Pyrrolo [2, 3-d] pyrimidines as antiviral agents

33 Pages·2013·3.27 MB·English

US006342501B1
(12) United States Patent (10) Patent N0.: US 6,342,501 B1
Townsend et al. (45) Date of Patent: Jan. 29, 2002
(54) PYRROLO[2,3-D] PYRIMIDINES AS Sharon M. Bennett et al., “Synthesis and Antiviral Activity
ANTIVIRAL AGENTS of Some Acyclic and C—Acylic Pyrrolo[2,3—d]pyrirnidine
Nucleoside Analogues” J. Med. Chem. 33:2162—2173
(75) Inventors: Leroy B. Townsend; John C. Drach, (1990).
both of Ann Arbor, MI (US) Ahmed, R. et al., “Viral Persistance” in: Fundamental Virol
ogy, 2nd Ed., Fields et al. (Eds.), Raven Press, New York,
(73) Assignee: The Regents of the University of
pp. 241—265 (1991).
Michigan, Ann Arbor, MI (US)
Alford, C. A. et al., “Congenital and Perinatal Cytomega
lovirus Infections” Rev. Infect. Dis. 12(Suppl. 7):S745—S753
( * ) Notice: Subject to any disclaimer, the term of this
(1990).
patent is extended or adjusted under 35
U.S.C. 154(b) by 0 days. Alford, C. A. et al., “Cytomegalovirus” in: The Human
Herpesviruses, RoiZman et al. (Eds), Raven Press, New
York, pp. 227—255 (1993).
(21) Appl. No.: 09/229,391
“Antiviral Drugs” in: Drug Evaluations Annual 1993 (Chap
(22) Filed: Jan. 11, 1999 ter 76), American Medical Association, p. 1723 (1993).
Bergstrom, D. E. et al., “Antiviral activity of C—5 substituted
Related US. Application Data
tubercidin analogues” J. Med. Chem. 27:285—292 (1984).
Biron, K. K. et al., “Metabolic activation of the nucleoside
(63) Continuation-in-part of application No. 08/690,472, ?led on
analog 9—[2—hydroxy—1—(hydroxymethyl)ethoxy]methyl
Jul. 26, 1996, now abandoned, which is a continuation of
application No. 08/357,762, ?led on Dec. 15, 1994, now Pat. guanine in human diploid ?broblasts infected with human
No. 5,543,413, which is a continuation of application No. cytomegalovirus” PNAS USA 82:2473—2477 (1985).
08/201,695, ?led on Feb. 25, 1994, now abandoned.
(List continued on next page.)
(51) Int. Cl.7 .................... .. C07D 487/04; A61K 31/52;
A61P 31/22 Primary Examiner—Mukund J. Shah
Assistant Examiner—Thomas C McKenzie
(52) US. Cl. ...................................... .. 514/258; 544/280 (74) Attorney, Agent, or Firm—Antoinette F. Konski;
McCutchen, Doyle, Brown & Enersen, LLP
(58) Field of Search ......................... .. 514/258; 544/280 (57) ABSTRACT
(56) References Cited
This invention relates to a novel class of 4,5,6,7-substituted
non-nucleoside, non-phosphorylatable pyrrolo[2,3-d]
U.S. PATENT DOCUMENTS
pyrimidines which exhibit both signi?cantly lower levels of
4,680,176 A 7/1987 Berns et al. cytotoxicity and superior antiviral activity than known
4,709,011 A 11/1987 Cohen et al. nucleoside, non-nucleoside, and non-nucleoside, non
4,892,865 A 1/1990 Townsend et al. phosphorylatable pyrrolo[2,3-d]pyrimidine derivatives, par
4,927,830 A 5/1990 Townsend et al.
ticularly against human DNA viruses such as cytomegalovi
4,968,686 A 11/1990 Townsend et al.
5,399,580 A 3/1995 Daluge rus (HCMV) and herpes simplex virus type 1 (HSV-1).
These compounds are represented by the following formula:
5,543,413 A 8/1996 Townsend et al.
5,679,342 A 10/1997 Houghton et al.
FOREIGN PATENT DOCUMENTS
W0 WO 94/13676 6/1994
W0 WO 95/23151 8/1995
OTHER PUBLICATIONS
“Fields Virology, Third Ed.”, B. N. Fields et al Eds.,
Lippincott—Raven, Philadelphia, ,p. 18, 431, 2228*
“The Condensed Chemical Dictionary”, 9th Ed., Gessner G.
wherein: R4 is —NRlR2 or 0x0; R5 is —CN, or
Hawley Ed., Van Nostrand, New York, p 25 .*
“Webster’s New World Dictionary, College Ed.” no author —CSNR1R2, or —CONR1R2; R6 is —H, or halo, or
—NR1R2; wherein R1 and R2 are independently —H or an
listed, World Publishing, 1962, p. 396*
aliphatic group; and R7 is of the formula R3—Ar, wherein
“Fields Virology, Third Ed.”, B. N. Fields et al eds., Lip
pincott—Raven, Philadelphia, 1996, p. 431.* R3 is an aliphatic group and Ar is an unsubstituted aryl or an
aryl independently substituted with halo, nitro, amino, or
Thomas E. Renau et al., “Synthesis of Non—nucleoside
Analogs of Toyocamycin, Sangivamycin, and Thiosangiva aliphatic groups; provided that when R5 is a —CN or
mycin: In?uence of Various 7—Substituents on Antiviral —CSNH2, and R6 is a —H or —NH2, and Ar is a —C6H5
or a phenyl substituted with only one aliphatic group, R3 is
Activity” J. Med.Chem. 39:873—880 (1996).
an aliphatic group other than methyl such that —R3— is not
Thomas E. Renau et al., “Synthesis of Non—nucleoside
a —CH2—; and pharmaceutically acceptable salts, prodrugs
Analogs of Toyocaymcin, Sangivamycin, and Thiosangiva
and derivatives thereof.
mycin: The Effect of Certain 4— and 4.6 substituents on the
Antiviral Activity of Pyrrolo[2,3—d]pyrimidines” J. Med.
Chem. 39:3470—3476 (1996). 51 Claims, No Drawings
US 6,342,501 B1
Page 2
OTHER PUBLICATIONS Prichard, M. N. et al., “A three dimensional model to
analyZe drug—drug interactions” Antiviral Res. 14:181—206
Chrisp, P. et al., “Foscarnet. A review of its antiviral activity,
(1990).
pharmacokinetic properties and therapeutic use in immuno
compromised patients With cytomegalovirus retinitis” Drugs Prichard, M. N. et al., “Three—dimensional analysis of the
41:104—129 (1991). synergistic cytotoXicity of ganciclovir and Zidovudine”Anti
Collins, P. et al., “Relative potencies of anti—herpes com microb. Agents & Chemother. 35:1060—1065 (1991).
pounds” Ann. N.I/.Acad. Sci. 284:49—59 (1977). Renau, T. E. et al., “Design, synthesis and activity against
Crumpacker, C. S., “Ganciclovir” New England J. Med. human cytomeglovirus of non—phosphorlatable analogs of
335:721—729 (1996). toyocamycin, sangivamycin and thiosangivarnycin” Bioor.
Declerq, E. et al., “Antirhinovirus activity of purine nucle
& Med. Chem. Lett. 2:1755—1760 (1992).
osid analogs” Antimicrob. Agents Chemother. 29:482—487
(1986). Renau, T. E. et al., “Improved synthesis and biological
Drach, J. C. et al., “The selective inhibition of viral DNA evaluation of an acyclic thiosangivamycin active against
synthesis by chemotherapeutic agents: An indicator of clini human cytomegalovirus” Antiviral Res. 19:15—28 (1992).
cal usefulness” Ann. N.I/.Acad. Sci. 284:396—409 (1997). Renau, T. E. et al., “Relationship betWeen cytotoXicity and
Field, A. K. et al., “The end of innocence revisited: Resis conversion of thiosangivamycin analogs to toyocamycin
tance of herpesvirus to antiviral drugs” C lin. Microbiol. Rev. ananlogs in cell culture medium” Biochem. Pharmacol
7:1—13 (1994). 48:801—807. (1994).
Gallant, J. E. et al., “Incidence and natural history of
Renau, T. E. et al., “Antiherpetic activity, cytotoXicity and
cytomegalovirus disease in patients With advanced immu
metabolism of non—nucleoside analogs related to toyocamy
node?ciency virus disease treated With Zidovudine” J. Infect.
cin, sangivamycin and thiosangivarnycin” SiXth Interna
Dis. 166:1223—1227 (1992).
tional Conference on Antiviral Research, Venice, Italy,
Gibbs, E. P. J. et al., “Bovine herpesviruses. Part I: Bovine
25—30 Apr. 1993,AntiviralRes., vol. 20, Suppl. 1 (1993), p.
herpesvirus 1” Vet. Bull. 47:317—343 (1997).
118 (Abstract No. 138).
Goldstein, A., “Analysis of a single curve With graded
responses” in: Biostatistics: An Introductory TeXt, Mac Renau, T. E. et al., “Spontaneous oxidation of thiosangiva
Millan Co., NeW York, pp. 156—161 (1964). mycin analogs by cell culture medium ameliorates cytotoX
Gupta, P. K. et al., “Synthesis, cytotoXicity, and antiviral icity” 206th National American Chemical Society Meeting,
activity of some acyclic analogues of the pyrrolo[2,3—d] Chicago, IL, 22—27 Aug. 1993,Abstr Pap. Am. Chem. Soc.
pyrimidine nucleoside antibiotics tubercidin, toyocamycin, 206(1—2) MEDI (1993), (Abstract No. 133).
and sangivamycin” J. Med. Chem. 32:402—408 (1989).
Renau, T. E. et al., “Activity against human cytomegalovi
Hermann, Jr., E. C., “The detection, assay and evaluation of
rus, cytotoXicity and mode of action fo a non—nucleoside
antiviral drugs” Prog. Med. Virol. 3:158—192 (1961).
pyrrolo 2,3—d pyrimidine” Seventh International Conference
Hirsch, M. S. et al., “Antiviral therapy” Scienti?c Ameri
can:76—85 (Apr. 1987). on Antiviral Research, Charleston, SC, Mar. 1994,Antiviral
Res., vol. 23, Suppl. 1 (1994), p. 91(Abstract No. 104).
Hitchcock, M. J. et al., “Cidofovir, a neW agent With potent
anti—herpesvirus activity” Antiviral Chem. & Chemother. Renau, T. E. et al., “Structure—activity relationships of
7:115—127 (1996). non—nucleoside pyrrolopyrimidine analogs active against
Hsiung, G. D. et al., “Evaluation of neW antiviral agents: II. human cytomegalovirus” Seventh International Conference
The use of animal models” Antiviral Res. 12:239—258 on Antiviral Research, Charleston, SC, Mar. 1994,Antiviral
(1989). Res., vol. 23, Suppl. 1(1994), p. 91(Abstract No. 105).
Hu, J. M. et al., “Evaluation of neW antiviral agents: I. In
RoiZman, B. et al., “Herpesvirus and their replication” in:
vitro perspectives” Antiviral. Res. 11:217—232(1989).
Fundamental Virology (Chapter 29), Fields et al. (Eds.),
Kim, D. W. et al., “C—terminal domain of the hepatitis C
Raven Press, NeW York, pp. 607—636 (1986).
virus NS3 protein contains an RNA helicase activity” Bio
chem. Biophys. Res. Comm. 215:160—166 (1995). RoiZman, B. et al., “Herpes Simplex Viruses and Their
Kucera, L. S. et al., “Activity of triciribine and Replication” in: Fundamental Virology, 2nd Ed., Fields et al.
triciribine—5—monophosphate against human immunode? (Eds.), Raven Press, NeW York, pp. 849—895 (1991).
ciency virus types 1 and 2” AIDS Res. Human Retroviruses
SaXena, N. K. et al., “Synthesis and antiviral activity of
9:307—314 (1993).
some 7—(2—hydroXyethoXy) methyl pyraZolo [3, 4—d] pyri
Lain, S. et al., “RNA helicase: A novel activity associated
midine analogues of sangivamycin and toyocamycin” J.
With a protein encoded by a positive strand RNA virus”
Med. Chem. 33:1980—1983 (1990).
Nucl. Acids Res. 18:7003—7006 (1990).
LaleZari, J. P. et al., “(S)—1— Shipman, Jr., C. et al., “Evaluation of
[3—hydroXy—2—(phosphonylmethoXy)propyl ]cytosine 4—2—hydroXyethyl)—1—pipraaZineethanesulfonic acids
(cidofovir): results of a phase I/II study of a novel antiviral (HEPES) as a tissue culture buffer” Proc. Soc. Exp. Biol.
nucleotide analogue” J. Infect. Dis. 171:788—796 (1995). 130:305—310 (1969).
Murphy, F. A. et al., “Virus taXonomy”in: Fundamental
SidWell, R. W. et al., “Use of disposable micro tissue culture
Virology, 2nd Ed., Fields et al. (Eds.), Raven Press, NeW
plates for antiviral and interferon induction studies” Appl.
York, pp. 9—36 (1991).
Microbiol 22:797—801 (1971).
Prichard, M. N. et al., “A microtiter virus yield reduction
assay for the evaluation of antiviral compounds against Stinski, M. F., “Cytomegalovirus and its replication” in:
human cytomegalovirus and herpes simplex virus” J. Virol. Fundamental Virology, 2nd Ed., Fields et al. (Eds.), Raven
Meth. 28:101—106 (1990). Press, NeW York, pp. 929—950 (1991).
US 6,342,501 B1
Page 3
SWayZe, E. E. et al., “The improved preparation of a Watson, J. D. et al., in: Molecular Biology of the Gene,
versatile synthon for the synthesis of pyrrolo[2,3—a' ] pyri Fourth Edition, Benjamin/Cummings Publ. Co., Menlo
midines” in: Nucleic Acid Chemistry: Improved and NeW
Park, CA, pp. 904,933 (1987).
Synthetic Procedures, Methods and Techniques, ToWnsend,
L. B. et al., (Eds.), Wiley—Interscience, NeW York, Part 1V, White, E. L. et al., “A TIBO derivative, R82913, is a potent
pp. 16—18 (1991).
inhibitor of HIV—1 reverse trancriptase With heteropolymer
SWayZe, E. E. et al., “Synthesis, antiproliferative, and anti
templates” Antiviral Res. 16:257—266 (1991).
viral evaluation of certain acyclic 6—substituted pyrro1o[2,
3—a' ] —pyrimidine nucleoside analogs related to sangivamy
Wingard, J. R. et al., “Cytomegalovirus infections in bone
cin and toyocamycin” Nucleosides & Nucleotides
marroW transplant recipients given intensive cytoreductive
11:1507—1527 (1992).
therapy” Rev. Infect. Dis. 12(Supp1. 7):S793—S804 (1990).
Turk, S. R. et al., “Pyrrolo [2,3—d ] pyrimidine nucleosides
as inhibitors of human cytomegalovirus” Antimicrob. Agents
& Chemother. 31:544—550 (1987). * cited by examiner
US 6,342,501 B1
1 2
PYRROLO[2,3-D] PYRIMIDINES AS more acceptable levels of cytotoxicity than tubercidin,
ANTIVIRAL AGENTS sangivarnycin, toyocarnycin and thiosangivarnycin as Well
as the nucleoside derivatives described above have been
CROSS-REFERENCE TO RELATED APPLICATIONS reported. These prior art pyrrolo[2,3-d]pyrirnidine non
This application is a continuation-in-part of US. patent nucleoside derivatives are described beloW.
application Ser. No. 08/690,472, ?led Jul. 26, 1997, noW
ToWnsend et al. (US. Pat. Nos. 4,927,830 and 4,968,686)
abandoned Which is a continuation of US. patent application
disclose the use of, inter alia, several 4-arnino -pyrrolo[2,3
Ser. No. 08/357,762, ?led Dec. 15, 1994, now US. Pat. No.
d]pyrirnidine-5 -thiocarboxarnides and 4,6-diarnino -pyrrolo
5,543,413, Which is a continuation of US. patent application
[2,3-d]pyrirnidine -5 -thiocarboxarnides variously substituted
Ser. No. 08/201,695, ?led Feb. 25, 1994, noW abandoned, 10
the contents of Which are hereby incorporated by reference at the 7-position With —CH2OCH(CH2OH)2,
into the present disclosure. —CH2OCH2CH2OH and —CH(CH2OH)(OCH(CH2OH)2)
as antiviral agents.
STATEMENT OF RIGHTS TO INVENTIONS
Gupta et al. (J. Med. Chem., 32: 402—408, 1989) disclose
MADE UNDER FEDERALLY SPONSORED 15
the use of, inter alia, several 4-arnino-pyrrolo[2,3-d]
RESEARCH
pyrirnidine-5-thiocarboxarnides and 4-arnino-pyrrolo[2,3-d]
This invention was made in part with Government support pyrirnidine-5-carbonitriles variously substituted at the
under contract number NO1-AI72641 aWarded by the 7-position by —CH2OCH(CH2OH)2 and —CH(CH2OH)
National Institute of Allergy and Infectious Diseases. The
(OCH(CH2OH)2) as antiviral agents.
Government has certain rights in this invention.
Gupta et al. (J. Med. Chern., 32:1420—1425, 1989) dis
TECHNICAL FIELD close the use of, inter alia, several 4-arnino.-pyrrolo[2,3-d]
pyrirnidine-5-thiocarboxarnides and 4-arnino-pyrrolo[2,3-d]
The present invention relates to neW non
phosphorylatable, non-nucleoside pyrrolo[2,3-d] pyrirnidine-5-carbonitriles substituted at the 7-position by
25
pyrirnidines and their use in the treatment of viral infections. —CH2OCH2CH2OH as antiviral agents.
Renau et al. (Antiviral Res., 19:15—28, 1992) disclose the
BACKGROUND OF THE INVENTION
use of 4-arnino-pyrrolo[2,3-d]pyrirnidine-5
Broad spectrurn antiviral activity of pyrrolo[2,3-d] thiocarboxarnide and 4-arninopyrrolo[2,3-d]pyrirnidine-5
pyrirnidine nucleosides such as tubercidin, sangivarnycin carbonitrile substituted at the 7-position by —CH2—
and toyocarnycin and some substituted derivatives previ OCH2—CH2—OH as antiviral agents.
ously has been reported. Activity of those cornpounds
against speci?c viruses, such as RNA rhinovirus and DNA SWayZe et al. (Nucleosides and Nucleosides,
herpes simplex virus type 1 and type 2 also has been 11:1507—1527, 1992) disclose the use of, inter alia, 4,6
reported. See, for example, Bergstrorn, D. E. et al., J. Med. 35 diarnino-pyrrolo[2,3-d]pyrirnidine -5-thiocarboxarnides and
Chem. 27:285—292 (1984); and DeClercq, E. et al.,Antimi 4,6-diarnino-pyrrolo[2,3-d]pyrirnidine-5carbonitriles vari
crab. Agents Chem0ther., 29:482—487 (1986). ously substituted at the 7-position by —CH2—OCH2—
Pyrrolo[2,3-d]pyrirnidine nucleosides are particularly CH2—OH and —CH2 —OCH(CH2—OH)2 as antiviral
attractive as potential antiviral agents because of their sta agents.
bility toWard the action of tWo major enzymes of bioactive
A limited number of pyrrolo[2,3-d]pyrirnidine non
purine nucleoside inactivation, dearnination by adenosine
nucleoside, non-phosphorylatable derivatives Which exhibit
dearninase and glycosidic bond cleavage by purine nucleo
irnproved antiviral activity and more acceptable levels of
side phosphorylases. Unfortunately, many of the pyrrolo[2,
cytotoxicity than tubercidin, sangivarnycin, toyocarnycin
3-d]pyrirnidine nucleosides Which have been previously
described as having potential antiviral activity also exhibit 45 and thiosangivarnycin as Well as the nucleoside derivatives
unacceptable levels of cytotoxicity, thereby dirninishing described above have been reported.
their usefulness in treatment of viral infections. For example, Renau et al. (Bioorg & Med Chem. Lett.,
Anurnber of pyrrolo[2,3-d]pyrirnidine nucleoside deriva 2:1755—1760, 1992) disclose the use of, inter alia, several
tives Which exhibit irnproved antiviral activity and more 4-arnino-pyrrolo[2,3-d]pyrirnidine-5-thiocarboxarnides and
acceptable levels of cytotoxicity than tubercidin, 4-arnino-pyrrolo[2,3-d]pyrirnidine-5-carbonitriles variously
sangivarnycin, toyocarnycin and thiosangivarnycin have
substituted at the 7-position With —CH2—OCH2—CH2—
been reported. These prior art pyrrolo[2,3-d]pyrirnidine
OH, —CH2—OCH(CH2—OH)2, CH3, —CH2—CH=CH2,
nucleoside derivatives are described beloW.
and —CH2—CH2—CH3 as antiviral agents.
ToWnsend et al. (US. Pat. No. 4,892,865) disclose the use
55
of, inter alia, several 4-arnino-pyrrolo[2,3-d]pyrirnidine-5
BRIEF DESCRIPTION OF THE INVENTION
carbonitriles and 4-arninopyrrolo[2,3-d]pyrirnidine-5
thiocarboxarnides substituted at the 7-position with 2,3‘
One aspect of the present invention relates to a novel class
dideoxy-2‘,3‘-didehydro-[3-D-ribofuranose and 2,3‘
of 4,5,6,7-substituted non-nucleoside, non-phosphorylatable
dideoxyribofuranose as antiviral agents. pyrrolo[2,3-d]pyrirnidines Which exhibit both signi?cantly
Renau et al. (Bioorg. & Med. Chem. Lett., 2:1755—1760, loWer levels of cytotoxicity and superior antiviral activity
1992) disclose the use of, inter alia, 4-arnino-pyrrolo[2,3-d] than knoWn nucleoside, non-nucleoside, and non
pyrirnidine -5-thiocarboxarnides and 4-arnino-pyrrolo[2,3 nucleoside, non-phosphorylatable pyrrolo[2,3-d]pyrirnidine
d]pyrirnidine-5-carbonitriles substituted at the 7-position derivatives, particularly against human DNA viruses such as
With [3-D-ribofuranose as antiviral agents. 65 cytornegalovirus (HCMV) and herpes simplex virus type 1
A number of pyrrolo[2,3-d]pyrirnidine non-nucleoside (HSV-1). Many of these compounds are represented by the
derivatives Which exhibit irnproved antiviral activity and following formula:
US 6,342,501 B1
3 4
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is
—(CH2)3—C6H5 (1350)
R4 R5
N/ | \ R.
s; .\
R4 is —NH2; R5 is —CN; R is —H; and R7 is —CH2—
CH —C H 1358 Or 1368 ;
2 6 5
wherein: R4 is —NH2; R is —CN; R6 is —NH2; and R7 is —CH2—
CH2—C6H5 (13695);
R4 is —NRlR2 or 0110;
R5 is —CN, or —CSNR1R2, or —CONR1R2; R4 is —NHCH3; R is —CN; R6 is —NH2; and R7 is
—CH2—C6H4-3-NO2 (1425);
R6 is —H, or halo, or —NR1R2;
wherein R1 and R2 are independently —H or an aliphatic
15
group; and R7 is of the formula —R3Ar, Wherein R3 is
an aliphatic group and Ar is an unsubstituted aryl or an R4 is —NH2; R5 is —CN; R6 is —NH2 and R7 is —CH2—
aryl independently substituted With halo, nitro, amino, C6H4-4-F (1365);
or aliphatic groups; provided that When R5 is a —CN R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
or —CSNH2, and R6 is a —H or —NH2, and Ar is a C6H4-4-C1 (1356);
—C6H5 or a phenyl substituted With only one aliphatic R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
group, R3 is an aliphatic group other than methyl such C6H4-4-Br (1389);
that —R3— is not a —CH2—; and pharmaceutically R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
acceptable salts, prodrugs and derivatives thereof. C6H4-4-NO2 (1348);
The present invention also provides a compound having R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
the structure: 25 C6H4-4-NH2 (1352)
R4 R5
/
Nk I \ R6 R4 is -oXo; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-CH3 (1441);
\
N N\ R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH
(CHs)—C6Hs (1363);
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
35 C6H4-4-F (1353);
Wherein:
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
R4 is —NRlR2 or 0110; C6H4-4-C1 (1355);
R5 is —CN Or —CSNR1R2;
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
R6 is —H, or halo, or —NR1R2; C6H4-3-C1 (1461);
Wherein R1 and R2 are independently —H or an aliphatic R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
group; and R7 is of the formula R3—Ar, Wherein R3 is C6H3-3,4-(C1)2 (1462);
an aliphatic group and Ar is an unsubstituted aryl or an R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
aryl independently substituted With halo, nitro, amino,
C6H4-4-Br (1373);
or aliphatic groups; provided that When R6 is a —H or R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
—NH2 and Ar is —C6H5 or a phenyl substituted With 45 C6H4-4-NO2 (1374);
only one aliphatic group, R3 is an aliphatic group other
than methyl such that —R3— is not a —CH2—; and
pharmaceutically acceptable salts, prodrugs and deriva
R4 is —NH2; R5 is —CN; R6 is —Br and R7 is —CH2—
tives thereof. CH2—C6H5 (1351);
In one embodiment, R4 is —NH2; R5 is —CN and R6 is R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is
—H. In another embodiment, R4 is —NH2; R5 is —CSNH2 —(CH2)3—C6H5 (1347); and
and R6 is —H. In yet another embodiment, R4 is —NH2; R5 R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
is —CN and R6 is —NH2. In yet another embodiment, R4 is CH=CH—C6H5 (1361).
—NH2; R5 is —CN and R6 is a halo group. In yet another
In one embodiment, the present invention provides for a
embodiment, the halo group is a bromo or chloro. 55 compound having the structure:
Some embodiments comprise a pyrrolo[2,3-d]pyrimidine
compound having the folloWing structural features:
R4
R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH
(CH3)—C6H4 (1414);
R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH2—
C6H4-4-F (1429);
and R7 is —CH2—
C6H4-4-Cl (1444);
and R7 is —CH2—
C6H4-4-NO2 (1360) 65
and R7 is —CH2— Wherein:
C6H4-3-NO2 (1362); R4 is —NRlR2 or 0x0;
US 6,342,501 B1
5 6
R5 is —CONR1R2; aliphatic group, R3 is an aliphatic group other than
R6 is —H, or halo, or —NR1R2; methyl such that —R3— is not a —CH2—; and its
pharmaceutically acceptable salts, prodrugs and deriva
wherein R1 and R2 are independently —H or an aliphatic
tives thereof.
group; and R7 is of the formula R3—Ar, Wherein R3 is
In one embodiment, R4 is —NH2; R5 is —CN or
an aliphatic group and Ar is an unsubstituted aryl or an
aryl independently substituted With halo, nitro, amino, —CONR1R2 and R6 is a halo group. In another
embodiment, R1 and R2 are independently —H or an ali
or aliphatic groups; and pharmaceutically acceptable
phatic group and the halo group is a chloro or bromo.
salts, prodrugs and derivatives thereof.
Some embodiments comprise a pyrrolo[2,3-d]pyrimidine
In one embodiment, R4 is —NH2; R5 is —CONR1R2 and compound having the folloWing structural features:
R6 is a halo group. In another embodiment, R1 and R2 are 10
R4 is -oXo; R5 is —CN; R6 is —Br; and R7 is —CH2—
independently —H or an aliphatic group and the halo group C6H4-4-CH3 (1441);
is a chloro or bromo. In yet another embodiment, R4 is R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH
—NH2; R5 is —CONH2 and R6 is bromo. (CH3)—C6H5 (1363);
Some embodiments comprise a pyrrolo[2,3-d]pyrimidine R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
compound having the folloWing structural features: 15 C6H4-4-F (1353);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R5 is —CONH2; R6 is —Br; and R7 is
—CH2C6H5 (659);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
—CH(CH3)—C6H5 (1428); C6H4-4-Cl (1355);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R 5 is —CN; R6 is —Br; and R7 is —CH2—
—CH2—C6H4-2-CH3 (836); C6H4-3-Cl (1461);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
—CH2—C6H4-3-CH3 (826); C6H3-3,4-(Cl)2 (1462);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
—CH2—C6H4-4-CH3 (658); 25 C6H4-4-Br (1373);
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-NO2 (1374);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R5 is —CONH2; R6 is —Br; and R7 is
—CH2—C6H4-4-OCH3 (839);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH—CH3; R5 is —CN; R6 is —Br; and R7 is
—CH2—C6H4-4-F (1419);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R5 is —CN; R6 is —Br and R7 is —CH2—
—CH2—C6H4-4-NO2 (1412); CH2—C6H5 (1351);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R5 is —CONH2; R6 is —Br; and R7 is
—CH2—C6H4-3-NO2 (1421 ); 35
R4 is —NH2; R5 is —CONH2; R6 is —Br; and R7 is R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is
—CH2—C6H4-4-C1 (1443) —(CH2)3C6H5 (1347); and
R4 is —NH2; R5 is —CONH2; R6 is —Br; and R7 is R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
—CH2—C6H4-4-CH3 (1427); CH=CH—C6H5 (1361).
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is Yet another embodiment provides for a compound having
—CH2—CH2—C6H5 (1396); the structure
R4 is —NH2; R5 is —CONH2; R6 is —Br; and R7 is
—CH2—CH2—C6H5 (1409); and R4
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is
—CH2—CH2—CH2—C6H5 (1362) 45
Another embodiment provides for a compound having the
structure
Wherein:
R4 is —NRlR2 or 0x0;
R5 is —CN, or —CSNR1R2, or —CONR1R2;
55 R6 is —H, or halo, or —NR1R2;
Wherein R1 and R2 are independently —H or an aliphatic
group; and R7 is of the formula R3—Ar, Wherein R3 is
Wherein: an aliphatic group and Ar is an aryl independently
R4 is —NRlR2 or 0110; substituted With halo, nitro, amino groups; and phar
R5 is —CN, or —CSNR1R2, or —CONR1R2; maceutically acceptable salts, prodrugs and derivatives
R6 is halo; thereof.
Wherein R1 and R2 are independently —H or an aliphatic In one embodiment, R4 is —NH2; R5 is —CN or
group; and R7 is of the formula R3—Ar, Wherein R3 is —CONR1R2; R6 is —H or a halo group. In another
an aliphatic group and Ar is an unsubstituted aryl or an embodiment, R1 and R2 are independently —H or an ali
aryl independently substituted With halo, nitro, amino, 65 phatic group and the halo group is a chloro or bromo.
or aliphatic groups; provided that When R6 is bromo Some embodiments comprise a pyrrolo[2,3-d]pyrimidine
and Ar is —C6H5 or a phenyl substituted With only one compound having the folloWing structural features:
US 6,342,501 B1
8
In another embodiment, R1 and R2 are independently —H or
an aliphatic group and the halo group is a chloro or bromo.
and R7 is —CH2— Some embodiments comprise a pyrrolo[2,3-d]pyrimidine
compound having the folloWing structural features:
and R7 is —CH2—
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH
and R7 is —CH2— (CH3)—C6H5 (1363);
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is (CH3)—C6H5 (1451);
—CH213 C6H4-4-F (1419);
10 R4 is —NH2; R5 —CN; R6 is —H; and R7 is —CH2—
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is
CH2—C6H5 (1368);
—CH2—C6H4-4-NO2 (1412);
R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is
—CH2—C6H4-3-NO2 (1421)
R4 is —NH2; R5 is —CONH2; R6 is —Br; and R7 is R4 is —NH2; R5 is —CSNH2; R6 is —H; and R7 is
15
R4 is —NH2; R is —CN; R6 is —Br; and R7 is —CH2—
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
C6H4-4-Cl (1388) or (1355);
CH2—C6H5 (1369);
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-3-Cl (1461); R4 is —NH2; R5 is —CSNH2; R6 is —H; and R7 is
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H3-3,4-(Cl)2 (1462); R4 is —NH2; R5 is —CONH2; R6 is —H; and R7 is
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-Br (1373);
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-NO2 (1331); 25
R4 is —NH—CH3; R5 is —CN; R6 is —Br; and R7 is
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-3-NO2 (1374);
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2— R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-F (1365); CH2—C6H5 (1351);
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2— R4 is —NH2; R5 is —CONH2; R6 is —Br; and R7 is
C6H4-4-Cl (1356)
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2— R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is
C6H4-4-Br (1389);
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-NO2 (1348); 35
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
C6H4-4-NH2 (1352); R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
C6H4-3-NO2 (1425); and R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH2—
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2— CH=CH—C6H5 (1372); and
C6H4-4-NH2 (1455).
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
In one aspect, the present invention provides for a com CH=CH—C6H5 (1329).
pound having the structure
The present invention provides for a pharmaceutical com
position comprising a therapeutically effective amount of
45
one or more compounds of the above embodiments, their
pharmaceutically acceptable salts, prodrugs or derivatives
and a pharmaceutically acceptable carrier. Such pharmaceu
tical compositions can be used to treat or prevent a variety
of viral infections such as HCMV, HSV-l, HBV, HCV,
among others.
One embodiment of the present invention has a compound
having the folloWing structure (1429):
Wherein:
R4 is —NRlR2 or 0110; 55
NH; _N
R5 is —CN, or —CSNR1R2, or —CONR1R2;
R6 is —H, or halo, or —NR1R2;
N / I \
Wherein R1 and R2 are independently —H or an aliphatic
group; and R7 is of the formula R3—Ar, Wherein R3 is KN N
an aliphatic group and Ar is an unsubstituted aryl or an
aryl independently substituted With halo, nitro, amino,
or aliphatic groups; provided that R3 is an aliphatic
group other than methyl such that —R3— is not a
—CH2—; and pharmaceutically acceptable salts, pro
drugs and derivatives thereof. 65
In one embodiment, R4 is —N2; R5 —CN or —CONR1R2 Another embodiment of the present invention has a com
or —CSNR1R2; and R6 is —H or —NH2, or a halo group. pound having the folloWing structure (1444):
US 6,342,501 B1
10
NH; _N
/
“L | \ NH:
\N N
Cl 10
Cl
Another embodiment of the present invention has a com
Another embodiment of the present invention has a com 5 pound having the following structure (1389):
pound having the following structure (1360):
20
N/ I \
KN N
25
//o
T
0. Yet another embodiment of the present invention has a
30 compound having the folloWing structure (1348):
NH
Yet another embodiment of the present invention has a 2 —N
compound having the folloWing structure (1353):
N/
K |\ NH:
35
NH; _ N N N
/
L I \ Br
40
\N N
45 Another embodiment of the present invention has a com
pound having the folloWing structure (1446):
A further embodiment of the present invention has a
S
compound having the folloWing structure (1365): NHZ NHZ
50
N/
L | \ NH: N
55
\N N
Another embodiment of the present invention has a com One further embodiment of the present invention has a
pound having the folloWing structure (1356): compound having the folloWing structure (1351):
65
US 6,342,501 B1
11 12
NH; _N
NH2 5 NH;
/
NL I \ Br
N/ I \
\N N
KN N
10
15
Another embodiment of the present invention has a com
pound having the following structure (1368): The present invention provides for a method for treating
or preventing a viral infection comprising administering an
effective amount of one or more compounds of the folloWing
structure:
N
Wherein:
R4 is —NRlR2 or 0x0;
R5 is —CN, or —CSNR1R2, or —CONR1R2;
R6 is —H, or halo, or —NR1R2;
Yet another embodiment of the present invention has a Wherein R1 and R2 are independently —H or an aliphatic
compound having the following structure (1369): group; and R7 is of the formula R3—Ar, Wherein R3 is
an aliphatic group and Ar is an unsubstituted aryl or an
aryl independently substituted With halo, nitro, amino,
or aliphatic groups; and pharmaceutically acceptable
salts, prodrugs and derivatives thereof.
45
In one embodiment of the above method, the one or more
compounds have the folloWing structure:
NHZ
55
Wherein:
Another speci?c embodiment of the present invention has R4 is —NRlR2 or 0x0;
a compound having the folloWing structure (1413): R5 is —CN or —CSNR1R2;
65
US 6,342,501 B1
13 14
R6 is —H, or halo, or —NR1R2; R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
wherein R1 and R2 are independently —H or an aliphatic C6H4-4-Br (1373);
group; and R7 is of the formula R3—Ar, Wherein R3 is R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
an aliphatic group and Ar is an unsubstituted aryl or an C6H4-4-NO2 (1374);
aryl independently substituted With halo, nitro, amino,
or aliphatic groups.
In another embodiment, R4 is —NH2; R5 is —CN and R6 R4 is —NH2; R5 is —CN; R6 is —Br and R7 is —CH2—
CH2—C6H5 (1351);
is —H. In another embodiment, R4 is —NH2; R5 is
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is
—CSNH2 and R6 is —H. In another embodiment, R4 is
—NH2; R5 is —CN and R6 is —NH2. In another 10 —(CH2)3—C6H5 (1347); and
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
embodiment, R4 is NH2; R5 is —CN and R6 ) is a halo
CH=CH—C6H5 (1361).
group. In another embodiment, the halo group is a bromo or
chloro. In another embodiment of the method, one or more
compounds have the folloWing structure:
Some embodiments comprise a pyrrolo[2,3-d]pyrimidine
compound having the folloWing structural features: 15
R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH R4 R5
(CH3)—C6H4 (1414);
R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH2— /
C6H4-4-F (1429); IL | \ R.
R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH2— \
C6H4-4-Cl (1444); N N\
R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH2—
C6H4-4-NO2 (1360);
R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH2—
Wherein:
C6H4-3-NO2 (1362); 25
R4 is —NRlR2 or 0x0;
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is
R5 is —CONR1R2;
R6 is —H, or halo, or —NR1R2;
R4 is —NH2; R5 is —CSNH2; R6 is —H; and R7 is
Wherein R1 and R2 are independently —H or an aliphatic
group; and R7 is of the formula R3—Ar, Wherein R3 is
R4 is —NH2; R5 is —CSNH2; R6 is —H; and R7 is
an aliphatic group and Ar is an unsubstituted aryl or an
aryl independently substituted With halo, nitro, amino,
R4 is —NH2; R5 is —CN; R6 is —H; and R7 is —CH2—
or aliphatic groups.
CH2—C6H5 (1368);
In another embodiment, one or more compounds have the
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH
folloWing structure:
(cH3)—c6H5 (1451); 35
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
R4 is —NHCH3; R5 is —CN; R6 is —NH2; and R7 is
C6H4-3-NH2 (1455);
R4 is —NH2; R5 is —CN; R6 is —NH2 and R7 is —CH2—
C6H4-4-F (1365);
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
C6H4-4-Cl (1356); Wherein:
R4 is —NH2; R6 is —CN; R6 is —NH2; and R7 is —CH2—
R4 is —NRlR2 or 0x0;
C6H4-4-Br (1389);
R5 is —CN, or —CSNR1R2, or —CONR1R2;
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2— R6 is halo;
C6H4-4-NO2 (1348);
Wherein R1 and R2 are independently —H or an aliphatic
R4 is —NH2; R5 is —CN; R6 is —NH2; and R7 is —CH2—
group; and R7 is of the formula R3—Ar, Wherein R3 is
C6H4-4-NH2 (1352);
an aliphatic group and Ar is an unsubstituted aryl or an
R4 is —NH2; R6 is —CN; R6 is —H; and R7 is —CH2— aryl independently substituted With halo, nitro, amino,
or aliphatic groups.
In another embodiment of the method, the one or more
compounds have the folloWing structure:
R4 is —oXo; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-CH3 (1441);
R4
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH
(CH2)—C6H5 (1363);
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-F (1353);
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-4-Cl (1355);
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2—
C6H4-3-Cl (1461); 65
R4 is —NH2; R5 is —CN; R6 is —Br; and R7 is —CH2— Wherein:
C6H3-3,4-(Cl)2 (1462); R4 is —NR1 R2 or 0x0;