising administering a therapeutically effective amount of a
compound of formula I or a pharmaceutically acceptable salt or
ester thereof, in combination with at least one additional
therapeutic agent.
[0035] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g. a human) in need thereof
comprising administering a therapeutically effective amount of a
compound of formulas 1-111 or a pharmaceutically acceptable salt or
ester thereof, in combination with at least one additional
therapeutic agent.
[0036] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g. a human) in need thereof,
comprising administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0037] a) a first pharmaceutical composition comprising a compound
of formula I or a pharmaceutically acceptable salt or ester
thereof; and
[0038] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
Pneumovirinae viruses.
[0039] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g. a human) in need thereof,
comprising administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0040] a) a first pharmaceutical composition comprising a compound
of formulas 1-111 or a pharmaceutically acceptable salt or ester
thereof; and
[0041] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
Pneumovirinae viruses.
[0042] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g. a human) in need thereof,
comprising administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0043] a) a therapeutic agent selected from a compound a of formula
I and pharmaceutically acceptable salts and esters thereof; and
[0044] b) a therapeutic agent active against infectious
Pneumovirinae viruses.
[0045] Another embodiment provides a method of treating a
Pneumovirinae infection in a mammal (e.g. a human) in need thereof,
comprising administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0046] a) a therapeutic agent selected from a compound of formulas
1-111 and pharmaceutically acceptable salts and esters thereof;
and
[0047] b) a therapeutic agent active against infectious
Pneumovirinae viruses.
[0048] Another embodiment provides a method of treating a
respiratory syncytial virus infection in a mammal (e.g. a human) in
need thereof, comprising administering a therapeutically effective
amount of a combination pharmaceutical agent comprising:
[0049] a) a first pharmaceutical composition comprising a compound
of formula I or a pharmaceutically acceptable salt or ester
thereof; and
[0050] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
respiratory syncytial viruses.
[0051] Another embodiment provides a method of treating a
respiratory syncytial virus infection in a mammal (e.g. a human) in
need thereof, comprising administering a therapeutically effective
amount of a combination pharmaceutical agent comprising:
[0052] a) a first pharmaceutical composition comprising a compound
of formulas 1-111 or a pharmaceutically acceptable salt or ester
thereof; and
[0053] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
respiratory syncytial viruses.
[0054] Another embodiment provides a method of treating a
respiratory syncytial virus infection in a mammal (e.g. a human) in
need thereof, comprising administering a therapeutically effective
amount of a combination pharmaceutical agent comprising:
[0055] a) a therapeutic agent selected from a compound of formula I
and pharmaceutically acceptable salts and esters thereof; and
[0056] b) a therapeutic agent active against infectious
Pneumovirinae viruses.
[0057] Another embodiment provides a method of treating a
respiratory syncytial virus infection in a mammal (e.g. a human) in
need thereof, comprising administering a therapeutically effective
amount of a combination pharmaceutical agent comprising:
[0058] a) a therapeutic agent selected from a compound of formulas
1-111 and pharmaceutically acceptable salts and esters thereof;
and
[0059] b) a therapeutic agent active against infectious
Pneumovirinae viruses.
[0060] Another embodiment provides a compound of formula I or a
pharmaceutically acceptable salt or ester thereof, for use in
medical therapy.
[0061] Another embodiment provides a compound of formulas 1-111 or
a pharmaceutically acceptable salt or ester thereof for use in
medical therapy.
[0062] Another embodiment provides a compound of formula I or a
pharmaceutically acceptable salt or ester thereof, for use in the
prophylactic or therapeutic treat a viral infection caused by a
Pneumovirinae virus or a respiratory syncytial virus.
[0063] Another embodiment provides a compound of formulas 1-111 or
a pharmaceutically acceptable salt or ester thereof, for use in the
prophylactic or therapeutic treat a viral infection caused by a
Pneumovirinae virus or a respiratory syncytial virus.
[0064] Another embodiment provides the use of a compound of formula
I or a pharmaceutically acceptable salt or ester thereof, for the
manufacture of a medicament useful for the treatment of a viral
infection caused by a Pneumovirinae virus or a respiratory
syncytial virus in a mammal (e.g. a human).
[0065] Another embodiment provides the use of a compound of
formulas 1-111 or a pharmaceutically acceptable salt or ester
thereof for the manufacture of a medicament useful for the
treatment of a viral infection caused by a Pneumovirinae virus or a
respiratory syncytial virus in a mammal (e.g. a human).
[0066] Another embodiment provides processes and novel
intermediates disclosed herein which are useful for preparing a
compound of formula I or a compound of formulas 1-111.
[0067] Another embodiment provides novel methods for synthesis,
analysis, separation, isolation, purification, characterization,
and testing of the compounds as disclosed herein.
DETAILED DESCRIPTION
Definitions
[0068] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0069] When trade names are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0070] The term "alkyl" refers to a straight or branched
hydrocarbon. For example, an alkyl group can have 1 to 20 carbon
atoms (i.e, C.sub.1-C.sub.20 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 (g-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).
[0071] The term "alkoxy" refers to a group having the formula
--O-alkyl, in which an alkyl group, as defined above, is attached
to the parent molecule via an oxygen atom. The alkyl portion of an
alkoxy group can have 1 to 20 carbon atoms (i.e., C.sub.1-C.sub.20
alkoxy), 1 to 12 carbon atoms (i.e., C.sub.1-C.sub.12 alkoxy), or 1
to 6 carbon atoms (i.e., C.sub.1-C.sub.6 alkoxy). Examples of
suitable alkoxy groups include, but are not limited to, methoxy
(--O--CH.sub.3 or --OMe), ethoxy (--OCH.sub.2CH.sub.3 or -OEt),
t-butoxy (--O--C(CH.sub.3).sub.3 or -OtBu) and the like.
[0072] The term "haloalkyl" refers to an alkyl group, as defined
above, in which one or more hydrogen atoms of the alkyl group is
replaced with a halogen atom. The alkyl portion of a haloalkyl
group can have 1 to 20 carbon atoms (i.e., C.sub.1-C.sub.20
haloalkyl), 1 to 12 carbon atoms (i.e., C.sub.1-C.sub.12
haloalkyl), or 1 to 6 carbon atoms (i.e., C.sub.1-C.sub.6 alkyl).
Examples of suitable haloalkyl groups include, but are not limited
to, --CF.sub.3, --CHF.sub.2, --CFH.sub.2, --CH.sub.2CF.sub.3, and
the like.
[0073] The term "alkenyl" refers to a straight or branched
hydrocarbon 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).
[0074] The term "alkynyl" refers to a straight or branched
hydrocarbon 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 alkenyl), 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.ident.CH),
propargyl (--CH.sub.2C.ident.CH), and the like.
[0075] The term "halogen" or "halo" refers to F, Cl, Br, or I.
[0076] The term "aryl" refers to an aromatic hydrocarbon radical
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. For example, an aryl group
can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10
carbon atoms. Typical aryl groups include, but are not limited to,
radicals derived from benzene (e.g., phenyl), substituted benzene,
naphthalene, anthracene, biphenyl, and the like.
[0077] The term "arylalkyl" refers to an acyclic alkyl radical in
which one of the hydrogen atoms bonded to a carbon atom, typically
a terminal or sp.sup.3 carbon atom, is replaced with an aryl
radical. Typical arylalkyl groups include, but are not limited to,
benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The
arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl
moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon
atoms.
[0078] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the drug
substance, i.e., active ingredient, as a result of spontaneous
chemical reaction(s), enzyme catalyzed chemical reaction(s),
photolysis, and/or metabolic chemical reaction(s). A prodrug is
thus a covalently modified analog or latent form of a
therapeutically active compound.
[0079] One skilled in the art will recognize that substituents and
other moieties of the compounds of formula I should be selected in
order to provide a compound which is sufficiently stable to provide
a pharmaceutically useful compound which can be formulated into an
acceptably stable pharmaceutical composition. Compounds of formula
I which have such stability are contemplated as falling within the
scope of the present invention.
[0080] The term "heterocycle" or "heterocyclyl" as used herein
includes by way of example and not limitation those heterocycles
described in Paquette, Leo A.; Principles of Modern Heterocyclic
Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters
1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds. A
Series of Monographs" (John Wiley & Sons, New York, 1950 to
present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am.
Chem. Soc. (1960) 82:5566. In one specific embodiment of the
invention "heterocycle" includes a "carbocycle" as defined herein,
wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been
replaced with a heteroatom (e.g. O, N, or S). The terms
"heterocycle" or "heterocyclyl" includes saturated rings, partially
unsaturated rings, and aromatic rings (i.e., heteroaromatic rings).
Substituted heterocyclyls include, for example, heterocyclic rings
substituted with any of the substituents disclosed herein including
carbonyl groups. A non-limiting example of a carbonyl substituted
heterocyclyl is:
##STR00003##
[0081] Examples of heterocycles include by way of example and not
limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl),
thiazolyl, tetrahydrothiophenyl, sulfur oxidized
tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,
indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,
piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl,
pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl,
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl,
phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,
benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,
isatinoyl, and bis-tetrahydrofuranyl:
##STR00004##
[0082] By way of example and not limitation, carbon bonded
heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine,
position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a
pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4,
or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or
tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or
thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or
isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4
of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or
position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more
typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,
4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,
5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,
5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or
5-thiazolyl.
[0083] By way of example and not limitation, nitrogen bonded
heterocycles are bonded at position 1 of an aziridine, azetidine,
pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,
imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,
2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole,
indoline, 1H-indazole, position 2 of a isoindole, or isoindoline,
position 4 of a morpholine, and position 9 of a carbazole, or
.beta.-carboline. Still more typically, nitrogen bonded
heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl,
1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
[0084] The term "heteroaryl" refers to an aromatic heterocyclyl
having at least one heteroatom in the ring. Non-limiting examples
of suitable heteroatoms which can be included in the aromatic ring
include oxygen, sulfur, and nitrogen. Non-limiting examples of
heteroaryl rings include all of those aromatic rings listed in the
definition of "heterocyclyl", including pyridinyl, pyrrolyl,
oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl,
benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl,
isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl,
pyridazyl, pyrimidyl, pyrazyl, etc.
[0085] The term "carbocycle" or "carbocyclyl" refers to a saturated
(i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl,
cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms
as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about
20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 7
ring atoms, still more typically 5 or 6 ring atoms. Bicyclic
carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo
[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged
as a bicyclo [5,6] or [6,6] system, or spiro-fused rings.
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, and
phenyl. Non-limiting examples of bicyclo carbocycles includes
naphthyl, tetrahydronapthalene, and decaline.
[0086] The term "cycloalkyl" refers to a saturated or partially
unsaturated ring having 3 to 7 carbon atoms as a monocycle, 7 to 12
carbon atoms as a bicycle, and up to about 20 carbon atoms as a
polycycle. Monocyclic cycloalkyl groups have 3 to 7 ring atoms,
still more typically 5 or 6 ring atoms. Bicyclic cycloalkyl groups
have 7 to 12 ring atoms, e.g., arranged as a bicyclo (4,5), (5,5),
(5,6) or (6,6) system, or 9 or 10 ring atoms arranged as a bicyclo
(5,6) or (6,6) system. Cycloalkyl groups include hydrocarbon mono-,
bi-, and poly-cyclic rings, whether fused, bridged, or spiro.
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,
bicyclo[3.1.0]hex-6-yl and the like.
[0087] The term "carbocyclylalkyl" refers to an acyclic alkyl
radical in which one of the hydrogen atoms bonded to a carbon atom
is replaced with a carbocyclyl radical as described herein.
Typical, but non-limiting, examples of carbocyclylalkyl groups
include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,
cyclopentylmethyl and cyclohexylmethyl.
[0088] Selected substituents comprising the compounds of formula I
may be present to a recursive degree. In this context, "recursive
substituent" means that a substituent may recite another instance
of itself. The multiple recitations may be direct or indirect
through a sequence of other substituents. Because of the recursive
nature of such substituents, theoretically, a large number of
compounds may be present in any given embodiment. One of ordinary
skill in the art of medicinal chemistry understands that the total
number of such substituents is reasonably limited by the desired
properties of the compound intended. Such properties include, by
way of example and not limitation, physical properties such as
molecular weight, solubility or log P, application properties such
as activity against the intended target, and practical properties
such as ease of synthesis. Recursive substituents may be an
intended aspect of the invention. One of ordinary skill in the art
of medicinal chemistry understands the versatility of such
substituents. To the degree that recursive substituents are present
in an embodiment of the invention, they may recite another instance
of themselves, 0, 1, 2, 3, or 4 times.
[0089] "Protecting group" refers to a moiety of a compound that
masks or alters the properties of a functional group or the
properties of the compound as a whole. The chemical substructure of
a protecting group varies widely. One function of a protecting
group is to serve as an intermediate in the synthesis of the
parental drug substance. Chemical protecting groups and strategies
for protection/deprotection are well known in the art. See:
"Protective Groups in Organic Chemistry", Theodora W. Greene (John
Wiley & Sons, Inc., New York, 1991. Protecting groups are often
utilized to mask the reactivity of certain functional groups, to
assist in the efficiency of desired chemical reactions, e.g. making
and breaking chemical bonds in an ordered and planned fashion.
Protection of functional groups of a compound alters other physical
properties besides the reactivity of the protected functional
group, such as the polarity, lipophilicity (hydrophobicity), and
other properties which can be measured by common analytical tools.
Chemically protected intermediates may themselves be biologically
active or inactive.
[0090] Protected compounds may also exhibit altered, and in some
cases, optimized properties in vitro and in vivo, such as passage
through cellular membranes and resistance to enzymatic degradation
or sequestration. In this role, protected compounds with intended
therapeutic effects may be referred to as prodrugs. Another
function of a protecting group is to convert the parental drug into
a prodrug, whereby the parental drug is released upon conversion of
the prodrug in vivo. Because active prodrugs may be absorbed more
effectively than the parental drug, prodrugs may possess greater
potency in vivo than the parental drug. Protecting groups are
removed either in vitro, in the instance of chemical intermediates,
or in vivo, in the case of prodrugs. With chemical intermediates,
it is not particularly important that the resulting products after
deprotection, e.g. alcohols, be physiologically acceptable,
although in general it is more desirable if the products are
pharmacologically innocuous.
[0091] "Prodrug moiety" means a labile functional group which
separates from the active inhibitory compound during metabolism,
systemically, inside a cell, by hydrolysis, enzymatic cleavage, or
by some other process (Bundgaard, Hans, "Design and Application of
Prodrugs" in Textbook of Drug Design and Development (1991), P.
Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic
Publishers, pp. 113-191). Enzymes which are capable of an enzymatic
activation mechanism with, for example any phosphate or phosphonate
prodrug compounds of the invention, include but are not limited to,
amidases, esterases, microbial enzymes, phospholipases,
cholinesterases, and phosphases. Prodrug moieties can serve to
enhance solubility, absorption and lipophilicity to optimize drug
delivery, bioavailability and efficacy. A prodrug moiety may
include an active metabolite or drug itself.
[0092] It is to be noted that all tautomers, atropisomers,
polymorphs, pseudopolymorphs of compounds disclosed herein and
pharmaceutically acceptable salts and esters thereof are embraced
by the present invention.
[0093] A compound disclosed herein and its pharmaceutically
acceptable salts may exist as different polymorphs or
pseudopolymorphs. As used herein, crystalline polymorphism means
the ability of a crystalline compound to exist in different crystal
structures. The crystalline polymorphism may result from
differences in crystal packing (packing polymorphism) or
differences in packing between different conformers of the same
molecule (conformational polymorphism). As used herein, crystalline
pseudopolymorphism means the ability of a hydrate or solvate of a
compound to exist in different crystal structures. The
pseudopolymorphs of the instant invention may exist due to
differences in crystal packing (packing pseudopolymorphism) or due
to differences in packing between different conformers of the same
molecule (conformational pseudopolymorphism). The instant invention
comprises all polymorphs and pseudopolymorphs of the compounds
disclosed herein
[0094] A compound disclosed herein and its pharmaceutically
acceptable salts may also exist as an amorphous solid. As used
herein, an amorphous solid is a solid in which there is no
long-range order of the positions of the atoms in the solid. This
definition applies as well when the crystal size is two nanometers
or less. Additives, including solvents, may be used to create the
amorphous forms of the instant invention. The instant invention
comprises all amorphous forms of the compounds disclosed herein and
their pharmaceutically acceptable salts.
[0095] The modifier "about" used in connection with a quantity is
inclusive of the stated value and has the meaning dictated by the
context (e.g., includes the degree of error associated with
measurement of the particular quantity).
[0096] The term "treating", as used herein, unless otherwise
indicated, means reversing, alleviating, inhibiting the progress
of, or preventing the disorder or condition to which such term
applies, or one or more symptoms of such disorder or condition. The
term "treatment", as used herein, refers to the act of treating, as
"treating" is defined immediately above.
[0097] The term "therapeutically effective amount", as used herein,
is the amount of compound disclosed herein present in a composition
described herein that is needed to provide a desired level of drug
in the secretions and tissues of the airways and lungs, or
alternatively, in the bloodstream of a subject to be treated to
give an anticipated physiological response or desired biological
effect when such a composition is administered by the chosen route
of administration.
[0098] The precise amount will depend upon numerous factors, for
example the particular disclosed herein, the specific activity of
the composition, the delivery device employed, the physical
characteristics of the composition, its intended use, as well as
patient considerations such as severity of the disease state,
patient cooperation, etc., and can readily be determined by one
skilled in the art and in reference to the information provided
herein.
[0099] The term "normal saline" means a water solution containing
0.9% (w/v) NaCl.
[0100] The term "hypertonic saline" means a water solution
containing greater than 0.9% (w/v) NaCl. For example, 3% hypertonic
saline would contain 3% (w/v) NaCl.
[0101] Physiologically acceptable salts (e.g. pharmaceutically
acceptable salt) of the compounds of the invention include salts
derived from an appropriate base, such as an alkali metal or an
alkaline earth (for example, Na.sup.+, Li.sup.+, K.sup.+, Ca.sup.+2
and Mg.sup.+2), ammonium and NR.sub.4. Physiologically acceptable
salts of a nitrogen atom or an amino group include (a) acid
addition salts formed with inorganic acids, for example,
hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids,
phosphoric acid, nitric acid and the like; (b) salts formed with
organic acids such as, for example, acetic acid, oxalic acid,
tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic
acid, citric acid, malic acid, ascorbic acid, benzoic acid,
isethionic acid, lactobionic acid, tannic acid, palmitic acid,
alginic acid, polyglutamic acid, naphthalenesulfonic acid,
methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,
naphthalenedisulfonic acid, polygalacturonic acid, malonic acid,
sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate,
pamoate, salicylic acid, stearic acid, phthalic acid, mandelic
acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic
acid, glycine, serine, threonine, alanine, isoleucine, leucine and
the like; and (c) salts formed from elemental anions for example,
chlorine, bromine, and iodine. Physiologically acceptable salts of
a compound of a hydroxy group include the anion of said compound in
combination with a suitable cation such as Na.sup.+ and
NR.sub.4.sup.+. Each R is independently selected from H and
(C.sub.1-C.sub.8)alkyl.
[0102] For therapeutic use, salts of active ingredients of the
compounds of the invention will be physiologically acceptable, i.e.
they will be salts derived from a physiologically acceptable acid
or base. However, salts of acids or bases which are not
physiologically acceptable may also find use, for example, in the
preparation or purification of a physiologically acceptable
compound. All salts, whether or not derived from a physiologically
acceptable acid or base, are within the scope of the present
invention.
[0103] It is to be understood that the compositions herein comprise
compounds disclosed herein in their un-ionized, as well as
zwitterionic form, and combinations with stoichiometric amounts of
water as in hydrates.
[0104] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and l, D and L, or (+) and (-) are
employed to designate the sign of rotation of plane-polarized light
by the compound, with S, (-), or 1 meaning that the compound is
levorotatory while a compound prefixed with R, (+), or d is
dextrorotatory. For a given chemical structure, these stereoisomers
are identical except that they are mirror images of one another. A
specific stereoisomer may also be referred to as an enantiomer, and
a mixture of such isomers is often called an enantiomeric mixture.
A 50:50 mixture of enantiomers is referred to as a racemic mixture
or a racemate, which may occur where there has been no
stereoselection or stereospecificity in a chemical reaction or
process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0105] The compounds disclosed herein have chiral centers, e.g.
chiral carbon. The compounds of the invention include enriched or
resolved optical isomers at any or all asymmetric, chiral atoms. In
other words, the chiral centers apparent from the depictions are
provided as the chiral isomers. Individual enantiomers or
diasteromers, isolated or synthesized, substantially free of their
enantiomeric or diastereomeric partners, are all within the scope
of the invention. The stereoisomeric mixtures can separated into
their individual, substantially optically pure isomers through
well-known techniques such as, for example, the separation of
diastereomeric salts formed with optically active adjuncts, e.g.,
acids or bases followed by conversion back to the optically active
substances. Typically, the desired optical isomer is synthesized by
means of stereospecific reactions, beginning with the appropriate
stereoisomer of the desired starting material.
[0106] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0107] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0108] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography. Enantiomers" refer to two stereoisomers of a
compound which are non-superimposable mirror images of one
another.
[0109] It is to be understood that for compounds disclosed herein
when a bond is drawn in a non-stereochemical manner (e.g. flat) the
atom to which the bond is attached includes all stereochemical
possibilities. It is also to understood that when a bond is drawn
in a stereochemical manner (e.g. bold, bold-wedge, dashed or
dashed-wedge) the atom to which the stereochemical bond is attached
has the stereochemistry as shown unless otherwise noted.
[0110] Accordingly, in one embodiment, the compounds disclosed
herein are greater than 50% a single enantiomer. In another
embodiment, the compounds disclosed herein are at least 80% a
single enantiomer. In another embodiment, the compounds disclosed
herein are at least 90% a single enantiomer. In another embodiment,
the compounds disclosed herein are at least 98% a single
enantiomer. In another embodiment, the compounds disclosed herein
are at least 99% a single enantiomer. In another embodiment, the
compounds disclosed herein are greater than 50% a single
diastereomer. In another embodiment, the compounds disclosed herein
are at least 80% a single diastereomer. In another embodiment, the
compounds disclosed herein are at least 90% a single diastereomer.
In another embodiment, the compounds disclosed herein are at least
98% a single diastereomer. In another embodiment, the compounds
disclosed herein are at least 99% a single diastereomer.
[0111] In one embodiment compounds are represented by formula I and
Ia (and salts and esters, thereof) as shown below wherein one
position of chirality is marked with an asterisk.
##STR00005##
[0112] The stereochemistry at the carbon marked with an asterisk as
shown above for formula I is the (S) stereochemistry provided that
A is ranked the lowest (3) or highest (1) of the three substituents
of the asterisk carbon following the Cahn-Ingold-Prelog system or
the (R) stereochemistry provided that A is ranked number 2 of the
three substituents of the asterisk carbon following the
Cahn-Ingold-Prelog system (March, J., Advanced Organic Chemistery,
4.sup.th Addition, John Wiley and Sons, pages 109-111). The
stereochemistry at the carbon marked with an asterisk as shown
above for formula Ia is the (S) stereochemistry. In one embodiment,
the compounds of formula I and Ia are greater than 50% a single
stereoisomer at the asterisk position. In another embodiment, the
compounds of formula I and Ia are at least 60% a single
stereoisomer at the asterisk position. In another embodiment, the
compounds of formula I and Ia are at least 70% a single
stereoisomer at the asterisk position. In another embodiment, the
compounds of formula I and Ia are at least 80% a single
stereoisomer at the asterisk position. In another embodiment, the
compounds of formula I and Ia are at least 90% a single
stereoisomer at the asterisk position. In another embodiment, the
compounds of formula I and Ia are at least 95% a single
stereoisomer at the asterisk position.
[0113] In one embodiment compounds are represented by formula I and
Ia (and salts and esters, thereof) as shown below wherein three
positions of chirality are marked with an asterisk.
##STR00006##
[0114] The stereochemistry at the carbon marked with an asterisk 1
(*1) as shown above for formula I is the (S) stereochemistry
provided that A is ranked the lowest (3) or highest (1) of the
three substituents of the asterisk 1 (*1) carbon following the
Cahn-Ingold-Prelog system or the (R) stereochemistry provided that
A is ranked number 2 of the three substituents of the asterisk 1
(*1) carbon following the Cahn-Ingold-Prelog system. The
stereochemistry at the carbon marked with an asterisk 1 (*1) as
shown above for formula Ia is the (S) stereochemistry. The
stereochemistry at the carbon marked with an asterisk 2 (*2) as
shown above for formula I and formula Ia is the (S)
stereochemistry. The stereochemistry at the carbon marked with an
asterisk 3 (*3) as shown above for formula I and formula Ia is the
(R) stereochemistry. In one embodiment, the compounds of formula I
and Ia are greater than 50% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
I and Ia are at least 60% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
I and Ia are at least 70% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
I and Ia are at least 80% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
I and Ia are at least 90% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds formula I
and Ia are at least 95% a single stereoisomer at each of the
asterisk positions.
[0115] In one embodiment compounds are represented by formulas II
or IIa or salts or esters thereof, wherein one position of
chirality is marked with an asterisk.
##STR00007##
[0116] The stereochemistry at the carbon marked with an asterisk as
shown above for formula II is the (S) stereochemistry provided that
A is ranked the lowest (3) or highest (1) of the three substituents
of the asterisk carbon following the Cahn-Ingold-Prelog system or
the (R) stereochemistry provided that A is ranked number 2 of the
three substituents of the asterisk carbon following the
Cahn-Ingold-Prelog system. The stereochemistry at the carbon marked
with an asterisk as shown above for formula IIa is the (S)
stereochemistry. In one embodiment, the compounds of formula I and
IIa are greater than 50% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula II and
IIa are at least 60% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula II and
IIa are at least 70% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula II and
IIa are at least 80% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula II and
IIa are at least 90% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula II and
IIa are at least 95% a single stereoisomer at the asterisk
position.
[0117] One embodiment provides compounds of formula I and IIa (and
salts and esters, thereof) as shown below wherein three positions
of chirality are marked with an asterisk.
##STR00008##
[0118] The stereochemistry at the carbon marked with an asterisk 1
(*1) as shown above for formula II is the (S) stereochemistry
provided that A is ranked the lowest (3) or highest (1) of the
three substituents of the asterisk 1 (*1) carbon following the
Cahn-Ingold-Prelog system or the (R) stereochemistry provided that
A is ranked number 2 of the three substituents of the asterisk 1
(*1) carbon following the Cahn-Ingold-Prelog system. The
stereochemistry at the carbon marked with an asterisk 1 (*1) as
shown above for formula IIa is the (S) stereochemistry. The
stereochemistry at the carbon marked with an asterisk 2 (*2) as
shown above for formula II and formula IIa is the (R)
stereochemistry. The stereochemistry at the carbon marked with an
asterisk 3 (*3) as shown above for formula I and formula Ia is the
(S) stereochemistry. In one embodiment, the compounds of formula II
and IIa are greater than 50% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
II and IIa are at least 60% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
I and Ia are at least 70% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
II and IIa are at least 80% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
II and IIa are at least 90% a single stereoisomer at each of the
asterisk positions. In another embodiment, the compounds of formula
II and IIa are at least 95% a single stereoisomer at each of the
asterisk positions.
[0119] One embodiment provides for compounds of formulas III or
IIIa or salts or esters thereof. Compounds of formula III and IIIa
are shown below wherein one position of chirality is marked with an
asterisk.
##STR00009##
[0120] The stereochemistry at the carbon marked with an asterisk as
shown above for formula III is the (S) stereochemistry provided
that A is ranked the lowest (3) or highest (1) of the three
substituents of the asterisk carbon following the
Cahn-Ingold-Prelog system or the (R) stereochemistry provided that
A is ranked number 2 of the three substituents of the asterisk
carbon following the Cahn-Ingold-Prelog system. The stereochemistry
at the carbon marked with an asterisk as shown above for formula
IIIa is the (S) stereochemistry. In one embodiment, the compounds
of formula III and IIIa are greater than 50% a single stereoisomer
at the asterisk position. In another embodiment, the compounds of
formula III and IIIa are at least 60% a single stereoisomer at the
asterisk position. In another embodiment, the compounds of formula
III and IIIa are at least 70% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula III and
IIIa are at least 80% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula III and
IIIa are at least 90% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula III and
IIIa are at least 95% a single stereoisomer at the asterisk
position.
[0121] One embodiment provides compounds of formula III and IIIa
(and salts and esters, thereof) as shown below wherein three
positions of chirality are marked with an asterisk.
##STR00010##
[0122] The stereochemistry at the carbon marked with an asterisk 1
(*1) as shown above for formula III is the (S) stereochemistry
provided that A is ranked the lowest (3) or highest (1) of the
three substituents of the asterisk 1 (*1) carbon following the
Cahn-Ingold-Prelog system or the (R) stereochemistry provided that
A is ranked number two of the three substituents of the asterisk 1
(*1) carbon following the Cahn-Ingold-Prelog system. The
stereochemistry at the carbon marked with an asterisk 1 (*1) as
shown above for formula IIIa is the (S) stereochemistry. The
stereochemistry at the carbon marked with an asterisk 2 (*2) as
shown above for formula III and formula IIIa is the (R)
stereochemistry. The stereochemistry at the carbon marked with an
asterisk 3 (*3) as shown above for formula III and formula IIIa is
the (R) stereochemistry. In one embodiment, the compounds of the
invention of formula III and IIIa are greater than 50% a single
stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of the invention of formula III and IIIa
are at least 60% a single stereoisomer at each of the asterisk
positions. In another embodiment, the compounds of the invention of
formula III and IIIa are at least 70% a single stereoisomer at each
of the asterisk positions. In another embodiment, the compounds of
the invention of formula III and IIIa are at least 80% a single
stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of the invention of formula III and IIIa
are at least 90% a single stereoisomer at each of the asterisk
positions. In another embodiment, the compounds of the invention of
formula III and IIIa are at least 95% a single stereoisomer at each
of the asterisk positions.
[0123] One embodiment provides for compounds of formulas IV or IVa
or salts or esters thereof. Compounds of formula IV and IVa are
shown wherein one position of chirality is marked with an
asterisk.
##STR00011##
[0124] The stereochemistry at the carbon marked with an asterisk as
shown above for formula IV is the (S) stereochemistry provided that
A is ranked the lowest (3) or highest (1) of the three substituents
of the asterisk carbon following the Cahn-Ingold-Prelog system or
the (R) stereochemistry provided that A is ranked number 2 of the
three substituents of the asterisk carbon following the
Cahn-Ingold-Prelog system. The stereochemistry at the carbon marked
with an asterisk as shown above for formula IVa is the (S)
stereochemistry. In one embodiment, the compounds of formula IV and
IVa are greater than 50% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula IV and
IVa are at least 60% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula IV and
IVa are at least 70% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula IV and
IVa are at least 80% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula IV and
IVa are at least 90% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formula IV and
IVa are at least 95% a single stereoisomer at the asterisk
position.
[0125] One embodiment provides compounds of formula IV and IVa (and
salts and esters, thereof) as shown below wherein three positions
of chirality are marked with an asterisk.
##STR00012##
[0126] The stereochemistry at the carbon marked with an asterisk 1
(*1) as shown above for formula IV is the (S) stereochemistry
provided that A is ranked the lowest (3) or highest (1) of the
three substituents of the asterisk 1 (*1) carbon following the
Cahn-Ingold-Prelog system or the (R) stereochemistry provided that
A is ranked number 2 of the three substituents of the asterisk 1
(*1) carbon following the Cahn-Ingold-Prelog System. The
stereochemistry at the carbon marked with an asterisk 1 (*1) as
shown above for formula IVa is the (S) stereochemistry. The
stereochemistry at the carbon marked with an asterisk 2 (*2) as
shown above for formula IV and formula IVa is the (S)
stereochemistry. The stereochemistry at the carbon marked with an
asterisk 3 (*3) as shown above for formula IV and formula IVa is
the (S) stereochemistry. In one embodiment, the compounds of
formula IV and IVa are greater than 50% a single stereoisomer at
each of the asterisk positions. In another embodiment, the
compounds of formula IV and IVa are at least 60% a single
stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formula IV and IVa are at least 70% a
single stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formula IV and IVa are at least 80% a
single stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formula IV and IVa are at least 90% a
single stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formula IV and IVa are at least 95% a
single stereoisomer at each of the asterisk positions.
[0127] Each of the compounds of formulas 1-24 described herein have
a core represented by formula V wherein a position of chirality is
marked with an asterisk (wherein R represents an amine).
##STR00013##
[0128] The stereochemistry at the carbon marked with an asterisk as
shown for formula V is the (S) stereochemistry. In one embodiment,
the compounds of formulas 1-24 are greater than 50% a single
stereoisomer at the asterisk position. In another embodiment, the
compounds of formulas 1-24 are at least 60% a single stereoisomer
at the asterisk position. In another embodiment, the compounds of
formulas 1-24 are at least 70% a single stereoisomer at the
asterisk position. In another embodiment, the compounds of formulas
1-24 are at least 80% a single stereoisomer at the asterisk
position. In another embodiment, the compounds of formulas 1-24 are
at least 90% a single stereoisomer at the asterisk position. In
another embodiment, the compounds of formulas 1-24 are at least 95%
a single stereoisomer at the asterisk position.
[0129] Each of the compounds of formula 25-111 described herein
have a core represented by formula VI wherein two positions of
chirality are marked with an asterisk.
##STR00014##
[0130] The stereochemistry at the carbon marked with an asterisk 1
(1) as shown for formula VI is the (S) stereochemistry. The
stereochemistry at the carbon marked with an asterisk 2 (2) as
shown for formula VI is the (S) stereochemistry. In one embodiment,
the compounds of formulas 25-111 are greater than 50% a single
stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formulas 25-111 are at least 60% a
single stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formulas 25-111 are at least 70% a
single stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formulas 25-111 are at least 80% a
single stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formulas 25-111 are at least 90% a
single stereoisomer at each of the asterisk positions. In another
embodiment, the compounds of formulas 25-111 are at least 95% a
single stereoisomer at each of the asterisk positions.
[0131] The compounds disclosed herein also include molecules that
incorporate isotopes of the atoms specified in the particular
molecules. Non-limiting examples of these isotopes include D, T,
.sup.14C, .sup.13C and .sup.15N.
[0132] Whenever a compound described herein is substituted with
more than one of the same designated group, e.g., "R" or "R.sup.1",
then it will be understood that the groups may be the same or
different, i.e., each group is independently selected. Wavy lines,
, indicate the site of covalent bond attachments to the adjoining
substructures, groups, moieties, or atoms.
[0133] The compounds of the invention can also exist as tautomeric
isomers in certain cases. Although only one delocalized resonance
structure may be depicted, all such forms are contemplated within
the scope of the invention.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0134] Reference will now be made in detail to certain embodiments,
examples of which are illustrated in the accompanying description,
structures and formulas. While the invention will be described in
conjunction with the enumerated embodiments, it will be understood
that they are not intended to limit the invention to those
embodiments. On the contrary, the invention is intended to cover
all alternatives, modifications, and equivalents, which may be
included within the full scope of the present invention as
described herein.
[0135] Specific values listed below for radicals, substituents, and
ranges, are for illustration only; they do not exclude other
defined values or other values within defined ranges for the
radicals and substituents. Specific values listed are values for
compounds of formula I, II, III, IV as well as sub-formulas of
these formulas (e.g. formula Ia, IIa, IIIa and IVa).
[0136] A specific group of compounds of formula I are compounds of
formula Ia.
##STR00015##
and salts and esters, thereof.
[0137] A specific value for R.sup.3 is H.
[0138] A specific value for n is 3.
[0139] A specific value for R.sup.4 is H.
[0140] A specific value for A is --(CH.sub.2).sub.3--.
[0141] A specific value for Ar is phenyl, pyridyl,
1,2,3,4-tetrahydronaphthyl, indazolyl, 1,6-naphthyridyl,
2,3,-dihydroindanyl, quinolyl, indolyl, 4H-benzo][d][1,3]dioxanyl,
pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,
1,2,3,4-tetrahydroquinolyl, benzo[d][1,3]dioxolyl, quinoxalyl,
isoquinolyl, naphthyl, thiophenyl, pyrazolyl,
4,5,6,7-tetrahydrobenzothiophenyl or pyrazolo[3,4,b]pyridinyl,
wherein any phenyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, indazolyl,
1,6-naphthyridyl, 2,3,-dihydroindanyl, quinolyl, indolyl,
4H-benzo][d][1,3]dioxanyl, pyrazolo[1,5-a]pyridinyl,
imidazo[1,2-a]pyridinyl, 1,2,3,4-tetrahydroquinolyl,
benzo[d][1,3]dioxolyl, quinoxalyl, isoquinolyl, naphthyl,
thiophenyl, pyrazolyl, 4,5,6,7-tetrahydrobenzothiophenyl or
pyrazolo[3,4,b]pyridinyl of Ar is optionally substituted with 1 to
5 R.sup.6.
[0142] A specific value for Ar is phenyl, monocyclic-heterocycle or
bicyclic-heterocycle, wherein any phenyl, monocyclic-heterocycle or
bicyclic-heterocycle of Ar is optionally substituted with 1 to 5
R.sup.6.
[0143] A specific value for Ar is phenyl, monocyclic-heterocycle or
bicyclic-heterocycle, wherein the monocyclic-heterocycle or
bicyclic-heterocycle consists or 1-10 carbon atoms and 1-5
heteroatoms within the ring system and wherein any phenyl,
monocyclic-heterocycle or bicyclic-heterocycle of Ar is optionally
substituted with 1 to 5 R.sup.6.
[0144] A specific value for Ar is phenyl optionally substituted by
1, 2, 3, 4, or 5 R.sup.6 groups.
[0145] A specific value for Ar is phenyl optionally substituted by
1, 2, 3, or 4 R.sup.6 groups.
[0146] A specific value for Ar is phenyl optionally substituted by
1, 2, or 3 R.sup.6 groups.
[0147] A specific value for Ar is naphthyl optionally substituted
by 1, 2, 3, 4, or 5 R.sup.6 groups.
[0148] A specific value for Ar is naphthyl optionally substituted
by 1, 2, 3, or 4 R.sup.6 groups.
[0149] A specific value for Ar is naphthyl optionally substituted
by 1, 2, or 3 R.sup.6 groups.
[0150] A specific value for Ar is phenyl optionally substituted by
1, 2, 3, 4, or 5 R.sup.6 groups selected from halogen, alkyl,
alkoxy, --CH.sub.2OH, CF.sub.3, --O--CF.sub.3, --O--CF.sub.2,
--O--(C.sub.3-C.sub.6 cycloalkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --SO.sub.2--C.sub.1-C.sub.6 alkyl,
--S(.dbd.O)--C.sub.1-C.sub.6 alkyl, an oxadiazole optionally
substituted by CH.sub.3, and a triazole ring optionally substituted
by CH.sub.3; or two R.sup.6 groups on the phenyl ring together with
the atoms to which they are attached form a benzodioxole,
benzodioxine, or dihydroindene ring.
[0151] A specific value for Ar is phenyl substituted by 1, 2, 3, or
4 R.sup.6 groups selected from halogen, alkyl, alkoxy,
--CH.sub.2OH, CF.sub.3, --O--CF.sub.3, --O--CF.sub.2,
--O--(C.sub.3-C.sub.6 cycloalkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --SO.sub.2--C.sub.1-C.sub.6 alkyl,
--S(.dbd.O)--C.sub.1-C.sub.6 alkyl, an oxadiazole optionally
substituted by CH.sub.3, and a triazole ring optionally substituted
by CH.sub.3; or two R.sup.6 groups on the phenyl ring together with
the atoms to which they are attached form a benzodioxole,
benzodioxine, or dihydroindene ring.
[0152] A specific value for Ar is phenyl optionally substituted by
1, 2, or 3 R.sup.6 groups selected from halogen, alkyl, alkoxy,
--CH.sub.2OH, CF.sub.3, --O--CF.sub.3, --O--CF.sub.2,
--O--(C.sub.3-C.sub.6 cycloalkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --SO.sub.2--C.sub.1-C.sub.6 alkyl,
--S(.dbd.O)--C.sub.1-C.sub.6 alkyl, an oxadiazole optionally
substituted by CH.sub.3, and a triazole ring optionally substituted
by CH.sub.3; or two R.sup.6 groups on the phenyl ring together with
the atoms to which they are attached form a benzodioxole,
benzodioxine, or dihydroindene ring.
[0153] A specific value for Ar is naphthyl optionally substituted
by 1, 2, 3, 4, or 5 R.sup.6 groups selected from halogen, alkyl,
alkoxy, --CH.sub.2OH, CF.sub.3, --O--CF.sub.3, --O--CF.sub.2,
--O--(C.sub.3-C.sub.6 cycloalkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --SO.sub.2--C.sub.1-C.sub.6 alkyl,
--S(.dbd.O)--C.sub.1-C.sub.6 alkyl, an oxadiazole optionally
substituted by CH.sub.3, and a triazole ring optionally substituted
by CH.sub.3; or two R.sup.6 groups on the phenyl ring together with
the atoms to which they are attached form a benzodioxole,
benzodioxine, or dihydroindene ring.
[0154] A specific value for Ar is naphthyl optionally substituted
by 1, 2, 3, or 4 R.sup.6 groups selected from halogen, alkyl,
alkoxy, --CH.sub.2OH, CF.sub.3, --O--CF.sub.3, --O--CF.sub.2,
--O--(C.sub.3-C.sub.6 cycloalkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --SO.sub.2--C.sub.1-C.sub.6 alkyl,
--S(.dbd.O)--C.sub.1-C.sub.6 alkyl, an oxadiazole optionally
substituted by CH.sub.3, and a triazole ring optionally substituted
by CH.sub.3; or two R.sup.6 groups on the phenyl ring together with
the atoms to which they are attached form a benzodioxole,
benzodioxine, or dihydroindene ring.
[0155] A specific value for Ar is naphthyl optionally substituted
by 1, 2, or 3 R.sup.6 groups selected from halogen, alkyl, alkoxy,
--CH.sub.2OH, CF.sub.3, --O--CF.sub.3, --O--CF.sub.2,
--O--(C.sub.3-C.sub.6 cycloalkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --SO.sub.2--C.sub.1-C.sub.6 alkyl,
--S(.dbd.O)--C.sub.1-C.sub.6 alkyl, an oxadiazole optionally
substituted by CH.sub.3, and a triazole ring optionally substituted
by CH.sub.3; or two R.sup.6 groups on the phenyl ring together with
the atoms to which they are attached form a benzodioxole,
benzodioxine, or dihydroindene ring.
[0156] A specific value for Ar is pyridine optionally substituted
by 1, 2, 3, 4, or 5 R.sup.6 groups.
[0157] A specific value for Ar is pyridine optionally substituted
by 1, 2, 3, or 4 R.sup.6 groups.
[0158] A specific value for Ar is pyridine optionally substituted
by 1, 2, or 3 R.sup.6 groups.
[0159] A specific value for Ar is pyridine optionally substituted
by 1, 2, 3, 4, or 5 R.sup.6 groups independently selected from
halogen, alkyl, alkoxy, --CH.sub.2OH, phenyl and CF.sub.3.
[0160] A specific value for Ar is pyridine optionally substituted
by 1, 2, 3, or 4 R.sup.6 groups. independently selected from
halogen, alkyl, alkoxy, --CH.sub.2OH, phenyl and CF.sub.3.
[0161] A specific value for Ar is pyridine optionally substituted
by 1, 2, or 3 R.sup.6 groups. independently selected from halogen,
alkyl, alkoxy, --CH.sub.2OH, phenyl and CF.sub.3.
[0162] Individual embodiments provide compounds of the formula I
wherein Ar is, respectively, indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine, naphthyridine, in which, in each embodiment the
Ar group is either unsubstituted or substituted by 1, 2, 3, 4, or 5
R.sup.6 groups.
[0163] Individual embodiments provide compounds of the formula I
wherein Ar is, respectively, indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine, naphthyridine, in which, in each embodiment the
Ar group is either unsubstituted or substituted by 1, 2, 3, or 4
R.sup.6 groups.
[0164] Individual embodiments provide compounds of the formula I
wherein Ar is, respectively, indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine, naphthyridine, in which, in each embodiment the
Ar group is either unsubstituted or substituted by 1, 2, or 3
R.sup.6 groups.
[0165] Individual embodiments provide compounds of the formula I
wherein Ar is, respectively, indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine, naphthyridine, in which, in each embodiment the
Ar group is either unsubstituted or substituted by 1, 2, or 3
substituents selected from halogen, alkyl, alkoxy, CF.sub.3,
--O--CF.sub.3, and --O--CF.sub.2.
[0166] A specific value for Ar is indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine or naphthyridine, wherein indazole,
imidazopyridazine, benzothiophene, benzoimidazole, indazole,
quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole,
triazolopyrimidine, pyrazolopyridine or naphthyridine are not
substituted.
[0167] A specific value for Ar is indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine or naphthyridine, wherein indazole,
imidazopyridazine, benzothiophene, benzoimidazole, indazole,
quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole,
triazolopyrimidine, pyrazolopyridine or naphthyridine are each
optionally substituted by 1, 2, 3, 4, or 5 R.sup.6 groups.
[0168] A specific value for Ar is indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine or naphthyridine, wherein indazole,
imidazopyridazine, benzothiophene, benzoimidazole, indazole,
quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole,
triazolopyrimidine, pyrazolopyridine or naphthyridine are each
optionally substituted by 1, 2, 3, or 4 R.sup.6 groups.
[0169] A specific value for Ar is indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine or naphthyridine, wherein indazole,
imidazopyridazine, benzothiophene, benzoimidazole, indazole,
quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole,
triazolopyrimidine, pyrazolopyridine or naphthyridine are each
optionally substituted by 1, 2, or 3, or 4 R.sup.6 groups.
[0170] A specific value for Ar is indazole, imidazopyridazine,
benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline,
quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine,
pyrazolopyridine or naphthyridine, wherein indazole,
imidazopyridazine, benzothiophene, benzoimidazole, indazole,
quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole,
triazolopyrimidine, pyrazolopyridine or naphthyridine are each
optionally substituted by 1, 2, or 3 substituents selected from
halogen, alkyl, alkoxy, CF.sub.3, --O--CF.sub.3, and
--O--CF.sub.2.
[0171] A specific value for R.sup.6 is OR.sup.11, CN,
S(O).sub.pR.sup.a, halogen, (C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl or C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl,
wherein any (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl of
R.sup.6 is optionally substituted with one or more oxo, halogen,
hydroxy, NH.sub.2, CN, N.sub.3, N(R.sup.a).sub.2, NHR.sup.a, SH,
SR.sup.a, S(O).sub.pR.sup.a, OR.sup.a, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2,
--C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a.
[0172] Another specific value for R.sup.6 is OR.sup.11, CN,
S(O).sub.pR.sup.a, halogen, (C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.4-C.sub.8)carbocyclylalkyl,
NR.sup.11C(O)R.sup.11 or NR.sup.11S(O).sub.pR.sup.a, wherein any
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl of
R.sup.6 is optionally substituted with one or more oxo, halogen,
hydroxy, NH.sub.2, CN, N.sub.3, N(R.sup.a).sub.2, NHR.sup.a, SH,
SR.sup.a, S(O).sub.pR.sup.a, OR.sup.a, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2,
--C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NRC(O)NH.sub.2, NHC(O)NHR.sup.a,
NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH, .dbd.NOH,
.dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a.
[0173] A specific value for Ar is:
##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020##
[0174] Another specific value for Ar is:
##STR00021## ##STR00022## ##STR00023## ##STR00024##
##STR00025##
[0175] In one embodiment the invention provides a compound of
formula I:
##STR00026##
[0176] or a salt or ester, thereof;
wherein:
[0177] A is --(C(R.sup.4).sub.2).sub.n-- wherein any one
C(R.sup.4).sub.2 of said --(C(R.sup.4).sub.2)-- may be optionally
replaced with --O--, --S--, --S(O).sub.p--, NH or NR.sup.a;
[0178] n is 3, 4, 5 or 6;
[0179] each p is 1 or 2;
[0180] Ar is a C.sub.2-C.sub.20 heterocyclyl group or a
C.sub.6-C.sub.20 aryl group, wherein the C.sub.2-C.sub.20
heterocyclyl group or the C.sub.6-C.sub.20 aryl group is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.6;
[0181] each R.sup.3, R.sup.4 or R.sup.6 is independently H, oxo,
OR.sup.11, NR.sup.11R.sup.12, NR.sup.11C(O)R.sup.11,
NR.sup.11C(O)OR.sup.11, NR.sup.11C(O)NR.sup.11R.sup.12, N.sub.3,
CN, NO.sub.2, SR.sup.11, S(O).sub.pR.sup.a,
NR.sup.11S(O).sub.pR.sup.a, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)SR.sup.11, --S(O).sub.p(OR.sup.11),
--SO.sub.2NR.sup.11R.sup.12, --NR.sup.11S(O).sub.p(OR.sup.11),
NR.sup.11SO.sub.pNR.sup.11R.sup.12,
NR.sup.11C(.dbd.NR.sup.11)NR.sup.11R.sup.12, halogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl;
[0182] or two R.sup.4 on adjacent carbon atoms, when taken
together, may optionally form a double bond between the two carbons
to which they are attached or may form a
(C.sub.3-C.sub.7)cycloalkyl ring wherein one carbon atom of said
(C.sub.3-C.sub.7)cycloalkyl ring may be optionally replaced by
--O--, --S--, --S(O).sub.p--, --NH-- or --NR.sup.a--;
[0183] four R.sup.4 on adjacent carbon atoms, when taken together,
may optionally form an optionally substituted C.sub.6 aryl
ring;
[0184] two R.sup.4 on the same carbon atom, when taken together,
may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring wherein one
carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be
optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or
--NR.sup.a--;
[0185] two R.sup.6 on adjacent carbon atoms, when taken together,
may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring wherein one
carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be
optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or
--NR.sup.a--;
[0186] each R.sup.a is independently (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl
wherein any (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)alkenyl or (C.sub.2-C.sub.8)alkynyl of R.sup.a is
optionally substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl, and wherein any
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of R.sup.a is optionally
substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl or (C.sub.1-C.sub.8)alkyl;
[0187] each R.sup.11 or R.sup.12 is independently H,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.4-C.sub.8)carbocyclylalkyl,
--C(.dbd.O)R.sup.a, --S(O).sub.pR.sup.a, or
aryl(C.sub.1-C.sub.8)alkyl; or R.sup.11 and R.sup.12 taken together
with a nitrogen to which they are both attached form a 3 to 7
membered heterocyclic ring wherein any one carbon atom of said
heterocyclic ring can optionally be replaced with --O--, --S--,
--S(O).sub.p--, --NH--, --NR.sup.a-- or --C(O)--; and
[0188] wherein each (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of each R.sup.6, R.sup.11 or
R.sup.12 is, independently, optionally substituted with one or more
oxo, halogen, hydroxy, NH.sub.2, CN, N.sub.3, N(R.sup.a).sub.2,
NHR.sup.a, SH, SR.sup.a, S(O).sub.pR.sup.a, OR.sup.a,
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a,
--C(O)H, --C(.dbd.O)OR.sup.a, --C(.dbd.O)OH,
--C(.dbd.O)N(R.sup.a).sub.2, --C(.dbd.O)NHR.sup.a,
--C(.dbd.O)NH.sub.2, NHS(O)R.sup.a, NR.sup.aS(O).sub.pR.sup.a,
NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a, NHC(O)OR.sup.a,
NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a;
[0189] provided the compound is not:
##STR00027##
[0190] A specific group of compounds of formula I are compounds of
formula Ia:
##STR00028##
and salts and esters, thereof; provided the compound does not
include:
##STR00029##
[0191] In one embodiment the compounds of formula I or Ia do not
include:
##STR00030##
[0192] In one embodiment a compound of formula I is selected
from:
##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##
##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040##
##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045##
##STR00046##
and salts and esters, thereof.
[0193] In one embodiment a compound of formula I is selected
from:
##STR00047## ##STR00048## ##STR00049##
and salts and esters, thereof.
[0194] One embodiment provides a compound of formula II or IIa:
##STR00050##
or a salt or ester, thereof, provided the compound is not
##STR00051##
[0195] In one embodiment the compounds of formula II or IIa do not
include:
##STR00052##
[0196] One embodiment provides a compound of formula III or
IIIa:
##STR00053##
or a salt or ester, thereof, provided the compound is not:
##STR00054##
[0197] In one embodiment the compounds of formula III or IIIa do
not include:
##STR00055##
[0198] One embodiment provides a compound of formula IV or IVa:
##STR00056##
or a salt or ester, thereof, provided the compound is not
##STR00057##
[0199] In one embodiment the compounds of formula IV or IVa do not
include:
##STR00058##
[0200] One embodiment provides for a mixture of a compound of
formula III with a corresponding compound of formula IV. The
mixture of the compound of formula III with the corresponding
compound of formula IV is thus a mixture of trans diastereomers
wherein the trans substituents are the substituents connected to
the carbon marked with an asterisk 2 (*2) and the carbon marked
with an asterisk 2 (*3). The invention also provides a mixture of a
compound of formula IIIa with a corresponding compound of formula
IVa. The mixture of the compound of formula IIIa with the
corresponding compound of formula IVa is thus a mixture of trans
diastereomers wherein the trans substituents are the substituents
connected to the carbon marked with an asterisk 2 (*2) and the
carbon marked with an asterisk 2 (*3).
[0201] One embodiment does not include:
##STR00059##
[0202] In one embodiment a compound is selected from:
##STR00060##
and salts and esters, thereof, or a mixture of a compound of
formula IIIa and a corresponding compound of formula IVa or a salt
or ester, thereof; wherein Ar is selected from:
##STR00061## ##STR00062## ##STR00063## ##STR00064##
[0203] In one embodiment a compound is selected from:
##STR00065##
and salts and esters, thereof, or a mixture of a compound of
formula IIIa and a corresponding compound of formula IVa or a salt
or ester, thereof; wherein Ar is selected from:
##STR00066## ##STR00067## ##STR00068## ##STR00069##
[0204] One embodiment provides a pharmaceutical composition
comprising a compound of formula II, IIa, II, IIIa, IV or IVa or a
pharmaceutically acceptable salt or ester thereof, and a
pharmaceutically acceptable carrier.
[0205] One embodiment provides a pharmaceutical composition
comprising a mixture of a compound of formula III and a
corresponding compound of formula IV or pharmaceutically acceptable
salts or esters thereof, and a pharmaceutically acceptable
carrier.
[0206] One embodiment provides a pharmaceutical composition
comprising a mixture of a compound of formula IIIa and a
corresponding compound of formula IVa or pharmaceutically
acceptable salts or esters thereof, and a pharmaceutically
acceptable carrier.
[0207] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a compound of
formula II, IIa, III, IIIa, IV or IVa or a pharmaceutically
acceptable salt or ester thereof.
[0208] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a mixture of a
compound of formula III and a corresponding compound of formula IV
or pharmaceutically acceptable salts or esters thereof.
[0209] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a mixture of a
compound of formula IIIa and a corresponding compound of formula
IVa or pharmaceutically acceptable salts or esters thereof.
[0210] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a, tautomer,
polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a
compound of formula II, IIa, III, IIIa, IV or IVa or a
pharmaceutically acceptable salt or ester thereof.
[0211] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a, tautomer,
polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a
compound a mixture of a compound of formula III and a corresponding
compound of formula IV or pharmaceutically acceptable salts or
esters thereof.
[0212] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a, tautomer,
polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a
mixture of a compound of formula IIIa and a corresponding compound
of formula IVa or pharmaceutically acceptable salts or esters
thereof.
[0213] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof by administering a therapeutically effective amount of a
compound of formula II, IIa, III, IIIa, IV or IVa or a
pharmaceutically acceptable salt or ester thereof.
[0214] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof by administering a therapeutically effective amount of a
mixture of a compound of formula II and a corresponding compound of
formula IV or pharmaceutically acceptable salts or esters
thereof.
[0215] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof by administering a therapeutically effective amount of a
mixture of a compound of formula IIIa and a corresponding compound
of formula IVa or pharmaceutically acceptable salts or esters
thereof.
[0216] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof by administering a therapeutically effective amount of a
tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or
solvate of a compound of formula II, IIa, III, IIIa, IV or IVa or a
pharmaceutically acceptable salt or ester thereof.
[0217] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof by administering a therapeutically effective amount of a
tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or
solvate of a mixture of a compound of formula III and a
corresponding compound of formula IV or pharmaceutically acceptable
salts or esters thereof.
[0218] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof by administering a therapeutically effective amount of a
tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or
solvate of a mixture of a compound of formula IIIa and a
corresponding compound of formula IVa or pharmaceutically
acceptable salts or esters thereof.
[0219] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a compound of
formula II, IIa, III, IIIa, IV or IVa or a pharmaceutically
acceptable salt or ester thereof, and a pharmaceutically acceptable
diluent or carrier.
[0220] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a mixture of a
compound of formula III and a corresponding compound of formula IV
or pharmaceutically acceptable salts or esters thereof, and a
pharmaceutically acceptable diluent or carrier.
[0221] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a mixture of a
compound of formula IIIa and a corresponding compound of formula
IVa or pharmaceutically acceptable salts or esters thereof, and a
pharmaceutically acceptable diluent or carrier.
[0222] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a compound of
formula II, IIa, III, IIIa, IV or IVa or a pharmaceutically
acceptable salt or ester thereof, in combination with at least one
additional therapeutic agent.
[0223] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a mixture of a
compound of formula III and a corresponding compound of formula IV
or pharmaceutically acceptable salts or esters thereof, in
combination with at least one additional therapeutic agent.
[0224] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof by
administering a therapeutically effective amount of a mixture of a
compound of formula IIIa and a corresponding compound of formula
IVa or pharmaceutically acceptable salts or esters thereof, in
combination with at least one additional therapeutic agent.
[0225] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof, by
administering a therapeutically effective amount of a combination
pharmaceutical agent comprising:
[0226] a) a first pharmaceutical composition comprising a compound
of formula II, IIa, III, IIIa, IV or IVa or a pharmaceutically
acceptable salt or ester thereof; and
[0227] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
Pneumovirinae viruses.
[0228] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof, by
administering a therapeutically effective amount of a combination
pharmaceutical agent comprising:
[0229] a) a first pharmaceutical composition comprising a mixture
of a compound of formula III and a corresponding compound of
formula IV, or pharmaceutically acceptable salts or esters thereof;
and
[0230] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
Pneumovirinae viruses.
[0231] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof, by
administering a therapeutically effective amount of a combination
pharmaceutical agent comprising:
[0232] a) a first pharmaceutical composition comprising a mixture
of a compound of formula IIIa and a corresponding compound of
formula IVa or pharmaceutically acceptable salts or esters thereof;
and
[0233] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
Pneumovirinae viruses.
[0234] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof, by
administering a therapeutically effective amount of a combination
pharmaceutical agent comprising:
[0235] a) a compound of formula II, IIa, III, IIIa, IV or IVa or a
pharmaceutically acceptable salt or ester thereof; and
[0236] b) a therapeutic agent active against infectious
Pneumovirinae viruses.
[0237] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof, by
administering a therapeutically effective amount of a combination
pharmaceutical agent comprising:
[0238] a) a mixture of a compound of formula III and a
corresponding compound of formula IV or pharmaceutically acceptable
salts or esters thereof; and
[0239] b) a therapeutic agent active against infectious
Pneumovirinae viruses.
[0240] One embodiment provides a method of treating a Pneumovirinae
infection in a mammal (e.g. a human) in need thereof, by
administering a therapeutically effective amount of a combination
pharmaceutical agent comprising:
[0241] a) a mixture of a compound of formula IIIa and a
corresponding compound of formula IVa or pharmaceutically
acceptable salts or esters thereof; and
[0242] b) a therapeutic agent active against infectious
Pneumovirinae viruses.
[0243] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof, by administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0244] a) a first pharmaceutical composition comprising a compound
of formula II, IIa, III, IIIa, IV or IVa or a pharmaceutically
acceptable salt or ester thereof; and
[0245] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
respiratory syncytial viruses.
[0246] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof, by administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0247] a) a mixture of a compound of formula III and a
corresponding compound of formula IV or pharmaceutically acceptable
salts or esters thereof; and
[0248] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
respiratory syncytial viruses.
[0249] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof, by administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0250] a) a mixture of a compound of formula IIIa and a
corresponding compound of formula IVa or a pharmaceutically
acceptable salt thereof a pharmaceutically acceptable salt or ester
thereof; and
[0251] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent active against infectious
respiratory syncytial viruses.
[0252] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof, by administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0253] a) a compound of formula II, IIa, III, IIIa, IV or IVa or a
pharmaceutically acceptable salt or ester thereof; and
[0254] b) a therapeutic agent active against infectious respiratory
syncytial viruses.
[0255] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof, by administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0256] a) a mixture of a compound of formula III and a
corresponding compound of formula IV or pharmaceutically acceptable
salts or esters thereof; and
[0257] b) a therapeutic agent active against infectious respiratory
syncytial viruses.
[0258] One embodiment provides a method of treating a respiratory
syncytial virus infection in a mammal (e.g. a human) in need
thereof, by administering a therapeutically effective amount of a
combination pharmaceutical agent comprising:
[0259] a) a mixture of a compound of formula IIIa and a
corresponding compound of formula IVa or pharmaceutically
acceptable salts or esters thereof; and
[0260] b) a therapeutic agent active against infectious respiratory
syncytial viruses.
[0261] One embodiment provides a compound of formula II, IIa, III,
IIIa, IV or IVa or a pharmaceutically acceptable salt or ester
thereof for use in medical therapy.
[0262] One embodiment provides a mixture of a compound of formula
III and a corresponding compound of formula IV a pharmaceutically
acceptable salts or esters thereof, for use in medical therapy.
[0263] One embodiment provides a mixture of a compound of formula
IIIa and a corresponding compound of formula IVa or
pharmaceutically acceptable salts or esters thereof, for use in
medical therapy.
[0264] One embodiment provides a compound of formula II, IIa, III,
IIIa, IV or IVa or a pharmaceutically acceptable salt or ester
thereof, for use in the prophylactic or therapeutic treat a viral
infection caused by a Pneumovirinae virus or a respiratory
syncytial virus.
[0265] One embodiment provides a mixture of a compound of formula
III and a corresponding compound of formula IV or pharmaceutically
acceptable salts or esters thereof, for use in the prophylactic or
therapeutic treat a viral infection caused by a Pneumovirinae virus
or a respiratory syncytial virus.
[0266] One embodiment provides a mixture of a compound of formula
IIIa and a corresponding compound of formula IVa or
pharmaceutically acceptable salts or esters thereof, for use in the
prophylactic or therapeutic treat a viral infection caused by a
Pneumovirinae virus or a respiratory syncytial virus.
[0267] One embodiment provides the use of a compound of formula II,
IIa, III, IIIa, IV or IVa or a pharmaceutically acceptable salt or
ester thereof, for the manufacture of a medicament useful for the
treatment of a viral infection in a mammal (e.g. a human) caused by
a Pneumovirinae virus or a respiratory syncytial virus.
[0268] One embodiment provides the use of a mixture of a compound
of formula III and a corresponding compound of formula IV or
pharmaceutically acceptable salts or esters thereof, for the
manufacture of a medicament useful for the treatment of a viral
infection in a mammal (e.g. a human) caused by a Pneumovirinae
virus or a respiratory syncytial virus.
[0269] One embodiment provides the use of a mixture of a compound
of formula IIIa and a corresponding compound of formula IVa or
pharmaceutically acceptable salts or esters thereof, for the
manufacture of a medicament useful for the treatment of a viral
infection in a mammal (e.g. a human) caused by a Pneumovirinae
virus or a respiratory syncytial virus.
[0270] In one embodiment a compound is selected from:
##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##
##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079##
##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084##
##STR00085## ##STR00086## ##STR00087## ##STR00088##
and salts and esters thereof.
[0271] One embodiment provides a compound selected from:
##STR00089##
[0272] wherein W is:
##STR00090## ##STR00091##
or a salt, or stereoisomer thereof.
[0273] In another embodiment the compound is selected from:
##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096##
##STR00097##
##STR00098##
wherein Y is selected from:
##STR00099## ##STR00100## ##STR00101## ##STR00102##
##STR00103##
or a salt, or stereoisomer thereof.
[0274] In another embodiment the compound is selected from:
##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108##
##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113##
##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118##
##STR00119##
and salts and esters thereof.
Esters of Compounds of the Invention.
[0275] The compounds disclosed herein also include "esters" of the
compounds of the invention. Accordingly, one example of esters of
the compounds of the invention include esters wherein a hydroxyl
group of the compound of the invention is an ester. These esters of
the invention are typically labile and thus the ester may be
converted to the corresponding hydroxyl group in vivo (e.g. after
administration). Esters include those esters based on carbon and
phosphorus.
[0276] Typical esters include: (R.sup.aO).sub.2P(.dbd.O)O--,
(HO).sub.2P(.dbd.O)O--, (C.sub.1-C.sub.8)alkyl(C.dbd.O)O--,
C.sub.6-C.sub.20aryl(C.dbd.O)O--,
C.sub.2-C.sub.20heterocyclyl(C.dbd.O)O-- or
(C.sub.4-C.sub.8)carbocyclylalkyl(C.dbd.O)O-- wherein each
(C.sub.1-C.sub.8)alkyl(C.dbd.O)O--, C.sub.6-C.sub.20
aryl(C.dbd.O)O--, C.sub.2-C.sub.20heterocyclyl(C.dbd.O)O-- or
(C.sub.4-C.sub.8)carbocyclylalkyl(C.dbd.O)O--, is independently,
optionally substituted with one or more oxo, halogen, hydroxy,
NH.sub.2, CN, N.sub.3, N(R.sup.a).sub.2, NHR.sup.a, SH, SR.sup.a,
S(O).sub.pR.sup.a, OR.sup.a, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2,
--C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a;
[0277] each R.sup.a is independently (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl
wherein any (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)alkenyl or (C.sub.2-C.sub.8)alkynyl of R.sup.a is
optionally substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl, and wherein any
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of R.sup.a is optionally
substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl or (C.sub.1-C.sub.8)alkyl; and
[0278] each p is 1 or 2.
[0279] It is to be understood that the point of connection of the
esters (R.sup.aO).sub.2P(.dbd.O)O--, (HO).sub.2P(.dbd.O)O--,
(C.sub.1-C.sub.8)alkyl(C.dbd.O)O--, C.sub.6-C.sub.20
aryl(C.dbd.O)O--, C.sub.2-C.sub.20 heterocyclyl(C.dbd.O)O-- and
(C.sub.4-C.sub.8)carbocyclylalkyl(C.dbd.O)O-- to the compound of
the invention is through the oxygen of the ester.
[0280] In one embodiment the compounds of formula I include
compounds of formula Ib
##STR00120##
[0281] or a salt or ester, thereof;
wherein:
[0282] A is --(C(R.sup.4).sub.2).sub.n-- wherein any one
C(R.sup.4).sub.2 of said --(C(R.sup.4).sub.2).sub.n-- may be
optionally replaced with --O--, --S--, --S(O).sub.p--, NH or
NR.sup.a;
[0283] n is 3, 4, 5 or 6;
[0284] each p is 1 or 2;
[0285] Ar is a C.sub.2-C.sub.20 heterocyclyl group or a
C.sub.6-C.sub.20 aryl group, wherein the C.sub.2-C.sub.20
heterocyclyl group or the C.sub.6-C.sub.20 aryl group is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.6;
[0286] each R.sup.3, R.sup.4 or R.sup.6 is independently H, oxo,
OR.sup.11, NR.sup.11R.sup.12, NR.sup.11C(O)R.sup.11,
NR.sup.11C(O)OR.sup.11, NR.sup.11C(O)NR.sup.11R.sup.12, N.sub.3,
CN, NO.sub.2, SR.sup.11, S(O).sub.pR.sup.a,
NR.sup.11S(O).sub.pR.sup.a, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)SR.sup.11, --S(O)(OR.sup.11),
--SO.sub.2NR.sup.11R.sup.12, --NR.sup.11S(O).sub.p(OR.sup.11),
--NR.sup.11SO.sub.pNR.sup.11R.sup.12,
NR.sup.11C(.dbd.NR.sup.11)NR.sup.11R.sup.12, halogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl;
[0287] two R.sup.4 on adjacent carbon atoms, when taken together,
may optionally form a double bond between the two carbons to which
they are attached or may form a (C.sub.3-C.sub.7)cycloalkyl ring
wherein one carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring
may be optionally replaced by --O--, --S--, --S(O).sub.p--, --NH--
or --NR.sup.a--;
[0288] four R.sup.4 on adjacent carbon atoms, when taken together,
may optionally form an optionally substituted C.sub.6 aryl
ring;
[0289] two R.sup.4 on the same carbon atom, when taken together,
may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring wherein one
carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be
optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or
--NR.sup.a--;
[0290] two R.sup.6 on adjacent carbon atoms, when taken together,
may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring wherein one
carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be
optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or
--NR.sup.a--;
[0291] each R.sup.11 is independently (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl
wherein any (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)alkenyl or (C.sub.2-C.sub.8)alkynyl of R.sup.a is
optionally substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl, and wherein any
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of R.sup.a is optionally
substituted with one or more OH, NH.sub.2, CO.sub.2H,
C.sub.2-C.sub.20 heterocyclyl or (C.sub.1-C.sub.8)alkyl;
[0292] each R.sup.11 or R.sup.12 is independently H,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.4-C.sub.8)carbocyclylalkyl,
--C(.dbd.O)R.sup.a, --S(O).sub.pR.sup.a, or
aryl(C.sub.1-C.sub.8)alkyl; or R.sup.11 and R.sup.12 taken together
with a nitrogen to which they are both attached form a 3 to 7
membered heterocyclic ring wherein any one carbon atom of said
heterocyclic ring can optionally be replaced with --O--, --S--,
--S(O).sub.p--, --NH--, --NR.sup.a-- or --C(O)--;
[0293] wherein each (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20
heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or
(C.sub.4-C.sub.8)carbocyclylalkyl of each R.sup.6, R.sup.11 or
R.sup.12 is, independently, optionally substituted with one or more
oxo, halogen, hydroxy, NH.sub.2, CN, N.sub.3, N(R.sup.a).sub.2,
NHR.sup.a, SH, SR.sup.a, S(O).sub.pR.sup.a, OR.sup.a,
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a,
--C(O)H, --C(.dbd.O)OR.sup.a, --C(.dbd.O)OH,
--C(.dbd.O)N(R.sup.a).sub.2, --C(.dbd.O)NHR.sup.a,
--C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a), NR.sup.aC(O)NH.sub.2, NHC(O)NHR.sup.a,
NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, --NH, --NOH,
.dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a), NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a; and
[0294] R.sup.x is H, (R.sup.aO).sub.2P(.dbd.O)--,
(HO).sub.2P(.dbd.O)O--, (C.sub.1-C.sub.8)alkyl(C.dbd.O)--,
C.sub.6-C.sub.20 aryl(C.dbd.O)--,
C.sub.2-C.sub.20heterocyclyl(C.dbd.O)-- or
(C.sub.4-C.sub.8)carbocyclylalkyl(C.dbd.O)--, wherein each
(C.sub.1-C.sub.8)alkyl(C.dbd.O)--, C.sub.6-C.sub.20
aryl(C.dbd.O)--, C.sub.2-C.sub.20 heterocyclyl(C.dbd.O)-- or
(C.sub.4-C.sub.8)carbocyclylalkyl(C.dbd.O)-- is independently,
optionally substituted with one or more oxo, halogen, hydroxy,
NH.sub.2, CN, N.sub.3, N(R.sup.a).sub.2, NHR.sup.a, SH, SR.sup.a,
S(O).sub.pR.sup.a, OR.sup.a, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2,
--C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.a;
[0295] provided the compound is not:
##STR00121##
[0296] A specific value for R.sup.x is H, (HO).sub.2P(.dbd.O)--,
(C.sub.1-C.sub.8)alkyl(C.dbd.O)-- or
C.sub.2-C.sub.20heterocyclyl(C.dbd.O)--, wherein each
(C.sub.1-C.sub.8)alkyl(C.dbd.O)-- or
C.sub.2-C.sub.20heterocycyl(C.dbd.O)-- is independently, optionally
substituted with one or more oxo, halogen, hydroxy, NH.sub.2, CN,
N.sub.3, N(R.sup.a).sub.2, NHR.sup.a, SH, SR.sup.a,
S(O).sub.pR.sup.a, OR.sup.a, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2,
--C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, NHS(O).sub.pR.sup.a,
NR.sup.aS(O).sub.pR.sup.a, NHC(O)R.sup.a, NR.sup.aC(O)R.sup.a,
NHC(O)OR.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)NHR.sup.a,
NR.sup.aC(O)N(R.sup.a).sub.2, NR.sup.aC(O)NH.sub.2,
NHC(O)NHR.sup.a, NHC(O)N(R.sup.a).sub.2, NHC(O)NH.sub.2, .dbd.NH,
.dbd.NOH, .dbd.NOR.sup.a, NR.sup.aS(O).sub.pNHR.sup.a,
NR.sup.aS(O).sub.pN(R.sup.a).sub.2, NR.sup.aS(O).sub.pNH.sub.2,
NHS(O).sub.pNHR.sup.a, NHS(O).sub.pN(R.sup.a).sub.2,
NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or
R.sup.8.
[0297] Another specific value for R.sup.x is H,
(HO).sub.2P(.dbd.O)--, (C.sub.1-C.sub.8)alkyl(C.dbd.O)-- or
C.sub.2-C.sub.20heterocyclyl(C.dbd.O)--, wherein each
(C.sub.1-C.sub.8)alkyl(C.dbd.O)-- or
C.sub.2-C.sub.20heterocyclyl(C.dbd.O)-- is independently,
optionally substituted with one or more NH.sub.2, --C(.dbd.O)OH or
NR.sup.aC(O)R.sup.a.
[0298] Another specific value for R.sup.x is:
##STR00122##
Preparation of Compounds of the Invention
[0299] The compounds of formulas I and Ia were be prepared by the
procedures described in examples 3, 4 and 6-31. The compounds of
formulas 1-24 (i.e. compounds of formula V) were prepared by the
procedures described in example 1 and example 4. The compounds of
formulas 25-111 (i.e. compounds of formula VI) were prepared by the
procedures described in examples 2, 4 and 5.
[0300] The compounds of formula II and IIa can be prepared
following the procedures described in examples 3, 4, 5 and 6 by
using intermediate 9b instead of intermediate 9a.
[0301] The compounds of formulas III, IIIa, IV and IVa can be
prepared following the procedures described in examples 3, 4, 5 and
6 by using the enantiomers of trans-3-cyano-4-hydroxypyrrolidine
instead of the cis enantiomers. The enantiomers of
trans-3-cyano-4-hydroxypyrrolidine can be prepared following
literature procedures (Schauss, S. E., et al., Organic Letters,
2(7), 2000, pages 1001-1004).
Pharmaceutical Formulations
[0302] The compounds of this invention 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.
[0303] 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, of the invention 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.
[0304] 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.
[0305] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the
active ingredient; as a powder or granules; as 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.
[0306] 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.
[0307] 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.
[0308] 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.
[0309] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
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.
[0310] Emulgents and emulsion stabilizers suitable for use in the
formulation of the invention include Tween.RTM. 60, Span.RTM. 80,
cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl
mono-stearate and sodium lauryl sulfate.
[0311] 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.
[0312] Pharmaceutical formulations according to the present
invention comprise a combination according to the invention
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, 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.
[0313] 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.
[0314] Aqueous suspensions of the invention 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.
[0315] 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.
[0316] Dispersible powders and granules of the invention 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.
[0317] The pharmaceutical compositions of the invention 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.
[0318] The pharmaceutical compositions of the invention may be in
the form of a sterile injectable preparation, 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 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.
[0319] 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.
[0320] 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.
[0321] 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.
[0322] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0323] 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.
[0324] In another aspect, the invention is a novel, efficacious,
safe, nonirritating and physiologically compatible inhalable
composition comprising a compound of formula I or a compound of
formulas 1-111, 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 formula I or
formulas 1-111 is formulated for aerosol delivery using a
nebulizer, pressurized metered dose inhaler (pMDI), or dry powder
inhaler (DPI).
[0325] 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.
[0326] 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 formula I or formulas 1-111 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
pun. If an aerosol contains a large number of particles with a MMAD
larger than 5 un, 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 nm, then the particles have
a tendency to remain suspended in the inhaled air and are
subsequently exhaled during expiration.
[0327] When formulated and delivered according to the method of the
invention, the aerosol formulation for nebulization delivers a
therapeutically efficacious dose of the compound of formula I or
formulas 1-111 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 formula I or
formulas 1-111. 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
formula I or formulas 1-111 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.
[0328] In another embodiment of the instant invention, a compound
of formula I or formulas 1-111 or a pharmaceutically acceptable
salt thereof, is delivered as a dry inhalable powder. The compounds
of the invention 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 formula I or formulas 1-111 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 formula I or formulas 1-111
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.
[0329] 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.
[0330] In another preferred embodiment, a compound of formula I or
formulas 1-111 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. No. 5,458,135; U.S. Pat. No.
5,740,794; U.S. Pat. No. 5,775,320; U.S. Pat. No. 5,785,049; U.S.
Pat. No. 3,906,950; U.S. Pat. No. 4,013,075; U.S. Pat. No.
4,069,819; U.S. Pat. No. 4,995,385; U.S. Pat. No. 5,522,385; U.S.
Pat. No. 4,668,218; U.S. Pat. No. 4,667,668; U.S. Pat. No.
4,805,811 and U.S. Pat. No. 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 formula I or formulas 1-111, 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.
[0331] In another preferred embodiment, a compound of formula I or
formulas 1-111 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. No. 5,261,538; U.S. Pat. No.
5,544,647; U.S. Pat. No. 5,622,163; U.S. Pat. No. 4,955,371; U.S.
Pat. No. 3,565,070; U.S. Pat. No. 3,361,306 and U.S. Pat. No.
6,116,234. In preferred embodiments, a compound of formula I or
formulas 1-111, 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.
[0332] 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.
[0333] 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.
[0334] 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.
[0335] It should be understood that in addition to the ingredients
particularly mentioned above the formulations of this invention may
include other agents conventional in the art having regard to the
type of formulation in question, for example those suitable for
oral administration may include flavoring agents.
[0336] The invention further provides veterinary compositions
comprising at least one active ingredient as above defined together
with a veterinary carrier therefor.
[0337] 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.
[0338] Compounds of the invention are used to provide controlled
release pharmaceutical formulations containing as active ingredient
one or more compounds of the invention ("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.
[0339] 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
[0340] One or more compounds of the invention (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 of this invention is that they are orally
bioavailable and can be dosed orally.
Combination Therapy
[0341] Compositions of the invention 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.
[0342] 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 formula I or formulas
1-111. The additional agents are preferably administered orally or
by direct inhalation. For example, other preferred additional
therapeutic agents in combination with the compounds of formula I
or formulas 1-111 for the treatment of viral respiratory infections
include, but are not limited to, bronchodilators and
corticosteroids.
[0343] 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 formula I or compounds of formulas 1-111 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.
[0344] Other anti-inflamatory agents working through
anti-inflamatory cascade mechanisms are also useful as additional
therapeutic agents in combination with the compounds of formula I
or the compounds of formulas 1-111 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, P13K, 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).
[0345] Combinations comprising inhaled .beta.2-adrenoreceptor
agonist bronchodilators such as formoterol, albuterol or salmeterol
with the compounds of formula I or formulas 1-111 are also
suitable, but non-limiting, combinations useful for the treatment
of respiratory viral infections.
[0346] 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 formula I or
formulas 1-111 are also suitable, but non-limiting, combinations
useful for the treatment of respiratory viral infections.
[0347] 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 formula I or formulas 1-111 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]-pyrrolidine-2-car-
bonyl}-pyrrolidine-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);
I-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.
[0348] The compounds of formula I or formulas 1-111 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 formula I
or formulas 1-111 may be combined with expectorants to treat both
the infection and symptoms of respiratory infections. A
non-limiting example of an expectorant is guaifenesin.
[0349] 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 formula I or
formulas 1-111 may also be combined with nebulized hypertonic
saline particularly when the Pneumovirinae virus infection is
complicated with bronchiolitis. The combination of the compounds of
formula I or formulas 1-111 with hypertonic saline may also
comprise any of the additional agents discussed above. In a
preferred aspect, nebulized about 3% hypertonic saline is used.
[0350] It is also possible to combine any compound of the invention
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.
[0351] Co-administration of a compound of the invention with one or
more other active therapeutic agents generally refers to
simultaneous or sequential administration of a compound of the
invention and one or more other active therapeutic agents, such
that therapeutically effective amounts of the compound of the
invention and one or more other active therapeutic agents are both
present in the body of the patient.
[0352] Co-administration includes administration of unit dosages of
the compounds of the invention before or after administration of
unit dosages of one or more other active therapeutic agents, for
example, administration of the compounds of the invention within
seconds, minutes, or hours of the administration of one or more
other active therapeutic agents. For example, a unit dose of a
compound of the invention 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 of the
invention within seconds or minutes. In some cases, it may be
desirable to administer a unit dose of a compound of the invention
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 of the
invention.
[0353] 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.
[0354] Another embodiment provides for methods of treating
Pneumovirinae virus infection in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of formula I or formulas 1-111, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof.
[0355] Another embodiment provides for methods of treating
Pneumovirinae virus infection in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of formula I or formulas 1-111, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, and at least one
additional active therapeutic agent.
[0356] Another embodiment provides for methods of treating Human
respiratory syncytial virus infection in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of formula I or formulas 1-111, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, and at least one
additional active therapeutic agent.
Metabolites of the Compounds of the Invention
[0357] Also falling within the scope of this invention 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, the invention includes novel and unobvious compounds
produced by a process comprising contacting a compound of this
invention with a mammal for a period of time sufficient to yield a
metabolic product thereof. Such products typically are identified
by preparing a radiolabelled (e.g. .sup.14C or .sup.3H) compound of
the invention, 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 of the invention even if
they possess no HSV antiviral activity of their own.
[0358] 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 of the invention 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.
Tissue Distribution
[0359] It has also been discovered that certain compounds of the
invention show high lung to plasma ratios which may be beneficial
for therapy. One particular group of compounds of the invention
that demonstrate this property are compounds that include an amine
functional group.
EXAMPLES
[0360] Certain abbreviations and acronyms are used in describing
the experimental details. Although most of these would be
understood by one skilled in the art, Table 1 contains a list of
many of these abbreviations and acronyms.
TABLE-US-00001 TABLE 1 List of abbreviations and acronyms.
Abbreviation Meaning Ac.sub.2O acetic anhydride AIBN
2,2'-azobis(2-methylpropionitrile) Bn benzyl BnBr benzylbromide BSA
bis(trimethylsilyl)acetamide BzCl benzoyl chloride CDI carbonyl
diimidazole DABCO 1,4-diazabicyclo[2.2.2]octane DBN
1,5-diazabicyclo[4.3.0]non-5-ene DDQ
2,3-dichloro-5,6-dicyano-1,4-benzoquinone DBU
1,5-diazabicyclo[5.4.0]undec-5-ene DCA dichloroacetamide DCC
dicyclohexylcarbodiimide DCM dichloromethane DIPEA
N,N-diisopropylethylamine DMA dimethylacetamide DMAP
4-dimethylaminopyridine DME 1,2-dimethoxyethane DMTCl
dimethoxytrityl chloride DMSO dimethylsulfoxide DMTr
4,4'-dimethoxytrityl DMF dimethylformamide EtOAc ethyl acetate ESI
electrospray ionization HATU
2-(1H-7-azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uronium
hexafluorophosphate Methanaminium HMDS hexamethyldisilazane HPLC
High pressure liquid chromatography IPA isopropyl alcohol LDA
lithium diisopropylamide LRMS low resolution mass spectrum MCPBA
meta-chloroperbenzoic acid MeCN acetonitrile MeOH methanol MMTC
mono methoxytrityl chloride m/z or m/e mass to charge ratio
MH.sup.+ mass plus 1 MH.sup.- mass minus 1 MsOH methanesulfonic
acid MS or ms mass spectrum NBS N-bromosuccinimide Ph phenyl rt or
r.t. room temperature TBAF tetrabutylammonium fluoride TMSCl
chlorotrimethylsilane TMSBr bromotrimethylsilane TMSI
iodotrimethylsilane TMSOTf (trimethylsilyl)trifluoromethylsulfonate
TEA triethylamine TBA tributylamine TBAP tributylammonium
pyrophosphate TBSCl t-butyldimethylsilyl chloride TEAB
triethylammonium bicarbonate TFA trifluoroacetic acid TLC or tlc
thin layer chromatography Tr triphenylmethyl Tol 4-methylbenzoyl
Turbo 1:1 mixture of isopropylmagnesium chloride and Grignard
lithium chloride .delta. parts per million down field from
tetramethylsilane
[0361] The invention will now be illustrated by the preparation of
the following non-limiting compounds of the invention. It is to be
understood that individual steps described herein may be combined.
It is also to be understood that separate batches of a compound may
be combined and then carried forth in the next synthetic step.
Example 1
Procedure for the Preparation of Compounds of Formulas 1-24
##STR00123##
[0363] In 50 mL, singled necked, round bottomed flask was placed
(s)-N-(4-chloro-2-(2-(5-chloro-6-methylpyrazolo[1,5-a]pyrimidine-2-yl)pip-
eridine-1-carbonyl)phenyl)methanesulfonamide (A1), (1200 mg, 2.49
mmol) in DMA (10.8 mL). The amines (R-(Boc)) (0.12 mmol) were
placed in separate 2-ml vials. Then, into each vial was dispensed a
solution of A1 (0.2 mL, 0.041 mmol) followed by 0.1 mL of
K.sub.2CO.sub.3 (2M) or DIPEA. The resulting reaction mixtures were
placed on a hot plate at 85.degree. C. for 16 h. Then, to each
reaction mixture was added EtOAc (4 mL), washed with saturated
NaHCO.sub.3 (2 mL.times.2), and concentrated in Genevac to give A2
as a solid. The crude product A2 was redissolved in dichloromethane
(0.5 mL) followed by the addition of TFA (0.2 mL). After the
reaction mixture was stirred at room temperature for 1 h, it was
loaded onto the CUBCX column. The mixture was washed with
MeOH:EtOAc (1:4, 4 mL) and MeOH:dichloromethane (1:4, 4 mL), eluted
with 7 N NH.sub.4OMe:EtOAc (3:7, 4 mL), and concentrated to afford
the final compound (i.e. compounds 1-24).
TABLE-US-00002 Compound calculated observed Formula Compound MW MW
1 ##STR00124## 520.056 520.5 2 ##STR00125## 532.067 532.5 3
##STR00126## 582.127 582.6 4 ##STR00127## 608.165 608.6 5
##STR00128## 520.056 520.2 6 ##STR00129## 532.067 532.5 7
##STR00130## 546.094 546.6 8 ##STR00131## 582.127 582.5 9
##STR00132## 590.103 590.6 10 ##STR00133## 546.094 546.6 11
##STR00134## 546.094 546.6 12 ##STR00135## 590.103 590.6 13
##STR00136## 652.218 652.7 14 ##STR00137## 576.076 576.5 15
##STR00138## 560.121 560.6 16 ##STR00139## 558.105 558.6 17
##STR00140## 622.192 622.7 18 ##STR00141## 544.078 544.6 19
##STR00142## 576.076 576.6 20 ##STR00143## 560.121 560.6 21
##STR00144## 558.105 558.5 22 ##STR00145## 574.148 574.6 23
##STR00146## 589.119 589.6 24 ##STR00147## 560.121 560.5
Example 2
General Procedure for the Preparation of Compounds of Formulas
25-111
##STR00148##
[0365] In 50 mL, singled necked, round bottomed flask was placed
tert-butyl
(S)-1-(6-methyl-2-((S)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrro-
lidin-3-ylcarbamate (B1) (2640 mg, 6.59 mmol) and TEA (1.83 mL,
13.2 mmol) in DMF (8.8 mL). The carboxylic acids B2 (between 0.10
mmol and 0.50 mmol) were placed in 132 separate 2-ml vials. Then,
into each vial was dispensed a solution of B1 (0.050 mmol) followed
by the addition of HATU (38 mg, 0.10 mmol). The resulting reaction
mixtures were placed on an orbital shaker at room temperature for
16 h. Then, to each reaction mixture was added EtOAc (4 mL), washed
with sat. NaHCO.sub.3 (2 mL.times.2), and concentrated in Genevac
to give B3 as a solid. The crude product B3 was redissolved in
dichloromethane (0.5 mL) followed by the addition of TFA (0.2 mL).
After the reaction mixture was stirred at room temperature for 1 h,
it was loaded onto the CUBCX column. The mixture was washed with
MeOH:EtOAc (1:4, 4 mL) and MeOH:dichloromethane (1:4, 4 mL), eluted
with 7 N NH.sub.4OMe:EtOAc (3:7, 4 mL), and concentrated to afford
the final compound (i.e. compounds 25-111).
TABLE-US-00003 Compound calculated observed formula Structure MW MW
25 ##STR00149## 436.535 437.6 26 ##STR00150## 423.496 424.5 27
##STR00151## 434.544 435.6 28 ##STR00152## 492.933 493.5 29
##STR00153## 513.621 514.6 30 ##STR00154## 456.953 457.5 31
##STR00155## 458.61 459.6 32 ##STR00156## 447.518 448.6 33
##STR00157## 454.525 455.5 34 ##STR00158## 490.652 491.7 35
##STR00159## 486.542 487.6 36 ##STR00160## 486.542 487.6 37
##STR00161## 506.504 507.6 38 ##STR00162## 444.543 445.6 39
##STR00163## 454.525 455.5 40 ##STR00164## 478.988 479.6 41
##STR00165## 456.554 457.6 42 ##STR00166## 481.604 482.6 43
##STR00167## 444.543 445.5 44 ##STR00168## 490.505 491.5 45
##STR00169## 483.595 484.6 46 ##STR00170## 455.566 456.6 47
##STR00171## 486.58 487.6 48 ##STR00172## 480.544 481.6 49
##STR00173## 452.99 453.5 50 ##STR00174## 456.554 457.6 51
##STR00175## 474.609 475.6 52 ##STR00176## 473.556 474.6 53
##STR00177## 485.636 486.6 54 ##STR00178## 444.543 445.6 55
##STR00179## 474.573 475.6 56 ##STR00180## 478.988 479.6 57
##STR00181## 509.561 510.6 58 ##STR00182## 496.634 497.2 59
##STR00183## 497.622 498.6 60 ##STR00184## 459.598 460.6 61
##STR00185## 448.527 449.5 62 ##STR00186## 502.598 503.6 63
##STR00187## 497.043 497.6 64 ##STR00188## 458.57 459.6 65
##STR00189## 475.553 476.5 66 ##STR00190## 488.636 489.6 67
##STR00191## 514.624 515.6 68 ##STR00192## 455.566 456.6 69
##STR00193## 438.963 439.5 70 ##STR00194## 435.532 436.6 71
##STR00195## 423.496 424.5 72 ##STR00196## 454.525 455.6 73
##STR00197## 440.498 441.5 74 ##STR00198## 474.396 474.5 75
##STR00199## 454.525 455.5 76 ##STR00200## 484.407 484.5 77
##STR00201## 436.535 437.5 78 ##STR00202## 436.535 437.6 79
##STR00203## 440.498 441.5 80 ##STR00204## 481.604 482.6 81
##STR00205## 423.496 424.2 82 ##STR00206## 456.953 457.5 83
##STR00207## 439.951 440.5 84 ##STR00208## 448.571 449.6 85
##STR00209## 462.598 463.6 86 ##STR00210## 473.503 474.6 87
##STR00211## 432.572 433.6 88 ##STR00212## 432.572 433.6 89
##STR00213## 452.99 453.5 90 ##STR00214## 497.446 497.5 91
##STR00215## 436.535 437.6 92 ##STR00216## 448.571 449.6 93
##STR00217## 439.951 440.5 94 ##STR00218## 484.604 485.6 95
##STR00219## 504.038 504.6 96 ##STR00220## 455.566 456.6 97
##STR00221## 484.604 485.6 98 ##STR00222## 458.57 459.6 99
##STR00223## 539.505 539.5 100 ##STR00224## 474.396 474.5 101
##STR00225## 445.531 446.5 102 ##STR00226## 506.014 506.6 103
##STR00227## 466.608 467.5 104 ##STR00228## 507.948 508.5 105
##STR00229## 507.948 508.5 106 ##STR00230## 506.96 507.5 107
##STR00231## 453.522 454.6 108 ##STR00232## 444.543 445.2 109
##STR00233## 490.505 491.6 110 ##STR00234## 433.56 434.5 111
##STR00235## 452.534 453.5
Example 3
General Procedure for the Preparation of Compounds 112-191
##STR00236##
[0367] In 50 mL, singled necked, round bottomed flask was placed
tert-butyl
(3S,4R)-4-hydroxy-1-(6-methyl-2-((S)-piperidin-2-yl)pyrazolo[1,5-a]pyrimi-
din-5-yl)pyrrolidine-3-carbonitrile (C1) (1932 mg, 5.90 mmol) and
TEA (1.64 mL, 11.8 mmol) in DMF (13 mL). The carboxylic acids C2
0.040 mmol) were placed in separate 2-ml vials. Then, into each
vial was dispensed a solution of C1 (0.037 mmol) followed by the
addition of HATU (15.2 mg, 0.04 mmol). The resulting reaction
mixtures were placed on an orbital shaker at room temperature for
16 h. Then, to each reaction mixture was added EtOAc (4 mL), washed
with sat. NaHCO.sub.3 (2 mL.times.2), and concentrated in Genevac.
Then, it was loaded onto the CUSIL column, washed with EtOAc:Hexane
(1:1, 4 mL), eluted with MeOH:EtOAc (5:95, 3 mL), and concentrated
in Genevac to give the final compound (i.e. compounds 112-191).
TABLE-US-00004 Compound calculated formula Compound MW observed MW
112 ##STR00237## 523.44 523.4 113 ##STR00238## 460.538 461.5 114
##STR00239## 518.927 519.4 115 ##STR00240## 465.945 466.4 116
##STR00241## 482.947 483.4 117 ##STR00242## 473.512 474.5 118
##STR00243## 480.519 481.5 119 ##STR00244## 516.646 517.6 120
##STR00245## 512.536 513.5 121 ##STR00246## 512.536 513.5 122
##STR00247## 532.498 533.5 123 ##STR00248## 470.537 471.5 124
##STR00249## 480.519 481.5 125 ##STR00250## 507.598 508.5 126
##STR00251## 478.528 479.5 127 ##STR00252## 482.548 483.5 128
##STR00253## 507.598 508.5 129 ##STR00254## 512.574 513.5 130
##STR00255## 506.538 507.5 131 ##STR00256## 478.984 479.5 132
##STR00257## 500.603 501.5 133 ##STR00258## 499.55 500.5 134
##STR00259## 511.63 512.5 135 ##STR00260## 470.537 471.5 136
##STR00261## 504.982 505.4 137 ##STR00262## 535.555 536.5 138
##STR00263## 522.628 523.5 139 ##STR00264## 485.592 486.5 140
##STR00265## 474.521 475.5 141 ##STR00266## 528.592 528.5 142
##STR00267## 523.037 523.5 143 ##STR00268## 484.564 485.5 144
##STR00269## 514.63 515.6 145 ##STR00270## 540.618 541.5 146
##STR00271## 464.957 465.4 147 ##STR00272## 461.526 462.4 148
##STR00273## 499.497 500.5 149 ##STR00274## 480.519 481.5 150
##STR00275## 466.492 467.5 151 ##STR00276## 469.549 470.5 152
##STR00277## 500.39 500.5 153 ##STR00278## 480.519 481.5 154
##STR00279## 510.401 510.4 155 ##STR00280## 462.529 463.5 156
##STR00281## 462.529 463.5 157 ##STR00282## 466.492 467.2 158
##STR00283## 507.598 508.5 159 ##STR00284## 445.527 446.2 160
##STR00285## 449.49 450.2 161 ##STR00286## 557.396 558.1 162
##STR00287## 484.604 485.3 163 ##STR00288## 481.56 482.2 164
##STR00289## 456.51 457.2 165 ##STR00290## 474.565 475.2 166
##STR00291## 460.538 462.2 167 ##STR00292## 488.592 489.5 168
##STR00293## 499.497 500.5 169 ##STR00294## 458.566 459.5 170
##STR00295## 478.984 479.5 171 ##STR00296## 523.44 523.4 172
##STR00297## 462.529 463.5 173 ##STR00298## 474.565 475.5 174
##STR00299## 510.598 511.5 175 ##STR00300## 470.537 471.5 176
##STR00301## 445.527 446.5 177 ##STR00302## 499.402 499.4 178
##STR00303## 466.564 467.5 179 ##STR00304## 445.527 446.5 180
##STR00305## 506.61 507.5 181 ##STR00306## 436.538 437.4 182
##STR00307## 482.976 483.5 183 ##STR00308## 490.63 491.5 184
##STR00309## 498.509 499.5 185 ##STR00310## 483.576 484.5 186
##STR00311## 482.947 483.4 187 ##STR00312## 484.564 485.5 188
##STR00313## 494.983 495.5 189 ##STR00314## 502.501 503.5 190
##STR00315## 497.003 497.5 191 ##STR00316## 513.606 514.5
Example 4
Procedure for the Preparation of Intermediate A1
Intermediate 1
##STR00317##
[0369] N-Boc-(S)-piperidine-2-carboxylic acid (5.0 g, 22 mmol) in
DMF (100 mL) was treated with Cs.sub.2CO.sub.3 (3.5 g, 10.9 mmol)
and MeI (1.5 mL, 24 mmol). The mixture was stirred for 4 hours and
diluted with MTBE (250 mL). The mixture was washed with water
(2.times.100 mL) and saturated sodium chloride solution
(1.times.100 mL). The solution was dried over anhydrous sodium
sulfate and concentrated to afford the ester intermediate 1 which
was used without further purification.
[0370] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 4.80 (m, 1H),
3.97 (m, 1H), 3.73 (s, 3H), 2.93 (m, 1H), 2.18 (app d, J=13.2 Hz,
1H), 1.67 (m, 2H), 1.45 (br s, 10H), 1.20 (app t, J=13.5 Hz,
1H).
[0371] R.sub.f=0.90 (30% EtOAc-hexanes).
Intermediate 2
##STR00318##
[0373] (S)-1-Boc-piperidine-2-carboxylic acid (25 g, 109 mmol,
Sigma-Aldrich) in DMF (500 mL) was treated sequentially with
MeNHOMe.HCl (11.2 g, 115 mmol), N-methylmorpholine (36 mL, 327
mmol), HOBt (16.2 g, 120 mmol), and EDCI (23 g, 120 mmol) and
stirred for 18 h. The solution was diluted with EtOAc (1000 mL) and
washed with H.sub.2O (2.times.500 mL) and saturated NaCl solution
(500 mL). The solution was dried over MgSO.sub.4, filtered and
concentrated. The residue was subjected to a 330 g SiO.sub.2
Combiflash High Performance Gold column (0-100% EtOAc-hexanes
gradient) to afford the Weinreb amide intermediate 2:
[0374] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 5.06 (br m, 1H),
3.93 (br m, 1H), 3.77 (br s, 3H), 3.18 (s, 3H), 2.01 (app d, J=13.5
Hz, 1H), 1.71 (m, 4H), 1.45 (s, 9H).
[0375] LCMS (ESI) m/z 273 [M+H].sup.+, t.sub.R=2.31 min.
[0376] HPLC (RP: 6-98% MeCN--H.sub.2O gradient, 0.05% TFA modifier)
t.sub.R=4.423 min.
[0377] R.sub.f=0.60 (50% EtOAc-hexanes).
Intermediate 3
##STR00319##
[0379] To a solution of acetonitrile (5 ml, 93.8 mmol) in dry THF
(50 ml) at -78.degree. C. was added dropwise NaN(TMS).sub.2 (34 ml,
68 mmol, 2M in hexanes). The solution was warmed up to -40.degree.
C. and stirred for 20 min. The solution was then cooled down to
-78.degree. C. and a solution of the ester (Intermediate 1) (7.6 g,
31.1 mmol) in THF (20 ml) was added dropwise. The solution was
warmed up to -40.degree. C. and stirred for 2 h. The solution was
then cooled down to -78.degree. C. and a solution of acetic acid
(4.8 ml, 80 mmol) in THF (20 ml) added dropwise. The solution was
then warmed to RT and volatiles were removed under reduced pressure
at 40.degree. C. The resulting residue was dissolved in EtOAc (300
mL) and the organic phase was washed with brine twice. Volatiles
were removed under reduced pressure at 40.degree. C.
[0380] .sup.1H NMR (DMSO, 300 MHz) .delta. 4.63 (br s, 1H),
4.18-4.13 (m, 1H), 3.82-3.78 (m, 1H), 3.65 (s, 2H), 2.85-2.63 (m,
1H), 1.65-1.52 (m, 9H), 1.38 (s, 9H).
[0381] LCMS m/z: 153 [M-Boc group+H], t.sub.R=2.50 min.
[0382] The residue was dissolved in EtOH (150 ml) and hydrazine
acetate (4.5 g, 47 mmol) was added. The solution was stirred for 16
h at RT. Volatiles were removed under reduced pressure at
40.degree. C., EtOAc added (200 mil) and the organic phase washed
with aqueous dilute NaHCO.sub.3, then H.sub.2O followed by brine.
Volatiles were removed under reduced pressure at 40.degree. C., the
resulting residue was purified by silica gel column (DCM/MeOH,
gradient from 0% to 20%) to afford the product intermediate.
[0383] LCMS m/z [M+H].sup.+ C.sub.13H.sub.22N.sub.4O.sub.2
requires: 266.34. Found 266.84.
[0384] HPLC (min, purity) t.sub.R=2.13, 100%.
[0385] .sup.1H NMR (DMSO, 300 MHz) 11.20 (br s, 1H), 5.09 (m, 1H),
5.07 (s, 1H), 4.67 (br s, 2H), 3.81 (app d, J=12.0 Hz, 1H), 2.72
(app br t, J=12.0 Hz, 1H), 2.08 (app d, J=12.9 Hz, 1H), 1.57 (m,
4H), 1.39 (s, 9H); MS (ESI) m/z 267 [M+H].sup.+, t.sub.R=1.97 min.
(3.5 min method); HPLC (Chiral: Chiralpak AD-H, isocratic
n-heptane-isopropanol 70:30). t.sub.R (desired)=22.42 min, t.sub.R
(enantiomer of desired isomer)=25.67 min; %/ee=93.
Intermediate 3 via Weinreb Amide
##STR00320##
[0387] MeCN (3.20 mL, 60.7 mmol) in THF (50 mL) was cooled to
-78.degree. C. under Ar. NaHMDS solution (1.0 M in THF, 36.8 mL,
36.8 mmol) was added dropwise over 5 min, during which time an
off-white suspension had formed. The suspension was warmed to
-20.degree. C. and stirred for 20 min. The suspension was cooled to
-78.degree. C. and transferred via cannula to the Weinreb amide
intermediate 2 (5.02 g, 18.4 mmol) in THF (50 mL) at -78.degree. C.
over 5 min. The suspension is warmed to -45.degree. C. and stirred
for 3 h, during which time the suspension became a yellow solution.
The solution was cooled to -78.degree. C. and AcOH (4.2 mL in 10 mL
THF, 73.6 mmol) was added dropwise. The solution was warmed to room
temperature and diluted with EtOAc (100 mL). The solution was
washed with H.sub.2O (50 mL) and saturated NaCl solution (50 mL).
The solution was dried over MgSO.sub.4 and concentrated to afford
the cyano ketone which was used without further purification.
[0388] The crude .alpha.-cyano ketone was used in the next reaction
with hydrazine acetate to synthesize desired amino pyrazole
intermediate 3 as described above.
[0389] MS (ESI) m/z 267 [M+H].sup.+, t.sub.R=1.81 min.
[0390] HPLC (RP: 6-98% MeCN--H.sub.2O gradient, 0.05% TFA modifier)
t.sub.R=3.212 min (>95% purity @254 nM).
[0391] HPLC (Chiral: Chiralpak AD-H 250 4.6 mm, 5 micron; isocratic
n-heptane-isopropanol 70:30) t.sub.R (a isomer, desired)=22.35 min,
t.sub.R (b isomer)=25.78 min; .alpha.=1.15; %/ee=>90%.
Intermediate 4
##STR00321##
[0393] (E)-ethyl-3-Ethoxy-2-methylacrylate (Intermediate 32) (11.8
g, 67.6 mmol) and Cs.sub.2CO.sub.3 (22.0 g, 67.6 mmol) were added
to a solution of intermediate 3 (12.0 g, 45.1 mmol) at room
temperature and the reaction mixture was heated to 130.degree. C.
After 17 h, the reaction mixture was allowed to cool to room
temperature and was concentrated under reduced pressure. The crude
residue was diluted with ethyl acetate (250 mL) and was filtered.
The resulting filtrate was concentrated under reduced pressure and
the residue was purified via SiO.sub.2 column chromatography (330 g
SiO.sub.2 Combiflash HP Gold Column, 0-100% ethyl acetate/hexanes)
to afford intermediate 4.
[0394] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 12.01 (br s, 1H),
7.99 (s, 1H), 5.73 (s, 1H), 5.42 (br s, 1H), 4.01 (br d, J=12.2 Hz,
1H), 2.81 (br t, J=11.2 Hz, 1H), 2.29 (d, J=13.5 Hz, 1H), 2.07 (d,
J=1.1 Hz, 3H), 1.87-1.69 (m, 1H), 1.68-1.41 (m, 4H), 1.48 (s, 9H).
.sup.13C NMR (CDCl.sub.3, 100 MHz): .delta. 162.87, 156.34, 155.43,
140.16, 135.00, 113.29, 86.50, 79.75, 28.41, 27.79, 25.27, 21.00,
19.88, 13.38.
[0395] LCMS (ESI) m/z 333.0 [M+H].sup.+, t.sub.R=2.24 min.
[0396] HPLC t.sub.R (min), purity %: 3.969, 99%.
[0397] R.sub.f=0.50 (EtOAc).
[0398] Chiral HPLC, 98% ee (Chiralpak IC 5 mM, 4.6 150 mm, 10-95%
MeCN/H.sub.2O, 0.05% trifluoroacetic acid modifier) (S)-isomer
t.sub.R=22.234 min, (R)-isomer t.sub.R=20.875 min.
Intermediate 5
##STR00322##
[0400] POCl.sub.3 (5.60 mL, 59.8 mmol) was added to intermediate 4
(993.4 mg, 2.99 mmol) at room temperature and the reaction mixture
was heated to 100.degree. C. After 2 h, the reaction mixture was
allowed to cool to room temperature and was concentrated under
reduced pressure to afford intermediate 5 which was used directly
in the following step.
[0401] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 9.40 (br d,
J=7.6 Hz, 1H), 9.27-9.16 (m, 2H), 6.85 (s, 1H), 4.54 (t, J=112.4
Hz, 1H), 3.32 (d, J=12.8 Hz, 1H), 3.08 (q, J=8.81 Hz, 1H), 2.33 (s,
3H), 2.23-2.14 (m, 1H), 1.92-1.61 (m, 5H).
[0402] LCMS (ESI) m/z 251.1 [M+H].sup.+, t.sub.R=0.21 min.
[0403] HPLC t.sub.R=2.35 min.
Intermediate A1
##STR00323##
[0405] HATU (1.37 g, 3.59 mmol) was added to a solution of
5-chloro-2-(methylsulfonamido) benzoic acid (823 mg, 3.29 mmol) in
DMF (15.0 mL), and the reaction mixture was stirred at room
temperature. After 1 h, a solution of crude intermediate 5 (220 mg,
2.99 mmol) in DMF (1 mL) was added followed by the addition of
triethylamine (2.00 mL, 14.3 mmol), and the reaction mixture was
stirred at room temperature for 19 h. The reaction mixture was
partitioned between ethyl acetate (250 mL) and saturated aqueous
sodium bicarbonate solution (200 mL), and the layers were
separated. The organic layer was washed with saturated aqueous
sodium bicarbonate solution (200 mL) and saturated sodium chloride
solution (200 mL), was dried over Na.sub.2SO.sub.4, and was
concentrated under reduced pressure. The crude residue was purified
via SiO.sub.2 column chromatography (12 g SiO.sub.2 Combiflash HP
Gold Column, 0-100% ethyl acetate/hexanes) to afford intermediate
A1 (736.2 mg, 51% (2-steps)) as a white solid.
[0406] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 10.05 (br s,
0.2H), 9.13 (br s, 1H), 8.95 (br s, 1H), 8.81 (br s, 0.2H), 7.70
(d, J=8.8 Hz, 1H), 7.56 (d, J=8.8 Hz, 0.2H), 7.40 (dd, J=8.8, 2.4
Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.31 (d, J=4.4 Hz, 0.2H), 6.45 (s,
1H), 6.40 (br s, 0.2H), 6.28 (br d, J=4.4 Hz, 1H), 5.01 (br s,
0.2H), 4.54 (br d, J=14.0 Hz, 0.2H), 3.35 (br d, J=13.2 Hz, 1H),
3.15-3.03 (m, 1H), 2.92 (s, 3H), 2.39 (s, 3H), 2.13-1.98 (m, 1H),
1.90-1.59 (m, 2H), 1.59-1.31 (m, 3H).
[0407] .sup.13C NMR (CDCl.sub.3, 100 MHz): .delta. 167.09, 156.12,
153.13, 147.86, 135.68, 131.79, 131.66, 131.38, 130.12, 125.91,
125.44, 117.08, 93.74, 47.65, 44.07, 39.81, 27.83, 25.47, 19.78,
16.90.
[0408] LCMS (ESI) m/z 482.1 [M+H].sup.+, t.sub.R=2.79 min.
[0409] HPLC t.sub.R (min), purity %: 5.438, 99%.
[0410] R.sub.f=0.47 (50% EtOAc/hexanes).
[0411] Chiral HPLC, 99% ee (Chiralpak IC 5 mM, 4.6 150 mm, 10-95%
MeCN/H.sub.2O, 0.05% trifluoroacetic acid modifier) (S)-isomer
t.sub.R=29.739 min, (R)-isomer t.sub.R=29.495 min.
Example 5
Procedure for the Preparation of Intermediate B1
##STR00324##
[0413] To a solution of intermediate 5 (100.0 mg, 0.35 mmol) in
MeOH (1.74 mL) was added (S)-tert-butyl pyrrolidin-3-ylcarbamate
(648 mg, 3.48 mmol) and triethylamine (970 .mu.L, 6.96 mmol) at
room temperature, and the reaction mixture was heated to 70.degree.
C. After 4 h, the reaction mixture was allowed to cool to room
temperature and was concentrated under reduced pressure. The crude
residue was purified by preparatory HPLC (5-100% MeCN/H.sub.2O,
0.1% trifluoroacetic acid modifier) to afford intermediate B1.
[0414] LCMS (ESI) m/z 401.23 [M+H].sup.+, t.sub.R=1.86 min.
Example 6
Procedure for the Preparation of Intermediate C1
Intermediate 7
##STR00325##
[0416] A mixture of cis/trans tert-butyl
3-cyano-4-hydroxypyrrolidine-1-carboxylate was separated on a
silica column (200-300) eluting with ethyl acetate:petroleum
ether=1:10, ethyl acetate:petroleum ether=1:5 to give intermediate
7 (earlier eluting peak, 30 g, 46%) as white solid.
[0417] TLC (Eluent: ethyl acetate:petroleum ether=1:1): Starting
material cis/trans mixture (R.sub.f=0.4 and 0.45).
[0418] .sup.1H NMR: (400 MHz DMSO) .delta. 4.60-4.48 (m, 1H),
3.8-3.65 (m, 1H), 3.51-3.63 (m, 1H), 3.5-3.3 (m, 2H), 2.9-3.1 (m,
1H), 2.70 (s, 1H), 1.3-1.45 (s, 9H).
Intermediate 8
##STR00326##
[0420] To mixture of intermediate 7 (10 g, 0.047 mol) and imidazole
(6.4 g, 0.094 mol) in DMF (100 ml) was added TBDPSCl (14.2 g, 0.05
mol) dropwise and the mixture was stirred at room temperature
overnight. 10% citric acid was added and extracted with ethyl
acetate, dried and concentrated, purified by silica gel column
chromatography (ethyl acetate: petroleum ether=1:50 to 1:25) to
give intermediate 8.
[0421] TLC Information (Eluent: petroleum ether:ethyl acetate=1:1),
starting material R.sub.f=0.40, product R.sub.f=0.90.
[0422] .sup.1H NMR (400 MHz DMSO) .delta. 7.74-7.62 (m, 4H),
7.47-7.41 (m, 6H), 4.51 (m, 1H), 3.8-3.65 (m, 1H), 3.51-3.63 (m,
1H), 3.5-3.3 (m, 2H), 2.9-3.1 (m, 1H), 1.3-1.45 (s, 9H).
Intermediates 9a and 9b
##STR00327##
[0424] Intermediate 8 was separated by chiral SFC (see below) to
give intermediate 9a (earlier eluting) and intermediate 9b (later
eluting).
[0425] Column: ChiralPak IC-H, 250 50 mmI.D, mobile Phase:
CO.sub.2/iPrOH (35% isocratic), retention time (9a) 1.94 min,
retention time (9b): 2.73 min.
Intermediate 10a
##STR00328##
[0427] A solution of intermediate 9a (16.3 g, 0.036 mol) in
CH.sub.2Cl.sub.2 (200 mL) at r.t was added TBAF (8.0 g, 0.025 mol).
The reaction mixture was stirred at r.t for 30 min, then diluted
with CH.sub.2Cl.sub.2 (500 mL), and washed with saturated aq. NH4Cl
and brine, dried over MgSO.sub.4, filtered, and concentrated. The
crude product was purified by silica gel chromatography (petroleum
ether: ethyl acetate=10:1 to 2:1) to afford intermediate 10a.
[0428] TLC Information (10a) (Eluent: petroleum ether:ethyl
acetate=1:1).
1. Starting material (R.sub.f=0.90).
2. Reaction Mixture (Product: R.sub.f=0.4).
[0429] .sup.1H NMR (10a): 400 MHz DMSO .delta.4.60-4.58 (m, 1H),
3.87-3.79 (m, 1H), 3.69-3.64 (m, 1H), 3.56-3.49 (m, 2H), 2.9-3.1
(m, 1H), 1.4-1.5 (s, 9H).
Intermediate C1
##STR00329##
[0431] A solution of intermediate 17 (Example 18: prepared from 1 g
BOC intermediate 10a) was dissolved in MeOH (10 ml), to the
solution was added intermediate 5 (944 mg, 3.76 mmol) and NEt.sub.3
(2 ml). The reaction mixture was heated at 70.degree. overnight.
The solvent was evaporated and the residue was purified with
purified by combi-flash column chromatography (0-100% MeOH/DCM) to
afford intermediate C1.
[0432] LCMS (m/z) 327.40[M+H].sup.+
[0433] MW 326.19.
Example 7
Preparation of Phosphate (--P(O)OH.sub.2) Compound 192
##STR00330##
[0435] Compound 192 can be prepared from intermediate D1
(preparation described directly below) by treating a solution of D1
in THF at about 0.degree. C. with POCl.sub.3 and triethylamine. The
reaction mixture can be stirred at about 0.degree. C. for a period
of time and quenched with triethylammonium bicarbonate buffer (1M).
The mixture can then be concentrated and purified by HPLC to give
the desired product.
[0436] Compound 192 can also be prepared by the following
protocol.
##STR00331##
[0437] Intermediate D1 (100 mg, 0.18 mmol) was dissolved in THF (2
ml), and the reaction mixture was cooled to 0.degree. C. using an
ice bath. To the above solution was added POCl.sub.3 (110 mg, 0.72
mmol) followed by pyridine (71 mg, 0.9 mmol). The reaction mixture
was stirred at 0.degree. C. for 30 mins before it was quenched with
saturated NaHCO.sub.3. Washed the aqueous layer with DCM twice (20
mL), the aqueous layer was lyopholized and the residue was then
purified by prep HPLC (Gemini C18, 100 30 mm, 5 micron column)
using a gradient of water/acetonitrile 0-100 to afford the title
compound 192.
[0438] LCMS (m/z) 638.12 [M+H].sup.+, Tr=2.87 min.
[0439] CALC. MW 638.03.
[0440] Accordingly one embodiment includes compound 192 and salts
thereof, as well as methods and intermediates that are useful for
the preparation of compound 192 and intermediate D1.
[0441] In a similar manner the corresponding phosphate prodrugs
(--P(O)OH.sub.2) of the compounds of formulas I, Ia, II, IIa, III,
IIIa, IV and IVa can also be prepared. Accordingly, one embodiment
includes the phosphate compounds (--P(O)OH.sub.2) of the compounds
of formulas I, Ia, II, IIa, III, IIIa, IV and IVa and salts
thereof.
Preparation of Intermediate D1
##STR00332##
[0443] The starting chloride intermediate A1 (0.92 g, 1.9 mmol) was
dissolved in iPrOH (10 mL) and treated with triethylamine (0.45 mL,
0.33 g) and the intermediate 17 (0.45 g) and then heated to a
gentle reflux under nitrogen. After heating overnight the solution
was cooled and diluted with ethyl acetate and brine. The organic
layer was separated and concentrated under reduced pressure. The
crude product was purified by silica gel chromatography (50-100%
ethyl acetate in hexanes) to afford the product as a white solid
(1.15 g). LCMS (ESI) m/z 558.2 [M+H].sup.+, t.sub.R=2.17 min.
[0444] Using similar procedures the corresponding compounds 193,
194 and 195 can also be prepared. Accordingly, one embodiment
includes compounds 193, 194 and 195 and salts thereof.
##STR00333##
Example 8
Preparation of Compound 196
##STR00334##
[0446] Compound 196 was prepared according to the general procedure
cited below LCMS (m/z) 446.04 [M+H].sup.+
[0447] MW 445.22
[0448] General Procedure
##STR00335##
[0449] In 50 mL, singled necked, round bottomed flask was placed
intermediate C1 (1932 mg, 5.90 mmol) and TEA (1.64 mL, 11.8 mmol)
in DMF (13 mL). The carboxylic acid (0.040 mmol) was placed in a
separate 2-ml vial. Then, into the vial was dispensed a solution of
intermediate C1 (0.037 mmol) followed by the addition of HATU (15.2
mg, 0.04 mmol). The resulting reaction mixture was placed on an
orbital shaker at room temperature for 16 h. Then, to the reaction
mixture was added EtOAc (4 mL), washed with sat. NaHCO.sub.3 (2
mL.times.2), and concentrated in Genevac. The crude residue was
loaded onto the CUSIL column, washed with EtOAc:Hexane (1:1, 4 mL),
eluted with MeOH:EtOAc (5:95, 3 mL), and concentrated in Genevac to
give the final compound 196.
Example 9
Preparation of Intermediate 11
##STR00336##
[0451] To an oven dried 50 mL round-bottom flask, methyl
2-bromo-5-methylbenzoate (352 mg, 1.54 mmol), sultam (236 mg, 1.95
mmol), cesium carbonate (732 mg, 2.25 mmol), palladium acetate
(40.4 mg, 0.18 mmol), and Xanphos (136 mg, 0.235 mmol) were added
and flask was placed under argon. Reagents were suspended in 8 mL
of anhydrous dioxane and mixture was heated at 100.degree. C.
overnight. After cooling to room temperature, reaction mixture was
filtered, washing with ethyl acetate. Combined filtrate was
concentrated under reduced pressure and resulting film was purified
by silica gel column chromatography (25-100% Ethyl Acetate in
Hexanes) to yield intermediate 11.
[0452] .sup.1H-NMR (DMSO, 400 MHz): .delta. 7.75 (d, 1H), 7.44 (m,
1H), 7.35 (m, 1H), 3.89 (s, 3H), 3.81 (t, 2H), 3.28 (t, 2H), 2.55
(m, 2H), 2.39 (s, 3H).
[0453] LCMS m/z [M+H].sup.+ C.sub.12H.sub.15NO.sub.4S requires:
270.07. Found 270.12.
Example 10
Preparation of Intermediate 12
##STR00337##
[0455] Lithium hydroxide monohydrate (496 mg, 11.8 mmol) was added
to a solution of intermediate 11 (316 mg, 1.17 mmol) in 22 mL of
THF and 12 mL of water at room temperature. Reaction mixture was
heated at 60.degree. C. for two hours. After cooling to room
temperature, reaction mixture was acidified with 40 mL of 1N
HCl.sub.(aq) and extracted with ethyl acetate (3.times.30 mL). The
combined organic layers were washed 50 mL of Brine, separated,
dried (MgSO.sub.4), filtered, and concentrated under reduced
pressure to yield intermediate 12.
[0456] .sup.1H-NMR (DMSO, 400 MHz): .delta. 12.9 (s, 1H), 7.57 (d,
J=1.6 Hz, 1H), 7.41-7.34 (m, 2H), 3.66 (t, J=6.8 Hz, 2H), 3.28 (m,
2H), 2.37 (m, 2H), 2.33 (s, 3H).
[0457] LCMS m/z [M+H].sup.+ C.sub.11H.sub.13NO.sub.4S requires:
254.06. Found 254.18.
Example 11
Preparation of Compound 197
##STR00338##
[0459] HATU (70 mg, 0.185 mmol) was added to a solution of
intermediate 12 (40 mg, 0.16 mmol) in 3 mL of anhydrous DMF at room
temperature. After 60 minutes of stirring, intermediate C1 (40 mg,
0.123 mmol) was added followed immediately by triethylamine (0.030
mL, 0.213 mmol). Reaction mixture stirred at room temperature
overnight under argon. Mixture was then poured into 30 mL of
H.sub.2O and extracted three times with 30 mL of ethyl acetate. The
combined organic layers were washed with 50 mL brine, dried
(MgSO.sub.4), filtered, and concentrated under reduced pressure
leaving a residue. Product was purified by prep HPLC (15-100%
Acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1%
trifluoroacetic acid)) to yield compound 197 as a trifluoroacetic
acid salt, after lyophilization.
[0460] LCMS m/z [M+H].sup.+ C28H.sub.33N7O.sub.4S requires: 564.23.
Found 564.13.
[0461] HPLC Tr (min), purity %: 5.33, 99%
Example 12
Preparation of Intermediate 13
##STR00339##
[0463] Step 1: Sodium azide (158 mg, 2.43 mmol) was added to a
solution of methyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97
mmol) in 3 mL of DMF at room temperature. After stirring overnight,
reaction mixture was quenched with 25 mL of water. Aqueous was
extracted with ethyl acetate (3.times.30 mL) and combined organics
were washed with water (2.times.40 mL) and 50 mL of brine. Organics
were dried (Na.sub.2SO.sub.4), filtered, and concentrated under
reduced pressure to yield methyl 2-(azidomethyl)-5-chlorobenzoate
which was used in the next step without further purification.
[0464] Step 2: Lithium hydroxide monohydrate (794 mg, 18.9 mmol)
was added to a solution of methyl 2-(azidomethyl)-5-chlorobenzoate
(426 mg, 1.88 mmol), from the previous step, in 27 mL of 1:1:1
THF:methanol:water at room temperature. After stirring overnight,
reaction mixture was quenched with 20 mL of 2N HCl.sub.(aq), and
extracted with ethyl acetate (3.times.30 mL). Combined organics
were washed with brine, dried (MgSO.sub.4), filtered, and
concentrated under reduced pressure to yield intermediate 13.
[0465] .sup.1H-NMR (DMSO, 400 MHz): 7.88 (m, 1H), 7.70-7.65 (m,
1H), 7.54 (m, 1H), 4.78 (s, 2H).
Example 13
Preparation of Compound 198
##STR00340##
[0467] Following the procedure for the synthesis of compound 197,
beginning with intermediate 13 (36.2 mg, 0.171 mmol) and
intermediate C1 (40 mg, 0.123 mmol), compound 198 was synthesized
as a trifluoroacetic acid salt after lyophilization.
[0468] LCMS m/z [M+H].sup.+ C.sub.25H.sub.26ClN.sub.9O.sub.2
requires: 520.19. Found 520.03.
[0469] HPLC Tr (min), purity %: 6.34, 97%.
Example 14
Preparation of Intermediate 14
##STR00341##
[0471] To a solution of methyl 2-amino-5-bromobenzoate (7.38 g,
32.0 mmol) and pyridine (6.3 mL, 81.5 mmol) in 100 mL of anhydrous
CH.sub.2Cl.sub.2, was added slowly methane sulfonylchloride (6.5
mL, 79.9 mmol). After stirring overnight, reaction mixture was
quenched with 100 mL of 1N HCl (q). Aqueous mixture was extracted
with ethyl acetate (3.times.120 mL) and combined organic layers
were washed 200 mL brine. Organics were dried (MgSO.sub.4),
filtered, and concentrated under reduced pressure to yield
intermediate 14. Silica gel column chromatography (0-30% Ethyl
Acetate in Hexanes), yielded intermediate 14.
[0472] .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 10.4 (s, 1H),
8.22 (s, 1H), 7.63 (s, 2H), 3.96 (s, 3H), 3.05 (s, 3H)
[0473] LCMS m/z [M+H]C.sub.9H.sub.10BrNO.sub.4S requires: 307.95.
Found 308.06.
Example 15
Preparation of Intermediate 15
##STR00342##
[0475] A 2.65 M solution of NaOH in water (2.65 mL, 7.02 mmol) was
added to a solution of intermediate 14 in 9 mL of THF with strong
stirring. The reaction mixture was stirred at room temperature over
night. The mixture was then acidified with 10 mL of 1N HCl and
extracted with ethyl acetate (3.times.20 mL). The combined organic
layers were washed 30 mL of brine, separated, dried (MgSO.sub.4),
filtered, and concentrated under reduced pressure to yield
intermediate 15.
[0476] .sup.1H-NMR (DMSO, 300 MHz): .delta. 10.6 (s, 1H), 8.05 (s,
1H), 7.79 (d, 1H), 7.55 (d, 1H), 3.18 (s, 3H).
[0477] LCMS m/z [M+H].sup.+ C.sub.8H.sub.8BrNO.sub.4S requires:
291.94. Found 291.90.
Example 16
Preparation of Compound 199
##STR00343##
[0479] Following the procedure for the synthesis of compound 197,
beginning with intermediate 15 (47 mg, 0.160 mmol) and intermediate
C1 (40 mg, 0.123 mmol), compound 199 was synthesized as a
trifluoroacetic acid salt, after lyophilization.
[0480] LCMS m/z [M+H].sup.+ C.sub.25H.sub.28BrN.sub.7O.sub.4S
requires: 602.11. Found 602.78
[0481] HPLC Tr (min), purity %: 6.52, 80%
Example 17
Preparation of Intermediate 16
##STR00344##
[0483] DMF (0.070 mL, 0.908 mmol) was added slowly to a suspension
of 5-methyl-2-(methylsulfonamido)benzoic acid (1.01 g, 4.59 mmol)
and oxalyl chloride (1.6 mL, 18.3 mmol) in 11 mL of anhydrous
dichloromethane. After 3 hours, reaction mixture was concentrated
and dried in-vacuo to yield intermediate 16 which was used in the
next step without further purification.
[0484] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 10.2 (s, 1H),
7.92 (s, 1H), 7.64 (m, 1H), 7.39 (m, 1H), 3.03 (s, 3H), 2.35 (s,
3H).
Example 18
Preparation of Intermediate 17
##STR00345##
[0486] The BOC pyrollidine intermediate 10a (1 g, 4.7 mmol) was
added to HCOOH (5 ml) and was heated at 40.degree. C. for 2 h. The
solvent was evaporated under reduced pressure and preheated IPA
(100.degree. C.) was added to dissolve the residue, white
precipitate formed after the IPA solution cooled down. The product
was filtered and washed with IPA to give intermediate 17 that was
used without further purification in subsequent reactions.
Example 19
Preparation of Intermediate 18
##STR00346##
[0488] Triethylamine (0.58 mL, 4.16 mmol) was added slowly to a
mixture of intermediate 17 (479 mg, 2.01 mmol) and intermediate 5
(573 mg, 2.00 mmol) in 10 mL of dichloromethane under argon at
0.degree. C. After 3 hours, LC/MS indicated full conversion to
desired product. The reaction mixture was concentrated and dried
in-vacuo to yield intermediate 18 that was used in the next steps
without further purification.
[0489] LCMS m/z [M+H].sup.+ C.sub.21H.sub.24ClN.sub.5O.sub.3S
requires: 462.13. Found 462.32.
Example 20
Preparation of Compound 200
##STR00347##
[0491] Triethylamine (0.100 mL, 0.717 mmol) was added to a mixture
of intermediate 18 (102 mg, 0.221 mmol) and intermediate 17 (50 mg,
0.316 mmol) in 3 mL of methanol at room temperature. After heating
at 75.degree. C. overnight, reaction mixture was cooled to room
temperature and concentrated under reduced pressure. The remaining
residue was purified by silica gel column chromatography (10-75%
ethyl acetate in hexanes) to yield compound 200.
[0492] LCMS m/z [M+H].sup.+ C.sub.26H.sub.31N.sub.7O.sub.4S
requires: 538.22. Found 538.01.
[0493] HPLC Tr (min), purity %: 6.10, 97%.
Example 21
Preparation of Compound 201
##STR00348##
[0495] 2-Methoxy-5-chlorobenzoic acid (29 mg, 0.17 mmol) and HATU
(76 mg, 0.2 mmol) were dissolved in DMF (2 ml). The reaction
mixture was stirred at room temperature for 10 mins. To the above
solution was added intermediate C1 (35 mg, 0.1 mmol) and NEt.sub.3
(55 .mu.l). The reaction was stirred at room temperature for 30
mins and was quenched with brine (10 ml) and then extracted with
EtOAc (20 ml). The organic layer was washed with brine twice (10
ml) and then was evaporated under reduced pressure. The residue was
purified with prep HPLC (0-100% CH.sub.3CN/H.sub.2O) to afford
compound 201.
[0496] LCMS (m/z) 495.17 [M+H].sup.+.
[0497] MW 493.97.
Example 22
Preparation of Compound 202
##STR00349##
[0499] The title compound was prepared according to the procedure
for compound 201 starting from intermediate C1 and
2-methyl-5-chlorobenzoic acid.
[0500] LCMS (m/z) 479.20 [M+H].sup.+.
[0501] MW 477.97.
Example 23
Preparation of Intermediate 19
##STR00350##
[0503] 2-Amino-5-methylbenzoic acid (316 mg, 2.09 mmol), HATU (992
mg, 2.61 mmol) were dissolved in anhydrous DMF (2 ml). After
activation for 1 hour, intermediate 5 (500 mg, 1.74 mmol) and
triethylamine (0.7 mil) was added to the above solution. The
reaction was stirred under nitrogen for 2 hours. Solvents were
removed by rotary evaporation. The residue was purified with silica
gel column chromatography to provide intermediate 19.
[0504] LCMS m/z [M+H].sup.+ C.sub.20H.sub.22ClN.sub.5O requires:
384.15. Found 383.99.
[0505] HPLC Tr (min), purity %: 2.00, 98%.
Example 24
Preparation of Intermediate 20
##STR00351##
[0507] Intermediate 19 (320 mg, 0.84 mmol) was dissolved in
pyridine (2 ml). Then acetyl chloride (78 mg, 1.0 mmol) was added
to the above solution. The reaction was stirred under nitrogen for
30 mins. Solvents were removed by rotary evaporation. The residue
was purified with silica gel column chromatography to provide
intermediate 20.
[0508] LCMS m/z [M+H].sup.+ C22H.sub.24ClNSO.sub.2 requires:
426.16. Found 425.89.
[0509] HPLC Tr (min), purity %: 2.40, 98%.
Example 25
Preparation of Compound 203
##STR00352##
[0511] The title compound was prepared in 25% yield according to
the procedure for compound 201 starting from intermediate 20 and
the cis and trans mixture of 3-cyano-4-hydroxypyrrolidine. Compound
203 was obtained as a mixture of all 4 isomers at the
pyrrolidine.
[0512] LCMS (m/z) 501.87 [M+H].sup.+.
[0513] MW 500.58.
Example 26
Preparation of Compound 204
##STR00353##
[0515] Intermediate D1 (Example 7) (0.100 g) was dissolved in DMF
(2 ml) and Boc-L-valine (0.075 g), DMAP (0.02 g) and HATU (0.096 g)
added with stirring at room temperature. After 5 h, the solution
was diluted with MeCN (2 ml) and water (4 ml) and was purified with
preparatory HPLC to yield the corresponding ester. The ester was
dissolved in dioxane (2 ml) and HCl (4M in dioxane, 2 ml) was added
with stirring. After 2 h, volatiles were removed at room
temperature and the crude product was purified with preparatory
HPLC to yield compound 204.
[0516] LCMS (m/z) 657.23, Tr=1.64 min.
[0517] MW 657.18.
Example 27
Preparation of Compound 205
##STR00354##
[0519] The title compound was prepared in an analogous way as
described for compound 204 above utilizing proline to afford the
product compound 205.
[0520] LCMS (m/z) 655.21, Tr=1.58 min.
[0521] CALC. MW 655.17.
Example 28
Preparation of Compound 206
##STR00355##
[0523] Intermediate D1 (Example 7) (200 mg, 0.36 mmol) was
dissolved in DCM (2 ml), to the above solution was added
Boc-Glycine (90 mg, 0.6 mmol) and EDCI (111 mg, 0.58 mmol) followed
by DMAP (23 mg, 0.18 mmol). The reaction mixture was stirred at
room temperature for 3 hours. To the above reaction mixture was
added TFA (0.1 ml) and stirred at room temperature for 1 h. The
solvent was evaporated under reduced pressure and purified with
prep HPLC (Gemini C18, 100 30 mm, 5 micron column) using a gradient
of water/acetonitrile 0-100 to afford the title compound 206.
[0524] LCMS (m/z) 615.24 [M+H].sup.+, Tr=2.67 min.
[0525] CALC. MW 615.22.
Example 29
Preparation of Compound 207
##STR00356##
[0527] Into oven-dried, argon purged flask were placed intermediate
D1 (Example 7) (140 mg, 0.25 mmol), succinic anhydride (55 mg, 0.55
mmol) and catalytic amount (1 mg) of 4-dimethylaminopyridine. The
flask was sealed with septa and repurged with argon three times.
Dry tetrahydrofuran (20 mL) was added into the reaction mixture via
syringe, followed by diisopropylethylamine (72 mg, 0.56 mmol). This
reaction mixture was heated for 14 hours at 70.degree. C. to
achieve the full conversion. The solvent was evaporated, the
residue was dissolved in ethyl acetate (30 mL) and this solution
was washed twice with 10% solution of citric acid (30 mL), brine
(30 mL), dried over magnesium sulfate, filtered and evaporated. The
residue was purified by silica gel chromatography using gradient of
dichloromethane/methanol (from 10/0 to 9/1) to afford the title
compound 207.
[0528] TLC R.sub.f=0.49 (10% methanol in dichloromethane, silica
gel).
[0529] LCMS (m/z) 658.2 (100%) and 660.2 (44%) [M+H].sup.+; 655.8
(100%) and 657.9 (40%) [M-H].sup.+,
[0530] Tr=3.96 min., purity >99%.
For C.sub.29H.sub.32ClN.sub.7O.sub.7S Calc. MW 657.2 (100%) and
659.2 (37%).
[0531] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 9.19 (s, 1H), 8.73 (s,
1H), 7.61 (d, J=8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.25 (s, 1H),
6.14 (s, 1H), 6.03 (s, 1H), 5.51 (s, 1H), 5.23 (s, 1H), 4.04 (m,
3H), 3.75 (m, 1H), 3.34 (m, 1H), 3.19 (m, 1H), 3.06 (m, 1H), 2.84
(m, 2H), 2.66 (m, 3H), 2.29 (m, 3H), 2.00-1.22 (m, 6H).
Example 30
Preparation of Compound 208
##STR00357##
[0533] Into oven-dried, argon purged flask were placed intermediate
D1 (Example 7) (56 mg, 0.1 mmol), niacin (19 mg, 0.15 mmol) and
4-dimethylaminopyridine (18 mg, 0.15 mmol). The flask was sealed
with septa and repurged with argon three times. Dry dichloromethane
(20 mL) was added into the reaction mixture via syringe, followed
by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67
mg, 0.3 mmol). This reaction mixture was repurged with argon three
times and stirred at room temperature for 10 minutes to achieve the
full conversion. The solvent was evaporated, the residue was
dissolved in ethyl acetate (30 mL) and this solution was washed
twice with 5% solution of citric acid (30 mL), saturated solution
of NaHCO.sub.3 (30 mL), water (30 mL), brine (30 mL), dried over
magnesium sulfate, filtered and evaporated. The residue was
purified by silica gel chromatography using gradient of
dichloromethane/methanol (from 10/0 to 95/5) to afford the title
compound.
[0534] TLC R.sub.f=0.78 (5% methanol in dichloromethane, silica
gel).
[0535] LCMS (m/z) 663.3 (100%) and 665.2 (43%) [M+H].sup.+; 661.2
(100%) and 663.2 (38%) [M-H].sup.+, T.sub.r=4.19 min., purity
>99%.
For C.sub.31H.sub.31ClN.sub.8O.sub.5S Calc. MW 662.2 (100%) and
664.2 (38%).
[0536] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 9.21 (s, 1H), 8.77 (d,
J=4.2 Hz, 1H), 8.74 (s, 1H), 8.31 (d, J=7.9 Hz, 1H), 7.61 (d, J=8.8
Hz, 1H), 7.39 (dd, J=7.9 Hz, J=4.2 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H),
7.24 (s, 1H), 6.14 (m, 1H), 6.02 (s, 1H), 5.73 (m, 1H), 4.16 (m,
4H), 3.88 (m, 1H), 3.47 (m, 1H), 3.00 (s, 1H), 3.06 (m, 1H), 2.82
(s, 3H), 2.31 (s, 3H), 1.60-1.22 (m, 6H).
Example 31
Preparation of Compound 209
##STR00358##
[0538] Into oven-dried, argon purged flask were placed compound 207
(123 mg, 0.19 mmol) and 2-morpholinoethanamine (27 mg, 0.21 mmol).
The flask was sealed with septa and repurged with argon three
times. Reaction flask was placed in an ice-bath. 6 mL of dry
acetonitrile were added into the reaction mixture via syringe,
followed by diisopropylethylamine (97 mg, 0.75 mmol) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (107 mg, 0.28 mmol). This reaction mixture was
repurged three times with argon, the ice-bath was removed and the
reaction mixture was stirred at room temperature for 5 minutes to
achieve the full conversion. The solvent was evaporated and the
residue was purified by silica gel chromatography (triethylamine
neutralized silica gel) using gradient of dichloromethane/methanol
(from 10/0 to 9/1) to afford the title compound 209.
[0539] TLC R.sub.f=0.57 (10% methanol in dichloromethane, silica
gel).
[0540] LCMS (m/z) 770.3 (100%) and 772.2 (51%) [M+H].sup.+; 768.2
(100%) and 770.1 (43%) [M-H].sup.+, Tr=2.95 min., purity
>99%.
For C.sub.35H.sub.44ClN.sub.9O.sub.7S Calc. MW 769.3 (100%) 771.3
(37%).
[0541] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 9.23 (s, 1H), 8.72 (s,
1H), 7.62 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.25 (m, 1H),
6.14 (m, 1H), 6.00 (s, 2H), 5.51 (m, 1H), 5.23 (s, 2H), 4.03 (m,
1H), 3.75 (m, 1H), 3.64 (m, 6H), 3.26 (m, 2H), 3.19 (m, 1H), 3.06
(m, 2H), 2.80 (s, 3H), 2.73 (m, 2H), 2.45 (m, 2H), 2.38 (m, 3H),
2.28 (s, 3H), 1.94-1.22 (m, 4H).
Example 32
Preparation of Intermediate 32
##STR00359##
[0543] A solution of 1-ethoxy-propene (5.1 mL, 46 mmol) in pyridine
(3.4 mL) was added slowly via addition funnel (.about.1 drop/sec)
to neat trichloroacetyl chloride (4.7 mL, 42 mmol) at -10.degree.
C. under an argon atmosphere. The reaction mixture was then allowed
to slowly warm to 23.degree. C. After 20 h, the reaction mixture
was diluted with dichloromethane (50 mL) and the resulting mixture
was washed with 0.01N HCl (3 50 mL) and brine (50 m L), was dried
over anhydrous sodium sulfate, and was concentrated under reduced
pressure. To the crude residue was added sodium ethoxide (21 wt %
in ethanol, 7.1 g, 44 mmol) slowly via syringe. After 30 min, the
reaction mixture was partitioned between dichloromethane (500 mL)
and water (500 mL). The phases were split and the aqueous layer was
extracted with dichloromethane (500 mL). The combined organic
extracts were dried over anhydrous sodium sulfate, and were
concentrated to afford intermediate 32.
[0544] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.28 (app s, 1H), 4.09
(q, J=7.1 Hz, 2H), 3.96 (q, J 7.1 Hz, 2H), 1.66 (s, 3H), 1.25 (t,
J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H).
Antiviral Activity
[0545] Another embodiment relates to methods of inhibiting viral
infections, comprising the step of treating a sample or subject
suspected of needing such inhibition with a composition of the
invention.
[0546] Samples suspected of containing a virus include natural or
man-made materials such as living organisms; tissue or cell
cultures; biological samples such as biological material samples
(blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva,
tissue samples, and the like); laboratory samples; food, water, or
air samples; bioproduct samples such as extracts of cells,
particularly recombinant cells synthesizing a desired glycoprotein;
and the like. Typically the sample will be suspected of containing
an organism which induces a viral infection, frequently a
pathogenic organism such as a tumor virus. Samples can be contained
in any medium including water and organic solvent\water mixtures.
Samples include living organisms such as humans, and manmade
materials such as cell cultures.
[0547] If desired, the anti-virus activity of a compound described
herein after application of the composition can be observed by any
method including direct and indirect methods of detecting such
activity. Quantitative, qualitative, and semi-quantitative methods
of determining such activity are all contemplated. Typically one of
the screening methods described above are applied, however, any
other method such as observation of the physiological properties of
a living organism are also applicable.
[0548] The antiviral activity of a compound described herein can be
measured using standard screening protocols that are known. For
example, the antiviral activity of a compound can be measured using
the following general protocols.
Respiratory Syncytial Virus (RSV) Antiviral Activity and
Cytotoxicity Assays
Anti-RSV Activity
[0549] Antiviral activity against RSV was determined using an in
vitro cytoprotection assay in Hep2 cells. In this assay, compounds
inhibiting the virus replication exhibit cytoprotective effect
against the virus-induced cell killing were quantified using a cell
viability reagent. The method used was similar to methods
previously described in published literature (Chapman et al.,
Antimicrob Agents Chemother. 2007, 51(9):3346-53.)
[0550] Hep2 cells were obtained from ATCC (Manassas, VI) and
maintained in MEM media supplemented with 10% fetal bovine serum
and penicillin/streptomycin. Cells were passaged twice a week and
kept at subconfluent stage. Commercial stock of RSV strain A2
(Advanced Biotechnologies, Columbia, Md.) was titered before
compound testing to determine the appropriate dilution of the virus
stock that generated desirable cytopathic effect in Hep2 cells.
[0551] For antiviral tests, Hep2 cells were seeded into 96-well
plates 24 hours before the assay at a density of 3,000 cells/well.
On a separate 96well plate, compounds to be tested were serially
diluted in cell culture media. Eight concentrations in 3-fold
serial dilution increments were prepared for each tested compound
and 100 uL/well of each dilution was transferred in duplicate onto
plates with seeded Hep2 cells. Subsequently, appropriate dilution
of virus stock previously determined by titration was prepared in
cell culture media and 100 uL/well was added to test plates
containing cells and serially diluted compounds. Each plate
included three wells of infected untreated cells and three wells of
uninfected cells that served as 0% and 100% virus inhibition
control, respectively. Following the infection with RSV, testing
plates were incubated for 4 days in a tissue culture incubator.
After the incubation, RSV-induced cytopathic effect was determined
using a Cell TiterGlo reagent (Promega, Madison, Wis.) followed by
a luminescence read-out. The percentage inhibition was calculated
for each tested concentration relative to the 0% and 100%
inhibition controls and the EC50 value for each compound was
determined by non-linear regression as a concentration inhibiting
the RSV-induced cytopathic effect by 50%. Ribavirin (purchased from
Sigma, St. Louis, Mo.) was used as a positive control for antiviral
activity.
[0552] Compounds were also tested for antiviral activity against
RSV in Hep2 cells using a 384 well format. Compounds were diluted
in DMSO using a 10-step serial dilution in 3-fold increments via
automation in 4 adjacent replicates each. Eight compounds were
tested per dilution plate. 0.4 uL of diluted compounds were then
stamped via Biomek into 384-well plates (Nunc 142761 or 164730
w/lid 264616) containing 20 .mu.L of media (Mediatech Inc. MEM
supplemented with Glutamine, 10% FBS and Pen/Strep). DMSO and a
suitable positive control compound, such as 80 .mu.M GS-329467 or
10 .mu.M 427346 was used for the 100% and 0% cell killing controls,
respectively.
[0553] Hep2 cells (1.0.times.10.sup.5 cells/ml) were prepared as
above in batch to at least 40 mls excess of the number of sample
plates (8 mls cell mix per plate) and infected with vendor supplied
(ABI) RSV strain A2 to arrive at an MOI of 1:1000 (virus:cell #) or
1:3000 (vol virus: cell vol). Immediately after addition of virus,
the RSV infected Hep2 cell suspension was added to each stamped
384-well plate at 20 .mu.l per well using a uFlow dispenser, giving
a final volume of 40 L/well, each with 2000 infected cells. The
plates were then incubated for 5 days at 37.degree. C. and 5%
CO.sub.2. Following incubation, the plates were equilibrated to
room temperature in a biosafety cabinet hood for 1.5 hrs and 40
.mu.L of Cell-Titer Glo viability reagent (Promega) was added to
each well via uFlow. Following a 10-20 minute incubation, the
plates were read using an EnVision or Victor Luminescence plate
reader (Perkin-Elmer). The data was then uploaded and analyzed on
the Bioinformatics portal under the RSV Cell Infectivity and
8-plate EC50-Hep2-384 or 8-plate EC50-Hep2-Envision protocols.
[0554] Multiple point data generated in the assay was analysed
using Pipeline Pilot (Accelrys, Inc., Version 7.0) to generate a
dose response curve based on least squares fit to a 4-parameter
curve. The generated formula for the curve was then used to
calculate the % inhibition at a given concentration. The %
inhibition reported in the table was then adjusted based on the
normalization of the bottom and top of the curve % inhibition
values to 0% and 100% respectively.
[0555] Representative activities for the compounds of the invention
against RSV-induced cytopathic effects are shown in the Table
below.
TABLE-US-00005 Compound Percent inhibition formula at 0.5 .mu.M 1
100 2 100 3 100 4 100 5 100 6 100 7 100 8 90 9 99 10 95 11 92 12 89
13 82 14 81 15 82 16 71 17 70 18 70 19 70 20 63 21 58 22 55 23 48
24 30 25 100 26 84 27 100 28 100 29 71 30 100 31 100 32 79 33 99 34
13 35 100 36 98 37 100 38 100 39 100 40 95 41 4 42 9 43 88 44 100
45 45 46 100 47 90 48 100 49 99 50 15 51 100 52 71 53 25 54 100 55
5 56 84 57 13 58 61 59 52 60 100 61 100 62 11 63 100 64 100 65 97
66 95 67 21 68 37 69 100 70 56 71 98 72 100 73 99 74 100 75 100 76
99 77 100 78 100 79 100 80 14 81 96 82 100 83 99 84 100 85 100 86
80 87 100 88 100 89 100 90 100 91 100 92 100 93 44 94 88 95 21 96
65 97 100 98 97 99 100 100 100 101 16 102 16 103 100 104 56 105 31
106 100 107 100 108 99 109 100 110 36 111 n.d. 112 100 113 100 114
100 115 98 116 100 117 46 118 99 119 n.d. 120 100 121 92 122 100
123 98 124 100 125 n.d. 126 82 127 n.d. 128 n.d. 129 87 130 100 131
96 132 97 133 56 134 35 135 100 136 83 137 n.d. 138 65 139 100 140
100 141 n.d. 142 100 143 100 144 80 145 60 146 100 147 n.d. 148 77
149 100 150 99 151 100 152 100 153 100 154 90 155 100 156 100 157
98 158 n.d. 159 91 160 71 161 61 162 100 163 100 164 n.d. 165 92
166 100 167 100 168 44 169 100 170 100 171 100 172 100 173 98 174
58 175 91 176 97 177 99 178 100 179 93 180 94 181 83 182 93 183 100
184 100 185 100 186 100 187 100 188 100 189 89 190 100 191 n.d. 192
100 193 n.d 194 n.d 195 n.d 196 96 197 100 198 100 199 100 200 100
201 100 202 100 203 100 204 100 205 100 206 100 207 100 208 100 209
100 (n.d. not determined)
Cytotoxicity
[0556] Cytotoxicity of tested compounds was determined in
uninfected Hep2 cells in parallel with the antiviral activity using
the cell viability reagent in a similar fashion as described before
for other cell types (Cihlar et al., Antimicrob Agents Chemother.
2008, 52(2):655-65). The same protocol as for the determination of
antiviral activity was used for the measurement of compound
cytotoxicity except that the cells were not infected with RSV.
Instead, fresh cell culture media (100 uL/well) without the virus
was added to tested plates with cells and prediluted compounds.
Cells were then incubated for 4 days followed by a cell viability
test using CellTiter Glo reagent and a luminescence read-out.
Untreated cell and cells treated with 50 ug/mL puromycin (Sigma,
St. Louis, Mo.) were used as 100% and 0% cell viability control,
respectively. The percent of cell viability was calculated for each
tested compound concentration relative to the 0% and 100% controls
and the CC50 value was determined by non-linear regression as a
compound concentration reducing the cell viability by 50%.
[0557] To test for compound cytotoxicity in Hep2 cells using a 384
well format, compounds were diluted in DMSO using a 10-step serial
dilution in 3-fold increments via automation in 4 adjacent
replicates each. Eight compounds were tested per dilution plate.
0.4 uL of diluted compounds were then stamped via Biomek into
384-well plates (Nunc 142761 or 164730 w/lid 264616) containing 20
.mu.L of media (Mediatech Inc. MEM supplemented with Glutamine, 10%
FBS and Pen/Strep). 50 .mu.g/mL puromycin and DMSO were used for
the 100% and 0% cytotoxicity controls, respectively.
[0558] Hep2 cells (1.0.times.10.sup.5 cells/ml) were added to each
stamped plate at 20 ul per well to give a total of 2000 cells/well
and a final volume of 40 .mu.L/well. Usually, the cells were batch
prediluted to 1.0.times.10.sup.5 cells/mL in excess of the number
of sample plates and added at 20 ul per well into each assay plate
using a uFlow dispenser. The plates were then incubated for 4 days
at 37.degree. C. and 5% CO.sub.2. Following incubation, the plates
were equilibrated to room temperature in a biosafety cabinet hood
for 1.5 hrs and 40 .mu.L of Cell-Titer Glo viability reagent
(Promega) was added to each well via uFlow. Following a 10-20
minute incubation, the plates were read using an EnVision or Victor
Luminescence plate reader (Perkin-Elmer). The data was then
uploaded and analyzed on the Bioinformatics portal (Pipeline Pilot)
under the Cytotoxicity assay using the 8-plate CC50-Hep2 or 8-plate
CC50-Hep2 Envision protocols. Compounds tested for Anti-RSV
activity were also tested in this cytotoxicity assay.
[0559] All publications, patents, and patent documents cited herein
above are incorporated by reference herein, as though individually
incorporated by reference.
[0560] The invention has been described with reference to various
specific and preferred embodiments and techniques. However, one
skilled in the art will understand that many variations and
modifications may be made while remaining within the spirit and
scope of the invention.
* * * * *
References