U.S. patent application number 11/537017 was filed with the patent office on 2007-05-17 for triazolopyrimidines and related analogs as hsp90-inhibitors.
This patent application is currently assigned to Conforma Therapeutics Corporation. Invention is credited to Marcus F. Boehm, Kevin D. Hong, Srinivas Rao Kasibhatla.
Application Number | 20070111997 11/537017 |
Document ID | / |
Family ID | 34381103 |
Filed Date | 2007-05-17 |
United States Patent
Application |
20070111997 |
Kind Code |
A1 |
Kasibhatla; Srinivas Rao ;
et al. |
May 17, 2007 |
Triazolopyrimidines and related analogs as HSP90-inhibitors
Abstract
Triazolopyrimidines and related compounds are described and
demonstrated or predicted to have utility as Heat Shock Protein 90
(HSP90) inhibiting agents in the treatment and prevention of
various HSP90 mediated disorders, e.g., proliferative disorders.
Method of synthesis and use of such compounds are also described
and claimed.
Inventors: |
Kasibhatla; Srinivas Rao;
(San Diego, CA) ; Hong; Kevin D.; (San Diego,
CA) ; Boehm; Marcus F.; (San Diego, CA) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
94304-1050
US
|
Assignee: |
Conforma Therapeutics
Corporation
San Diego
CA
|
Family ID: |
34381103 |
Appl. No.: |
11/537017 |
Filed: |
September 29, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10946628 |
Sep 20, 2004 |
7129244 |
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11537017 |
Sep 29, 2006 |
|
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60504135 |
Sep 18, 2003 |
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60591467 |
Jul 26, 2004 |
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Current U.S.
Class: |
514/227.8 ;
514/234.5; 514/252.16; 514/261.1 |
Current CPC
Class: |
A61P 21/00 20180101;
A61P 3/00 20180101; A61P 19/02 20180101; A61P 9/10 20180101; A61P
19/04 20180101; A61P 37/02 20180101; A61P 17/02 20180101; C07D
471/04 20130101; A61P 11/00 20180101; A61P 25/08 20180101; A61P
35/00 20180101; A61P 17/00 20180101; A61P 13/12 20180101; C07D
473/00 20130101; C07D 487/04 20130101; A61P 1/16 20180101; A61P
9/00 20180101; A61P 37/06 20180101; A61P 31/16 20180101; A61P 29/00
20180101; A61P 25/00 20180101; A61P 31/00 20180101; A61P 43/00
20180101; A61P 35/02 20180101 |
Class at
Publication: |
514/227.8 ;
514/234.5; 514/252.16; 514/261.1 |
International
Class: |
A61K 31/541 20060101
A61K031/541; A61K 31/5377 20060101 A61K031/5377; A61K 31/519
20060101 A61K031/519 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. (canceled)
19. (canceled)
20. (canceled)
21. (canceled)
22. A method of treating an individual having an HSP90 mediated
disorder comprising administering to said individual a
pharmaceutical composition comprising a pharmaceutically effective
amount of a compound of Formula I: ##STR34## or a polymorph,
solvate, ester, tautomer, enantiomer, pharmaceutically acceptable
salt or prodrug thereof, wherein: R.sup.1 is halogen, --OR.sup.11,
--SR.sup.11 or lower alkyl; R.sup.2 is --NHR.sup.8; R.sup.4 is
--CHR.sup.12--, --C(O)--, --C(S)--, --S(O)-- or --SO.sub.2--;
R.sup.5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
the aryl group is substituted with 3 to 5 substituents, the
heteroaryl group is substituted with 2 to 5 substituents, the
alicyclic group is substituted with 3 to 5 substituents, the
heterocyclic group is substituted with 3 to 5 substituents, and the
substituents are selected from the group consisting of halogen,
lower alkyl, lower alkenyl, lower alkynyl, --SR.sup.8, --OR.sup.8,
--CN, --C(O)OH, --C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10 lower
aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl,
heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino,
oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,
pyridinyl, thiophene, furanyl, indole, indazole, phosphonates,
phosphates, phosphoramides, sulfonates, sulfones, sulfates,
sulphonamides, carbamates, ureas, thioureas and thioamides, wherein
R.sup.8 and R.sup.10 taken together optionally form a ring of 3-7
ring atoms and optionally 1-3 of the ring atoms are heteroatoms
selected from the group of O, S and N; R.sup.8 is hydrogen, lower
alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
or --C(O)R.sup.9; R.sup.9 is H, lower alkyl, lower alkenyl, lower
alkynyl, lower aryl, lower heteroaryl, --NR.sup.10R.sup.10, or
--OR.sup.11, wherein R.sup.10 and R.sup.10 taken together
optionally form a ring of 3-7 ring atoms and optionally 1-3 of the
ring atoms are heteroatoms selected from the group of O, S and N;
R.sup.10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl,
lower alkenyl, or lower alkynyl, R.sup.11 is lower alkyl, lower
alkenyl, lower alkynyl, lower heteroaryl or lower aryl; and
R.sup.12 is hydrogen or lower alkyl; provided that when R.sup.5 is
alicyclic, the ring system does not contain any tetra-substituted
sp.sup.3 ring carbons.
23. The method of claim 22, wherein: R.sup.1 is halogen; R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--; and R.sup.5 is aryl or
heteroaryl, wherein each of the aryl and heteroaryl is monocyclic
or bicyclic and is substituted with 3 to 5 substituents.
24. The method of claim 22, wherein R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is a phenyl having at least
three substituents.
25. The method of claim 22, wherein R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2 and R.sup.5 is a pyridyl having at least two
substituents.
26. The method of claim 22, wherein R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is an 1-oxy-pyridyl
(N-oxy-pyridyl) having at least two substituents.
27. The method of claim 22, wherein the HSP90 mediated disorder is
selected from the group of inflammatory diseases, infections,
autoimmune disorders, stroke, ##STR35## ischemia, cardiac
disorders, neurological disorders, fibrogenetic disorders,
proliferative disorders, tumors, leukemias, neoplasms, cancers,
carcinomas, metabolic diseases, and malignant disease.
28. The method of claim 27 wherein the fibrogenetic disorder is
further selected from the group of scleroderma, polymyositis,
systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid
formation, interstitial nephritis and pulmonary fibrosis.
29. The method of claim 22, further comprising administering at
least one therapeutic agent selected from the group of cytotoxic
agents, anti-angiogenesis agents and anti-neoplastic agents.
30. The method of claim 29, wherein the at least one
anti-neoplastic agent is selected from the group of alkylating
agents, anti-metabolites, epidophyllotoxins; antineoplastic
enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones,
platinum coordination complexes, biological response modifiers and
growth inhibitors, hormonal/anti-hormonal therapeutic agents, and
haematopoietic growth factors.
31. (canceled)
32. (canceled)
33. (canceled)
34. (canceled)
35. (canceled)
Description
[0001] This application relates and claims priority to U.S.
application Ser. No. 10/946,628, filed Sep. 20, 2004, and U.S.
Provisional Application Ser. No. 60/504,135, filed Sep. 18, 2003
and U.S. Provisional Application Ser. No. 60/591,467, filed Jul.
26, 2004. This application also relates to three other U.S. Utility
applications Ser. No. 10/946,645 filed Sep. 20, 2004 (now
Publication No. 20050113340; Ser. No. 10/946,637 filed Sep. 20,
2004 (now Publication No. 2005-119282) and Ser. No. 10/945,851
filed Sep. 20, 2004 (now Publication No. 20050107343. This
application further relates to International Application
PCT/US02/35069, filed Oct. 30, 2002, (now Publication No.
WO03/37860). All the above cited U.S. utility applications,
provisional applications and international application are
expressly incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates in general to triazolopyrimidines and
their related analogs and their broad-spectrum utility, e.g., in
inhibiting heat shock protein 90 (HSP90) to thereby treat or
prevent HSP90-mediated diseases.
BACKGROUND
[0003] HSP90s are ubiquitous chaperone proteins that are involved
in folding, activation and assembly of a wide range of proteins,
including key proteins involved in signal transduction, cell cycle
control and transcriptional regulation. Researchers have reported
that HSP90 chaperone proteins are associated with important
signaling proteins, such as steroid hormone receptors and protein
kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4,
and ErbB-2 (Buchner J. TIBS 1999, 24, 136-141; Stepanova, L. et al.
Genes Dev. 1996, 10, 1491-502; Dai, K. et al. J. Biol. Chem. 1996,
271, 22030-4). Studies further indicate that certain co-chaperones,
e.g., HSP70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1,
immunophilins, p23, and p50, may assist HSP90 in its function (see,
e.g., Caplan, A. Trends in Cell Biol. 1999, 9, 262-68).
[0004] Ansamycin antibiotics, e.g., herbimycin A (HA), geldanamycin
(GM), and 17-allylaminogeldanamycin (17-AAG) are thought to exert
their anticancerous effects by tight binding of the N-terminus
pocket of HSP90, thereby destabilizing substrates that normally
interact with HSP90 (Stebbins, C. et al. Cell 1997, 89, 239-250).
This pocket is highly conserved and has weak homology to the
ATP-binding site of DNA gyrase (Stebbins, C. et al., supra;
Grenert, J. P. et al. J. Biol. Chem. 1997, 272, 23843-50). Further,
ATP and ADP have both been shown to bind this pocket with low
affinity and to have weak ATPase activity (Proromou, C. et al. Cell
1997, 90, 65-75; Panaretou, B. et al. EMBO J. 1998, 17, 4829-36).
In vitro and in vivo studies have demonstrated that occupancy of
this N-terminal pocket by ansamycins and other HSP90 inhibitors
alters HSP90 function and inhibits protein folding. At high
concentrations, ansamycins and other HSP90 inhibitors have been
shown to prevent binding of protein substrates to HSP90 (Scheibel,
T. H. et al. Proc. Natl. Acad. Sci. USA 1999, 96,1297-302; Schulte,
T. W. et al. J. Biol. Chem. 1995, 270, 24585-8; Whitesell, L., et
al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328). Ansamycins
have also been demonstrated to inhibit the ATP-dependent release of
chaperone-associated protein substrates (Schneider, C. L. et al.
Proc. Natl. Acad. Sci., USA 1996, 93, 14536-41; Sepp-Lorenzino et
al. J. Biol. Chem. 1995, 270, 16580-16587). In either event, the
substrates are degraded by a ubiquitin-dependent process in the
proteasome (Schneider, C. L., supra; Sepp-Lorenzino, L., et al. J.
Biol. Chem. 1995, 270, 16580-16587; Whitesell, L. et al. Proc.
Natl. Acad. Sci. USA 1994, 91, 8324-8328).
[0005] HSP90 substrate destabilization occurs in tumor and
non-transformed cells alike and has been shown to be especially
effective on a subset of signaling regulators, e.g., Raf (Schulte,
T. W. et al. Biochem. Biophys. Res. Commun. 1997, 239, 655-9;
Schulte, T. W., et al. J. Biol. Chem. 1995, 270, 24585-8), nuclear
steroid receptors (Segnitz, B.; U. Gehring J. Biol. Chem. 1997,
272, 18694-18701; Smith, D. F. et al. Mol. Cell. Biol. 1995, 15,
6804-12), v-Src (Whitesell, L., et al. Proc. Natl. Acad. Sci. USA
1994, 91, 8324-8328) and certain transmembrane tyrosine kinases
(Sepp-Lorenzino, L. et al. J. Biol. Chem. 1995, 270, 16580-16587)
such as EGF receptor (EGFR) and HER2/Neu (Hartmann, F., et al. Int.
J. Cancer 1997, 70, 221-9; Miller, P. et al. Cancer Res. 1994, 54,
2724-2730; Mimnaugh, E. G., et al. J. Biol. Chem. 1996, 271,
22796-801; Schnur, R. et al. J. Med. Chem. 1995, 38, 3806-3812),
CDK4, and mutant p53. Erlichman et al. Proc. AACR 2001, 42,
abstract 4474. The ansamycin-induced loss of these proteins leads
to the selective disruption of certain regulatory pathways and
results in growth arrest at specific phases of the cell cycle
(Muise-Heimericks, R. C. et al. J. Biol. Chem. 1998, 273,
29864-72), and apoptosis, and/or differentiation of cells so
treated (Vasilevskaya, A. et al. Cancer Res., 1999, 59, 3935-40).
Ansamycins thus hold great promise for the treatment and/or
prevention of many types of cancers and proliferative disorders,
and also hold promise as traditional antibiotics. However, their
relative insolubility makes them difficult to formulate and
administer, and they are not easily synthesized and currently must,
at least in part, be generated through fermentation. Further, the
dose limiting toxicity of ansamycins is hepatic.
[0006] In addition to anti-cancer and antitumorgenic activity,
HSP90 inhibitors have also been implicated in a wide variety of
other utilities, including use as anti-inflammation agents,
anti-infectious disease agents, agents for treating autoimmunity,
agents for treating stroke, ischemia, multiple sclerosis, cardiac
disorders, central nervous system related disorders and agents
useful in promoting nerve regeneration (See, e.g., Rosen et al. WO
02/09696 (PCT/US01/23640); Degranco et al. WO 99/51223
(PCT/US99/07242); Gold, U.S. Pat. No. 6,210,974 B1; DeFranco et
al., U.S. Pat. No. 6,174,875. Overlapping somewhat with the above,
there are reports in the literature that fibrogenetic disorders
including but not limited to scleroderma, polymyositis, systemic
lupus, rheumatoid arthritis, liver cirrhosis, keloid formation,
interstitial nephritis, and pulmonary fibrosis also may be
treatable with HSP90 inhibitors. Strehlow, WO 02/02123
(PCT/US01/20578). Still further HSP90 modulation, modulators and
uses thereof are reported in Application Nos. PCT/US03/04283,
PCT/US02/35938, PCT/US02/16287, PCT/US02/06518, PCT/US98/09805,
PCT/US00/09512, PCT/US01/09512, PCT/US01/23640, PCT/US01/46303,
PCT/US01/46304, PCT/US02/06518, PCT/US02/29715, PCT/US02/35069,
PCT/US02/35938, PCT/US02/39993, 60/293,246, 60/371,668, 60/335,391,
60/128,593, 60/337,919, 60/340,762, 60/359,484 and 60/331,893.
[0007] Recently, purine derivatives showing HSP90 inhibitory
activity have been reported, e.g., in PCT/US02/35069;
PCT/US02/36075. Purine moieties are well accepted bioisosteres for
a variety of ATP-dependent molecular targets, see, JP 10025294;
U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,772,606; U.S. Pat. No.
6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083;
European Patent 0178178; Eur. J. Med. Chem. 1994, 29(1), 3-9; and
J. Het. Chem. 1990, 27(5), 1409. However, compounds having the
desired potency, selectivity and pharmaceutical properties required
for effective HSP90 inhibition in vivo have not been reported.
Therefore, a need remains for additional novel and potent HSP90
inhibitors that meet the demanding biological and pharmaceutical
criteria required to proceed towards human clinical trials.
SUMMARY OF THE INVENTION
[0008] The present invention is directed towards heterocyclic
compounds, in particular towards triazolopyrimidines and related
compounds that show broad utility, e.g., in inhibiting HSP90 and
treating and/or preventing diseases that are HSP90-dependent.
[0009] In one aspect, the invention comprises the heterocyclic
compounds as specified below in Formulae A and I and compounds that
are produced by a synthetic process of the invention. Also included
in the scope of the present invention are stereoisomeric forms,
including the individual enantiomers and diastereomers, racemic
mixtures, and diastereomeric mixtures, as well as polymorphs,
solvates, esters, tautomers, pharmaceutically acceptable salts and
prodrugs of these compounds. Stereoisomers of the compounds of the
present invention may be isolated by standard resolution techniques
such as, for example, fractional crystallization and chiral column
chromatography.
[0010] In one embodiment, the invention provides compounds of
Formula A, or a polymorph, solvate, ester, tautomer, diastereomer,
enantiomer, pharmaceutically acceptable salt or prodrug thereof,
which show utility by inhibiting HSP90 and treating and/or
preventing diseases that are HSP90-dependent. ##STR1## wherein:
[0011] X.sup.1 and X.sup.2 are the same or different and each is
nitrogen or --CR.sup.6;
[0012] X.sup.3 is nitrogen or --CR.sup.3 wherein R.sup.3 is
hydrogen, OH, a keto tautomer, --OR.sup.8, --CN, halogen, lower
alkyl, or --C(O)R.sup.9;
[0013] X.sup.4 is nitrogen or --CR.sup.6 when X.sup.3 is nitrogen,
and X.sup.4 is --CR.sup.6R.sup.7 when X.sup.3 is --CR.sup.3;
[0014] R.sup.1 is halogen, --OR.sup.8, --SR.sup.8, or lower
alkyl;
[0015] R.sup.2 is --NR.sup.8R.sup.10;
[0016] R.sup.4 is --(CH.sub.2).sub.n-- wherein n=0-3, --C(O),
--C(S), --SO.sub.2--, or --SO.sub.2N--; and
[0017] R.sup.5 is alkyl, aromatic, heteroaromatic, alicyclic, or
heterocyclic, each of which is optionally bi-or tri-cyclic, and
optionally substituted with H, halogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower alicyclic, aralkyl, aryloxyalkyl,
alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3,
--SR.sup.8, --OR.sup.8, --CN, --CO.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10.
[0018] In certain embodiments, there are exclusionary provisos with
respect to compounds disclosed in JP 10025294; U.S. Pat. No.
4,748,177; U.S. Pat. No. 4,748,177; U.S. Pat. No. 6,369,092; WO
00/06573; WO 02/055521; WO 02/055082; WO 02/055083; Eur. J. Med.
Chem. 1994, 29(1), 3-9; and J. Het. Chem. 1990, 27(5), 1409, which
disclose compounds with --R.sup.4R.sup.5 comprising ribose or a
derivative thereof, or a sugar or derivative thereof; and compounds
where --R.sup.4R.sup.5 is a phosphonate or phosphonic acid, or is
substituted with a phosphonate or phosphonic acid; or compounds
where R.sup.4 is --CH.sub.2-- or --(CH.sub.2).sub.n-- that are
connected through an oxygen atom to another group.
[0019] In another embodiment, the invention provides compounds of
Formula I, or a polymorph, solvate, ester, tautomer, diastereomer,
enantiomer, pharmaceutically acceptable salt or prodrug thereof,
which show utility for inhibiting HSP90 and treating and/or
preventing diseases that are HSP90-dependent, ##STR2## wherein:
[0020] R.sup.1 is halogen, --OR.sup.11, --SR.sup.11 or lower
alkyl;
[0021] R.sup.2 is --NHR.sup.8;
[0022] R.sup.4 is --CHR.sup.12--, --C(O)--, --C(S)--, --S(O)-- or
--SO.sub.2--;
[0023] R.sup.5 is aryl, heteroaryl, alicyclic, or heterocyclic,
wherein: [0024] the aryl group is substituted with 3 to 5
substituents, [0025] the heteroaryl group is substituted with 2 to
5 substituents, [0026] the alicyclic group is substituted with 3 to
5 substituents, [0027] the heterocyclic group is substituted with 3
to 5 substituents, and [0028] the substituents are selected from
the group consisting of halogen, lower alkyl, lower alkenyl, lower
alkynyl, --SR.sup.8, --OR.sup.8, --CN, --C(O)OH, --C(O)R.sup.9,
--NO.sub.2, --NR.sup.8R.sup.10, lower aryl, heteroaryl, alicyclic,
lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,
dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N;
[0029] R.sup.8 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, lower aryl, lower heteroaryl, or --C(O)R.sup.9;
[0030] R.sup.9 is H, lower alkyl, lower alkenyl, lower alkynyl,
lower aryl, lower heteroaryl, --NR.sup.10R.sup.10, or --OR.sup.11,
wherein R.sup.10 and R.sup.10 taken together optionally form a ring
of 3-7 ring atoms and optionally 1-3 of the ring atoms are
heteroatoms selected from the group of O, S and N;
[0031] R.sup.10 is hydrogen, lower alkyl, lower heteroaryl, lower
aryl, lower alkenyl, or lower alkynyl,
[0032] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
heteroaryl or lower aryl; and
[0033] R.sup.12 is hydrogen or lower alkyl;
provided that when R.sup.5 is alicyclic, the ring system does not
contain any tetra-substituted sp.sup.3 ring carbons.
[0034] In another embodiment, the invention provides compounds, or
a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, which show
utility for inhibiting HSP90 and treating and/or preventing
diseases that are HSP90-dependent, that are prepared by the process
comprising:
[0035] reacting a compound of formula Y and a compound of formula
Z, wherein:
[0036] Y is a represented by any one of the following formulae:
##STR3##
[0037] Z is L.sup.1-R.sup.4--R.sup.5; wherein: [0038] L.sup.1 is
halogen, NR.sup.8R.sup.10, triflate, tosylate, or mesylate; [0039]
R.sup.4 is --CHR.sup.12--, --C(O)--, --C(S)--, --S(O)-- or
--SO.sub.2--; [0040] R.sup.5 is aryl, heteroaryl, alicyclic, or
heterocyclic, wherein: [0041] the aryl group is substituted with 3
to 5 substituents, [0042] the heteroaryl group is substituted with
2 to 5 substituents, [0043] the alicyclic group is substituted with
3 to 5 substituents, [0044] the heterocyclic group is substituted
with 3 to 5 substituents, and [0045] the substituents are selected
from the group consisting of halogen, lower alkyl, lower alkenyl,
lower alkynyl, --SR.sup.8, --OR.sup.8, --CN, --C(O)OH,
--C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, lower aryl,
heteroaryl, alicyclic, lower heterocyclic, arylalkyl,
heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino,
oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,
pyridinyl, thiophene, furanyl, indole, indazole, phosphonates,
phosphates, phosphoramides, sulfonates, sulfones, sulfates,
sulphonamides, carbamates, ureas, thioureas and thioamides, wherein
R.sup.8 and R.sup.10 taken together optionally form a ring of 3-7
ring atoms and optionally 1-3 of the ring atoms are heteroatoms
selected from the group of O, S and N; [0046] R.sup.8 is hydrogen,
lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower
heteroaryl, or --C(O)R.sup.9; [0047] R.sup.9 is H, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10, or --OR.sup.11, wherein R.sup.10 and R.sup.10
taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the
group of O, S and N; [0048] R.sup.10 is hydrogen, lower alkyl,
lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
[0049] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
heteroaryl or lower aryl; [0050] R.sup.12 is hydrogen or lower
alkyl; [0051] R.sup.21 is halogen, --OR.sup.8, --SR.sup.8 or lower
alkyl; [0052] R.sup.22 is --NR.sup.8R.sup.10; [0053] R.sup.24 is
--NH.sub.2, --NO.sub.2 or --NO; [0054] R.sup.25 is halogen or --OH;
[0055] R.sup.26 is --C(O)NH.sub.2 or C(O)OEt; and [0056] R.sup.27
is --NH.sub.2, --OH or halogen;
[0057] provided that when R.sup.5 is alicyclic, the ring system
does not contain any tetra-substituted sp.sup.3 ring carbons.
[0058] In another aspect, the present invention is directed to
pharmaceutical compositions comprising the compounds of the
invention, in particular, the compounds of Formulae A or I, and
compounds formed by the process of the invention, and their
polymorphs, solvates, esters, tautomers, diastereomer, enantiomers,
pharmaceutically acceptable salts and prodrugs thereof, and one or
more pharmaceutical excipients, for use in treatment or prevention
of diseases that are HSP90-dependent.
[0059] In another aspect, the invention features a method of
treating an individual having an HSP90-mediated disorder by
administering to the individual a pharmaceutical composition that
comprises a pharmaceutically effective amount of a compound of
Formulae A or I, or a polymorph, solvate, ester, tautomer,
diastereomer, enantiomer, pharmaceutically acceptable salt or
prodrug thereof.
[0060] In one embodiment, the invention provides a method for
treating an individual having a disorder selected from the group of
inflammatory diseases, infections, autoimmune disorders, stroke,
ischemia, cardiac disorder, neurological disorders, fibrogenetic
disorders, proliferative disorders, tumors, leukemias, neoplasms,
cancers, carcinomas, metabolic diseases, and malignant disease.
[0061] In yet another embodiment, the invention provides a method
for treating an individual having a fibrogenetic disorder, such as,
for example, scleroderma, polymyositis, systemic lupus, rheumatoid
arthritis, liver cirrhosis, keloid formation, interstitial
nephritis and pulmonary fibrosis.
[0062] In another embodiment, the invention provides a combination
therapy comprising the administration of a pharmaceutically
effective amount of a compound of Formulae A or I, or a polymorph,
solvate, ester, tautomer, diastereomer, enantiomer,
pharmaceutically acceptable salt and prodrug thereof, according to
any of the preceding aspects or embodiments, and at least one
therapeutic agent selected from the group of cytotoxic agents,
anti-angiogenesis agents and anti-neoplastic agents. The
anti-neoplastic agent may be selected from the group of alkylating
agents, anti-metabolites, epidophyllotoxins antineoplastic enzymes,
topoisomerase inhibitors, procarbazines, mitoxantrones, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents, and
haematopoietic growth factors.
[0063] Any of the above described aspects and embodiments of the
invention can be combined where practical.
[0064] The individual compounds, methods and compositions
prescribed do not preclude the utilization of other, unspecified
steps and agents, and those of ordinary skill in the art will
appreciate that additional steps and compounds may also be combined
usefully within the spirit of various aspects and embodiments of
the invention.
[0065] Advantages of the invention depend on the specific aspect
and embodiment and may include one or more of: ease of synthesis
and/or formulation, solubility, and IC.sub.50 relative to
previously existing compounds in the same or different classes of
HSP90 inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0066] I. Definitions
[0067] A "pharmaceutically acceptable derivative or prodrug" means
any pharmaceutically acceptable salt, ester, salt of an ester or
other derivative of a compound of this invention, which, upon
administration to a recipient, is capable of providing, either
directly or indirectly, a compound of this invention or a
pharmaceutically active metabolite or residue thereof. Particularly
favored derivatives or prodrugs are those that increase the
bioavailability of the compounds of this invention when such
compounds are administered to a patient (e.g., by allowing orally
administered compound to be more readily absorbed into blood) or
which enhance delivery of the parent compound to a biological
compartment (e.g., the brain or lymphatic system).
[0068] A "pharmaceutically acceptable salt" may be prepared for any
compound of the invention having a functionality capable of forming
a salt, for example, an acid or base functionality.
Pharmaceutically acceptable salts may be derived from organic or
inorganic acids and bases. Compounds of the invention that contain
one or more basic functional groups, e.g., amino or alkylamino, are
capable of forming pharmaceutically acceptable salts with
pharmaceutically acceptable organic and inorganic acids. These
salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or by separately
reacting a purified compound of the invention in its free base form
with a suitable organic or inorganic acid, and isolating the salt
thus formed. Examples of suitable acid salts include acetate,
adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptanoate,
glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, malonate, methanesulfonate,
2-napthalenesulfonate, nicotinate, nitrate, oxalate, palmoate,
pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,
pivalate, propionate, salicylate, succinate, sulfate, tartrate,
thiocyanate, tosylate and undeconate. Other acids, such as oxalic,
while not in themselves pharmaceutically acceptable, may be
employed in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their pharmaceutically
acceptable acid addition salts. See, e.g., Berge et al.
"Pharmaceutical Salts", J. Pharm. Sci. 1977, 66:1-19.
[0069] Compounds of the present invention that contain one or more
acidic functional groups are capable of forming pharmaceutically
acceptable salts with pharmaceutically acceptable bases. The term
"pharmaceutically acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present invention. These salts can likewise be
prepared in situ during the final isolation and purification of the
compounds, or by separately reacting the purified compound in its
free acid form with a suitable base, such as the hydroxide,
carbonate or bicarbonate of a pharmaceutically acceptable metal
cation, with ammonia, or with a pharmaceutically acceptable organic
primary, secondary or tertiary amine. Representative alkali or
alkaline earth salts include the lithium, sodium, potassium,
calcium, magnesium, and aluminum salts and the like. Illustrative
examples of some of the bases that can be used include sodium
hydroxide, potassium hydroxide, choline hydroxide, sodium
carbonate, N.sup.+(C.sub.1-4 alkyl).sub.4, and the like.
Representative organic amines useful for the formation of base
addition salts include ethylamine, diethylamine, ethylenediamine,
ethanolamine, diethanolamine, piperazine and the like. This
invention also envisions the quatemization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization. See, for example, Berge et al., supra.
[0070] Pharmaceutically acceptable prodrugs of the compounds of
this invention include, but are not limited to, esters, carbonates,
thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,
quaternary derivatives of tertiary amines, N-Mannich bases, Schiff
bases, aminoacid conjugates, phosphate esters, metal salts and
sulfonate esters.
[0071] Suitable positions for derivatization of the compounds of
the invention to create "prodrugs" include but are not limited,
2-amino substitution. Those of ordinary skill in the art have the
knowledge and means to accomplish this without undue
experimentation. Various forms of prodrugs are well known in the
art. For examples of such prodrug derivatives, see, e.g.,
[0072] a) Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and
Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.
42, p. 309-396;
[0073] b) Bundgaard, H. "Design and Application of Prodrugs" in A
Textbook of Drug Design and Development, Krosgaard-Larsen and H.
Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and
[0074] c) Bundgaard, H., Advanced Drug Delivery Review, 1992, 8,
1-38.
Each of which is incorporated herein by reference.
[0075] The term "prodrugs" as employed herein includes, but is not
limited to, the following groups and combinations of these
groups:
[0076] Amine Prodrugs: ##STR4##
[0077] Hydroxy Prodrugs: [0078] Acyloxyalkyl esters; [0079]
Alcoxycarbonyloxyalkyl esters; [0080] Alkyl esters; [0081] Aryl
esters; [0082] Disulfide containing esters.
[0083] The term "alkyl," alone or in combination, refers to an
optionally substituted straight-chain, or optionally substituted
branched-chain saturated hydrocarbon radical having from one to
thirty carbons, more preferably one to twelve carbons. Examples of
alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl,
octyl and the like. The term "cycloalkyl" embraces cyclic alkyl
radicals which include monocyclic, bicyclic, tricyclic, and higher
multicyclic alkyl radicals wherein each cyclic moiety has from
three to eight carbon atoms. Examples of cycloalkyl radicals
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the
like. A "lower alkyl" is a shorter alkyl, e.g., one containing from
one to six carbon atoms.
[0084] The term "alkenyl," alone or in combination, refers to an
optionally substituted straight-chain, or optionally substituted
branched-chain hydrocarbon radical having one or more carbon-carbon
double-bonds and having from two to thirty carbon atoms, more
preferably two to eighteen carbons. Examples of alkenyl radicals
include ethenyl, propenyl, butenyl, 1,3-butadienyl and the like.
The term "cycloalkenyl" refers to cyclic alkenyl radicals which
include monocyclic, bicyclic, tricyclic, and higher multicyclic
alkenyl radicals wherein each cyclic moiety has from three to eight
carbon atoms. A "lower alkenyl" refers to an alkenyl having from
two to six carbons.
[0085] The term "alkynyl," alone or in combination, refers to an
optionally substituted straight-chain or optionally substituted
branched-chain hydrocarbon radical having one or more carbon-carbon
triple-bonds and having from two to thirty carbon atoms, more
preferably from two to twelve carbon atoms, from two to six carbon
atoms as well as those having from two to four carbon atoms.
Examples of alkynyl radicals include ethynyl, 2-propynyl,
2-butynyl, 1,3-butadiynyl and the like. The term "cycloalkynyl"
refers to cyclic alkynyl radicals which include monocyclic,
bicyclic, tricyclic, and higher multicyclic alkynyl radicals
wherein each cyclic moiety has from three to eight carbon atoms. A
"lower alkynyl" refers to an alkynyl having from two to six
carbons.
[0086] The terms "heteroalkyl, heteroalkenyl and heteroalkynyl"
include optionally substituted alkyl, alkenyl and alkynyl
structures, as described above, and which have one or more skeletal
chain atoms selected from an atom other than carbon, e.g., oxygen,
nitrogen, sulfur, phosphorous or combinations thereof.
[0087] The term "carbon chain" embraces any alkyl, alkenyl,
alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group,
which are linear, cyclic, or any combination thereof. If the chain
is part of a linker and that linker comprises one or more rings as
part of the core backbone, for purposes of calculating chain
length, the "chain" only includes those carbon atoms that compose
the bottom or top of a given ring and not both, and where the top
and bottom of the ring(s) are not equivalent in length, the shorter
distance shall be used in determining the chain length. If the
chain contains heteroatoms as part of the backbone, those atoms are
not calculated as part of the carbon chain length.
[0088] The term "membered ring" can embrace any cyclic structure,
including aromatic, heteroaromatic, alicyclic, heterocyclic and
polycyclic fused ring systems as described below. The term
"membered" is meant to denote the number of skeletal atoms that
constitute the ring. Thus, for example, pyridine, pyran, and
pyrimidine are six-membered rings and pyrrole, tetrahydrofuran, and
thiophene are five-membered rings.
[0089] The term "aryl," alone or in combination, refers to an
optionally substituted aromatic hydrocarbon radical of six to
twenty ring atoms, and includes mono-aromatic rings and fused
aromatic ring. A fused aromatic ring radical contains from two to
four fused rings where the ring of attachment is an aromatic ring,
and the other individual rings within the fused ring may be
aromatic, heteroaromatic, alicyclic or heterocyclic. Further, the
term aryl includes mono-aromatic ring and fused aromatic rings
containing from six to twelve carbon atoms, as well as those
containing from six to ten carbon atoms. Examples of aryl groups
include, without limitation, phenyl, naphthyl, anthryl, chrysenyl,
and benzopyrenyl ring systems. The term "lower aryl" refers to an
aryl having six to ten skeletal ring carbons, e.g., phenyl and
naphthyl ring systems.
[0090] The term "heteroaryl" refers to optionally substituted
aromatic radicals containing from five to twenty skeletal ring
atoms and where one or more of the ring atoms is a heteroatom such
as, for example, oxygen, nitrogen, sulfur, selenium and phosphorus.
The term heteroaryl includes optionally substituted mono-heteroaryl
radicals and fused heteroaryl radicals having at least one
heteroatom (e.g., quinoline, benzothiazole). A fused heteroaryl
radical may contain from two to four fused rings and where the ring
of attachment is a heteroaromatic ring, the other individual rings
within the fused ring system may be aromatic, heteroaromatic,
alicyclic or heterocyclic. The term heteroaryl also includes
mono-heteroaryls or fused heteroaryls having from five to twelve
skeletal ring atoms, as well as those having from five to ten
skeletal ring atoms. Examples of heteroaryls include, without
limitation, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl,
indolyl, quinolinyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, benzothiozole,
benzimidazole, benzoxazoles, benzothiadiazole, benzoxadiazole,
benzotriazole, quinolines, isoquinolines, indoles, purinyl,
indolizinyl, thienyl and the like and their oxides. The term "lower
heteroaryl" refers to a heteroaryl having five to ten skeletal ring
atoms, e.g., pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or
furanyl.
[0091] The term "alicyclic" alone or in combination, refers to an
optionally substituted saturated or unsaturated nonaromatic
hydrocarbon ring system containing from three to twenty ring atoms.
The term alicyclic includes mono-alicyclic and fused alicyclic
radicals. A fused alicyclic may contain from two to four fused
rings where the ring of attachment is an alicyclic ring, and the
other individual rings within the fused-alicyclic radical may be
aromatic, heteroaromatic, alicyclic and heterocyclic. The term
alicyclic also includes mono-alicyclic and fused alicyclic radicals
containing from three to twelve carbon atoms, as well as those
containing from three to ten carbon atoms. Examples of alicyclics
include, without limitation, cyclopropyl, cyclopropenyl,
cyclobutyl, cyclopentyl, cyclodecyl, cyclododecyl,
cyclopentadienyl, indanyl, and cyclooctatetraenyl ring systems. The
term "lower alicyclic" refers to an alicyclic having three to ten
skeletal ring carbons, e.g., cyclopropyl, cyclopropenyl,
cyclobutyl, cyclopentyl, decalinyl, and cyclohexyl.
[0092] The term "heterocyclic" refers to optionally substituted
saturated or unsaturated nonaromatic ring radicals containing from
five to twenty ring atoms where one or more of the ring atoms are
heteroatoms such as, for example, oxygen, nitrogen, sulfur, and
phosphorus. The term alicyclic includes mono-heterocyclic and fused
heterocyclic ring radicals. A fused heterocyclic radical may
contain from two to four fused rings where the attaching ring is a
heterocyclic, and the other individual rings within the fused
heterocyclic radical may be aromatic, heteroaromatic, alicyclic or
heterocyclic. The term heterocyclic also includes mono-heterocyclic
and fused alicyclic radicals having from five to twelve skeletal
ring atoms, as well as those having from five to ten skeletal ring
atoms. Example of heterocyclics include without limitation,
tetrahydrofuranyl, benzodiazepinyl, tetrahydroindazolyl,
dihyroquinolinyl, and the like. The term "lower heterocyclic"
refers to a heterocyclic ring system having five to ten skeletal
ring atoms, e.g., dihydropyranyl, pyrrolidinyl, indolyl,
piperidinyl, piperazinyl, and the like.
[0093] The term "alkylaryl," alone or in combination, refers to an
aryl radical as defined above in which one H atom is replaced by an
alkyl radical as defined above, such as, for example, tolyl, xylyl
and the like.
[0094] The term "arylalkyl," or "araalkyl," alone or in
combination, refers to an alkyl radical as defined above in which
one H atom is replaced by an aryl radical as defined above, such
as, for example, benzyl, 2-phenylethyl and the like.
[0095] The term "heteroarylalkyl" refers to an alkyl radical as
defined above in which one H atom is replaced by a heteroaryl
radical as defined above, each of which may be optionally
substituted.
[0096] The term "alkoxy," alone or in combination, refers to an
alkyl ether radical, alkyl-O--, wherein the term alkyl is defined
as above. Examples of alkoxy radicals include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy,
tert-butoxy and the like.
[0097] The term "aryloxy," alone or in combination, refers to an
aryl ether radical wherein the term aryl is defined as above.
Examples of aryloxy radicals include phenoxy, benzyloxy and the
like.
[0098] The term "alkylthio," alone or in combination, refers to an
alkyl thio radical, alkyl-S--, wherein the term alkyl is as defined
above.
[0099] The term "arylthio," alone or in combination, refers to an
aryl thio radical, aryl-S--, wherein the term aryl is as defined
above.
[0100] The term "heteroarylthio" refers to the group
heteroaryl-S--, wherein the term heteroaryl is as defined
above.
[0101] The term "acyl" refers to a radical --C(O)R where R includes
alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic,
arylalkyl or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl,
aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroaryl
alkyl groups may be optionally substituted.
[0102] The term "acyloxy" refers to the ester group --OC(O)R, where
R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic,
heterocyclic, arylalkyl, or heteroarylalkyl wherein the alkyl,
alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic,
arylalkyl or heteroarylalkyl may be optionally substituted.
[0103] The term "carboxy esters" refers to --C(O)OR where R is
alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl
groups may be optionally substituted.
[0104] The term "carboxamido" refers to ##STR5##
[0105] where each of R and R' are independently selected from the
group consisting of H, alkyl, aryl, heteroaryl, alicyclic,
heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl,
aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups may
be optionally substituted.
[0106] The term "oxo" refers to .dbd.O.
[0107] The term "halogen" includes F, Cl, Br and I.
[0108] The terms "haloalkyl, haloalkenyl, haloalkynyl and
haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures,
as described above, that are substituted with one or more
fluorines, chlorines, bromines or iodines, or with combinations
thereof
[0109] The terms "perhaloalkyl, perhaloalkyloxy and perhaloacyl"
refer to alkyl, alkyloxy and acyl radicals as described above, that
all the H atoms are substituted with fluorines, chlorines, bromines
or iodines, or combinations thereof.
[0110] The terms "cycloalkyl, arylalkyl, aryl, heteroaryl,
alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl, and
heteroalkyl" include optionally substituted cycloalkyl, arylalkyl,
aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl,
haloalkyl and heteroalkyl groups.
[0111] The terms "alkylamino", refers to the group --NHR where R is
independently selected from alkyl.
[0112] The terms "dialkylamino", refers to the group --NRR' where R
and R' are alkyls.
[0113] The term "sulfide" refers to a sulfur atom covalently linked
to two atoms; the formal oxidation state of said sulfur is (II).
The term "thioether" may be used interchangeably with the term
"sulfide."
[0114] The term "sulfoxide" refers to a sulfur atom covalently
linked to three atoms, at least one of which is an oxygen atom; the
formal oxidation state of said sulfur atom is (IV).
[0115] The term "sulfone" refers to a sulfur atom covalently linked
to four atoms, at least two of which are oxygen atoms; the formal
oxidation state of said sulfur atom is (VI).
[0116] The terms "optional" or "optionally" mean that the
subsequently described event or circumstance may but need not
occur, and that the description includes instances where the event
or circumstance occurs and instances in which it does not. For
example, "aryl optionally mono- or di-substituted with an alkyl"
means that the alkyl may but need not be present, or either one
alkyl or two may be present, and the description includes
situations where the aryl is substituted with one or two alkyls and
situations where the aryl is not substituted with an alkyl.
[0117] "Optionally substituted" groups may be substituted or
unsubstituted. The substituents of an "optionally substituted"
group may include, without limitation, one or more substituents
independently selected from the following groups or designated
subsets thereof: lower alkyl, lower alkenyl, lower alkynyl, lower
aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl,
heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino,
dialkylamino, diarylalkylamino, alkylthio, arylthio,
heteroarylthio, oxo, oxa, carbonyl (--C(O)), carboxyesters
(--C(O)OR), carboxamido (--C(O)NH.sub.2), carboxy, acyloxy, --H,
halo, --CN, --NO.sub.2, --N.sub.3, --SH, --OH, --C(O)CH.sub.3,
perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl,
thiophene, furanyl, indole, indazole, esters, amides, phosphonates,
phosphonic acid, phosphates, phosphoramides, sulfonates, sulfones,
sulfates, sulphonamides, carbamates, ureas, thioureas and
thioamides, thioalkyls. An optionally substituted group may be
unsubstituted (e.g., --CH.sub.2CH.sub.3), fully substituted (e.g.,
--CF.sub.2CF.sub.3), monosubstituted (e.g., --CH.sub.2CH.sub.2F) or
substituted at a level anywhere in-between fully substituted and
monosubstituted (e.g., --CH.sub.2CF.sub.3).
[0118] The term "pyridine-1-oxy" also means "pyridine-N-oxy."
[0119] Some of the compounds of the present invention may contain
one or more chiral centers and therefore may exist in enantiomeric
and diastereomeric forms. The scope of the present invention is
intended to cover all isomers per se, as well as mixtures of cis
and trans isomers, mixtures of diastereomers and racemic mixtures
of enantiomers (optical isomers) as well. Further, it is possible
using well known techniques to separate the various forms, and some
embodiments of the invention may feature purified or enriched
species of a given enantiomer or diastereomer.
[0120] A "pharmacological composition" refers to a mixture of one
or more of the compounds described herein, or pharmaceutically
acceptable salts thereof, with other chemical components, such as
pharmaceutically acceptable carriers and/or excipients. The purpose
of a pharmacological composition is to facilitate administration of
a compound to an organism.
[0121] The phrase "pharmaceutically acceptable carrier" as used
herein means a pharmaceutically-acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material, involved in carrying or
transporting the subject agent from one organ, or portion of the
body, to another organ, or portion of the body. Each carrier must
be "acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the patient.
Some examples of materials which can serve as
pharmaceutically-acceptable carriers include: (1) sugars, such as
lactose, glucose and sucrose; (2) starches, such as corn starch and
potato starch; (3) cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)
powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa butter and suppository waxes; (9) oils,
such as peanut oil, cottonseed oil, safflower oil, sesame oil,
olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic compatible substances employed in pharmaceutical
formulations. A physiologically acceptable carrier should not cause
significant irritation to an organism and does not abrogate the
biological activity and properties of the administered
compound.
[0122] An "excipient" refers to an inert substance added to a
pharmacological composition to further facilitate administration of
a compound. Examples of excipients include but are not limited to
calcium carbonate, calcium phosphate, various sugars and types of
starch, cellulose derivatives, gelatin, vegetable oils and
polyethylene glycols.
[0123] A "pharmaceutically effective amount" means an amount which
is capable of providing a therapeutic and/or prophylactic effect.
The specific dose of compound administered according to this
invention to obtain therapeutic and/or prophylactic effect will, of
course, be determined by the particular circumstances surrounding
the case, including, for example, the specific compound
administered, the route of administration, the condition being
treated, and the individual being treated. A typical daily dose
(administered in single or divided doses) will contain a dosage
level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight
of an active compound of the invention. Preferred daily doses
generally will be from about 0.05 mg/kg to about 20 mg/kg and
ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as
clearance rate, half-life and maximum tolerated dose (MTD) have yet
to be determined but one of ordinary skill in the art can determine
these using standard procedures.
[0124] In some method embodiments, the preferred therapeutic effect
is the inhibition, to some extent, of the growth of cells
characteristic of a proliferative disorder, e.g., breast cancer. A
therapeutic effect will also normally, but need not, relieve to
some extent one or more of the symptoms other than cell growth or
size of cell mass. A therapeutic effect may include, for example,
one or more of 1) a reduction in the number of cells; 2) a
reduction in cell size; 3) inhibition (i.e., slowing to some
extent, preferably stopping) of cell infiltration into peripheral
organs, e.g., in the instance of cancer metastasis; 3) inhibition
(i.e., slowing to some extent, preferably stopping) of tumor
metastasis; 4) inhibition, to some extent, of cell growth; and/or
5) relieving to some extent one or more of the symptoms associated
with the disorder.
[0125] As used herein, the term IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response in an assay that measures
such response. In some method embodiments of the invention, the
"IC.sub.50" value of a compound of the invention can be greater for
normal cells than for cells exhibiting a proliferative disorder,
e.g., breast cancer cells. The value depends on the assay used.
[0126] By a "standard" is meant a positive or negative control. A
negative control in the context of HER2 expression levels is, e.g.,
a sample possessing an amount of HER2 protein that correlates with
a normal cell. A negative control may also include a sample that
contains no HER2 protein. By contrast, a positive control does
contain HER2 protein, preferably of an amount that correlates with
overexpression as found in proliferative disorders, e.g., breast
cancers. The controls may be from cell or tissue samples, or else
contain purified ligand (or absent ligand), immobilized or
otherwise. In some embodiments, one or more of the controls may be
in the form of a diagnostic "dipstick."
[0127] By "selectively targeting" is meant affecting one type of
cell to a greater extent than another, e.g., in the case of cells
with high as opposed to relatively low or normal HER2 levels.
[0128] II. Compounds of the Invention
[0129] Compounds of the invention and their polymorphs, solvates,
esters, tautomers, diastereomers, enantiomers, pharmaceutically
acceptable salts or prodrugs show utility for inhibiting HSP90 and
treating and preventing diseases that are HSP90-dependent.
[0130] One embodiment of the compounds of the invention is of
Formula A: ##STR6## or a polymorph, solvate, ester, tautomer,
diastereomer, enantiomer, pharmaceutically acceptable salt or
prodrug thereof, wherein:
[0131] X.sup.1 and X.sup.2 are the same or different and each is
nitrogen or --CR.sup.6;
[0132] X.sup.3 is nitrogen or --CR.sup.3 wherein R.sup.3 is
hydrogen, OH, a keto tautomer, --OR.sup.8, --CN, halogen, lower
alkyl, or --C(O)R.sup.9;
[0133] X.sup.4 is nitrogen or a group CR.sup.6 when X.sup.3 is
nitrogen, and X.sub.4 is --CR.sup.6R.sup.7 when X.sub.3 is
--CR.sup.3;
[0134] R.sup.1 is halogen, --OR.sup.8, --SR.sup.8, or lower
alkyl;
[0135] R.sup.2 is --NR.sup.8R.sup.10;
[0136] R.sup.4 is --(CH.sub.2).sub.n-- wherein n=0-3, --C(O),
--C(S), --SO.sub.2--, or --SO.sub.2N--; and
[0137] R.sup.5 is alkyl, aryl, heteroaryl, alicyclic, or
heterocyclic, each of which is optionally bi-or tricyclic, and
optionally substituted with H, halogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower alicyclic, araalkyl, aryloxyalkyl,
alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3,
--SR.sup.8, --OR.sup.8, --CN, --CO.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10;
[0138] with the provisos that:
[0139] the one not found or described in one or more of JP
10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,748,177; U.S.
Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO
02/055083; Eur. J. Med. Chem., 1994, 29(1), 3-9; and J. Het. Chem.
1990, 27(5), 1409;
[0140] --R.sup.4R.sup.5 is not a ribose or derivative thereof, or a
sugar or derivative thereof,
[0141] --R.sup.4R.sup.5 is not a phosphonate or phosphonic acid, or
substituted with phosphonate or phosphonic acid; and
[0142] when R.sup.4 is (CH.sub.2).sub.n where n=0 or 1, then
R.sup.4 and R.sup.5 are not connected with `O`, e.g.,
--CH.sub.2--O--CH.sub.2-- or
--CH.sub.2--CH.sub.2--O--CH.sub.2--.
[0143] In one embodiment, the compound, tautomer, pharmaceutically
acceptable salt, or prodrug thereof of Formula A, X.sub.1 and
X.sub.2 are the same or different and each is nitrogen or
--CR.sup.6; R.sup.1 is halogen, --OR.sup.8, --SR.sup.8, or lower
alkyl; R.sup.2 is --NR.sup.8R.sup.10; R.sup.3 is hydrogen, --OH or
keto tautomer, --OR.sup.8, halogen, --CN, lower alkyl, or
--C(O)R.sup.9; R.sup.4 is --(CH.sub.2).sub.n-- wherein n=0-3,
--C(O), --C(S), --SO.sub.2--, or --SO.sub.2N--; and R.sup.5 is
alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, each of
which is optionally bi- or tricyclic, and optionally substituted
with H, halogen, lower alkyl, --SR.sup.8, --OR.sup.8, --CN,
--CO.sub.2R.sup.9, --NO.sub.2 or --NR.sup.8R.sup.10; R.sup.8 is
hydrogen, lower alkyl, lower aryl or --(CO)R.sup.9; R.sup.9 is
lower alkyl, lower aryl, lower heteroaryl, --NR.sup.8R.sup.10 or
OR.sup.11; R.sup.11 is lower alkyl or lower aryl; and R.sup.10 is
hydrogen or lower alkyl.
[0144] In one embodiment, the compound, tautomer, pharmaceutically
acceptable salt thereof, or prodrug thereof of Formula A, R.sup.1
is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl
and C.sub.1-4 alkyl; and R.sup.2 is --NH.sub.2.
[0145] In another embodiment, R.sup.4 is --(CH.sub.2).sub.n--,
wherein n=0-3.
[0146] In another embodiment, R.sup.1 is selected from halogen,
hydroxyl, lower alkoxy, lower thioalkyl or C.sub.1-4 alkyl;
optionally wherein R.sup.2 is NH.sub.2.
[0147] In another embodiment, R.sup.4 is --(CH.sub.2).sub.n--,
wherein n=0-3.
[0148] In another embodiment, R.sup.4 is --(CH.sub.2).sub.n--,
wherein n=0-3, R.sup.1 is selected from halogen, hydroxyl, lower
alkoxy, lower thioalkyl, and C.sub.1-4 alkyl, and R.sup.2 is
optionally NH.sub.2.
[0149] In another embodiment, R.sup.1 is halogen, hydroxyl, lower
alkoxy, lower thioalkyl, or C.sub.1-4 alkyl; and R.sup.2 is
optionally NH.sub.2, R.sup.4 is --(CH.sub.2)--, and R.sup.5 is
phenyl, benzyl, or pyridyl, all optionally substituted with H,
halogen, lower alkyl, --SR.sup.8, --OR.sup.8 (or cyclic ethers such
as methylenedioxy), --CN, --C0.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10; R.sup.8 is hydrogen, lower alkyl, lower aryl or
--(CO)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.8R.sup.10 or --OR.sup.11; R.sup.11 is lower
alkyl or lower aryl; and R.sup.10 is hydrogen or lower alkyl.
[0150] In another embodiment R.sup.1 is halogen, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H or halogen, and
R.sup.5 is phenyl optionally substituted with H, halogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, perhaloalkyl,
perhaloalkyloxy, --CN, --NO.sub.2, --NH.sub.2 or
--CO.sub.2R.sup.11.
[0151] In another embodiment, R.sup.1 is halogen, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H, and R.sup.5 is
2-halo-3,5-dimethoxyphenyl optionally substituted with H, halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
perhaloalkyl, perhaloalkyloxy, --CN, --NO.sub.2, --NH.sub.2, or
--CO.sub.2R.sup.11 at the para (4-) position.
[0152] In another embodiment, R.sup.1 is chloro, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H and R.sup.5 is
2-chloro-3,4,5-trimethoxyphenyl.
[0153] In another embodiment, R.sup.1 is chloro, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H and R.sup.5 is
2-bromo-3,4,5-trimethoxyphenyl. In other embodiments, R.sup.5 is
selected from 2-iodo-3,4,5-trimethoxyphenyl,
2-fluoro-3,4,5-trimethoxyphenyl, and
2-bromo-3,4,5-trimethoxyphenyl.
[0154] Any of the forgoing embodiments can be combined where
feasible and appropriate.
[0155] In another aspect, the invention provides compounds of
Formula A1: ##STR7## or a polymorph, solvate, ester, tautomer,
diastereomer, enantiomer, pharmaceutically acceptable salt or
prodrug thereof, wherein:
[0156] X.sub.1 and X.sub.2 are the same or different and each is
nitrogen or CR.sub.6;
[0157] R.sub.1 is halogen, --OR.sub.8, --SR.sub.8, or lower
alkyl;
[0158] R.sub.2 is --NR.sub.8R.sub.10;
[0159] R.sub.4 is --CH.sub.2n--, where n=0-3, --C(O), --C(S),
--SO.sub.2--, or --SO.sub.2N--;
[0160] R.sub.5 is alkyl, aryl, heteroaryl, alicyclic, or
heterocyclic, all optionally bi-or tricyclic, and all optionally
substituted with H, halogen, lower alkyl, --SR.sub.8, --OR.sub.8,
--CN, --CO.sub.2R.sub.9, --NO.sub.2, or --NR.sub.8R.sub.10;
[0161] R.sub.8 is hydrogen, lower alkyl, lower aryl or
--(CO)R.sub.9;
[0162] R.sub.9 is lower alkyl, lower aryl, lower heteroaryl,
--NR.sub.8R.sub.10 or --OR.sub.11; R.sub.11 is lower alkyl or lower
aryl; and
[0163] R.sub.10 is hydrogen or lower alkyl.
[0164] In one embodiment of the compounds of Formula IV, a
tautomer, pharmaceutically acceptable salt thereof, or prodrug
thereof, R.sup.1 is halogen, hydroxyl, lower alkoxy, lower
thioalkyl, or C.sub.1-4 alkyl; and R.sup.2 is --NH.sub.2.
[0165] In one embodiment of the compounds of Formula IV, a
tautomer, pharmaceutically acceptable salt thereof, or prodrug
thereof, R.sup.1 is halogen, hydroxyl, lower alkoxy, lower
thioalkyl, or C.sub.1-4 alkyl; and R.sup.2 is --NH.sub.2; R.sup.4
is --CH.sub.2--, --C(O), --C(S), --SO.sub.2--.
[0166] In one embodiment of the compounds of Formula IV, a
tautomer, pharmaceutically acceptable salt thereof, or prodrug
thereof, R.sup.1 is halogen or C.sub.1-4 alkyl; and R.sup.2 is
NH.sub.2, R.sup.4 is --CH.sub.2--.
[0167] In one embodiment of the compounds of Formula IV, a
tautomer, pharmaceutically acceptable salt thereof, or prodrug
thereof, R.sup.1 is halogen, hydroxyl, lower alkoxy, lower
thioalkyl, or C.sub.1-4 alkyl; and R.sup.2 is NH.sub.2, R.sup.4 is
--(CH.sub.2).sub.n--, where n=0-3.
[0168] In one embodiment of the compounds of Formula IV, a
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.4 is --C(O) or --CH.sub.2--; R.sup.1 is halogen, lower alkoxy
or C.sub.1-4 alkyl; and R.sup.2 is NH.sub.2.
[0169] In another embodiment, the invention provides compounds of
Formula I: ##STR8## or a polymorph, solvate, ester, tautomer,
enantiomer, diastereomer, pharmaceutically acceptable salt or
prodrug thereof, wherein:
[0170] R.sup.1 is halogen, --OR.sup.11, --SR.sup.11 or lower
alkyl;
[0171] R.sup.2 is --NHR.sup.8;
[0172] R.sup.4 is --CHR.sup.12--, --C(O)--, --C(S)--, --S(O)-- or
--SO.sub.2--;
[0173] R.sup.5 is aryl, heteroaryl, alicyclic, or heterocyclic,
wherein: [0174] the aryl group is substituted with 3 to 5
substituents, [0175] the heteroaryl group is substituted with 2 to
5 substituents, [0176] the alicyclic group is substituted with 3 to
5 substituents, [0177] the heterocyclic group is substituted with 3
to 5 substituents, and [0178] the substituents are selected from
the group consisting of halogen, lower alkyl, lower alkenyl, lower
alkynyl, --SR.sup.8, --OR.sup.8, --CN, --C(O)OH, --C(O)R.sup.9,
--NO.sub.2, --NR.sup.8R.sup.10, lower aryl, heteroaryl, alicyclic,
lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,
dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N;
[0179] R.sup.8 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, lower aryl, lower heteroaryl, or --C(O)R.sup.9;
[0180] R.sup.9 is H, lower alkyl, lower alkenyl, lower alkynyl,
lower aryl, lower heteroaryl, --NR.sup.10R.sup.10, or --OR.sup.11,
wherein R.sup.10 and R.sup.10 taken together optionally form a ring
of 3-7 ring atoms and optionally 1-3 of the ring atoms are
heteroatoms selected from the group of O, S and N;
[0181] R.sup.10 is hydrogen, lower alkyl, lower heteroaryl, lower
aryl, lower alkenyl, or lower alkynyl,
[0182] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
heteroaryl or lower aryl; and
[0183] R.sup.12 is hydrogen or lower alkyl; provided that when
R.sup.5 is alicyclic, the ring system does not contain any
tetra-substituted sp.sup.3 ring carbons.
[0184] In one embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, diastereomer,
pharmaceutically acceptable salt or prodrug thereof, each of the
aryl, heteroaryl, alicyclic or heterocyclic group is monocyclic or
bicyclic.
[0185] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, diastereomer,
pharmaceutically acceptable salt or prodrug thereof, R.sup.1 is
halogen; and R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or
--C(O)R.sup.9.
[0186] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or --C(O)R.sup.9;
and R.sup.4 is lower alkyl.
[0187] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or --C(O)R.sup.9;
and R.sup.4 is --CHR.sup.12--.
[0188] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or --C(O)R.sup.9;
and R.sup.4 is --CH.sub.2--.
[0189] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.2 is --NHR.sup.8, where
R.sup.8 is hydrogen or --C(O)R.sup.9; and R.sup.4 is
--CH.sub.2--.
[0190] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is halogen; R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--; and R.sup.5 is aryl or
heteroaryl, wherein each of the aryl and heteroaryl is monocyclic
or bicyclic and is substituted with 3 to 5 substituents.
[0191] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo;
R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--; and R.sup.5 is aryl
or heteroaryl, wherein each of the aryl and heteroaryl is
monocyclic or bicyclic and is substituted with 3 to 5
substituents.
[0192] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is a phenyl having at least
three substituents.
[0193] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2 and R.sup.5 is a pyridyl having at least two
substituents.
[0194] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is 1-oxy-pyridyl (N-oxy-pyridyl)
having at least two substituents.
[0195] It should be understood that any of the foregoing
embodiments can be combined where feasible and appropriate.
[0196] In another embodiment, the invention provides compounds, or
polymorphs, solvates, esters, tautomers, pharmaceutically
acceptable salts or prodrugs thereof, prepared by the process
comprising:
[0197] reacting a compound of formula Y and a compound of formula
Z, wherein:
[0198] Y is a represented by any one of the following formulae:
##STR9##
[0199] Z is L.sup.1-R.sup.4--R.sup.5; wherein: [0200] L.sup.1 is
halogen, NR.sup.8R.sup.10, triflate, tosylate, or mesylate; [0201]
R.sup.4 is --CHR.sup.12--, --C(O)--, --C(S)--, --S(O)-- or
--SO.sub.2--; [0202] R.sup.5 is aryl, heteroaryl, alicyclic, or
heterocyclic, wherein: [0203] the aryl group is substituted with 3
to 5 substituents, [0204] the heteroaryl group is substituted with
2 to 5 substituents, [0205] the alicyclic group is substituted with
3 to 5 substituents, [0206] the heterocyclic group is substituted
with 3 to 5 substituents, and [0207] the substituents are selected
from the group consisting of halogen, lower alkyl, lower alkenyl,
lower alkynyl, --SR.sup.8, --OR.sup.8, --CN, --C(O)OH,
--C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, lower aryl,
heteroaryl, alicyclic, lower heterocyclic, arylalkyl,
heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino,
oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,
pyridinyl, thiophene, furanyl, indole, indazole, phosphonates,
phosphates, phosphoramides, sulfonates, sulfones, sulfates,
sulphonamides, carbamates, ureas, thioureas and thioamides, wherein
R.sup.8 and R.sup.10 taken together optionally form a ring of 3-7
ring atoms and optionally 1-3 of the ring atoms are heteroatoms
selected from the group of O, S and N; [0208] R.sup.8 is hydrogen,
lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower
heteroaryl, or --C(O)R.sup.9; [0209] R.sup.9 is H, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.11, or --OR.sup.11, wherein R.sup.10 and R.sup.10
taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the
group of O, S and N; [0210] R.sup.10 is hydrogen, lower alkyl,
lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
[0211] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
heteroaryl or lower aryl; [0212] R.sup.12 is hydrogen or lower
alkyl; [0213] R.sup.21 is halogen, --OR.sup.8, --SR.sup.8 or lower
alkyl; [0214] R.sup.22 is --NR.sup.8R.sup.10; [0215] R.sup.24 is
--NH.sub.2, --NO.sub.2 or --NO; [0216] R.sup.25 is halogen or --OH;
[0217] R.sup.26 is --C(O)NH.sub.2 or C(O)OEt; and [0218] R.sup.27
is --NH.sub.2, --OH or halogen;
[0219] provided that when R.sup.5 is alicyclic, the ring system
does not contain any tetra-substituted sp.sup.3 ring carbons.
[0220] In one embodiment of the compounds prepared by the process
of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, L.sup.1 is
--Cl, --Br or --NH.sub.2; R.sup.5 is aryl or heteroaryl.
[0221] In another embodiment of the compounds prepared by the
process of the invention, or a polyrnorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
R.sup.4 is --CH.sub.2--.
[0222] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, R.sup.5 is
aryl, heteroaryl, alicyclic, or heterocyclic, optionally mono- or
bicyclic.
[0223] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, L.sup.1 is
--Cl, --Br or --NH.sub.2; R.sup.4 is --CH.sub.2--; and R.sup.5 is
aryl or heteroaryl.
[0224] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, Y is a
triazolopyrimidine.
[0225] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, Y is a
triazole.
[0226] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, Y is a
pyrimidine.
[0227] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, the reaction
is performed in a solvent comprising a member selected from the
group of DMF, THF and DMSO.
[0228] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, the reaction
is performed in a solvent that comprises DMF.
[0229] It should be understood that any of the foregoing
embodiments can be combined where feasible and appropriate.
[0230] Illustrative species of the compounds of the invention that
are based on Formula I are described in TABLE 1. Prodrugs which can
be employed by these compounds include, but are not limited to,
those listed in the Definition section. TABLE-US-00001 TABLE 1
Exemplary Compounds of Formula I I ##STR10## No. Ex. R.sup.1
R.sup.4 R.sup.5 1 5 Cl CH.sub.2 3,4,5-Trimethoxyphenyl 2 6 Cl
CH.sub.2 2-Chloro-3,4,5-trimethoxyphenyl 3 8 Cl CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 4 10 Cl CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 5 Cl CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 6 Cl CH.sub.2 3,4,5-Trimethylphenyl
7 Cl CH.sub.2 2-Chloro-3,4,5-trimethylphenyl 8 Cl CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 9 Cl CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 10 Cl CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 11 Cl CH.sub.2
3,5-Dimethoxy-4-methylphenyl 12 Cl CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 13 Cl CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 14 Cl CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 15 Cl CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 16 Cl CH.sub.2
3,5-Dichloro-4-methylphenyl 17 Cl CH.sub.2
2,3,5-Trichloro-4-methylphenyl 18 Cl CH.sub.2
2-Bromo-3,5-dichloro-4-methylphenyl 19 Cl CH.sub.2
2-Iodo-3,5-dichloro-4-methylphenyl 20 Cl CH.sub.2
2-Fluoro-3,5-dichloro-4-methylphenyl 21 Cl CH.sub.2
3,5-Dibromo-4-methylphenyl 22 Cl CH.sub.2
2-Chloro-3,5-dibromo-4-methylphenyl 23 Cl CH.sub.2
2,3,5-Tribromo-4-methylphenylphenyl 24 Cl CH.sub.2
2-Iodo-3,5-dibromo-4-methylphenyl 25 Cl CH.sub.2
2-Fluoro-3,5-dibromo-4-methylphenyl 26 Cl CH.sub.2
3,5-Dichloro-4-methoxyphenyl 27 Cl CH.sub.2
2,3,5-Trichloro-4-methoxyphenyl 28 Cl CH.sub.2
2-Bromo-3,5-dichloro-4-methoxyphenyl 29 Cl CH.sub.2
2-Iodo-3,5-dichloro-4-methoxyphenyl 30 Cl CH.sub.2
2-Fluoro-3,5-dichloro-4-methoxyphenyl 31 Cl CH.sub.2
3,5-Dibromo-4-methoxyphenyl 32 Cl CH.sub.2
2-Chloro-3,5-dibromo-4-methoxyphenyl 33 Cl CH.sub.2
2,3,5-Tribromo-4-methoxyphenyl 34 Cl CH.sub.2
2-Iodo-3,5-dibromo-4-methoxyphenyl 35 Cl CH.sub.2
2-Fluoro-3,5-dibromo-4-methoxyphenyl 36 Cl CH.sub.2
3-Chloro-5-bromo-4-methylphenyl 37 Cl CH.sub.2
2,3-Dichloro-5-bromo-4-methylphenyl 38 Cl CH.sub.2
2,5-Dibromo-3-chloro-4-methylphenyl 39 Cl CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methylphenyl 40 Cl CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methylphenyl 41 Cl CH.sub.2
3-Chloro-5-bromo-4-methoxyphenylphenyl 42 Cl CH.sub.2
2,3-Dichloro-5-bromo-4-methoxyphenyl 43 Cl CH.sub.2
2,5-Dibromo-3-chloro-4-methoxyphenyl 44 Cl CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methoxyphenyl 45 Cl CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methoxyphenyl 46 Cl CH.sub.2
3-Bromo-5-chloro-4-methylphenyl 47 Cl CH.sub.2
2,5-Dichloro-3-bromo-4-methylphenyl 48 Cl CH.sub.2
2,3-Dibromo-5-chloro-4-methylphenyl 49 Cl CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methylphenyl 50 Cl CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methylphenyl 51 Cl CH.sub.2
3-Bromo-5-chloro-4-methoxyphenyl 52 Cl CH.sub.2
2,5-Dichloro-3-bromo-4-methoxyphenyl 53 Cl CH.sub.2
2,3-Dibromo-5-chloro-4-methoxyphenyl 54 Cl CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methoxyphenyl 55 Cl CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methoxyphenyl 56 Cl CH.sub.2
3,5-Dimethoxy-4-trifluoromethylphenyl 57 Cl CH.sub.2
2-Chloro-3,5-dimethoxy-4-trifluoromethylphenyl 58 Cl CH.sub.2
2-Bromo-3,5-dimethoxy-4-trifluoromethylphenyl 59 Cl CH.sub.2
2-Iodo-3,5-dimethoxy-4-trifluoromethylphenyl 60 Cl CH.sub.2
2-Fluoro-3,5-dimethoxy-4-trifluoromethylphenyl 61 Cl CH.sub.2
3,5-dibromo-4-trifluoromethoxyphenyl 62 Cl CH.sub.2
2-Chloro-3,5-dibromo-4-trifluoromethoxyphenyl 63 Cl CH.sub.2
2,3,5-Tribromo-4-trifluoromethoxyphenyl 64 Cl CH.sub.2
2-Iodo-3,5-dibromo-4-trifluoromethoxyphenyl 65 Cl CH.sub.2
2-Fluoro-3,5-dibromo-4-trifluoromethoxyphenyl 66 Cl CH.sub.2
3,5-Dimethyl-4-methoxyphenyl 67 Cl CH.sub.2
2-Chloro-3,5-dimethyl-4-methoxyphenyl 68 Cl CH.sub.2
2-Bromo-3,5-dimethyl-4-methoxyphenyl 69 Cl CH.sub.2
2-Iodo-3,5-dimethyl-4-methoxyphenyl 70 Cl CH.sub.2
2-Fluoro-3,5-dimethyl-4-methoxyphenyl 71 Cl CH.sub.2
3,5-Dimethyl-4-bromophenyl 72 Cl CH.sub.2
2-Chloro-3,5-dimethyl-4-bromophenyl 73 Cl CH.sub.2
2,4-Dibromo-3,5-dimethylphenyl 74 Cl CH.sub.2
2-Iodo-3,5-dimethyl-4-bromophenyl 75 Cl CH.sub.2
2-Fluoro-3,5-dimethyl-4-bromophenyl 76 Cl CH.sub.2
3,5-Dimethyl-4-chlorophenyl 77 Cl CH.sub.2
2,4-Dichloro-3,5-dimethylphenyl 78 Cl CH.sub.2
2-Bromo-3,5-dimethyl-4-chlorophenyl 79 Cl CH.sub.2
2-Iodo-3,5-dimethyl-4-chlorophenyl 80 Cl CH.sub.2
2-Fluoro-3,5-dimethyl-4-chlorophenyl 81 Br CH.sub.2
3,4,5-Trimethoxyphenyl 82 Br CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 83 Br CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 84 Br CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 85 Br CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 86 Br CH.sub.2
3,4,5-Trimethylphenyl 87 Br CH.sub.2 2-Chloro-3,4,5-trimethylphenyl
88 Br CH.sub.2 2-Bromo-3,4,5-trimethylphenyl 89 Br CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 90 Br CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 91 Br CH.sub.2
3,5-Dimethoxy-4-methylphenyl 92 Br CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 93 Br CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 94 Br CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 95 Br CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 96 Br CH.sub.2
3,5-Dichloro-4-methylphenyl 97 Br CH.sub.2
2,3,5-Trichloro-4-methylphenyl 98 Br CH.sub.2
2-Bromo-3,5-dichloro-4-methylphenyl 99 Br CH.sub.2
2-Iodo-3,5-dichloro-4-methylphenyl 100 Br CH.sub.2
2-Fluoro-3,5-dichloro-4-methylphenyl 101 Br CH.sub.2
3,5-Dibromo-4-methylphenyl 102 Br CH.sub.2
2-Chloro-3,5-dibromo-4-methylphenyl 103 Br CH.sub.2
2,3,5-Tribromo-4-methylphenylphenyl 104 Br CH.sub.2
2-Iodo-3,5-dibromo-4-methylphenyl 105 Br CH.sub.2
2-Fluoro-3,5-dibromo-4-methylphenyl 106 Br CH.sub.2
3,5-Dichloro-4-methoxyphenyl 107 Br CH.sub.2
2,3,5-Trichloro-4-methoxyphenyl 108 Br CH.sub.2
2-Bromo-3,5-dichloro-4-methoxyphenyl 109 Br CH.sub.2
2-Iodo-3,5-dichloro-4-methoxyphenyl 110 Br CH.sub.2
2-Fluoro-3,5-dichloro-4-methoxyphenyl 111 Br CH.sub.2
3,5-Dibromo-4-methoxyphenyl 112 Br CH.sub.2
2-Chloro-3,5-dibromo-4-methoxyphenyl 113 Br CH.sub.2
2,3,5-Tribromo-4-methoxyphenyl 114 Br CH.sub.2
2-Iodo-3,5-dibromo-4-methoxyphenyl 115 Br CH.sub.2
2-Fluoro-3,5-dibromo-4-methoxyphenyl 116 Br CH.sub.2
3-Chloro-5-bromo-4-methylphenyl 117 Br CH.sub.2
2,3-Dichloro-5-bromo-4-methylphenyl 118 Br CH.sub.2
2,5-Dibromo-3-chloro-4-methylphenyl 119 Br CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methylphenyl 120 Br CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methylphenyl 121 Br CH.sub.2
3-Chloro-5-bromo-4-methoxyphenylphenyl 122 Br CH.sub.2
2,3-Dichloro-5-bromo-4-methoxyphenyl 123 Br CH.sub.2
2,5-Dibromo-3-chloro-4-methoxyphenyl 124 Br CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methoxyphenyl 125 Br CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methoxyphenyl 126 Br CH.sub.2
3-Bromo-5-chloro-4-methylphenyl 127 Br CH.sub.2
2,5-Dichloro-3-bromo-4-methylphenyl 128 Br CH.sub.2
2,3-Dibromo-5-chloro-4-methylphenyl 129 Br CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methylphenyl 130 Br CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methylphenyl 131 Br CH.sub.2
3-Bromo-5-chloro-4-methoxyphenyl 132 Br CH.sub.2
2,5-Dichloro-3-bromo-4-methoxyphenyl 133 Br CH.sub.2
2,3-Dibromo-5-chloro-4-methoxyphenyl 134 Br CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methoxyphenyl 135 Br CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methoxyphenyl 136 Br CH.sub.2
3,5-Dimethoxy-4-trifluoromethylphenyl 137 Br CH.sub.2
2-Chloro-3,5-dimethoxy-4-trifluoromethylphenyl 138 Br CH.sub.2
2-Bromo-3,5-dimethoxy-4-trifluoromethylphenyl 139 Br CH.sub.2
2-Iodo-3,5-dimethoxy-4-trifluoromethylphenyl 140 Br CH.sub.2
2-Fluoro-3,5-dimethoxy-4-trifluoromethylphenyl 141 Br CH.sub.2
3,5-Dibromo-4-trifluoromethoxyphenyl 142 Br CH.sub.2
2-Chloro-3,5-dibromo-4-trifluoromethoxyphenyl 143 Br CH.sub.2
2,3,5-Tribromo-4-trifluoromethoxyphenyl 144 Br CH.sub.2
2-Iodo-3,5-dibromo-4-trifluoromethoxyphenyl 145 Br CH.sub.2
2-Fluoro-3,5-dibromo-4-trifluoromethoxyphenyl 146 Br CH.sub.2
3,5-Dimethyl-4-methoxyphenyl 147 Br CH.sub.2
2-Chloro-3,5-dimethyl-4-methoxyphenyl 148 Br CH.sub.2
2-Bromo-3,5-dimethyl-4-methoxyphenyl 149 Br CH.sub.2
2-Iodo-3,5-dimethyl-4-methoxyphenyl 150 Br CH.sub.2
2-Fluoro-3,5-dimethyl-4-methoxyphenyl 151 Br CH.sub.2
3,5-Dimethyl-4-bromophenyl 152 Br CH.sub.2
2-Chloro-3,5-dimethyl-4-bromophenyl 153 Br CH.sub.2
2,4-Dibromo-3,5-dimethylphenyl 154 Br CH.sub.2
2-Iodo-3,5-dimethyl-4-bromophenyl 155 Br CH.sub.2
2-Fluoro-3,5-dimethyl-4-bromophenyl 156 Br CH.sub.2
3,5-Dimethyl-4-chlorophenyl 157 Br CH.sub.2
2,4-Dichloro-3,5-dimethylphenyl 158 Br CH.sub.2
2-Bromo-3,5-dimethyl-4-chlorophenyl 159 Br CH.sub.2
2-Iodo-3,5-dimethyl-4-chlorophenyl 160 1 Cl CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 161 2 Cl CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 162 Cl CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-.yl 163 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 164 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxy-1-oxypyridin- 2-yl 165 Cl CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxy-1-oxypyridin- 2-yl 166 Cl CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 167 Cl CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 168 Cl CH.sub.2
6-Bromo-3,5-dimethyl-4-bromopyridin-2-yl 169 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-bromopyridin-2-yl 170 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-bromo-1-oxypyridin-2-yl 171 Cl CH.sub.2
4,6-Dibromo-3,5-dimethyl-1-oxypyridin-2-yl 172 Cl CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 173 Cl CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 174 Cl CH.sub.2
6-Bromo-3,5-dimethyl-4-chloropyridin-2-yl 175 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-chloropyridin-2-yl 176 Cl CH.sub.2
4,6-Dichloro-3,5-dimethyl-1-oxypyridrn-2-yl 177 Cl CH.sub.2
6-Bromo-3,5-dimethyl-4-chloro-1-oxypyridin-2-yl 178 Cl CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 179 Cl CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 180 Cl CH.sub.2
6-Bromo-3,5-dimethyl-4-iodopyridin-2-yl 181 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-iodopyridin-2-yl 182 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 183 Cl CH.sub.2
6-Bromo-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 184 Cl CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 185 Cl CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 186 Cl CH.sub.2
6-Bromo-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 187 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 188 Cl CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-1- oxypyridin-2-yl 189 Cl
CH.sub.2 6-Bromo-3,5-dimethyl-4-thiomethyl-1- oxypyridin-2-yl 190
Cl CH.sub.2 3,4,5-Trimethyl-pyridin-2-yl 191 Cl CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 192 Cl CH.sub.2
6-Bromo-3,4,5-trimethyl-pyridin-2-yl 193 Cl CH.sub.2
6-Chloro-3,4,5-trimethyl-pyridin-2-yl 194 Cl CH.sub.2
6-Chloro-3,4,5-trimethyl-1-oxypyridin-2-yl 195 Cl CH.sub.2
6-Bromo-3,4,5-trimethyl-1-oxypyridin-2-yl 196 Cl CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 197 Cl CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 198 Cl CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 199 Cl CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 200 Cl CH.sub.2 3-Chloro-4,5
,6-trimethoxy-1-oxypyridin-2-yl 201 Cl CH.sub.2
3-Bromo-4,5,6-trimethoxy-1-oxypyridin-2-yl 202 Cl CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 203 Cl CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 204 Cl CH.sub.2
3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 205 Cl CH.sub.2
3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 206 Cl CH.sub.2
3-Chloro-3,4,5-trimethoxy-1-oxypyridin-2-yl 207 Cl CH.sub.2
3-Bromo-3,4,5-trimethoxy-1-oxypyridin-2-yl 208 Cl CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 209 Cl CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 210 Cl CH.sub.2
3-Bromo-4,5,6-trimethyl-pyridin-2-yl 211 Cl CH.sub.2
3-Chloro-4,5,6-trimethyl-pyridin-2-yl 212 Cl CH.sub.2
3-Chloro-4,5,6-trimethyl-1-oxypyridin-2-yl 213 Cl CH.sub.2
3-Bromo-4,5,6-trimethyl-1-oxypyridin-.2-yl 214 Cl CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 215 Cl CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-2-yl 216 Cl CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-pyridin-2-yl 217 Cl CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-pyridin-2-yl 218 Cl CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-1-oxypyridin- 2-yl 219 Cl CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-1-oxypyridin- 2-yl 220 Cl CH.sub.2
4-Bromo-5,6-dimethoxy-pyridin-2-yl 221 Cl CH.sub.2
4-Bromo-5,6-dimethoxy-1-oxypyridin-2-yl 222 Cl CH.sub.2
3,4-Dibromo-5,6-dimethoxy-pyridin-2-yl 223 Cl CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-pyridin-2-yl 224 Cl CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-1-oxypyridin- 2-yl 225 Cl CH.sub.2
3,4-Dibromo-5,6-dimethoxy-1-oxypyridin-2-yl 226 Cl CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 227 Cl CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 228 Cl CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 229 Cl CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 230 Cl CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 231 Cl CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl
232 Cl CH.sub.2 4,6-Dimethyl-5-bromo-1-oxypyridin-pyridin-3-yl 233
Cl CH.sub.2 4,6-Dimethyl-5-chloro-1-oxypyridin-pyridin-3-yl 234 Cl
CH.sub.2 5,6-Dimethyl-4-bromo-1-oxypyridin-pyridin-3-yl 235 Cl
CH.sub.2 5,6-Dimethyl-4-chloro-1-oxypyridin-pyridin-3-yl 236 Cl
CH.sub.2 2,6-Dimethyl-3-methoxypyridin-4-yl 237 Cl CH.sub.2
2,6-Dimethyl-pyridin-4-yl 238 Cl CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 239 Cl CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 240 Cl CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 241 Cl CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 242 Cl CH.sub.2
2,6-Dichloro-3-bromopyridin-4-yl 243 Cl CH.sub.2
2,6-Dibromo-3-chloropyridin-4-yl 244 Cl CH.sub.2
2,3,6-Trichloro-pyridin-4-yl 245 Cl CH.sub.2
2,3,6-Tribromo-pyridin-4-yl 246 Cl CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 247 Cl CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 248 Cl CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 249 Cl CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 250 Cl CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 251 Cl CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 252 Cl CH.sub.2
2,6-Dichloro-3-bromo-1-oxy-pyridin-4-yl 253 Cl CH.sub.2
2,6-Dibromo-3-chloro-1-oxy-pyridin-4-yl 254 Cl CH.sub.2
2,3,6-Trichloro-1-oxy-pyridin-4-yl 255 Cl CH.sub.2
2,3,6-Tribromo-1-oxy-pyridin-4-yl 256 Cl CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 257 Cl CH.sub.2
5,6-Dimethyl-4-iodopyridin-3-yl 258 Cl CH.sub.2
4,5,6-Trichloropyridin-3-yl 259 Cl CH.sub.2
4,5,6-Tribromopyridin-3-yl 260 Br CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 261 Br CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 262 Br CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 263 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 264 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxy-1-oxypyridin- 2-yl 265 Br CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxy-1-oxypyridin- 2-yl 266 Br CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 267 Br CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 268 Br CH.sub.2
6-Bromo-3,5-dimethyl-4-bromopyridin-2-yl 269 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-bromopyridin-2-yl 270 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-bromo-1-oxypyridin-2-yl 271 Br CH.sub.2
4,6-Dibromo-3,5-dimethyl-1-oxypyridin-2-yl 272 Br CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 273 Br CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 274 Br CH.sub.2
6-Bromo-3,5-dimethyl-4-chloropyridin-2-yl 275 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-chloropyridin-2-yl 276 Br CH.sub.2
4,6-Dichloro-3,5-dimethyl-1-oxypyridin-2-yl 277 Br CH.sub.2
6-Bromo-3,5-dimethyl-4-chloro-1-oxypyridin-2-yl 278 Br CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 279 Br CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 280 Br CH.sub.2
6-Bromo-3,5-dimethyl-4-iodopyridin-2-yl 281 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-iodopyridin-2-yl 282 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 283 Br CH.sub.2
6-Bromo-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 284 Br CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 285 Br CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 286 Br CH.sub.2
6-Bromo-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 287 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 288 Br CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-1- oxypyridin-2-yl 289 Br
CH.sub.2 6-Bromo-3,5-dimethyl-4-thiomethyl-1- oxypyridin-2-yl 290
Br CH.sub.2 3,4,5-Trimethyl-pyridin-2-yl 291 Br CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 292 Br CH.sub.2
6-Bromo-3,4,5-trimethyl-pyridin-2-yl 293 Br CH.sub.2
6-Chloro-3,4,5-trimethyl-pyridin-2-yl 294 Br CH.sub.2
6-Chloro-3,4,5-trimethyl-1-oxypyridin-2-yl 295 Br CH.sub.2
6-Bromo-3,4,5-trimethyl-1-oxypyridin-2-yl 296 Br CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 297 Br CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 298 Br CH.sub.2
6-Bromo-3,4,5-trimethoxy-pyridin-2-yl 299 Br CH.sub.2
6-Chloro-3,4,5-trimethoxy-pyridin-2-yl 300 Br CH.sub.2
6-Chloro-3,4,5-trimethoxy-1-oxypyridin-2-yl 301 Br CH.sub.2
6-Bromo-3,4,5-trimethoxy-1-oxypyridin-2-yl 302 Br CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 303 Br CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 304 Br CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 305 Br CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 306 Br CH.sub.2
3-Chloro-4,5,6-trimethoxy-1-oxypyridin-2-yl 307 Br CH.sub.2
3-Bromo-4,5,6-trimethoxy-1-oxypyridin-2-yl 308 Br CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 309 Br CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 310 Br CH.sub.2
3-Bromo-4,5,6-trimethyl-pyridin-2-yl 311 Br CH.sub.2
3-Chloro-4,5,6-trimethyl-pyridin-2-yl 312 Br CH.sub.2
3-Chloro-4,5,6-trimethyl-1-oxypyridin-2-yl 313 Br CH.sub.2
3-Bromo-4,5,6-trimethyl-1-oxypyridin-2-yl 314 Br CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 315 Br CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-2-yl 316 Br CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-pyridin-2-yl 317 Br CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-pyridin-2-yl 318 Br CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-1-oxypyridin- 2-yl 319 Br CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-1-oxypyridin- 2-yl 320 Br CH.sub.2
4-Bromo-5,6-dimethoxy-pyridin-2-yl 321 Br CH.sub.2
4-Bromo-5,6-dimethoxy-1-oxypyridin-2-yl 322 Br CH.sub.2
3,4-Dibromo-5,6-dimethoxy-pyridin-2-yl 323 Br CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-pyridin-2-yl 324 Br CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-1-oxypyridin- 2-yl 325 Br CH.sub.2
3,4-Dibromo-5,6-dimethoxy-1-oxypyridin-2-yl 326 Br CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 327 Br CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 328 Br CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 329 Br CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 330 Br CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 331 Br CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 332 Br CH.sub.2
4,6-Dimethyl-5-bromo-1-oxypyridin-pyridin-3-yl 333 Br CH.sub.2
4,6-Dimethyl-5-chloro-1-oxypyridin-pyridin-3-yl 334 Br CH.sub.2
5,6-Dimethyl-4-bromo-1-oxypyridin-pyridin-3-yl 335 Br CH.sub.2
5,6-Dimethyl-4-chloro-1-oxypyridin-pyridin-3-yl 336 Br CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 337 Br CH.sub.2
2,6-Dimethyl-pyridin-4-yl 338 Br CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 339 Br CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 340 Br CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 341 Br CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 342 Br CH.sub.2
2,6-Dichloro-3-bromopyridin-4-yl 343 Br CH.sub.2
2,6-Dibromo-3-chloropyridin-4-yl 344 Br CH.sub.2
2,3,6-Trichloro-pyridin-4-yl 345 Br CH.sub.2
2,3,6-Tribromo-pyridin-4-yl 346 Br CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 347 Br CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 348 Br CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 349 Br CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 350 Br CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 351 Br CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 352 Br CH.sub.2
2,6-Dichloro-3-bromo1-oxy-pyridin-4-yl 353 Br CH.sub.2
2,6-Dibromo-3-chloro1-oxy-pyridin-4-yl 354 Br CH.sub.2
2,3,6-Trichloro-1-oxy-pyridin-4-yl 355 Br CH.sub.2
2,3,6-Tribromo-1-oxy-pyridin-4-yl 356 Br CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 357 Br CH.sub.2
5,6-Dimethyl-4-iodopyridin-3-yl 358 Br CH.sub.2
4,5,6-Trichloropyridin-3-yl 359 Br CH.sub.2
4,5,6-Tribromopyridin-3-yl 360 Cl CH.sub.2
4,5,6-Trimethoxy-3-chloropyridin-2-yl 361 Br CH.sub.2
4,5,6-Trimethoxy-3-chloropyridin-2-yl 362 Cl CH.sub.2
4,5,6-Trimethoxy-3-bromopyridin-2-yl 363 Br CH.sub.2
4,5,6-Trimethoxy-3-bromopyridin-2-yl 364 Cl CH.sub.2
4,5,6-Trimethoxy-pyridin-3-yl 365 Cl CH.sub.2
4,5,6-Trimethoxy-1-oxy-pyridin-3-yl 366 Cl CH.sub.2
2-Bromo-4,5,6-trimethoxy-pyridin-3-yl 367 Cl CH.sub.2
2-Chloro-4,5,6-trimethoxy-pyridin-3-yl 368 Cl CH.sub.2
2-Chloro-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 369 Cl CH.sub.2
2-Bromo-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 370 Cl CH.sub.2
4,5,6-Trimethyl-pyridin-3-yl 371 Cl CH.sub.2
4,5,6-Trimethyl-1-oxy-pyridin-3-yl 372 Cl CH.sub.2
2-Bromo-4,5,6-trimethyl-pyridin-3-yl 373 Cl CH.sub.2
2-Chloro-4,5,6-trimethyl-pyridin-3-yl 374 Cl CH.sub.2
2-Chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl 375 Cl CH.sub.2
2-Bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl 376 Cl CH.sub.2
2-Iodo-4,5,6-trimethyl-pyridin-3-yl 377 Cl CH.sub.2
2-Iodo-4,5,6-trimethyl-pyridin-3-yl 378 Br CH.sub.2
4,5,6-Trimethoxy-pyridin-3-yl 379 Br CH.sub.2
4,5,6-Trimethoxy-1-oxy-pyridin-3-yl 380 Br CH.sub.2
2-Bromo-4,5,6-trimethoxy-pyridin-3-yl 381 Br CH.sub.2
2-Chloro-4,5,6-trimethoxy-pyridin-3-yl 382 Br CH.sub.2
2-Chloro-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 383 Br CH.sub.2
2-Bromo-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 384 Br CH.sub.2
4,5,6-Trimethyl-pyridin-3-yl 385 Br CH.sub.2
4,5,6-Trimethyl-1-oxy-pyridin-3-yl 386 Br CH.sub.2
2-Bromo-4,5,6-trimethyl-pyridin-3-yl 387 Br CH.sub.2
2-Chloro-4,5,6-trimethyl-pyridin-3-yl 388 Br CH.sub.2
2-Chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl 389 Br CH.sub.2
2-Bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl
Compounds of interest in Table 1 are compounds 2, 3, 13, 82, 83,
162, 163, 168, 169, 174, 175, 180, 181, 186, 187, 192, 193, 198,
199, 204, 205, 210, 211, 228, 229, 230, 231, 232, 233, 234, 235,
236, 237, 250, 251, 262, 263, 268, 269, 274, 275, 280, 281, 286,
287, 292, 293, 298, 299, 304, 305, 310, 311, 316, 317, 328, 329,
338, 372, 373, 380 and 381 with selected compounds being 162, 163,
168, 169, 174, 175, 180, 181, 186, 187, 192, 193, 198, 199, 204,
205, 228, 229, 262, 263, 268, 269, 274, 275, 280, 281, 286, 287,
292, 293, 316, 317, 328, and 329.
[0231] III. Synthesis of the Compounds of the Invention
[0232] The compounds of Formula I (see Scheme 1) of the present
invention may be synthesized by various methods known in the art,
including those described in, for example, Parkanyi, J. Heterocyl.
Chem., 1990, 27(5), 1409-13; Beauchamp, U.S. Pat. No. 4,714,701,
1987; Meier, U.S. Pat. No. 5,204,353, 1993. Gillespie, WO
02/055083; Peterson, J. Med. Chem., 1990, 33(4), 1214-19. The
general synthetic strategy is outlined in Scheme 1 and consists of
three parts: (1) constructing the bicyclic system, starting from
either a pyrimidine or a 1,2,3-triazole, (2) appending the
R.sup.5--R.sup.4-group, and (3) further elaborating the ring
systems.
[0233] Importantly, one skilled in the art will recognize that the
sequence of events is not necessarily (1)-(2)-(3), and that these
events may be interchanged, provided there be no incompatibility
between the reagents and the functional groups specific to the
point in case. ##STR11##
[0234] The starting material and/or the intermediates of, e.g.,
Formulae 1, 2 or/and 4 can exist in tautomeric forms, and both
forms are indiscriminately described in the specification.
[0235] From Pyrimidines:
[0236] Method 1
[0237] Compounds of Formula I can be prepared from the commercially
available substituted pyrimidines compounds of Formula 1 where
R.sup.9 is OH or halogen, R.sup.10 is amino or protected amino or
any group that can be converted to amino, such as SMe, R.sup.11 is
H or NO.sub.2, R.sup.12 is Cl, (see Scheme 2) by treating with an
excess halogenating agent such as POCl.sub.3, oxalyl chloride, or
PCl.sub.5, and a formulating agent such as DMF to give compounds of
Formula 1 where R.sup.9 is halogen, and R.sup.12 is halogen,
followed by halogen displacement with an nucleophile, such as
NH.sub.2--R.sup.4--R.sup.5, in solvents such as EtOH, tBuOH etc. in
presence of organic bases such as Et.sub.3N, (i-Pr).sub.2NEt etc.
to yield a compound of Formula 2. Formula 2, where R.sup.11 is
NO.sub.2, may then be reduced with zinc and formic acid or sodium
dithionite to give compounds of Formula 2, where R.sup.11 is
NH.sub.2, see Dempcy, U.S. Publication No. 2003/0078413 A1.
Compounds of Formula I can then be prepared by diazotization with
an alkali metal nitrite such as NaNO.sub.2 in inorganic acids such
as HCl, followed by in situ cyclization. (See Beauchamp, U.S. Pat.
No. 4,714,701; Meier, U.S. Pat. No. 5,204,353) These compounds of
Formula I can be further modified as necessary. ##STR12##
[0238] Formula 2, where R.sup.11 is H, can be treated with
diazonium salts such as 4-chloroaniline diazonium salt prepared
from 4-chloroaniline and NaNO.sub.2 inorganic acids such as HCl to
give pyrimidine 5-azo- analog, that can be reduced with zinc dust
in EtOH/AcOH (1:1) solution to give compounds of Formula 2, where
R.sup.11 is NH.sub.2 (see Meier, U.S. Pat. No. 5,204,353).
[0239] Method 2 ##STR13##
[0240] Compounds of Formula I also can be prepared from the
commercially available substituted diamino pyrimidines compounds of
Formula 1 where R.sup.9 is OH or halogen, R.sup.10 is amino or
protected amino or any group that can be converted to amino, such
as SMe, R.sup.11 & R.sup.12 are NH.sub.2, (see Scheme 3)
following the diazotization method described earlier in Method 1 to
give compounds of Formula 4. Formula 4 can be alkylated in the
presence of a base such as K.sub.2CO.sub.3, NaH, Cs.sub.2CO.sub.3,
DBU etc. with/without the presence of halide such as NaI, KI,
(Bu).sub.3NI etc., and in a polar solvent such as DMF, THF, DMSO
etc. using electrophiles such as L.sup.1-R.sup.4--R.sup.5 where
L.sup.1 is a leaving group. Leaving groups include but are not
limited to, e.g., halogen, triflate, tosylate, mesylate etc. (See
Kasibhatla, WO 03/037860) Compounds of Formula I can also be
prepared from compounds of Formula 4 using Mitsunobu alkylation
conditions using L.sup.1-R.sup.4--R.sup.5 where L.sup.1 is
hydroxyl. (See Kozai, Chem. Pharm. Bull., 1999, 47(4),
574-575).
[0241] Method 3
[0242] From Triazole:
[0243] Compounds of Formula I can also be prepared from a
substituted triazole as shown in Scheme 4. Accordingly, compounds
of Formula 3, wherein R.sup.14 is NH.sub.2, R.sup.13 is
C(O)NH.sub.2 and R.sup.15 is H (commercially available), can be
alkylated in the presence of a base such as KOH, NaOH,
K.sub.2CO.sub.3, NaH, Cs.sub.2CO.sub.3, DBU etc. with/without the
presence of halide such as NaI, KI, (Bu).sub.3NI etc., and in a
polar solvent such as DMF, THF, DMSO etc. using electrophiles such
as L.sup.1-R.sup.4--R.sup.5 where L.sup.1 is a leaving group.
Leaving groups include but are not limited to, e.g., halogen,
triflate, tosylate, mesylate etc. to give compounds of Formula 6.
The ring closure can be achieved using many methods reported in the
literature (Alhede, J. Org. Chem., 1991, 2139 and references cited
therein) to give compounds of Formula I, wherein R.sup.1 is OH.
These compounds can be converted to the compounds of Formula I,
wherein R.sup.1 is Cl, using POCl.sub.3 as described earlier.
Alternately, we can also construct from Formula 3, wherein R.sup.14
is --OH or halide, R.sup.13 is --C(O)OEt by reacting with guanidine
hydrochloride as described in Chowdhury, J. Med. Chem. 1999, 42,
4300. ##STR14## Preparation of Electrophiles
L.sup.1-R.sup.4--R.sup.5 wherein L.sub.1 is a Leaving Group and of
Nucleophiles NH.sub.2--R.sup.4--R.sup.5. Synthesis of Benzyl Type
Electrophile: ##STR15##
[0244] The electrophiles can be prepared from the substituted
benzene derivatives using various methods reported in the
literature, see Jerry March, Advanced Organic Chemistry, 4.sup.th
edition; Larock, Comprehensive Organic Transformations, 1989, VCH,
New York. For example, compounds where L.sup.1 is --Br can be
prepared by reduction followed by halogenation of the benzoic acid
or aldehyde derivatives. These benzyl derivatives can also be
prepared by benzylic oxidation or benzylic halogenation. Further
modification of the benzyl ring can be done before or after the
triazolopurine alkylation step; for example halogenation was done
both ways. Synthesis of Pyridyl Methyl Type Electrophile:
##STR16##
[0245] These compounds can be prepared from many methods reported
in the literature. Morisawa et al. J. Med. Chem. 1974, 17, 1083;
Klaus, W. et al. J. Med. Chem. 1992, 35, 438; Abramovitch, R. A.;
Smith, E. M. "Pyridine-1-oxide in Pyridine and its Derivatives" in
The Chemistry of heterocyclic Compounds; Weissberger, A., Taylor,
E. C., Eds.; John Wieley, New York, 1974, Pt. 2, pp 1-261; Jeromin,
G. E. et al. Chem. Ber. 1987, 120, 649. Blanz, E. J., et al. J.
Med. Chem. 1970, 13, 1124; Smith, Kline and French, EP 0184322,
1986; Abblard, J. et al. Bull. Soc. Chim. Fr. 1972, 2466; Fisher,
B. E. et al. "The Structure of Isomaltol." J. Org. Chem. 1964, 29,
776. De Cat, A. et al. Bull. Soc. Chim. Belg. 1965, 74, 270;
Looker, J. H. et al. J. Org. Chem. 1979, 44, 3407. Ackerman, J. F.
Ph.D. Dissertation, University of Notre Dame, June, 1949. These
methods can be applied to the synthesis of quinoline, and
isoquinolines type compounds.
[0246] The compound R.sup.4--R.sup.5--NH.sub.2 is obtained by
treating R.sup.4--R.sup.5-L.sup.1 with ammonia at temperatures of
20-160.degree. C. in a pressure vessel, wherein L.sup.1 is leaving
group such as chloride, bromide, tosylate, mesylate etc. using
ammonia, or with sodium azide followed by hydrogenation.
Further Elaboration of the Ring Systems.
[0247] These modifications can be done at any stage depending upon
the incompatibility of the functional groups present.
Functional Group Interconversions of R.sup.1:
[0248] Compounds of Formula I, wherein R.sup.1 is OH, can be
converted to halides using standard conditions POCl.sub.3,
POBr.sub.3 etc. with/without a base such as
Et.sub.3N,N,N-dimethylaniline, (i-Pr).sub.2NEt etc. and
with/without a catalyst such as BnEt.sub.3N.sup.+Cl.sup.-, in polar
solvents such as CH.sub.3CN, CH.sub.2Cl.sub.2 etc. Related methods
include, but are not limited to, SOCl.sub.2/DMF (M. J. Robins, Can.
J. Chem. 1973, 12, 3161), PPh.sub.3/CCl.sub.4 (L. De Napoli, J.
Chem. Soc. Perkin Trans 1, 1994, 923), HMPT/CCl.sub.4 or HMPT/NBS
(E. A. Veliz, Tetrahedron Lett, 2000, 41, 1695) or
PPh.sub.3/I.sub.2 (X. Lin, Org. Letters, 2000, 2, 3497).
[0249] Compounds of Formula I, wherein R.sup.1 is NH.sub.2, can be
converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction
(Cl, Br, I) by means of a nitrosylating agent (NaNO.sub.2/H.sup.+,
NOBF.sub.4, RONO) and a halogen donor (BF.sub.4.sup.-, CuX.sub.2,
SbX.sub.3, where X is halogen).
[0250] Compounds of Formula I, wherein R.sup.1 is alkyl can be
prepared from compounds of Formula 4 where R.sup.1 is halogen and
trialkyl aluminum or dialkyl zinc (A. Holy, J. Med. Chem. 1999, 42,
2064).
[0251] Compounds of Formula I, wherein R.sup.1 is a halide can be
converted to compounds wherein R.sup.1 is NH.sub.2, OH, SH,
OR.sup.8, SR.sup.8 with standard reagents, e.g. NH.sub.3, NaOH,
thiourea, R.sup.8O.sup.-, R.sup.8S.sup.-, with or without a
catalyst (e.g. Pd, Ni, Cu, Lewis acid, H.sup.+) (e.g. B. G.
Ugarkar, J. Med. Chem. 2000, 43, 2883-2893 and 2894-2905).
[0252] Compounds of Formula I, wherein R.sup.1 is halogen or
another leaving group can be treated with ammonia to provide
compounds of Formula I wherein R.sup.1 is NH.sub.2 (F. Seela,
Liebigs. Ann. Chem. 1985, 315)
Functional Group Interconversions of R.sup.2:
[0253] Compounds of Formula I, wherein R.sup.2 is NH.sub.2 can be
temporarily protected, e.g. as an amide (Ac.sub.2O, PivCl), a
carbamate (tBoc).sub.2O) or amidine (DMF-DMA).
[0254] Compounds of Formula I, wherein R.sup.2 is NH.sub.2 can be
converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction
(Cl, Br, I) by means of a nitrosylating agent (NaNO.sub.2/H.sup.+,
NOBF.sub.4, RONO) and a halogen donor (BF4.sup.-, CuX.sub.2,
SbX.sub.3).
[0255] Compounds of Formula I, wherein R.sup.2 is a halide can be
converted to compounds wherein R.sup.2 is NH.sub.2, OH, SH,
OR.sup.8, SR.sup.8 with standard reagents, e.g. NH.sub.3, NaOH,
thiourea, R.sup.8O.sup.-, R.sup.8S.sup.-, with or without a
catalyst (e.g. Pd, Ni, Cu, Lewis acid, H.sup.+).
[0256] Compounds of Formula I, wherein R.sup.2 is SH can be
converted to halides (Br.sub.2). They can also be oxidized (e.g.
H.sub.2O.sub.2) and treated with ammonia to give a NH.sub.2 group
(S. M. Bennett, J. Med. Chem. 1990, 33, 2162).
[0257] Compounds of Formula I, wherein R.sup.2 is a sulfide, e.g.
MeS--, can be converted to a sulfone, e.g., MeSO.sub.2.sup.-, and
displaced with a nucleophile, e.g. NH.sub.3 or NH.sub.2--NH.sub.2,
N.sub.3.sup.-, CN.sup.-
[0258] Compounds of Formula I, wherein R.sup.2 is a sulfide, e.g.
MeS--, can be converted to a sulfone, e.g., MeSO.sub.2.sup.-, and
displaced with a nucleophile, e.g., NH.sub.3 or NH.sub.2--NH.sub.2,
N.sub.3.sup.-, CN.sup.-
Further Elaboration of R.sup.5:
[0259] R.sup.5, especially when it is aryl or heteroaryl, can be
further modified as needed, for example by halogenation, nitration,
palladium coupling of halogen, Friedel-Crafts alkylation/acylation,
etc. or these modifications can also be done before alkylation, see
Jerry March, Advanced Organic Chemistry. The heteroaromatic rings
can also be oxidized to their corresponding N-oxides using various
oxidizing agents such as H.sub.2O.sub.2, O.sub.3, MCPBA etc. in
polar solvents such as CH.sub.2Cl.sub.2, CHCl.sub.3, CF.sub.3COOH
etc. See Jerry March, Advanced Organic Chemistry, 4th edition,
Chapter 19. Examples of modifications are suggested in Scheme
5.
[0260] Also, if R.sup.5 is for instance a pyridine, it can be
converted to a N-oxide either before or after alkylation. ##STR17##
##STR18##
[0261] IV. Pharmaceutical Compositions, Dosing, and Modes of
Administration
[0262] The present invention is directed to the clinical use of the
heterocyclics, in particular, the triazolopyrimidine and their
related analogs of Formulae A, A1 and I, and their polymorphs,
solvates, esters, tautomers, enantiomers, pharmaceutically
acceptable salts and prodrugs thereof, for use in treatment or
prevention of diseases that are HSP90-dependent. For example, a
disorder such as inflammatory diseases, infections, autoimmune
disorders, stroke, ischemia, cardiac disorder, neurological
disorders, fibrogenetic disorders, proliferative disorders, tumors,
leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and
malignant disease. The fibrogenetic disorders include but are not
limited to scleroderma, polymyositis, systemic lupus, rheumatoid
arthritis, liver cirrhosis, keloid formation, interstitial
nephritis and pulmonary fibrosis.
[0263] The present invention features pharmaceutical compositions
comprising the compound of Formulae A, A1 and I, or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt thereof,
or prodrug thereof, of any of the preceding aspect and embodiments
and one or more pharmaceutical excipients.
[0264] Those of ordinary skill in the art are familiar with
formulation and administration techniques that can be employed with
the compounds and methods of the invention, e.g., as discussed in
Goodman and Gilman, The Pharmacological Basis of Therapeutics,
(current edition), Pergamon; and Remington's, Pharmaceutical
Sciences (current edition), Mack Publishing Co., Easton, Pa.
[0265] The compounds utilized in the methods of the instant
invention may be administered either alone or in combination with
pharmaceutically acceptable carriers, excipients or diluents, in a
pharmaceutical composition, according to standard pharmaceutical
practices. The compounds can be administered orally or
parenterally, including the intravenous, intramuscular,
intraperitoneal, subcutaneous, rectal and topical routes of
administration.
[0266] For example, the therapeutic or pharmaceutical compositions
of the invention can be administered locally to the area in need of
treatment. This may be achieved by, for example, but not limited
to, local infusion during surgery, topical application, e.g.,
cream, ointment, injection, catheter, or implant, said implant
made, e.g., out of a porous, non-porous, or gelatinous material,
including membranes, such as sialastic membranes, or fibers. The
administration can also be by direct injection at the site (or
former site) of a tumor or neoplastic or pre-neoplastic tissue.
[0267] Still further, the compounds or compositions of the
invention can be delivered in a vesicle, e.g., a liposome (see, for
example, Langer, Science 1990, 249, 1527-1533; Treat et al.,
Liposomes in the Therapy of Infectious Disease and Cancer,
Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp. 353-365,
1989).
[0268] The compounds and pharmaceutical compositions used in the
methods of the present invention can also be delivered in a
controlled release system. In one embodiment, a pump may be used
(see, Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et
al. Surgery, 1980, 88, 507; Saudek et al. N. Engl. J. Med. 1989,
321, (574). Additionally, a controlled release system can be placed
in proximity of the therapeutic target. (See, Goodson, Medical
Applications of Controlled Release, 1984, 2, 115-138).
[0269] The pharmaceutical compositions used in the methods of the
instant invention can also contain the active ingredient in a form
suitable for oral use, for example, as tablets, troches, lozenges,
aqueous or oily suspensions, dispersible powders or granules,
emulsions, hard or soft capsules, or syrups or elixirs.
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
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients may be, for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, such as microcrystalline cellulose, sodium
crosscarmellose, corn starch, or alginic acid; binding agents, for
example starch, gelatin, polyvinyl-pyrrolidone or acacia, and
lubricating agents, for example, magnesium stearate, stearic acid
or talc. The tablets may be un-coated or coated by known techniques
to mask the taste of the drug or delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a water soluble
taste masking material such as hydroxypropylmethyl-cellulose or
hydroxypropylcellulose, or a time delay material such as ethyl
cellulose, or cellulose acetate butyrate may be employed as
appropriate.
[0270] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water soluble carrier such as
polyethyleneglycol or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0271] Aqueous suspensions contain the active material in admixture
with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethylene-oxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.
[0272] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachisd oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example 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 anti-oxidant such as butylated
hydroxyanisol or alpha-tocopherol.
[0273] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
[0274] The compounds and pharmaceutical compositions used in the
methods of the instant invention may also be in the form of an
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example olive oil or arachis oil, or a mineral oil, for example
liquid paraffin or mixtures of these. Suitable emulsifying agents
may be naturally-occurring phosphatides, for example soy bean
lecithin, and esters or partial esters derived from fatty acids and
hexitol anhydrides, for example sorbitan monooleate, and
condensation products of the said partial esters with ethylene
oxide, for example polyoxyethylene sorbitan monooleate. The
emulsions may also contain sweetening agents, flavoring agents,
preservatives and antioxidants.
[0275] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative,
flavoring and coloring agents and antioxidant.
[0276] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous solution. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution.
[0277] The sterile injectable preparation may also be a sterile
injectable oil-in-water microemulsion where the active ingredient
is dissolved in the oily phase. For example, the active ingredient
may be first dissolved in a mixture of soybean oil and lecithin.
The oil solution then introduced into a water and glycerol mixture
and processed to form a microemulsion.
[0278] The injectable solutions or microemulsions may be introduced
into a patient's blood-stream by local bolus injection.
Alternatively, it may be advantageous to administer the solution or
microemulsion in such a way as to maintain a constant circulating
concentration of the instant compound. In order to maintain such a
constant concentration, a continuous intravenous delivery device
may be utilized. An example of such a device is the Deltec
CADD-PLUS.TM. model 5400 intravenous pump.
[0279] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension for
intramuscular and subcutaneous administration. 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, for example as a
solution in 1,3-butane diol. In addition, sterile, fixed oils are
conventionally 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
find use in the preparation of injectables.
[0280] The compounds of the present invention used in the methods
of the present invention may also be administered in the form of
suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the inhibitors with a
suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
include cocoa butter, glycerinated gelatin, hydrogenated vegetable
oils, mixtures of polyethylene glycols of various molecular weights
and fatty acid esters of polyethylene glycol.
[0281] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing a compound or composition of the
invention can be used. As used herein, topical application can
include mouth washes and gargles.
[0282] The compounds used in the methods of the present invention
can be administered in intranasal form via topical use of suitable
intranasal vehicles and delivery devices, or via transdermal
routes, using those forms of transdermal skin patches well known to
those of ordinary skill in the art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0283] The methods, compounds and compositions of the instant
invention may also be used in conjunction with other well known
therapeutic agents that are selected for their particular
usefulness against the condition that is being treated. For
example, the instant compounds may be useful in combination with
known anti-cancer and cytotoxic agents. Further, the instant
methods and compounds may also be useful in combination with other
inhibitors of parts of the signaling pathway that links cell
surface growth factor receptors to nuclear signals initiating
cellular proliferation.
[0284] The methods of the present invention may also be useful with
other agents that inhibit angiogenesis and thereby inhibit the
growth and invasiveness of tumor cells, including, but not limited
to VEGF receptor inhibitors, including ribozymes and antisense
targeted to VEGF receptors, angiostatin and endostatin.
[0285] Examples of antineoplastic agents that can be used in
combination with the compounds and methods of the present invention
include, in general, and as appropriate, alkylating agents,
anti-metabolites, epidophyllotoxins, antineoplastic enzymes,
topoisomerase inhibitors, procarbazines, mitoxantrones, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents and
haematopoietic growth factors. Exemplary classes of antineoplastic
include the anthracyclines, vinca drugs, mitomycins, bleomycins,
cytotoxic nucleosides, epothilones, discodermolides, pteridines,
diynenes and podophyllotoxins. Particularly useful members of those
classes include, for example, carminomycin, daunorubicin,
aminopterin, methotrexate, methopterin, dichloromethotrexate,
mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine,
gemcitabine, cytosine arabinoside, podophyllotoxin or
podo-phyllotoxin derivatives such as etoposide, etoposide phosphate
or teniposide, melphalan, vinblastine, vincristine, leurosidine,
vindesine, leurosine, paclitaxel and the like. Other useful
antineoplastic agents include estramustine, carboplatin,
cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan,
hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate,
dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan,
ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole
derivatives, interferons and interleukins.
[0286] When a compound or composition of the invention is
administered into a human subject, the daily dosage will normally
be determined by the prescribing physician with the dosage
generally varying according to the age, weight, and response of the
individual patient, as well as the severity of the patient's
symptoms.
[0287] In one exemplary application, a suitable amount of compound
is administered to a mammal undergoing treatment for cancer, for
example, breast cancer. Administration typically occurs in an
amount of between about 0.01 mg/kg of body weight to about 100
mg/kg of body weight per day (administered in single or divided
doses), more preferably at least about 0.1 mg/kg of body weight per
day. A particular therapeutic dosage can include, e.g., from about
0.01 mg to about 1000 mg of compound, and preferably includes,
e.g., from about 1 mg to about 1000 mg. The quantity of active
compound in a unit dose of preparation may be varied or adjusted
from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg,
more preferably 10 mg to 200 mg, according to the particular
application. The amount administered will vary depending on the
particular IC.sub.50 value of the compound used and the judgment of
the attending clinician taking into consideration factors such as
health, weight, and age. In combinational applications in which the
compound is not the sole active ingredient, it may be possible to
administer lesser amounts of compound and still have therapeutic or
prophylactic effect.
[0288] Preferably, the pharmaceutical preparation is in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component, e.g., an
effective amount to achieve the desired purpose.
[0289] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
amounts until the optimum effect under the circumstances is
reached. For convenience, the total daily dosage may be divided and
administered in portions during the day if desired.
[0290] The amount and frequency of administration of the compounds
and compositions of the present invention used in the methods of
the present invention, and if applicable other chemotherapeutic
agents and/or radiation therapy, will be regulated according to the
judgment of the attending clinician (physician) considering such
factors as age, condition and size of the patient as well as
severity of the disease being treated.
[0291] The chemotherapeutic agent and/or radiation therapy can be
administered according to therapeutic protocols well known in the
art. It will be apparent to those skilled in the art that the
administration of the chemotherapeutic agent and/or radiation
therapy can be varied depending on the disease being treated and
the known effects of the chemotherapeutic agent and/or radiation
therapy on that disease. Also, in accordance with the knowledge of
the skilled clinician, the therapeutic protocols (e.g., dosage
amounts and times of administration) can be varied in view of the
observed effects of the administered therapeutic agents (i.e.,
antineoplastic agent or radiation) on the patient, and in view of
the observed responses of the disease to the administered
therapeutic agents.
[0292] Also, in general, the compounds of the invention need not be
administered in the same pharmaceutical composition as a
chemotherapeutic agent, and may, because of different physical and
chemical characteristics, be administered by a different route. For
example, the compounds/compositions may be administered orally to
generate and maintain good blood levels thereof, while the
chemotherapeutic agent may be administered intravenously. The
determination of the mode of administration and the advisability of
administration, where possible, in the same pharmaceutical
composition, is well within the knowledge of the skilled clinician.
The initial administration can be made according to established
protocols known in the art, and then, based upon the observed
effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician.
[0293] The particular choice of compound (and where appropriate,
chemotherapeutic agent and/or radiation) will depend upon the
diagnosis of the attending physicians and their judgment of the
condition of the patient and the appropriate treatment
protocol.
[0294] The compounds/compositions of the invention (and where
appropriate chemotherapeutic agent and/or radiation) may be
administered concurrently (e.g., simultaneously, essentially
simultaneously or within the same treatment protocol) or
sequentially, depending upon the nature of the proliferative
disease, the condition of the patient, and the actual choice of
chemotherapeutic agent and/or radiation to be administered in
conjunction (i.e., within a single treatment protocol) with the
compound/composition.
[0295] In combinational applications and uses, the
compound/composition and the chemotherapeutic agent and/or
radiation need not be administered simultaneously or essentially
simultaneously, and the initial order of administration of the
compound/composition, and the chemotherapeutic agent and/or
radiation, may not be important. Thus, the compounds/compositions
of the invention may be administered first followed by the
administration of the chemotherapeutic agent and/or radiation; or
the chemotherapeutic agent and/or radiation may be administered
first followed by the administration of the compounds/compositions
of the invention. This alternate administration may be repeated
during a single treatment protocol. The determination of the order
of administration, and the number of repetitions of administration
of each therapeutic agent during a treatment protocol, is well
within the knowledge of the skilled physician after evaluation of
the disease being treated and the condition of the patient. For
example, the chemotherapeutic agent and/or radiation may be
administered first, especially if it is a cytotoxic agent, and then
the treatment continued with the administration of the
compounds/compositions of the invention followed, where determined
advantageous, by the administration of the chemotherapeutic agent
and/or radiation, and so on until the treatment protocol is
complete.
[0296] Thus, in accordance with experience and knowledge, the
practicing physician can modify each protocol for the
administration of a compound/composition for treatment according to
the individual patient's needs, as the treatment proceeds.
[0297] The attending clinician, in judging whether treatment is
effective at the dosage administered, will consider the general
well-being of the patient as well as more definite signs such as
relief of disease-related symptoms, inhibition of tumor growth,
actual shrinkage of the tumor, or inhibition of metastasis. Size of
the tumor can be measured by standard methods such as radiological
studies, e.g., CAT or MRI scan, and successive measurements can be
used to judge whether or not growth of the tumor has been retarded
or even reversed. Relief of disease-related symptoms such as pain,
and improvement in overall condition can also be used to help judge
effectiveness of treatment.
[0298] V. Assays for Determining HSP90 Binding and Downstream
Effect
[0299] A variety of in vitro and in vivo assays are available to
test the effect of the compounds of the invention on HSP90. HSP90
competitive binding assays and functional assays can be performed
as known in the art substituting in the compounds of the invention.
Chiosis et al. Chemistry & Biology 2001, 8, 289-299, describe
some of the known ways in which this can be done. For example,
competition binding assays using, e.g., geldanamycin or 17-AAG as a
competitive binding inhibitor of HSP90 can be used to determine
relative HSP90 affinity of the compounds of the invention by
immobilizing the compound of interest or other competitive
inhibitor on a gel or solid matrix, preincubating HSP90 with the
other inhibitor, passing the preincubated mix over the gel or
matrix, and then measuring the amount of HSP90 that retains or does
not retain on the gel or matrix.
[0300] Downstream effects can also be evaluated based on the known
effect of HSP90 inhibition on function and stability of various
steroid receptors and signaling proteins including, e.g., Raf1 and
HER2. Compounds of the present invention induce dose-dependent
degradation of these molecules, which can be measured using
standard techniques. Inhibition of HSP90 also results in
up-regulation of HSP90 and related chaperone proteins that can
similarly be measured. Antiproliferative activity on various cancer
cell lines can also be measured, as can morphological and
functional differentiation related to HSP90 inhibition.
[0301] Many different types of methods are known in the art for
determining protein concentrations and measuring or predicting the
level of proteins within cells and in fluid samples. Indirect
techniques include nucleic acid hybridization and amplification
using, e.g., polymerase chain reaction (PCR). These techniques are
known to the person of skill and are discussed, e.g., in Sambrook,
Fritsch & Maniatis Molecular Cloning: A Laboratory Manual, 2nd
ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989;
Ausubel, et al. Current Protocols in Molecular Biology, John Wiley
& Sons, NY, 1994, and, as specifically applied to the
quantification, detection, and relative activity of HER2/Neu in
patient samples, e.g., in U.S. Pat. Nos. 4,699,877, 4,918,162,
4,968,603, and 5,846,749. A brief discussion of two generic
techniques that can be used follows.
[0302] The determination of whether cells overexpress or contain
elevated levels of HER2 can be determined using well known antibody
techniques such as immunoblotting, radioimmunoassays, western
blotting, immunoprecipitation, enzyme-linked immunosorbant assays
(ELISA), and derivative techniques that make use of antibodies
directed against HER2. As an example, HER2 expression in breast
cancer cells can be determined with the use of an
immunohistochemical assay, such as the Dako Hercep.TM. test (Dako
Corp., Carpinteria, Calif.). The Hercep.TM. test is an antibody
staining assay designed to detect HER2 overexpression in tumor
tissue specimens. This particular assay grades HER2 expression into
four levels: 0, 1, 2, and 3, with level 3 representing the highest
level of HER2 expression. Accurate quantitation can be enhanced by
employing an Automated Cellular Imaging System (ACIS) as described,
e.g., by Press, M. et al. Modern Pathology 2000, 13, 225A.
[0303] Antibodies, polyclonal or monoclonal, can be purchased from
a variety of commercial suppliers, or may be manufactured using
well-known methods, e.g., as described in Harlow et al. Antibodies:
A Laboratory Manual, 2nd ed; Cold Spring Harbor Laboratory, Cold
Spring Harbor, N.Y., 1988.
[0304] HER2 overexpression can also be determined at the nucleic
acid level since there is a reported high correlation between
overexpression of the HER2 protein and amplification of the gene
that codes for it. One way to test this is by using RT-PCR. The
genomic and cDNA sequences for HER2 are known. Specific DNA primers
can be generated using standard, well-known techniques, and can
then be used to amplify template already present in the cell. An
example of this is described in Kurokawa, H. et al. Cancer Res.
2000, 60, 5887-5894. PCR can be standardized such that quantitative
differences are observed as between normal and abnormal cells,
e.g., cancerous and noncancerous cells. Well known methods
employing, e.g., densitometry, can be used to quantitate and/or
compare nucleic acid levels amplified using PCR.
[0305] Similarly, fluorescent in situ hybridization (FISH) assays
and other assays can be used, e.g., Northern and/or Southern
blotting. These rely on nucleic acid hybridization between the HER2
gene or mRNA and a corresponding nucleic acid probe that can be
designed in the same or a similar way as for PCR primers, above.
See, e.g., Mitchell M S, and Press M. F. Oncol., Suppl. 1999, 12,
108-116. For FISH, this nucleic acid probe can be conjugated to a
fluorescent molecule, e.g., fluorescein and/or rhodamine, that
preferably does not interfere with hybridization, and which
fluorescence can later be measured following hybridization. See,
e.g., Kurokawa, H et al, Cancer Res. 2000, 60, 5887-5894
(describing a specific nucleic acid probe having sequence
5'-FAM-NucleicAcid-TAMRA-p-3' sequence). ACIS-based approaches as
described above can be employed to make the assay more quantitative
(de la Torre-Bueno, J., et al. Modern Pathology 2000, 13,
221A).
[0306] Immuno and nucleic acid detection can also be directed
against proteins other than HSP90 and HER2, which proteins are
nevertheless affected in response to HSP90 inhibition.
[0307] The following examples are offered by way of illustration
only and are not intended to be limiting of the full scope and
spirit of the invention.
EXAMPLES
[0308] I. Materials and Methods
[0309] The chemical reagents used to create the novel products of
the invention below are all available commercially, e.g., from
Aldrich Chemical Co., Milwaukee, Wis., USA. Otherwise their
preparation is facile and known to one of ordinary skill in the
art, or it is referenced or described herein.
[0310] The final compounds were usually purified by preparative TLC
(silica gel 60 .ANG., Whatman Partisil PK6F) or flash
chromatography (silica gel 60 .ANG., EMD Chemicals) using
EtOAc/hexane or MeOH/CH.sub.2Cl.sub.2 as eluents. Rf's were
measured using silica gel TLC plates (silica gel 60 .ANG., EMD
Chemicals). Analytical HPLC chromatograms were obtained using a C18
column (Agilent Zorbax 300SB-C18; 5 microns; 4.6 mm.times.150 mm).
A gradient was applied between solvent A (0.1% TFA in H.sub.2O) and
solvent B (0.5% TFA in CH.sub.3CN) increasing the proportion of A
linearly from 5% (t=0) to 100% (t=7.00 min), with a constant flow
rate of 1 mL/min. The samples were diluted to typically 0.1-1 mg/mL
in MeOH or CH.sub.3CN and the injection volumes were typically 10
.mu.L. The column was not heated, and UV detection was effected at
254 nm. .sup.1H-NMR spectra were recorded on a Bruker Avance 400
MHz spectrometer.
[0311] The chemical names were generated using the Beilstein
Autonom 2.1 software.
[0312] II. General Procedures ##STR19##
[0313] General Procedure 1: Displacement of Chlorine with Amines
[0314] Ref: Helv. Chim Acta. 1986, 69, 1602-1613; U.S. Pat. No.
5,917,042
[0315] A mixture of benzylamine derivative or aminomethyl pyridine
derivative (5.88 mmole, 2.1 equivalents), triethylamine (1 ml, 7.2
mmole) and 4,6-dichloro-pyrimidine-2,5-diamine (0.5 g, 2.8 mmole),
was refluxed in n-BuOH or ethanol (10 mLs) for 3 to 18 hours. The
mixture was cooled to room temperature and was extracted with
CH.sub.2Cl.sub.2. The organic layer was washed with water and dried
with MgSO.sub.4 to afford the crude product. The pyridinyl
derivatives were purified by chromatography (100% EtOAc-10%
MeOH/EtOAc), whereas the benzyl derivatives were used without
further purification.
[0316] General Procedure 2: Cyclization to Form Triazolopyrimidine
Ring System
[0317] To a solution of
6-chloro-N.sup.4-benzyl-pyrimidine-2,4,5-triamine derivatives or
6-chloro-N.sup.4-pyridin-2-ylmethyl-pyrimidine-2,4,5-triamine
derivatives (0.57 mmole) in 25% HOAc/H.sub.2O, an aqueous solution
of NaNO.sub.2 (1.2 equivalents, 1 mL) was added dropwise at
0.degree. C. The reaction mixture was stirred for 15 minutes at
room temperature and filtered the crude product and purified by
column chromatography using 75% EtOAc/Hexanes-100% EtOAc.
[0318] General Procedure 3: Aromatic Ring Halogenation
[0319] A mixture of
7-chloro-3-benzyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine
derivatives (0.57 mmole) and NCS (N-chlorosuccinimide) or NBS
(N-bromosuccinimide) or NIS (N-iodosuccinimide) (1.5 equivalents)
in 10 mLs HOAc was stirred at 50.degree. C. for 1 to 15 hours to
afford the crude corresponding halogenated product which was
purified by chromatography (50-75% EtOAc/Hexanes).
[0320] General Procedure 4: N-Oxide Formation
[0321] A solution of the pyridine derivative (1 mmol) in
dichloromethane or chloroform (5 mL) was cooled by means of an
ice-bath, treated with m-CPBA (1.1 to 3 mmol) in three portions,
and allowed to warm to r.t. The mixture was extracted with
dichloromethane and washed with aqueous NaOH, followed by water.
Drying (Na.sub.2SO.sub.4) and concentration afforded the pyridine
N-oxide.
Example 1
7-Chloro-3-(4-methoxy-3,5-dimethylpyridin-2-yl)-3H-[1,2,3]triazolo[4,5-d]p-
yrimidin-5-ylamine
Step 1: Synthesis of
2-aminomethyl-4-methoxy-3,5-dimethylpyridine
[0322] A solution of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine
HCl (Aldrich 3.7 g, 16.6 mmole) in 7N NH.sub.3/MeOH (Aldrich, 200
mLs) was refluxed in a steel bomb for 15 hours. Removed the solvent
under reduced pressure, the residue was taken into 5%
MeOH/CH.sub.2Cl.sub.2 and filtering it through a thin layer of
silica gel afforded the product at 76% yield. HPLC RT was 2.850
min. .sup.1H (CDCl.sub.3) .delta. 8.18 (s, 1H), 4.32 (s, 2H), 3.76
(s, 3H), 2.23 (s, 3H), 2.18 (s, 3H).
Step 2: Synthesis of
6-chloro-N.sup.4-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-pyrimidine-2-
,4,5-triamine
[0323] A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and
2-aminomethyl-4-methoxy-3,5-dimethyl-pyridine was heated to reflux
in n-BuOH for 3 h, following the general procedure 1. HPLC RT was
3.597 min. .sup.1HNMR (CDCl.sub.3) .delta. 8.22 (s, 1H), 7.12 (br.
t, 1H), 4.61 (s, 2H), 4.56-4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s,
2H), 2.29 (s, 3H), 2.27 (s, 3H).
Step 3: Synthesis of
7-chloro-3-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-d]pyrimidin-5-ylamine
[0324] A solution of
6-chloro-N.sup.4-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-pyrimidine-2-
,4,5-triamine was treated with a cold aqueous solution of
NaNO.sub.2, following the general procedure 2. HPLC RT was 3.597
min. .sup.1HNMR (CDCl.sub.3): .delta. 8.22 (s, 1H), 7.12 (broad t,
1H), 4.61 (s, 2H), 4.56-4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s, 2H),
2.29 (s, 3H), 2.27 (s, 3H).
Example 2
7-Chloro-3-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-yl)-3H-[1,2,3]triazolo[-
4,5-d]pyrimidin-5-ylamine
[0325] The title compound was obtained by oxidation of
7-Chloro-3-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-d]pyrimidin-5-ylamine (see Example 1) with m-CPBA
(m-chloroperoxybenzoic acid) in methylene chloride, following the
general procedure 4. HPLC RT was 4.780 min. .sup.1HNMR (CDCl.sub.3)
.delta. 8.02 (s, 1H), 5.90 (s, 2H), 5.61 (s, 2H), 3.81 (s, 3H),
2.54 (s, 3H), 2.25(s, 3H).
Example 3
7-Chloro-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine
Step 1: Synthesis of
6-chloro-N.sup.4-(4-methoxy-benzyl)-pyrimidine-2,4,5-triamine
[0326] A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and
1-aminomethyl-4-methoxybenzene was refluxed in n-BuOH for 15 h,
following the general procedure 1. HPLC RT was 4.675 min.
.sup.1HNMR (CDCl.sub.3) .delta. 7.29-7.27 (d, 2H), 6.91-6.89 (d,
2H), 5.62 (br. t, 1H) 4.67 (s, 2H), 4.56-4.54 (d, 2H), 3.84 (s,
3H), 2.74 (s, 2H).
Step 2: Synthesis of
7-chloro-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamin-
e
[0327] A solution of
6-chloro-N.sup.4-(4-methoxy-phenyl)-pyrimidine-2,4,5-triamine was
treated with a cold aqueous solution of NaNO.sub.2, following the
general procedure 2. HPLC RT was 5.784 min. .sup.1HNMR
(CDCl.sub.3): .delta. 7.37-7.35 (d, 2H), 6.86-6.84 (d, 2H), 5.57
(s, 2H), 5.39 (s, 2H), 3.78 (s, 3H).
Example 4
Synthesis of
7-chloro-3-pyridin-2-ylmethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamin-
e
Step 1:
6-chloro-N.sup.4-pyridin-2-ylmethyl-pyrimidine-2,4,5-triamine
[0328] A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and
2-aminomethyl-pyridine was refluxed in n-BuOH for 15 h, following
the general procedure 1. HPLC RT was 2.573 min. .sup.1HNMR
(CDCl.sub.3) .delta. 8.60-8.59 (m, 1H), 7.69-7.66 (m, 1H),
7.31-7.29 (m, 1H), 7.25-7.20 (m, 1H), 6.55 (br. t, 1H) 4.63 (s,
2H), 4.73-4.71 (d, 2H), 1.84 (s, 2H).
Step 2: Synthesis of
7-chloro-3-pyridin-2-ylmethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamin-
e
[0329] A solution of
6-chloro-N.sup.4-pyridin-2-ylmethyl-pyrimidine-2,4,5-triamine was
treated with a cold aqueous solution of NaNO.sub.2, following the
general procedure 2. .sup.1HNMR (CDCl.sub.3): .delta. 8.60-8.59 (m,
1H), 7.71-7.67(m, 1H), 7.29-7.25 (m, 1H), 7.22-7.20 (m, 1H), 5.81
(s, 2H), 5.48 (s, 2H).
Example 5
Synthesis of
7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
-ylamine
Step 1:
6-chloro-N.sup.4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4,5-triami-
ne
[0330] A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and
1-aminomethyl-3,4-5-trimethoxybenzene in n-BuOH for 15 h, following
the general procedure 1. HPLC RT was 4.458 min. .sup.1HNMR
(CDCl.sub.3) .delta. 6.58 (s, 2H), 5.62 (br. t, 1H) 4.72 (s, 2H),
4.56-4.54 (d, 2H), 3.88 (s, 6H), 3.86 (s, 3H), 2.77 (s, 2H).
Step 2: Synthesis of
7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
-ylamine)
[0331] A solution of
6-chloro-N.sup.4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4,5-triamine
was treated with a cold aqueous solution of NaNO.sub.2, following
the general procedure 2. HPLC RT was 5.755 min. .sup.1HNMR
(CDCl.sub.3): .delta. 6.66 (s, 2H), 5.55 (s, 2H), 5.42 (s, 2H),
3.83 (s, 3H), 3.80 (s, 6H).
Example 6
Synthesis of
7-chloro-3-(2-chloro-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]py-
rimidin-5-ylamine
[0332] Chlorination of
7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
-ylamine) (CF 2137) with NCS (1.5 equivalents) was done following
the general procedure 3 to give the title compound: HPLC RT was
6.244 min. .sup.1HNMR (CDCl.sub.3): .delta. 6.53 (s, 1H), 5.70 (s,
2H), 5.48 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.75 (s,3H).
Example 7
7-Chloro-3-(2,6-dichloro-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d-
]pyrimidin-5-ylamine
[0333] Chlorination of
7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
-ylamine) with NCS (1.5 equivalents) was done following the general
procedure 3 to give the title compound: HPLC RT was 6.616 min.
.sup.1HNMR (CDCl.sub.3): .delta. 5.81 (s, 2H), 5.47 (s, 2H), 3.97
(s, 3H), 3.90(s, 6H).
Example 8
Synthesis of
7-chloro-3-(2-bromo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyr-
imidin-5-ylamine
[0334] Bromination of
7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
-ylamine) with NBS (1.5 equivalents) was done following the general
procedure 3 to give the title compound: HPLC RT was 6.541 min.
.sup.1HNMR (CDC1.sub.3): .delta. 6.52 (s, 1H), 5.74(s, 2H), 5.46
(s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.76 (s, 3H).
Example 9
7-Chloro-3-(2,6-dibromo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-5-ylamine
[0335] Bromination of
7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
-ylamine) with NBS (1.5 equivalents) was done following the general
procedure 3 to give the title compound: HPLC RT was 6.923 min.
.sup.1HNMR (CDCl.sub.3): .delta. 5.91 (s, 2H), 5.51 (s, 2H), 3.99
(s, 3H), 3.93(s, 6H).
Example 10
Synthesis of
7-chloro-3-(2-iodo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyri-
midin-5-ylamine
[0336] The title compound was obtained from iodination of
7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
-ylamine) with NIS (1.5 equivalents) following the general
procedure 3. HPLC RT was 6.497 min. .sup.1HNMR (CDCl.sub.3):
.delta. 6.47 (s, 1H), 5.73(s, 2H), 5.44 (s, 2H), 3.92 (s, 3H), 3.88
(s, 3H), 3.73 (s, 3H).
Example 11
Synthesis of
7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amine
Step 1:
6-chloro-N.sup.4-(3,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine
[0337] The title compound was obtained from a mixture of
4,6-dichloro-pyrimidine-2,5-diamine and
1-aminomethyl-3,5-dimethoxybenzene in n-BuOH for 15 h, following
the general procedure 1. HPLC RT was 4.835 min. .sup.1HNMR
(CDCl.sub.3) .delta. 6.46-6.47 (d, 2H), 6.38-6.37(d, 1H), 5.67 (br.
t, 1H) 4.63 (s, 2H), 4.53-4.52 (d, 2H), 3.81 (s, 6H), 2.72 (s,
2H).
Step 2: Synthesis of
7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amin
[0338] A solution of
6-chloro-N.sup.4-(3,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine
was treated with a cold aqueous solution of NaNO.sub.2, following
the general procedure 2. HPLC RT was 6.185 min. .sup.1HNMR
(CDCl.sub.3): .delta. 6.54-6.53 (d, 2H), 6.41-6.40 (d, 1H), 5.58
(s, 2H), 5.54 (s, 2H), 3.78 (s, 6H).
Example 12
Synthesis of
7-chloro-3-(2-chloro-3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrim-
idin-5-ylamine
[0339] The title compound was obtained by chlorination of
7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amine) with NCS (1.5 equivalents) in acetic acid at 50.degree. C.
for 1 h, following the general procedure 3. HPLC RT was 6.467 min.
.sup.1HNMR (CDCl.sub.3): .delta. 6.50-6.49 (d, 1H), 6.18-6.17 (d,
1H), 5.77(s, 2H), 5.44 (s, 2H), 3.91 (s, 3H), 3.72 (s, 3H).
Example 13
Synthesis of
7-chloro-3-(2-bromo-3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimi-
din-5-ylamine
[0340] The title compound was obtained by bromination of
7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amine) with NBS (1.5 equivalents) in acetic acid at 50.degree. C.
during 1 h, following the general procedure 3. HPLC RT was 6.573
min. .sup.1HNMR (d.sub.6-DMSO): .delta. 7.74 (s, 2H), 6.70-6.69 (d,
1H), 6.23-6.22 (d, 1H), 5.63(s, 2H), 3.87 (s, 3H), 3.71 (s,
3H).
Example 14
Synthesis of
7-chloro-3-(2-iodo-3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimid-
in-5-ylamine
[0341] The title compound was obtained by iodination of
7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amine) with NIS (1.5 equivalents) in acetic acid at 50.degree. C.
during 1 h, following the general procedure 3. HPLC RT was 6.739
min. .sup.1HNMR (d.sub.6-DMSO): .delta. 7.75 (s, 2H), 6.61-6.60 (d,
1H), 6.15-6.14 (d, 1H), 5.58(s, 2H), 3.86 (s, 3H), 3.70 (s,
3H).
Example 15
Synthesis of
7-Chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amine
Step 1:
6-chloro-N.sup.4-(2,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine
[0342] The title compound was obtained from a mixture of
4,6-dichloro-pyrimidine-2,5-diamine and
1-aminomethyl-2,5-dimethoxybenzene in n-BuOH for 15 h, following
the general procedure 1. HPLC RT was 4.601 min. .sup.1HNMR
(CDCl.sub.3) .delta. 6.91-6.90 (d, 1H), 6.82-6.80(m, 2H), 5.82 (br.
t, 1H) 4.62 (s, 2H), 4.59-4.58 (d, 2H), 3.85 (s, 3H), 2.78 (s, 3H),
2.75 (s, 2H).
Step 2: Synthesis of
7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amine
[0343] A solution of
6-chloro-N.sup.4-(2,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine
was treated with a cold aqueous solution of NaNO.sub.2, following
the general procedure 2. HPLC RT was 6.130 min. .sup.1HNMR
(CDCl.sub.3): .delta. 6.84-6.83 (m, 2H), 6.64-6.63 (d, 1H), 5.67
(s, 2H), 5.54 (s, 2H), 3.83 (s, 3H), 3.73 (s, 3H).
Example 16
Synthesis of
7-chloro-3-(4-bromo-2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimi-
din-5-ylamine
[0344] The title compound was obtained by bromination of
7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amine) with NBS (1.5 equivalents) in acetic acid at 50.degree. C.
during 1 h, following the general procedure 3. HPLC RT was 6.438
min. .sup.1HNMR (CDCl.sub.3): .delta. 7.11 (s, 1H), 6.80 (s, 1H),
5.63 (s, 2H), 5.57 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H).
Example 17
Synthesis of
7-chloro-3-(3-chloro-2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrim-
idin-5-ylamine
[0345] The title compound was obtained by chlorination of
7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl-
amine) with NCS (1.5 equivalents) in acetic acid at 50.degree. C.
during 1 h, following the general procedure 3. HPLC RT was 6.392
min. .sup.1HNMR (CDCl.sub.3): .delta. 6.91-6.90 (d, 1H), 6.67-6.66
(d, 1H), 5.70 (s, 2H), 5.43(s, 2H), 3.92 (s, 3H), 3.73 (s, 3H).
BIOLOGY EXAMPLES
Example A
rHSP90 Competitive Binding Assay
[0346] Five microgram of purified rHSP90 protein (Stressgen, BC,
Canada, #SPP-770) in phosphated buffered saline (PBS) was coated on
96 well plates by incubating overnight at 4.degree. C. Unbound
protein was removed and the coated wells were washed twice with 200
.mu.L PBS. DMSO controls (considered as untreated samples) or test
compounds were then added at 100-30-10-3-1-0.3 .mu.M dilutions (in
PBS), the plates mixed for 30 seconds on the plate shaker, and then
incubated for 60 min. at 37.degree. C. The wells were washed twice
with 200 .mu.L PBS, and 10 .mu.M biotinylated-geldanamycin
(biotin-GM) was added and incubated for 60 min. at 37.degree. C.
The wells were washed again twice with 200 .mu.L PBS, before the
addition of 20 .mu.g/mL streptavidin-phycoerythrin
(streptavidin-PE) (Molecular Probes, Eugene, Oreg.) and incubation
for 60 min. at 37.degree. C. The wells were washed again twice with
200 .mu.L PBS. Relative fluorescence units (RFU) was measured using
a SpectraMax Gemini XS Spectrofluorometer (Molecular Devices,
Sunnyvale, Calif.) with an excitation at 485 nm and emission at 580
nm; data was acquired using SOFTmax.RTM. PRO software (Molecular
Devices Corporation, Sunnyvale, Calif.). The background was defined
as the RFU generated from wells that were not coated with HSP90 but
were treated with the biotin-GM and streptavidin-PE. The background
measurements were substrated from each sample treated with
biotin-GM and streptavidin-PE measurements before other
computation. Percent inhibition of binding for each sample was
calculated from the background subtracted values as follows: %
binding inhibition=[RFU untreated-RFU treated]/RFU
untreated].times.100.
Example B
Cell Lysate Binding Assay
[0347] MCF7 breast carcinoma cell lysates were prepared by douncing
in lysing buffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl.sub.2,
100 mM KCl), and then incubated with or without test compound for
30 mins at 4.degree. C., followed by incubation with biotin-GM
linked to BioMag.TM. streptavidin magnetic beads (Qiagen) for 1 hr
at 4.degree. C. The tubes were placed on a magnetic rack, and the
unbound supernatant removed. The magnetic beads were washed three
times in lysis buffer and boiled for 5 mins at 95.degree. C. in
SDS-PAGE sample buffer. Samples were analyzed on SDS protein gels,
and Western blots done for rHSP90. Bands in the Western Blots were
quantitated using the Bio-rad Fluor-S MultiImager, and the %
inhibition of binding of rHSP90 to the biotin-GM was
calculated.
[0348] The lysate binding ability of selected compounds of the
invention based on the above assay is summarized in Table 2. The
IC.sub.50 reported is the concentration of test compound needed to
achieve 50% inhibition of the biotin-GM binding to rHSP90 in the
MCF7 cell lysates.
Example C
HER2 Degradation Assay
[0349] MCF7 breast carcinoma cells (ATCC) were grown in Dulbecco's
modified Eagle's medium (DMEM) containing 10% fetal bovine serum
(FBS) and 10 mM HEPES, and plated in 24 well plates (50%
confluent). Twenty-four hrs later (cells are 65-70% confluent),
test compounds were added and incubated overnight for 16 h. For the
less potent compounds, the amounts added were 100 .mu.M, 30 .mu.M,
10 .mu.M and 1 .mu.M, and for more potent compounds, the amounts
added were 1 .mu.M, 0.3 .mu.M, 0.1 .mu.M, 0.03 .mu.M, 0.01 .mu.M
and 0.003 .mu.M. The wells were washed with 1 mL phosphate buffered
saline (PBS), and 200 .mu.L trypsin was added to each well. After
trypsinization was complete, 50 .mu.L of FBS was added to each
well. Then 200 .mu.L cells was transferred to 96 well plates. The
cells were pipetted up and down to obtain a single cell suspension.
The plates were centrifuged at 2,500 rpm for 1 min using a Sorvall
Legend RT.TM. tabletop centrifuge (Kendro Laboratory Products,
Asheville, N.C.). The cells were then washed once in PBS containing
0.2% BSA and 0.2% sodium azide (BA buffer). Phycoerythrin (PE)
conjugated anti HER2/Neu antibody (Becton Dickinson, #340552), or
PE conjugated anti-keyhole limpet hemacyanin [KLH] (Becton
Dickinson, #340761) control antibody was added at a dilution of
1:20 and 1:40 respectively (final concentration was 1 .mu.g/mL) and
the cells were pipeted up and down to form a single cell
suspension, and incubated for 15 mins. The cells were washed twice
with 200 .mu.L BA buffer, and resuspended in 200 .mu.L BA buffer,
and transferred to FACSCAN tubes with an additional 250 .mu.L BA
buffer. Samples were analyzed using a FACSCalibur.TM. flow
cytometer (Becton Dickinson, San Jose, Calif.) equipped with
Argon-ion laser that emits 15 mW of 488 nm light for excitation of
the PE fluorochrome. 10,000 events were collected per sample. A
fluorescence histogram was generated and the mean fluorescence
intensity (MFI) of each sample was determined using Cellquest
software. The background was defined as the MFI generated from
cells incubated with control IgG-PE, and was subtracted from each
sample stained with the HER2/Neu antibody. Cells incubated with
DMSO was always done as untreated controls since the compounds were
resuspended in DMSO. Percent degradation of HER2 was calculated as
follows: % HER2 degraded=[(MF1 untreated cells-MF1 treated
cells)/MF1 untreated cell].times.100
[0350] The HER2 degradation ability of selected compounds of the
invention based on this assay is summarized in Table 2. IC.sub.50
is defined as the concentration at which there was 50% degradation
of the HER2/Neu protein.
Example D
MTS Assay
[0351] MTS assays measures the cytotoxicity of geldanamycin
derivatives. MTS
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfoph-
enyl)-2H-tetrazolium is a tetrazolium dye that is converted to a
formazan product by dehydrogenase enzymes of metabolically active
cells (Corey, A. et al. "Use of an aqueous soluble
tetrazolium/formazan assay for cell growth assays in culture,"
Cancer Commun. 1991, 3, 207-212). Cells were seeded in 96 well
plates at 2000 cells/well and allowed to adhere overnight in
Dulbecco's modified Eagle's medium supplemented with 10% fetal
bovine serum. The final culture volume was 100 .mu.l. Viable cell
number was determined by using the Celltiter 96 AQ.sub.ueous
Non-radioactive Cell Proliferation Assay (Promega, Madison Wis.).
The MTS/PMS (phenazine methosulfate) solution was mixed at a ratio
of 20:1, and 20 .mu.L was added per well to 100 .mu.l of culture
medium. After 2-4 hours, the formation of the formazan product was
measured at 490 nm absorbance using a multiwell plate
spectrophotometer. Background was determined by measuring the Abs
490 nm of cell culture medium and MTS-PMS in the absence of cells
and was subtracted from all values. Percent viable cells was
calculated as follows: % viable cells=(Abs at 490 nm treated
cells/Abs at 490 nm untreated cells).times.100
[0352] The effect of selected compounds of the invention on MCF7
breast carcinoma cells according to the MTS assay is summarized in
Table 2. IC.sub.50 was defined as the concentration of the compound
which gave rise to 50% viable cell number. TABLE-US-00002 TABLE 2
Biological Activities of Selected Compounds of Formula I Formula I
##STR20## HER2 MTS Ex IC.sub.50 IC.sub.50 S.No # Structure (.mu.M)
(.mu.M) 1 5 ##STR21## 15.0 ND 2 1 ##STR22## 0.4 8.0 3 7 ##STR23##
4.0 ND 4 6 ##STR24## 12.0 ND 5 9 ##STR25## 6.3 ND 6 8 ##STR26## 6.5
ND 7 10 ##STR27## 10.0 ND 8 12 ##STR28## 8.5 ND 9 13 ##STR29## 16.0
ND 10 16 ##STR30## 22.0 ND 11 17 ##STR31## 19.0 ND 12 2 ##STR32##
0.5 ND ND = not determined
[0353] The foregoing examples are not limiting and are merely
illustrative of various aspects and embodiments of the present
invention. All documents cited herein are indicative of the levels
of skill in the art to which the invention pertains and are
incorporated by reference herein in their entireties. None,
however, is admitted to be prior art.
[0354] One skilled in the art will readily appreciate that the
present invention is well adapted to carry out the objects and
obtain the ends and advantages mentioned, as well as those inherent
therein. The methods and compositions described illustrate
preferred embodiments, are exemplary, and are not intended as
limitations on the scope of the invention. Certain modifications
and other uses will occur to those skilled in the art, and are
encompassed within the spirit of the invention, as defined by the
scope of the claims.
[0355] The invention illustratively described herein suitably may
be practiced in the absence of any element or elements, limitation
or limitations which is not specifically disclosed herein. The
terms and expressions which have been employed are used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described, or portions thereof. It is
recognized that various modifications are possible within the scope
of the invention claimed. Thus, it should be understood that
although the present invention has been specifically disclosed by
preferred embodiments, optional features, modifications and
variations of the concepts herein disclosed may be resorted to by
those skilled in the art, and that such modifications and
variations are considered to be within the scope of this invention
as defined by the description and the appended claims.
[0356] In addition, where features or aspects of the invention are
described in terms of Markush groups or other grouping of
alternatives, e.g., genuses, those skilled in the art will
recognize that the invention is also thereby described in terms of
any individual member or subgroup of members of the Markush group
or subgenus, and exclusions of individual members as appropriate,
e.g., by proviso.
[0357] Other embodiments are within the following claims.
##STR33##
* * * * *