U.S. patent application number 11/196597 was filed with the patent office on 2005-12-22 for oxindole derivatives.
Invention is credited to Harris, Philip Anthony, Hunter, Robert N., Kuyper, Lee Frederick, Lackey, Karen Elizabeth, McNutt, Robert Walton JR., Peel, Michael Robert, Wood, Edgar Raymond III.
Application Number | 20050282810 11/196597 |
Document ID | / |
Family ID | 22863416 |
Filed Date | 2005-12-22 |
United States Patent
Application |
20050282810 |
Kind Code |
A1 |
Harris, Philip Anthony ; et
al. |
December 22, 2005 |
Oxindole derivatives
Abstract
The present invention is related to oxindole derivatives,
compositions containing the same, and methods of use and
manufacture of the same. Such compounds generally are useful
pharmacologically as agents in those disease states alleviated by
the alteration of mitogen activated signaling pathways in general,
and in particular in the inhibition or antagonism of protein
kinases, which pathologically involve aberrant cellular
proliferation. Such disease states include tumor growth,
restenosis, atherosclerosis, pain and thrombosis. In particular,
the present invention relates to a series of substituted oxindole
compounds, which exhibit Trk family protein tyrosine kinase
inhibition, and which are useful in cancer therapy and chronic pain
indications.
Inventors: |
Harris, Philip Anthony;
(Durham, NC) ; Hunter, Robert N.; (Durham, NC)
; Kuyper, Lee Frederick; (Durham, NC) ; Lackey,
Karen Elizabeth; (Durham, NC) ; McNutt, Robert Walton
JR.; (Durham, NC) ; Peel, Michael Robert;
(Durham, NC) ; Wood, Edgar Raymond III; (Durham,
NC) |
Correspondence
Address: |
GLAXOSMITHKLINE
CORPORATE INTELLECTUAL PROPERTY, MAI B475
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Family ID: |
22863416 |
Appl. No.: |
11/196597 |
Filed: |
August 3, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11196597 |
Aug 3, 2005 |
|
|
|
10362739 |
Feb 27, 2003 |
|
|
|
10362739 |
Feb 27, 2003 |
|
|
|
PCT/US01/26286 |
Aug 23, 2001 |
|
|
|
60229966 |
Sep 1, 2000 |
|
|
|
Current U.S.
Class: |
514/242 ;
514/323; 514/364; 514/381; 514/418 |
Current CPC
Class: |
C07D 487/04 20130101;
A61K 31/4245 20130101; A61K 31/4184 20130101; A61K 31/454 20130101;
C07D 403/12 20130101; A61K 31/4045 20130101; C07D 405/12 20130101;
A61P 29/02 20180101; A61P 7/02 20180101; A61K 31/53 20130101; A61P
29/00 20180101; C07D 209/14 20130101; A61K 31/405 20130101; C07D
209/34 20130101; A61K 31/4196 20130101; C07D 401/12 20130101; A61P
43/00 20180101; A61P 9/10 20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/242 ;
514/323; 514/381; 514/364; 514/418 |
International
Class: |
A61K 031/53; A61K
031/454; A61K 031/4245; A61K 031/4196; A61K 031/404 |
Claims
We claim:
1. A method of inhibiting TrkA kinase in a mammal, comprising
administering to said mammal an effective amount of a compound of
the formula II: 25or salts, solvates, or physiological functional
derivatives thereof wherein: R.sup.1 is hydrogen; R.sup.2 is
hydrogen; or R.sup.1 and R.sup.2 are optionally joined to form a
fused ring Het, wherein Het is a triazine ring; R.sup.3 is
hydrogen; R.sup.4 is selected from the group consisting of
hydrogen, 26R.sup.5 is hydrogen or 27R.sup.4 and R.sup.5 are
optionally joined to form a fused cyclic urea ring; and R.sup.6,
R.sup.7, and R.sup.8 are hydrogen.
2. A method as claimed in claim 1, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and R.sup.4 and
R.sup.5 are joined to form the fused cyclic urea ring
--N(H)C(O)N(H)--.
3. A method as claimed in claim 1, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and
R.sup.4 is 28
4. A method as claimed in claim 1, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and
R.sup.4 is 29
5. A method as claimed in claim 1, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and
R.sup.4 is --CH.sub.2--C(O)NH.sub.2.
6. A method as claimed in claim 1, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and
R.sup.4 is 30
7. A method as claimed in claim 1, wherein R.sup.1 and R.sup.2 are
joined to form a fused triazine ring; R.sup.3, R.sup.4, R.sup.6,
R.sup.7, and R.sup.8 are hydrogen; and R.sup.5 is 31
8. A method as claimed in claim 1, where the compound of formula
(II) is selected from the group:
5-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)me-
thyl]amino}-1,3-dihydro-2H-benzimidazol-2-one;
(3Z)-3-{[4-(1H-1,2,4-triazo-
l-1-yl)anilino]-methylene}-1,3-dihydro-2H-indol-2-one;
3-ethyl-3-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phe-
nyl)-2,6-piperidinedione;
(8Z)-8-{[3-(5-amino-1,3,4-oxadiazol-2-yl)anilino-
]methylene}-6,8-dihydro[1,2,3]triazolo[4,5-e]indol-7(3H)-one;
2-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)
methyl]amino}phenyl)ace- tamide; and
(3Z)-3-{[4-(1H-1,2,4-triazol-3-yl)anilino]methylene}-1,3-dihyd-
ro-2H-indol-2-one; or salts, solvates or physiologically functional
derivatives thereof.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention is related to oxindole derivatives,
compositions containing the same, and methods of use and
manufacture of the same. Such compounds generally are useful
pharmacologically as agents in those disease states alleviated by
the alteration of mitogen activated signaling pathways in general,
and in particular in the inhibition or antagonism of protein
kinases, which pathologically involve aberrant cellular
proliferation. Such disease states include tumor growth,
restenosis, atherosclerosis, pain and thrombosis. In particular,
the present invention relates to a series of substituted oxindole
compounds, which exhibit Trk family protein tyrosine kinase
inhibition, and which are useful in cancer therapy and chronic pain
indications.
[0002] Cell growth, differentiation, metabolism and function are
tightly controlled in higher eukaryotes. The ability of a cell to
rapidly and appropriately respond to the array of external and
internal signals it continually receives is of critical importance
in maintaining a balance between these processes (Rozengurt,
Current Opinion in Cell Biology 1992, 4, 161-5; Wilks, Progress in
Growth Factor Research 1990, 2, 97-111). The loss of control over
cellular regulation can often lead to aberrant cell function or
death, often resulting in a disease state in the parent
organism.
[0003] The protein kinases represent a large family of proteins
which play a central role in the regulation of a wide variety of
cellular processes and maintaining control over cellular function
(Hanks, et al., Science 1988, 241, 42-52). A partial list of such
kinases includes ab1, ATK, bcr-ab1, Blk, Brk, Btk, c-kit, c-met,
c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2,
ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5,
Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR,
Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie.sub.1,
tie.sub.2, TRK, Yes, and Zap70.
[0004] One of the most commonly studied pathways involving kinase
regulation is cellular signaling from receptors at the cell surface
to the nucleus (Crews and Erikson, Cell 1993, 74, 215-7). One
example of this pathway includes a cascade of kinases in which
members of the growth factor receptor tyrosine kinases (such as
EGF-R, PDGF-R, VEGF-R, IGF1-R, the Insulin receptor), deliver
signals through phosphorylation to other kinases such as Src
tyrosine kinase, and the Raf, Mek and Erk serine/threonine kinase
families (Crews and Erikson, Cell 1993, 74, 215-7; Ihle, et al.,
Trends in Biochemical Sciences 1994, 19, 222-7). Each of these
kinases is represented by several family members (Pelech and
Sanghera, Trends in Biochemical Sciences 1992, 17, 233-8) which
play related, but functionally distinct roles. The loss of
regulation of the growth factor signaling pathway is a frequent
occurrence in cancer as well as other disease states.
[0005] A variety of evidence suggests that nerve growth factor
(NGF) may be a mediator of some persistent pain states, including
neuropathic and inflammatory pain. For example: a) NGF is rapidly
elevated in inflamed tissues; b) NGF specific antibodies
substantially diminish inflammatory hypersensitivity; c) injection
of NGF into adult rats causes a profound hypersensitivity to
noxious heat and mechanical stimuli; and d) low level
administration of recombinant NGF induces hyperalgesia in healthy
humans. NGF produces hyperalgesia through several potential
mechanisms. NGF results in the upregulation of peptide
neurotransmitters in neurons that detect painful stimuli
(nociceptors). NGF increases the excitability of spinal cord
neurons to activation. Mast cells express NGF receptors and NGF
triggers the release of granules containing histamine and
serotonin. Histamine and serotonin are capable of sensitizing
nociceptors. (Wood, John (2000) Pathology of Visceral Pain:
Molecular Mechanisms and Therapeutic Implications II. Genetic
Aproaches to Pain Therapy. Am. J. Physiol 278(40), G507-G512.)
[0006] NGF binds to two different receptors, the neurotrophin
receptor p75 (p75NTR) and TrkA. p75NTR is a member of a family of
receptors that includes tumor necrosis factor receptor (TNFR) and
FAS/APO1. These receptors have in common a cysteine-rich motif in
the extracellular domain, a single transmembrane domain, and a
cytoplasmic domain. p75NTR signals in a fashion similar to TNFR and
FAS via the activation of NFkB, JNK, and ceramide production. The
functional significance of p75NTR in NGF mediated biological
responses is not clear. Proposed functions include a) modulation of
TrkA driven responses and b) induction of cell death in cells that
express p75NTR, but not TrkA.
[0007] TrkA appears to be the primary mediator of NGF driven
biological responses. The most compelling evidence for this comes
from NGF and TrkA knockout mice. Mice defective in either the
ligand or receptor component of this system have remarkably similar
phenotypes. Examples of these phenotypes include severe sensory
defects characterized by a complete loss of nociceptive activity
and deficiencies in thermoception. Anatomically these mice exhibit
extensive peripheral nervous system cell loss in trigeminal, dorsal
root, and sympathetic ganglia. Other evidence for the involvement
of TrkA in NGF driven responses comes from the study of the PC12
cell line. PC12 cells express high levels of p75NTR and TrkA. NGF
causes PC12 cells to differentiate into a neuronal phenotype
characterized by the development of axonal projections. Loss of
TrkA prevents PC12 cells from differentiating in response to NGF.
(Eggert, A. et al (2000) Molecular Dissection of TrkA Signal
Transduction Pathways Mediating Differentiation in human
Neuroblastoma Cells, Oncogene, 19(16), 2043-2051.)
[0008] There is evidence that Trk tyrosine kinases play a role in
the development of a variety of cancers including, for example,
breast and prostate cancer. (Guate, J. L. et al, (1999) Expresion
of p75LNGFR and Trk Neurotrophin Receptors in Normal and Neoplastic
Human Prostate. BJU Int. 84(4), 495-502; Tagliabue, E. et al, Nerve
Growth Factor cooperates with p185HER2 in Activating Growth of
Human Breast Carcinoma Cells, (2000) J. Biol. Chem. 275(8),
5388-5394.) Further, there is strong evidence that mediation of the
Trk kinase signaling will provide beneficial biological effects.
(LeSauteur, L. et al (1998) Development and Uses of Small Molecule
Ligands of TrkA Receptors. Adv. Behav. Biol. 49, 615-625; Zhu, Z.
et al (1999) Nerve Growth Factor Expression Correlates with
Perineural Invasion and Pain in Human Pancreatic Cancer, Journal of
Clinical Oncology, 17(8), 2419-28; Friess, H. et al, Nerve Growth
Factor and its High-Affinity Receptor in Chronic Pancreatitis
(1999) Annals of Surgery 230(5), 615-24.)
[0009] TrkA is a receptor tyrosine kinase that belongs to a
subfamily of tyrosine kinases that includes TrkB, and TrkC. TrkB
and TrkC are structurally similar to TrkA, but respond to different
ligands in the neurotrophin family. NGF signaling through TrkA has
been best characterized in the PC12 system and is similar to signal
transduction mechanisms of other tyrosine kinase receptors. NGF
exists as a homodimer. Binding of NGF promotes dimerization, and
autophoshphorylation of TrkA. Phosphorylation of TrkA increases the
catalytic activity of the kinase domain and creates binding sites
for SH2 domain containing cytoplasmic proteins. SH2 domain binding
events initiate the activation of several signal transduction
pathways such as PLCg, ras, PI3 kinase/AKT, and Raf/MEK/ERK.
(Frade, J. M. et al, (1998) Nerve growth factor: two receptors,
multiple functions, BioEssays 20: 137-145; Kaplan, D. R. et al,
(1997) Signal transduction by the neurotrophin receptors, Current
Opinion in Cell Biology. 9: 213-221; Barbacid, M. (1995)
Neurotrophic factors and their receptors, Current Opinion in Cell
Biology. 7:148-155; Snider, W. D. (1994) Functions of the
Neurotrophins during nervous system development: What the knockouts
are teaching us, Cell, 77:627-638.)
[0010] The selective inhibition of Trk family of kinases (TrkA,
TrkB, and TrkC) is therefore an object of the present
invention.
[0011] There is a continuing need in the medical field for new and
more effective treatments for cancer and for the relief of pain,
especially chronic pain. Because TrkA and other Trk kinases may
serve as a mediator of NGF driven biological responses, inhibitors
of TrkA and other Trk kinases may provide an effective treatment
for cancer and for chronic pain states. At present, there is an
unmet need for small molecule compounds that may be readily
synthesized and are potent inhibitors of TrkA and other Trk family
kinases. The present inventors have now discovered novel oxindole
derivative compounds that selectively inhibit the catalytic
activity of TrkA and/or other Trk family kinases thereby providing
new treatment strategies for those afflicted with cancer and
chronic pain. It is additionally possible that inhibitors of
certain kinases may have utility in the treatment of diseases when
the kinase is not misregulated, but is nonetheless essential for
maintenance of the disease state.
SUMMARY OF THE INVENTION
[0012] In one aspect of the present invention, there is provided
compounds of the formula (I): 1
[0013] wherein
[0014] Y, Z, A, and D are independently selected from the group
consisting of: carbon and nitrogen, with the provisos that: (1) Z
and D may be nitrogen, but otherwise no more than one of Y, Z, A,
and D may be nitrogen, and (2) when Y, Z, or A are nitrogen,
substituent R.sup.1, R.sup.2, or R.sup.3 designated for the
respective nitrogen atom is non-existent;
[0015] X is selected from the group consisting of: N, CH,
CCF.sub.3, and C(C.sub.1-12 aliphatic);
[0016] R.sup.1 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, thiol, hydroxy, hydroxy-C.sub.1-12 aliphatic,
Aryl, Aryl-C.sub.1-12 aliphatic, R.sup.9-Aryl-C.sub.1-12 aliphatic,
Cyc, Cyc-C.sub.1-6 aliphatic, Het, Het-C.sub.1-12 aliphatic,
C.sub.1-12 alkoxy, Aryloxy, amino, C.sub.1-12 aliphatic amino,
di-C.sub.1-12 aliphatic amino, di-C.sub.1-12 aliphatic
aminocarbonyl, di-C.sub.1-12 aliphatic aminosulfonyl, C.sub.1-12
alkoxycarbonyl, fluoro, bromo, iodo, cyano, sulfonamide, or nitro,
where R.sup.9, Aryl, Cyc and Het are as defined below;
[0017] R.sup.2 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, N-hydroxyimino-C.sub.1-12 aliphatic,
C.sub.1-12 alkoxy, hydroxy-C.sub.1-12 aliphatic, C.sub.1-12
alkoxycarbonyl, carboxyl C.sub.1-12 aliphatic, Aryl,
R.sup.9-Aryl-oxycarbonyl, R.sup.9-oxycarbonyl-Aryl, Het,
aminocarbonyl, C.sub.1-12 aliphatic-aminocarbonyl, Aryl-C.sub.1-12
aliphatic-aminocarbonyl, R.sup.9-Aryl-C.sub.1-12
aliphatic-aminocarbonyl, Het-C.sub.1-12 aliphatic-minocarbonyl,
hydroxy-C.sub.1-12 aliphatic-aminocarbonyl,
C.sub.1-12-alkoxy-C.sub.1-12 aliphatic-aminocarbonyl, C.sub.1-12
alkoxy-C.sub.1-12 aliphatic-amino, di-C.sub.1-12 aliphatic amino,
di-C.sub.1-12 aliphatic aminocarbonyl, di-C.sub.1-12 aliphatic
aminosulfonyl, halogen, hydroxy, C.sub.1-12 aliphatic-sulfonyl,
aminosulfonyl, and C.sub.1-12 aliphatic-aminosulfonyl, where
R.sup.9, Aryl and Het are as defined below, with the proviso that
where X is nitrogen, R.sup.2 is not chloro or
3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-th- iadiazin-5-yl; or
[0018] R.sup.1 and R.sup.2 are optionally joined to form a fused
ring selected from the group as defined for Het below, and said
fused ring is optionally substituted by a substituent selected from
the group consisting of: C.sub.1-12 aliphatic, halogen, nitro,
cyano, C.sub.1-12 alkoxy, amino, hydroxyl,
(R.sup.10,R.sup.11)-amino, and oxo;
[0019] R.sup.3 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, hydroxy, hydroxy C.sub.1-12 aliphatic,
di-C.sub.1-12 aliphatic amino, di-C.sub.1-12 aliphatic
aminocarbonyl, di-C.sub.1-12 aliphatic aminosulfonyl, C.sub.1-12
alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or
halogen, where Aryl and Het are as defined below, with the proviso
that where X is nitrogen R.sup.3, is not fluoro;
[0020] R.sup.2 and R.sup.3 are optionally joined to form a fused
ring selected from the group as defined for Het below, and said
fused ring is optionally substituted by C.sub.1-6 aliphatic or
C.sub.1-6 aliphatic-carbonyl;
[0021] R.sup.4, R.sup.5 and R.sup.6 may be the same or different
and are independently selected from the group consisting of:
hydrogen, C.sub.1-12 aliphatic, thiol, C.sub.1-6 aliphatic-thio,
di(trifluoromethyl)hydroxymet- hyl, carboxamide,
mono-C.sub.1-12aliphatic aminocarbonyl, hydroxy, hydroxy-C.sub.1-12
aliphatic, Aryl, Aryl-C.sub.1-12 aliphatic, R.sup.9-Aryl-C.sub.1-12
aliphatic, Cyc, Cyc-C.sub.1-6 aliphatic, Het, Het-C.sub.1-12
aliphatic, C.sub.1-12 alkoxy, Aryloxy, Het-oxy, amino,
(R.sup.10,R.sup.11)-amino-C-.sub.1-12 aliphatic aminocarbonyl,
(R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic alkoxycarbonyl,
(R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic aminocarbonylamino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic alkoxycarbonylamino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphaticsulfonyl,
Het-C.sub.1-6 aliphatic aminocarbonyl, Het-C.sub.1-6 aliphatic
aminocarbonylamino, Het-C.sub.1-6 alkoxycarbonylamino,
Het-C.sub.1-6 aliphatic carbonyl, Het-C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 aliphaticsulfonyl-C.sub.1-6 aliphatic aminoalkyl,
C.sub.1-6 aliphaticsulfonyl-C.sub.1-6 aliphatic aminoalkyl-Het-,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 aliphatic carbonylamino,
(C.sub.1-6 aliphatic carbonyl)(C.sub.1-6 aliphatic)amino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic carbonylamino,
[(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic carbonyl][C.sub.1-6
aliphatic]amino, (R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic
sulfonylamino, [(R.sup.10,R.sup.11)-amino-C.sub.1-6
aliphaticsulfonyl][C.sub.1-6 aliphatic]amino, halogen, cyano,
diethoxyphosphorylmethyl, nitro, trifluromethyl, and
trifluoromethoxy, where R.sup.9, R.sup.10, R.sup.11, Aryl, Cyc and
Het are as defined below, with the proviso that where X is
nitrogen, R.sup.4, R.sup.5 and R.sup.6 is not nitro;
[0022] R.sup.7 and R.sup.8 may be the same or different and are
independently selected from the group consisting of: hydrogen,
halogen, C.sub.1-2 alkoxy, hydroxy, C.sub.1-3-aliphatic, and
C.sub.1-3 aliphatic;
[0023] with the proviso that R.sup.4, R.sup.5, R.sup.6, R.sup.7,
and R.sup.8 cannot simultaneously be hydrogen;
[0024] wherein R.sup.7 may additionally be optionally fused to
R.sup.5 so as to form a fused benzo ring from the R.sup.5 to the
R.sup.7 positions and
[0025] wherein R.sup.4 may additionally be optionally fused to
R.sup.5 so as to form a fused cyclic urea ring from the R.sup.4 to
the R.sup.5 positions;
[0026] R.sup.9 is selected from the group consisting of: C.sub.1-12
aliphatic, hydroxy, C.sub.1-12 alkoxy and halogen;
[0027] R.sup.10 and R.sup.11 may be the same or different and are
independently selected from the group consisting of: hydrogen,
C.sub.1-6 aliphatic and Het;
[0028] Aryl is selected from the group consisting of: phenyl,
naphthyl, phenanthryl and anthracenyl;
[0029] Cyc is selected from the group consisting of: cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl,
and optionally has one or more degrees of unsaturation;
[0030] Het is a saturated or unsaturated heteroatom ring system
selected from the group consisting of: benzimidazole,
dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine,
dithiazole, dithiolane, furan, imidazole, isoquinoline, morpholine,
oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine,
oxadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole,
pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline,
tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole,
thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine
and triazole, where any of said heterocyclic rings may be
optionally substituted by a substituent selected from the group
consisting of: C.sub.1-12 aliphatic, hydroxy, C.sub.1-12 alkoxy,
(R.sup.10,R.sup.11)-amino, (R.sup.10,R.sup.11)-amino-C.sub.1-12
aliphatic, (R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic amino,
oxo and dioxo;
[0031] and the pharmaceutically acceptable salts, solvates,
polymorphs, physiologically functional derivatives, including
esters, amides, carbamates, solvates, hydrates, affinity reagents
and prodrugs thereof in either crystalline or amorphous form. The
esters, amides and carbamates, are preferably hydrolyzable and more
preferably are biohydrolyzable.
[0032] In another aspect of the present invention, there is
provided compounds of formula (II), 2
[0033] wherein
[0034] R.sup.1 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, thiol, hydroxy, hydroxy-C.sub.1-12 aliphatic,
Aryl, Aryl-C.sub.1-12 aliphatic, R.sup.9-Aryl-C.sub.1-12 aliphatic,
Cyc, Cyc-C.sub.1-6 aliphatic, Het, Het-C.sub.1-12 aliphatic,
C.sub.1-12 alkoxy, Aryloxy, amino, C.sub.1-12 aliphatic amino,
di-C.sub.1-12 aliphatic amino, di-C.sub.1-12 aliphatic
aminocarbonyl, di-C.sub.1-12 aliphatic aminosulfonyl, C.sub.1-12
alkoxycarbonyl, fluoro, bromo, iodo, cyano, sulfonamide, or nitro,
where R.sup.9, Aryl, Cyc and Het are as defined below;
[0035] R.sup.2 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, N-hydroxyimino-C.sub.1-12 aliphatic,
C.sub.1-12 alkoxy, hydroxy-C.sub.1-12 aliphatic, C.sub.1-12
alkoxycarbonyl, carboxyl C.sub.1-12 aliphatic, Aryl,
R.sup.9-Aryl-oxycarbonyl, R.sup.9-oxycarbonyl-Aryl, Het,
aminocarbonyl, C.sub.1-12 aliphatic-aminocarbonyl, Aryl-C.sub.1-12
aliphatic-aminocarbonyl, R.sup.9-Aryl-C.sub.1-12
aliphatic-aminocarbonyl, Het-C.sub.1-12 aliphatic-aminocarbonyl,
hydroxy-C.sub.1-12 aliphatic-aminocarbonyl,
C.sub.1-12-alkoxy-C.sub.1-12 aliphatic-aminocarbonyl, C.sub.1-12
alkoxy-C.sub.1-12 aliphatic-amino, di-C.sub.1-12 aliphatic amino,
di-C.sub.1-12 aliphatic aminocarbonyl, di-C.sub.1-12 aliphatic
aminosulfonyl, halogen, hydroxy, C.sub.1-12 aliphatic-sulfonyl,
aminosulfonyl, or one or more substituents selected from the group
consisting of: C.sub.1-12 aliphatic-aminosulfonyl, where R.sup.9,
Aryl and Het are as defined below;
[0036] R.sup.1 and R.sup.2 are optionally joined to form a fused
ring selected from the group as defined for Het below, and said
fused ring is optionally substituted by C.sub.1-12 aliphatic,
halogen, nitro, cyano, C.sub.1-12 alkoxy, amino, hydroxyl,
(R.sup.10,R.sup.11)-amino, or oxo;
[0037] R.sup.3 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, hydroxy, hydroxy C.sub.1-12 aliphatic,
di-C.sub.1-12 aliphatic amino, di-C.sub.1-12 aliphatic
aminocarbonyl, di-C.sub.1-12 aliphatic aminosulfonyl, C.sub.1-12
alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or
halogen, where Aryl and Het are as defined below;
[0038] R.sup.2 and R.sup.3 are optionally joined to form a fused
ring selected from the group as defined for Het below, and said
fused ring is optionally substituted by C.sub.1-6 aliphatic or
C.sub.1-6 aliphatic-carbonyl;
[0039] R.sup.4, R.sup.5 and R.sup.6 may be the same or different
and are independently selected from the group consisting of:
hydrogen, C.sub.1-12 aliphatic, thiol, C.sub.1-6 aliphatic-thio,
di(trifluoromethyl)hydroxymet- hyl, carboxamide,
mono-C.sub.1-12aliphatic aminocarbonyl, hydroxy, hydroxy-C.sub.1-12
aliphatic, Aryl, Aryl-C.sub.1-12 aliphatic, R.sup.9-Aryl-C.sub.1-12
aliphatic, Cyc, Cyc-C.sub.1-6 aliphatic, Het, Het-C.sub.1-12
aliphatic, C.sub.1-12 alkoxy, Aryloxy, Het-oxy, amino,
(R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic aminocarbonyl,
(R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic alkoxycarbonyl,
(R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic aminocarbonylamino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic alkoxycarbonylamino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphaticsulfonyl,
Het-C.sub.1-6 aliphatic aminocarbonyl, Het-C.sub.1-6 aliphatic
aminocarbonylamino, Het-C.sub.1-6 alkoxycarbonylamino,
Het-C.sub.1-6 aliphatic carbonyl, Het-C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 aliphaticsulfonyl-C.sub.1-6 aliphatic aminoalkyl,
C.sub.1-6 aliphaticsulfonyl-C.sub.1-6 aliphatic aminoalkyl-Het-,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 aliphatic carbonylamino,
(C.sub.1-6 aliphatic carbonyl)(C.sub.1-6 aliphatic)amino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic carbonylamino,
[(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic carbonyl][C.sub.1-6
aliphatic]amino, (R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic
sulfonylamino, [(R.sup.10,R.sup.11)-amino-C.sub.1-6
aliphaticsulfonyl][C.sub.1-6 aliphatic]amino, halogen, cyano,
diethoxyphosphorylmethyl, nitro, trifluromethyl, or
trifluoromethoxy, where R.sup.9, R.sup.10, R.sup.11, Aryl, Cyc and
Het are as defined below;
[0040] R.sup.7 and R.sup.8 may be the same or different and are
independently selected from the group consisting of: hydrogen,
halogen, C.sub.1-2 alkoxy, hydroxy, C.sub.1-3-aliphatic and
C.sub.1-3 aliphatic;
[0041] with the proviso that R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 cannot simultaneously be hydrogen;
[0042] wherein R.sup.7 may additionally be optionally fused to
R.sup.5 so as to form a fused benzo ring from the R.sup.5 to the
R.sup.7 positions; and
[0043] wherein R.sup.4 may additionally be optionally fused to
R.sup.5 so as to form a fused cyclic urea ring from the R.sup.4 to
the R.sup.5 positions;
[0044] R.sup.9 is selected from the group consisting of: C.sub.1-12
aliphatic, hydroxy, C.sub.1-12 alkoxy, or halogen;
[0045] R.sup.10 and R.sup.11 may be the same or different and are
independently selected from the group consisting of: hydrogen,
C.sub.1-6 aliphatic and Het;
[0046] Aryl is selected from the group consisting of: phenyl,
naphthyl, phenanthryl or anthracenyl;
[0047] Cyc is selected from the group consisting of: cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl,
and optionally has one or more degrees of unsaturation;
[0048] Het is a saturated or unsaturated heteroatom ring system
selected from the group consisting of: benzimidazole,
dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine,
dithiazole, dithiolane, furan, imidazole, isoquinoline, morpholine,
oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine,
oxadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole,
pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline,
tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole,
thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine
and triazole, where any of said heterocyclic rings may be
optionally substituted by a substituent selected from the group
consisting of: C.sub.1-12 aliphatic, hydroxy, C.sub.1-12 alkoxy,
(R.sup.10,R.sup.11)-amino, (R.sup.10,R.sup.11)-amino-C.sub.1-12
aliphatic, (R.sup.10,R.sup.11)-amino-C-.sub.1-12 aliphatic amino,
oxo or dioxo;
[0049] and the pharmaceutically acceptable salts, solvates, or
physiologically functional derivatives, including esters, amides,
carbamates, solvates, hydrates, affinity reagents and prodrugs
thereof in either crystalline or amorphous form. The esters, amides
and carbamates, are preferably hydrolyzable and more preferably are
biohydrolyzable.
[0050] In another aspect of the present invention, there is
provided compounds of formula (III): 3
[0051] wherein
[0052] R.sup.1 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, thiol, hydroxy, hydroxy-C.sub.1-12 aliphatic,
Aryl, Aryl-C.sub.1-12 aliphatic, R.sup.9-Aryl-C.sub.1-12 aliphatic,
Cyc, Cyc-C.sub.1-6 aliphatic, Het, Het-C.sub.1-12 aliphatic,
C.sub.1-12 alkoxy, Aryloxy, amino, C.sub.1-12 aliphatic amino,
di-C.sub.1-12 aliphatic amino, di-C.sub.1-12 aliphatic
aminocarbonyl, di-C.sub.1-12 aliphatic aminosulfonyl, C.sub.1-12
alkoxycarbonyl, fluoro, bromo, iodo, cyano, sulfonamide, or nitro,
where R.sup.9, Aryl, Cyc and Het are as defined below;
[0053] R.sup.2 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, N-hydroxyimino-C.sub.1-12 aliphatic,
C.sub.1-12 alkoxy, hydroxy-C.sub.1-12 aliphatic, C.sub.1-12
alkoxycarbonyl, carboxyl C.sub.1-12 aliphatic, Aryl,
R.sup.9-Aryl-oxycarbonyl, R.sup.9-oxycarbonyl-Aryl, Het,
aminocarbonyl, C.sub.1-12 aliphatic-aminocarbonyl, Aryl-C.sub.1-12
aliphatic-aminocarbonyl, R.sup.9-Aryl-C.sub.1-12
aliphatic-aminocarbonyl, Het-C.sub.1-12 aliphatic-aminocarbonyl,
hydroxy-C.sub.1-12 aliphatic-aminocarbonyl,
C.sub.1-12-alkoxy-C.sub.1-12 aliphatic-aminocarbonyl, C.sub.1-12
alkoxy-C.sub.1-12 aliphatic-amino, di-C.sub.1-12 aliphatic amino,
di-C-.sub.12 aliphatic aminocarbonyl, di-C.sub.1-12 aliphatic
aminosulfonyl, halogen, hydroxy, C.sub.1-12 aliphatic-sulfonyl,
aminosulfonyl, or one or more substituents selected from the group
consisting of: C.sub.1-12 aliphatic-aminosulfonyl, where R.sup.9,
Aryl and Het are as defined below, with the proviso that R.sup.2 is
not chloro or
3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl;
[0054] R.sup.1 and R.sup.2 are optionally joined to form a fused
ring selected from the group as defined for Het below, and said
fused ring is optionally substituted by C.sub.1-12 aliphatic,
halogen, nitro, cyano, C.sub.1-12 alkoxy, amino, hydroxyl,
(R.sup.10,R.sup.11)-amino, or oxo;
[0055] R.sup.3 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, hydroxy, hydroxy C.sub.1-12 aliphatic,
di-C.sub.1-12 aliphatic amino, di-C.sub.1-12 aliphatic
aminocarbonyl, di-C.sub.1-12 aliphatic aminosulfonyl, C.sub.1-12
alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or
halogen, where Aryl and Het are as defined below, with the proviso
R.sup.3 is not fluoro;
[0056] R.sup.2 and R.sup.3 are optionally joined to form a fused
ring selected from the group as defined for Het below, and said
fused ring is optionally substituted by C.sub.1-6 aliphatic or
C.sub.1-6 aliphatic-carbonyl;
[0057] R.sup.4, R.sup.5 and R.sup.6 may be the same or different
and are independently selected from the group consisting of:
hydrogen, C.sub.1-12 aliphatic, thiol, C.sub.1-6 aliphatic-thio,
di(trifluoromethyl)hydroxymet- hyl, carboxamide,
mono-C.sub.1-12aliphatic aminocarbonyl, hydroxy, hydroxy-C.sub.1-12
aliphatic, Aryl, Aryl-C.sub.1-12 aliphatic, R.sup.9-Aryl-C.sub.1-12
aliphatic, Cyc, Cyc-C.sub.1-6 aliphatic, Het, Het-C.sub.1-12
aliphatic, C.sub.1-12 alkoxy, Aryloxy, Het-oxy, amino,
(R.sup.10,R.sup.11)-amino-C-.sub.1-12 aliphatic aminocarbonyl,
(R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic alkoxycarbonyl,
(R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic aminocarbonylamino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic alkoxycarbonylamino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphaticsulfonyl,
Het-C.sub.1-6 aliphatic aminocarbonyl, Het-C.sub.1-6 aliphatic
aminocarbonylamino, Het-C.sub.1-6 alkoxycarbonylamino,
Het-C.sub.1-6 aliphatic carbonyl, Het-C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 aliphaticsulfonyl-C.sub.1-6 aliphatic aminoalkyl,
C.sub.1-6 aliphaticsulfonyl-C.sub.1-6 aliphatic aminoalkyl-Het-,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 aliphatic carbonylamino,
(C.sub.1-6 aliphatic carbonyl)(C.sub.1-6 aliphatic)amino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic carbonylamino,
[(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic carbonyl][C.sub.1-6
aliphatic]amino, (R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic
sulfonylamino, [(R.sup.10,R.sup.11)-amino-C.sub.1-6
aliphaticsulfonyl][C.sub.1-6 aliphatic]amino, halogen, cyano,
diethoxyphosphorylmethyl, nitro, trifluromethyl, or
trifluoromethoxy, where R.sup.9, R.sup.10, R.sup.11, Aryl, Cyc and
Het are as defined below, with the proviso that R.sup.4, R.sup.5
and R.sup.6 is not nitro;
[0058] R.sup.7 and R.sup.8 may be the same or different and are
independently selected from the group consisting of: hydrogen,
halogen, C.sub.1-2 alkoxy, hydroxy, C.sub.1-3-aliphatic and
C.sub.1-3 aliphatic;
[0059] with the proviso that R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 cannot simultaneously be hydrogen;
[0060] R.sup.9 is selected from the group consisting of: C.sub.1-12
aliphatic, hydroxy, C.sub.1-12 alkoxy, or halogen;
[0061] R.sup.10 and R.sup.11 may be the same or different and are
independently selected from the group consisting of: hydrogen,
C.sub.1-6 aliphatic and Het;
[0062] Aryl is selected from the group consisting of: phenyl,
naphthyl, phenanthryl or anthracenyl;
[0063] Cyc is selected from the group consisting of: cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any
one of which may have one or more degrees of unsaturation;
[0064] Het is a saturated or unsaturated heteroatom ring system
selected from the group consisting of: benzimidazole,
dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine,
dithiazole, dithiolane, furan, imidazole, isoquinoline, morpholine,
oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine,
oxadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole,
pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline,
tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole,
thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine
and triazole, where any of said heterocyclic rings may be
optionally substituted by a substituent selected from the group
consisting of: C.sub.1-12 aliphatic, hydroxy, C.sub.1-12 alkoxy,
(R.sup.10,R.sup.11)-amino, (R.sup.10,R.sup.11)-amino-C.sub.1-12
aliphatic, (R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic amino,
oxo or dioxo;
[0065] and the pharmaceutically acceptable salts, solvates,
physiologically functional derivatives, including esters, amides,
carbamates, solvates, hydrates, affinity reagents and prodrugs
thereof in either crystalline or amorphous form. The esters, amides
and carbamates, are preferably hydrolyzable and more preferably are
biohydrolyzable.
[0066] In another aspect of the present invention, there is
provided compounds of formula (IV): 4
[0067] wherein
[0068] Y, Z, A, and D are independently selected from the group
consisting of: carbon and nitrogen, with the provisos that: (1) Z
and D may be nitrogen, but otherwise no more than one of Y, Z, A,
and D may be nitrogen, and (2) when Y, Z, or A are nitrogen,
substituent R1, R2, or R3 designated for the respective nitrogen
atom is non-existent;
[0069] R.sup.1 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, thiol, hydroxy, hydroxy-C.sub.1-12 aliphatic,
Aryl, Aryl-C.sub.1-12 aliphatic, R.sup.9-Aryl-C.sub.1-12 aliphatic,
Cyc, Cyc-C.sub.1-6 aliphatic, Het, Het-C.sub.1-12 aliphatic,
C.sub.1-12 alkoxy, Aryloxy, amino, C.sub.1-12 aliphatic amino,
di-C.sub.1-12 aliphatic amino, di-C.sub.1-12 aliphatic
aminocarbonyl, di-C.sub.1-12 aliphatic aminosulfonyl, C.sub.1-12
alkoxycarbonyl, fluoro, bromo, iodo, cyano, sulfonamide, or nitro,
where R.sup.9, Aryl, Cyc and Het are as defined below;
[0070] R.sup.2 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, N-hydroxyimino-C.sub.1-12 aliphatic,
C.sub.1-12 alkoxy, hydroxy-C.sub.1-12 aliphatic, C.sub.1-12
alkoxycarbonyl, carboxyl C.sub.1-12 aliphatic, Aryl,
R.sup.9-Aryl-oxycarbonyl, R.sup.9oxycarbonyl-Aryl, Het,
aminocarbonyl, C.sub.1-12 aliphatic-aminocarbonyl, Aryl-C.sub.1-12
aliphatic-aminocarbonyl, R.sup.9-Aryl-C, 12aliphatic-aminocarbonyl,
Het-C.sub.1-12 aliphatic-aminocarbonyl, hydroxy-C.sub.1-12
aliphatic-aminocarbonyl, C.sub.1-12-alkoxy-C-.sub.1-12
aliphatic-aminocarbonyl, C.sub.1-12 alkoxy-C-.sub.1-12
aliphatic-amino, di-C.sub.1-12 aliphatic amino, di-C.sub.1-12
aliphatic aminocarbonyl, di-C.sub.11-.sub.12 aliphatic
aminosulfonyl, halogen, hydroxy, C.sub.1-12 aliphatic-sulfonyl,
aminosulfonyl, or one or more substituents selected from the group
consisting of: C.sub.1-12 aliphatic-aminosulfonyl, where R.sup.9,
Aryl and Het are as defined below;
[0071] R.sup.1 and R.sup.2 are optionally joined to form a fused
ring selected from the group as defined for Het below, and said
fused ring is optionally substituted by C.sub.1-12 aliphatic,
halogen, nitro, cyano, C.sub.1-12 alkoxy, amino, hydroxyl,
(R.sup.10,R.sup.11)-amino, or oxo;
[0072] R.sup.3 is selected from the group consisting of: hydrogen,
C.sub.1-12 aliphatic, hydroxy, hydroxy C.sub.1-12 aliphatic,
di-C.sub.1-12 aliphatic amino, di-C.sub.1-12 aliphatic
aminocarbonyl, di-C.sub.1-12 aliphatic aminosulfonyl, C.sub.1-12
alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or
halogen, where Aryl and Het are as defined below;
[0073] R.sup.2 and R.sup.3 are optionally joined to form a fused
ring selected from the group as defined for Het below, and said
fused ring is optionally substituted by C.sub.1-6 aliphatic or
C.sub.1-6 aliphatic-carbonyl;
[0074] R.sup.4, R.sup.5 and R.sup.6 may be the same or different
and are independently selected from the group consisting of:
hydrogen, C.sub.1-12 aliphatic, thiol, C.sub.1-6 aliphatic-thio,
di(trifluoromethyl)hydroxymet- hyl, carboxamide,
mono-C.sub.1-12aliphatic aminocarbonyl, hydroxy, hydroxy-C.sub.1-12
aliphatic, Aryl, Aryl-C.sub.1-12 aliphatic, R.sup.9-Aryl-C.sub.1-12
aliphatic, Cyc, Cyc-C.sub.1-6 aliphatic, Het, Het-C.sub.1-12
aliphatic, C.sub.1-12 alkoxy, Aryloxy, Het-oxy, amino,
(R.sup.10,R.sup.11)-amino-C-.sub.1-12 aliphatic aminocarbonyl,
(R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic alkoxycarbonyl,
(R.sup.10,R.sup.11)-amino-C-.sub.1-12 aliphatic aminocarbonylamino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic alkoxycarbonylamino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphaticsulfonyl,
Het-C.sub.1-6 aliphatic aminocarbonyl, Het-C.sub.1-6 aliphatic
aminocarbonylamino, Het-C.sub.1-6 alkoxycarbonylamino,
Het-C.sub.1-6 aliphatic carbonyl, Het-C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 aliphaticsulfonyl-C.sub.1-6 aliphatic aminoalkyl,
C.sub.1-6 aliphaticsulfonyl-C.sub.1-6 aliphatic aminoalkyl-Het-,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 aliphatic carbonylamino,
(C.sub.1-6 aliphatic carbonyl)(C.sub.1-6 aliphatic)amino,
(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic carbonylamino,
[(R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic carbonyl][C.sub.1-6
aliphatic]amino, (R.sup.10,R.sup.11)-amino-C.sub.1-6 aliphatic
sulfonylamino, [(R.sup.10,R.sup.11)-amino-C.sub.1-6
aliphaticsulfonyl][C.sub.1-6 aliphatic]amino, halogen, cyano,
diethoxyphosphorylmethyl, nitro, trifluromethyl, or
trifluoromethoxy, where R.sup.9, R.sup.10, R.sup.11, Aryl, Cyc and
Het are as defined below;
[0075] R.sup.7 and R.sup.8 may be the same or different and are
independently selected from the group consisting of: hydrogen,
halogen, C.sub.1-2 alkoxy, hydroxy, C.sub.1-6-aliphatic and
C.sub.1-3 aliphatic;
[0076] with the proviso that R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 cannot simultaneously be hydrogen;
[0077] wherein R.sup.7 may additionally be optionally fused to
R.sup.5 so as to form a fused benzo ring from the R.sup.5 to the
R.sup.7 positions; and
[0078] wherein R.sup.4 may additionally be optionally fused to
R.sup.5 so as to form a fused cyclic urea ring from the R.sup.4 to
the R.sup.5 positions;
[0079] R.sup.9 is selected from the group consisting of: C.sub.1-12
aliphatic, hydroxy, C.sub.1-12 alkoxy, or halogen;
[0080] R.sup.10 and R.sup.11 may be the same or different and are
independently selected from the group consisting of: hydrogen,
C.sub.1-6 aliphatic and Het;
[0081] Aryl is selected from the group consisting of: phenyl,
naphthyl, phenanthryl or anthracenyl;
[0082] Cyc is selected from the group consisting of: cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and
optionally has one or more degrees of unsaturation;
[0083] Het is a saturated or unsaturated heteroatom ring system
selected from the group consisting of: benzimidazole,
dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine,
dithiazole, dithiolane, furan, imidazole, isoquinoline, morpholine,
oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine,
oxadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole,
pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline,
tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole,
thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine
and triazole, where any of said heterocyclic rings may be
optionally substituted by a substituent selected from the group
consisting of: C.sub.1-12 aliphatic, hydroxy, C.sub.1-12 alkoxy,
(R.sup.10,R.sup.11)-amino, (R.sup.10,R.sup.11)-amino-C-.sub.1-12
aliphatic, (R.sup.10,R.sup.11)-amino-C.sub.1-12 aliphatic amino,
oxo or dioxo;
[0084] and the pharmaceutically acceptable salts, solvates,
physiologically functional derivatives, including esters, amides,
carbamates, solvates, hydrates, affinity reagents and prodrugs
thereof in either crystalline or amorphous form. The esters, amides
and carbamates, are preferably hydrolyzable and more preferably are
biohydrolyzable.
[0085] In another aspect of the present invention is a compound of
the formula II: 5
[0086] or salts, solvates, or physiological functional derivatives
thereof
[0087] wherein:
[0088] R.sup.1 is hydrogen;
[0089] R.sup.2 is hydrogen; or
[0090] R.sup.1 and R.sup.2 are optionally joined to form a fused
ring Het, wherein Het is a triazole ring;
[0091] R.sup.3 is hydrogen;
[0092] R.sup.4 is selected from the group consisting of
[0093] hydrogen 6
[0094] R.sup.5 is hydrogen or 7
[0095] R.sup.4 and R.sup.5 are optionally joined to form a fused
cyclic urea ring; and
[0096] R.sup.6, R.sup.7, and R.sup.8 are hydrogen.
[0097] While the ensuing discussion refers to the compound of
formula (I), it will be understood that the compounds of formula
(I) includes the compounds of formulas (II), (III) and (IV);
accordingly, references hereafter to formula (I) should hereafter
be understood to includes the compounds of formulas (II), (III) and
(IV) as well as the compounds of formula (I).
[0098] Due to the presence of an oxindole exocyclic double bond,
also included in the compounds of the invention are their
respective pure E and Z geometric isomers as well as mixtures of E
and Z isomers. The invention as described and claimed does not set
any limiting ratios on prevalence of Z to E isomers.
[0099] Likewise, it is understood that compounds of formula (I) as
used herein includes all tautomeric forms other than the specific
tautomer represented by the formula.
[0100] Certain of the compounds as described contain one or more
chiral, or asymmetric, centers and are therefore be capable of
existing as optical isomers that are either dextrorotatory or
levorotatory. Also included in the compounds of the invention are
the respective dextrorotatory or levorotatory pure preparations,
and mixtures thereof.
[0101] Certain compounds of formula (I) above are optionally
provided in stereoisomeric forms (e.g. they may contain one or more
asymmetric carbon atoms or may exhibit cis-trans isomerism). The
individual stereoisomers (enantiomers and diastereoisomers) and
mixtures of these are included within the scope of the present
invention. Likewise, it is understood that compounds of formula (I)
are optionally provided in various tautomeric forms within the
scope of the present invention.
[0102] The present invention also provides compounds of formula (I)
and pharmaceutically acceptable salts thereof (hereafter
collectively referred to as the "active compounds") for use in
therapy, and particularly in the treatment of disorders mediated by
a kinase, such as TrkA tyrosine kinase, including, for example,
cancers and chronic pain. In a further embodiment, the disorder
involves abnormal angiogenesis, such as arthritis, diabetic
retinopathy, macular degeneration and psoriasis.
[0103] A further aspect of the invention provides a method of
treating a disorder in a mammal, said disorder mediated by
inappropriate mitogen activated kinase activity, including
administering to said mammal a therapeutically effective amount of
a compound of formula (I) or a salt, solvate, or physiologically
functional derivative thereof. In one embodiment, the disorder is
cancer. In another embodiment the disorder is chronic pain. In a
further embodiment, the disorder involves abnormal angiogenesis,
such as arthritis, diabetic retinopathy, macular degeneration and
psoriasis.
[0104] In a related aspect the present invention comprises a method
for inhibiting a kinase comprising bringing said kinase into
contact with a compound of formula (I), or a salt, solvate, or
physiologically functional derivative thereof.
[0105] Another aspect of the present invention provides for the use
of a compound of formula (I), or a salt, solvate, or
physiologically functional derivative thereof, in the preparation
of a medicament for the treatment of a disorder mediated by
inappropriate TrkA activity. In one embodiment, the disorder is
cancer. In another embodiment, the disorder is chronic pain. In a
further embodiment, the disorder involves abnormal angiogenesis,
such as arthritis, diabetic retinopathy, macular degeneration and
psoriasis.
[0106] Additionally, compounds of formula (I) or salts, solvates,
or physiologically functional derivatives thereof, can be used in
the preparation of a medicament for the treatment of organ
transplant rejection, tumor growth, chemotherapy-induced mucositis,
radiation-induced mucositis, plantar-palmar syndrome,
chemotherapy-induced alopecia, chemotherapy-induced
thrombocytopenia, chemotherapy-induced leukopenia and hirsutism or
of treating a disease state selected from the group consisting of:
mucocitis, restenosis, atherosclerosis, rheumatoid arthritis,
angiogenesis, hepatic cirrhosis, glomerulonephritis, diabetic
nephropathy, malignant nephrosclerosis, chronic obstructive
pulmonary disease, thrombotic microangiopathy, aglomerulopathy,
psoriasis, diabetes mellitus, inflammation, a neurodegenerative
disease, macular degeneration, actinic keratosis and
hyperproliferative disorders.
[0107] Another aspect of the present invention provides the use of
an active compound of formula (I), in co-administration or
alternating administration with previously known anti-tumor
therapies for more effective treatment of such tumors.
[0108] Other aspects of the present invention related to the
inhibition of protein kinases are discussed in more detail
below.
[0109] The inappropriate TrkA activity referred to herein is any
TrkA activity that deviates from the normal TrkA activity expected
in a particular mammalian subject. Inappropriate TrkA activity may
take the form of, for instance, an abnormal increase in activity,
or an aberration in the timing and or control of TrkA activity.
Such inappropriate activity may result then, for example, from
overexpression or mutation of the protein kinase leading to
inappropriate or uncontrolled activation. Furthermore, it is also
understood that unwanted TrkA activity may reside in an abnormal
source, such as a malignancy. That is, the level of TrkA activity
does not have to be abnormal to be considered inappropriate, rather
the activity derives from an abnormal source.
[0110] Compounds synthesized as part of the present invention,
which are currently preferred, are listed in Tables 1 below.
Compounds are identified by the numbers shown in the first column;
variables below in the rest of the columns are with reference to
the generic structure (I). Corresponding IUPAC nomenclature are
disclosed in Table 2. Since all substituents at each point of
substitution are capable of independent synthesis of each other,
the tables are to be read as a matrix in which any combination of
substituents is within the scope of the disclosure and claims of
the invention.
1TABLE 1 (II) 8 Example R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5
R.sup.6 R.sup.7 R.sup.8 1 H H H --NHC(O)NH-- H H H 2 H H H 9 H H H
H 3 H H H 10 H H H H 4 N.dbd.N-- --NH-- H H 11 H H H 5 H H H
--CH.sub.2--C(O)NH.sub.2 H H H H 6 H H H 12 H H H H
[0111] Standard accepted nomenclature corresponding to the Examples
set forth in this specification are set forth below. In some cases
nomenclature is given for one or more possible isomers.
2TABLE 2 Example 1 5-{[(Z)-(2-oxo-1,2-dihydro-3H-in- dol-3-ylidene)
methyl]amino}-1,3-dihydro-2H-benzimidazol-2-one Example 2
(3Z)-3-{[4-(1H-1,2,4-triazol-1-yl)anilino]methylene}-1,3-
dihydro-2H-indol-2-one Example 3 3-ethyl-3-(4-{[(Z)-(2-oxo-1,-
2-dihydro-3H-indol-3- ylidene)methyl]amino}phenyl)-2,6-piperidined-
ione Example 4
(8Z)-8-{[3-(5-amino-1,3,4-oxadiazol-2-yl)anilino]met- hylene}-
6,8-dihydro[1,2,3]triazolo[4,5-e]indol-7(3H)-one Example 5
2-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)methyl]amino}phenyl)acetamide Example 6
(3Z)-3-{[4-(1H-1,2,4-triazol-3-yl)anilino]methylene}-1,3-
dihydro-2H-indol-2-one
[0112] The invention discloses thirteen different points of
substitution on structural formula (I). Each of these points of
substitution bears a substituent whose selection and synthesis as
part of this invention is independent of all other points of
substitution on formula (I). Each point of substitution is now
further described.
[0113] Preferred substitutions for Y, Z, A and D are nitrogen or
carbon. The most preferred substituents for D are nitrogen and
carbon. The most highly preferred substituent for Y, Z, A and D is
carbon.
[0114] Preferred substitutions at the R.sup.1 position include
hydrogen, fluoro, bromo, iodo, lower alkyl, cyano and nitro.
Alternatively, R.sup.1 is optionally joined with R.sup.2 to form a
fused ring structure selected from the group consisting of:
thiazole, imidazole, triazole and pyridine. Further, such fused
ring structures are optionally substituted by one or more
substituents selected from the group consisting of: halogen, amino,
lower alkyl substituted amino, lower alkyl and lower alkyl
carbonyl. In a preferred embodiment, R.sup.1 is selected from the
group, which includes hydrogen and methyl, or R.sup.1 is fused with
R.sup.2 to form a ring structure selected from the group, which
includes fused thiazole, fused triazole, and fused pyridine. In
another preferred embodiment, R.sup.1 is fused with R.sup.2 to form
a ring structure selected from the group, which includes fused
thiazole, pyridine and pyridine substituted by halogen or
methyl.
[0115] Preferred substitutions at the R.sup.2 position include
hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl,
C.sub.1-12 alkoxycarbonyl, Aryl, Het, aminocarbonyl, lower alkyl
aminocarbonyl, halogen and hydroxy. Alternatively, R.sup.2 is fused
with R.sup.1 to form a fused ring selected from the group, which
includes thiazole, imidazole, triazole and pyridine. Such fused
rings are optionally substituted by a substituent selected from the
group, which includes halogen, amino, lower alkyl substituted
amino, lower alkyl and lower alkyl carbonyl. Most preferably,
R.sup.2 is selected from the group, which includes hydroxyl,
hydroxy and lower alkyl, or is fused with R.sup.1 to form a ring
structure selected from the group, which includes fused thiazole,
fused triazole, and fused pyridine. In another preferred
embodiment, R.sup.2 is selected from the group which includes
hydroxy and hydroxymethyl, or is fused with R.sup.1 to form a fused
ring from the group which includes fused thiazole, pyridine and
pyridine substituted by halogen or methyl.
[0116] Preferred substitutions at R.sup.3 include hydrogen, lower
alkyl, lower alkenyl, halogen, phenyl, Het and alkoxy. Most
preferred are hydrogen, halogen, ethenyl and methyl. Most highly
preferred substitutions at R.sup.3 are hydrogen and bromo.
[0117] Preferred substitutions at R.sup.4 include hydrogen, lower
alkyl, hydroxy, hydroxy-lower alkyl, carboxamide, mono-lower alkyl
aminocarbonyl, substituted Aryl-lower alkyl, Het, Het-lower alkyl,
lower alkoxy, Aryloxy, Het-oxy, amino, mono- or di-lower
alkyl-amino lower alkyl aminocarbonyl, mono- or di-lower
alkyl-amino lower alkoxycarbonyl, mono- or di-lower alkyl-amino
lower alkyl aminocarbonylamino, mono- or di-lower alkyl-amino lower
alkoxycarbonylamino, lower alkyl carbonylamino, (lower alkyl
carbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino lower
alkyl carbonylamino, [mono- or di-lower alkyl-amino lower alkyl
carbonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower
alkyl sulfonylamino, [mono- or di-lower alkyl-amino lower alkyl
sulfonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower
alkyl sulfonyl, Het lower alkyl aminocarbonyl, Het lower alkyl
aminocarbonylamino, Het lower alkoxycarbonylamino, Het lower alkyl
carbonyl, Het lower alkoxycarbonyl, lower alkyl sulfonyl lower
alkyl aminoalkyl, lower alkyl sulfonyl-lower alkyl-aminoalkyl-Het-,
lower alkoxycarbonyl, halogen, cyano, diethoxyphosphorylmethyl,
trifluromethyl and trifluoromethoxy. The most preferred
substitutions are lower alkyl, hydroxy, hydroxy-lower alkyl,
carboxamide, mono-lower alkyl aminocarbonyl, substituted Aryl-lower
alkyl, Het, Het-lower alkyl, Het-oxy, mono- or di-lower alkyl-amino
lower alkyl aminocarbonyl, mono- or di-lower alkyl-amino lower
alkoxycarbonyl, mono- or di-lower alkyl-amino lower alkyl
aminocarbonylamino, mono- or di-lower alkyl-amino lower
alkoxycarbonylamino, lower alkyl carbonylamino, (lower alkyl
carbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino lower
alkyl carbonylamino, [mono- or di-lower alkyl-amino lower alkyl
carbonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower
alkyl sulfonylamino, [mono- or di-lower alkyl-amino lower alkyl
sulfonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower
alkyl sulfonyl, Het lower alkyl aminocarbonyl, Het lower alkyl
carbonyl, lower alkyl sulfonyl lower alkyl aminoalkyl, lower alkyl
sulfonyl-lower alkyl-aminoalkyl-Het-, halogen, cyano and
trifluromethyl. Most highly preferred are hydroxymethyl,
hydroxyethyl, 4-pyridylmethyl, 4-morpholino, acetamido,
N-methylacetamido, carboxamide, diethylaminoethylsulfonyl,
5-methyl-3-pyrazolon-1-yl and 3-ethyl-piperidine-2,6-dion-3-yl.
[0118] Preferred substitutions at R.sup.5 include hydrogen, lower
alkyl, hydroxy, hydroxy-lower alkyl, carboxamide, mono-lower alkyl
aminocarbonyl, substituted Aryl-lower alkyl, Het, Het-lower alkyl,
lower alkoxy, Aryloxy, Het-oxy, amino, mono- or di-lower
alkyl-amino lower alkyl aminocarbonyl, mono- or di-lower
alkyl-amino lower alkoxycarbonyl, mono- or di-lower alkyl-amino
lower alkyl aminocarbonylamino, mono- or di-lower alkyl-amino lower
alkoxycarbonylamino, lower alkyl carbonylamino, (lower alkyl
carbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino lower
alkyl carbonylamino, [mono- or di-lower alkyl-amino lower alkyl
carbonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower
alkyl sulfonylamino, [mono- or di-lower alkyl-amino lower alkyl
sulfonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower
alkyl sulfonyl, Het lower alkyl aminocarbonyl, Het lower alkyl
aminocarbonylamino, Het lower alkoxycarbonylamino, Het lower alkyl
carbonyl, Het lower alkoxycarbonyl, lower alkyl sulfonyl lower
alkyl aminoalkyl, lower alkyl sulfonyl-lower alkyl-aminoalkyl-Het-,
lower alkoxycarbonyl, halogen, cyano, diethoxyphosphorylmethyl,
trifluromethyl and trifluoromethoxy. The most preferred
substitutions are lower alkyl, hydroxy, hydroxy-lower alkyl,
carboxamide, mono-lower alkyl aminocarbonyl, substituted Aryl-lower
alkyl, Het, Het-lower alkyl, Het-oxy, mono- or di-lower alkyl-amino
lower alkyl aminocarbonyl, mono- or di-lower alkyl-amino lower
alkoxycarbonyl, mono- or di-lower alkyl-amino lower alkyl
aminocarbonylamino, mono- or di-lower alkyl-amino lower
alkoxycarbonylamino, lower alkyl carbonylamino, (lower alkyl
carbonyl)(lower alkyl) amino, mono- or di-lower alkyl-amino lower
alkyl carbonylamino, [mono- or di-lower alkyl-amino lower alkyl
carbonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower
alkyl sulfonylamino, [mono- or di-lower alkyl-amino lower alkyl
sulfonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower
alkyl sulfonyl, Het lower alkyl aminocarbonyl, Het lower alkyl
carbonyl, lower alkyl sulfonyl lower alkyl aminoalkyl, lower alkyl
sulfonyl-lower alkyl-aminoalkyl-Het-, halogen, cyano and
trifluromethyl. Most highly preferred are hydroxymethyl,
hydroxyethyl, 4-pyridylmethyl, 4-morpholino, acetamido,
N-methylacetamido, carboxamide, diethylaminoethylsulfonyl,
5-methyl-3-pyrazolon-1-yl and 3-ethyl-piperidine-2,6-dion-3-yl.
[0119] The most preferred substitution at R.sup.6 is hydrogen.
[0120] Preferred substitutions at R.sup.7 and R.sup.8 are hydrogen,
halogen and methyl.
[0121] Another preferred substitution at R.sup.7 includes the state
in which R.sup.7 is joined to R.sup.5 so as to form a fused benzo
ring from R.sup.5 to R.sup.7.
[0122] Another preferred substitution at R.sup.4 includes the state
in which R.sup.4 is joined to R.sup.5 so as to form a fused cyclic
urea ring from R.sup.4 to R.sup.5
[0123] Preferred substitutions at X include N, CH and CCH.sub.3.
Most preferred is CH.
[0124] Highly preferred compounds include 13
DETAILED DESCRIPTION OF THE INVENTION
[0125] Salts encompassed within the term "pharmaceutically
acceptable salts" refer to non-toxic salts of the compounds of this
invention which are generally prepared by reacting the free base
with a suitable organic or inorganic acid or by reacting the add
with a suitable organic or inorganic base. Representative salts
include the following salts: Acetate, Benzenesulfonate, Benzoate,
Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium
Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate,
Diethanolamine, Dihydrochloride, Edetate, Edisylate, Estolate,
Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide,
Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate,
Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
Metaphosphoric, Methylbromide, Methylnitrate, Methylsulfate,
Monopotassium Maleate, Mucate, Napsylate, Nitrate,
N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate,
Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium,
Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate,
Tartrate, Teoclate, Tosylate, Trifluoroacetate, Triethiodide,
Trimethylammonium and Valerate.
[0126] Other salts, which are not pharmaceutically acceptable, may
be useful in the preparation of compounds of formula (I) and these
form a further aspect of the invention.
[0127] Also included within the scope of the invention are the
individual isomers of the compounds represented by formula (I)
above as well as any wholly or partially equilibrated mixtures
thereof. The present invention also covers the individual isomers
of the compounds represented by formula above as mixtures with
isomers thereof in which one or more chiral asymmetric centers are
inverted.
[0128] As used herein, the term "aliphatic" refers to the terms
alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene.
[0129] As used herein, the term "lower" refers to a group having
between one and six carbons.
[0130] As used herein, the term "alkyl" refers to a straight or
branched chain hydrocarbon having from one to twelve carbon atoms,
optionally substituted with substituents selected from the group
which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,
lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto,
amino optionally substituted by alkyl, carboxy, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by a substituent selected from the group including
alkyl, nitro, cyano, halogen and lower perfluoroalkyl, multiple
degrees of substitution being allowed. Examples of "alkyl" as used
herein include, but are not limited to, n-butyl, n-pentyl,
isobutyl, isopropyl and the like.
[0131] As used herein, the term "alkylene" refers to a straight or
branched chain divalent hydrocarbon radical having from one to ten
carbon atoms, optionally substituted with substituents selected
from the group which includes lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen and lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "alkylene" as used herein include, but are not limited
to, methylene, ethylene, and the like.
[0132] As used herein, the term "alkenyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon double bond, optionally substituted with substituents
selected from the group which includes lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen and lower
perfluoroalkyl, multiple degrees of substitution being allowed.
[0133] As used herein, the term "alkenylene" refers to an straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon--carbon double bonds,
optionally substituted with substituents selected from the group
which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,
lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto,
amino optionally substituted by alkyl, carboxy, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen and lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "alkenylene" as used herein include, but are not
limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl,
and the like.
[0134] As used herein, the term "alkynyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon triple bond, optionally substituted with substituents
selected from the group which includes lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen and lower
perfluoroalkyl, multiple degrees of substitution being allowed.
[0135] As used herein, the term "alkynylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon--carbon triple bonds,
optionally substituted with substituents selected from the group
which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,
lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto,
amino optionally substituted by alkyl, carboxy, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen and lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "alkynylene" as used herein include, but are not
limited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.
[0136] As used herein, the term "cycloaliphatic" includes the terms
cycloalkyl, cycloalkylene, cycloalkenyl, cycloalkenylene,
cycloalkynyl and cycloalkylnylene.
[0137] As used herein, "cycloalkyl" refers to a alicyclic
hydrocarbon group with one or more degrees of unsaturation, having
from three to twelve carton atoms, optionally substituted with
substituents selected from the group which includes lower alkyl,
lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, nitro, cyano,
halogen and lower perfluoroalkyl, multiple degrees of substitution
being allowed. "Cycloalkyl" includes by way of Example cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and
the like.
[0138] As used herein, the term "cycloalkylene" refers to a
non-aromatic alicyclic divalent hydrocarbon radical having from
three to twelve carbon atoms, optionally substituted with
substituents selected from the group which includes lower alkyl,
lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, nitro, cyano,
halogen, lower perfluoroalkyl, multiple degrees of substitution
being allowed. Examples of "cycloalkylene" as used herein include,
but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl,
cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl,
cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
[0139] As used herein, the term "cycloalkenyl" refers to a
substituted alicyclic hydrocarbon radical having from three to
twelve carbon atoms and at least one carbon-carbon double bond in
the ring system, optionally substituted with substituents selected
from the group which includes lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen and lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "cycloalkenylene" as used herein include, but are not
limited to, 1-cyclopentene-3-yl, 1-cyclohexene-3-yl,
1-cycloheptene-4-yl, and the like.
[0140] As used herein, the term "cycloalkenylene" refers to a
substituted alicyclic divalent hydrocarbon radical having from
three to twelve carbon atoms and at least one carbon-carbon double
bond in the ring system, optionally substituted with substituents
selected from the group which includes lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "cycloalkenylene" as used herein include, but are not
limited to, 4,5-cyclopentene-1,3-diyl, 3,4-cyclohexene-1,1-diyl,
and the like.
[0141] As used herein, the term "heteroatom ring system" refers to
the terms heterocyclic, heterocyclyl, heteroaryl and heteroarylene.
Non-limiting examples of such heteroatom ring systems are recited
in the Summary of the Invention, above.
[0142] As used herein, the term "heterocyclic" or the term
"heterocyclyl" refers to a three to twelve-membered heterocyclic
ring having one or more degrees of unsaturation containing one or
more heteroatomic substitutions selected from S, SO, SO.sub.2, O,
or N, optionally substituted with substituents selected from the
group which includes lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Such a ring may be optionally fused to one or more of another
"heterocyclic" ring(s) or cycloalkyl ring(s). Examples of
"heterocyclic" include, but are not limited to, tetrahydrofuran,
pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine,
morpholine, tetrahydrothiopyran, tetrahydrothiophene, and the
like.
[0143] As used herein, the term "heterocyclylene" refers to a three
to twelve-membered heterocyclic ring diradical having one or more
degrees of unsaturation containing one or more heteroatoms selected
from S, SO, SO.sub.2, O, or N, optionally substituted with
substituents selected from the group which includes lower alkyl,
lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, nitro, cyano,
halogen and lower perfluoroalkyl, multiple degrees of substitution
being allowed. Such a ring may be optionally fused to one or more
benzene rings or to one or more of another "heterocyclic" rings or
cycloalkyl rings. Examples of "heterocyclylene" include, but are
not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,
pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,
piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,
morpholine-2,4-diyl, and the like.
[0144] As used herein, the term "aryl" refers to a benzene ring or
to an optionally substituted benzene ring system fused to one or
more optionally substituted benzene rings to form ring systems such
as anthracene, phenanthrene and napthalene, optionally substituted
with substituents selected from the group which includes lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally
substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl,
heteroaryl and aryl, multiple degrees of substitution being
allowed. Examples of aryl include, but are not limited to, phenyl,
2-naphthyl, 1-naphthyl, biphenyl, and the like.
[0145] As used herein, the term "arylene" refers to a benzene ring
diradical or to a benzene ring system diradical fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group which includes lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally
substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl,
heteroaryl and aryl, multiple degrees of substitution being
allowed. Examples of "arylene" include, but are not limited to,
benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and
the like.
[0146] As used herein, the term "heteroaryl" refers to a five-to
seven-membered aromatic ring, or to a polycyclic heterocyclic
aromatic ring, containing one or more nitrogen, oxygen, or sulfur
heteroatoms at any position, where N-oxides and sulfur monoxides
and sulfur dioxides are permissible heteroaromatic substitutions,
optionally substituted with substituents selected from the group
which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,
lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto,
amino optionally substituted by alkyl, carboxy, tetrazolyl,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,
heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower
perfluoroalkyl, heteroaryl, or aryl, multiple degrees of
substitution being allowed. For polycyclic aromatic ring systems,
one or more of the rings may contain one or more heteroatoms.
Examples of "heteroaryl" used herein are furan, thiophene, pyrrole,
imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole,
isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine,
pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline,
benzofuran, benzothiophene, indole and indazole, and the like.
[0147] As used herein, the term "heteroarylene" refers to a five-to
seven-membered aromatic ring diradical, or to a polycyclic
heterocyclic aromatic ring diradical, containing one or more
nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur
monoxides and sulfur dioxides are permissible heteroaromatic
substitutions, optionally substituted with substituents selected
from the group consisting of: lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl,
multiple degrees of substitution being allowed. For polycyclic
aromatic ring system diradicals, one or more of the rings may
contain one or more heteroatoms. Examples of "heteroarylene" used
herein are furan-2,5-diyl, thiophene-2,4-diyl,
1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl- ,
1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl,
pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl,
quinoline-2,3-diyl, and the like.
[0148] As used herein, the term "alkoxy" refers to the group
R.sub.aO--, where R.sub.a is aliphatic.
[0149] As used herein, the term "alkylsuffanyl" refers to the group
R.sub.aS--, where R.sub.a is aliphatic.
[0150] As used herein, the term "alkylsulfenyl" refers to the group
R.sub.aS(O)--, where R.sub.a is aliphatic.
[0151] As used herein, the term "alkylsulfonyl" refers to the group
RaSO.sub.2--, where R.sub.a is aliphatic.
[0152] As used herein, the term "acyl" refers to the group
R.sub.aC(O)--, where R.sub.a is aliphatic, cycloaliphatic, or
heterocyclyl.
[0153] As used herein, the term "aroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is aryl.
[0154] As used herein, the term "heteroaroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is heteroaryl.
[0155] As used herein, the term "alkoxycarbonyl" refers to the
group R.sub.aOC(O)--, where R.sub.a is aliphatic.
[0156] As used herein, the term "acyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is aliphatic, cycloaliphatic, or
heterocyclyl.
[0157] As used herein, the term "aroyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is aryl.
[0158] As used herein, the term "heteroaroyloxy" refers to the
group R.sub.aC(O)O--, where R.sub.a is heteroaryl.
[0159] As used herein, the term "optionally" is inclusive of
circumstances in which described condition is present and
circumstances in which the described condition is not present, for
example, where the term is used with reference to a chemical
substituent, it indicates the inclusion of embodiments in which the
specified substituent is present as well as embodiments in which
the specified substituent is not present.
[0160] As used herein, the term "substituted" indicates the
presence of the named substituent or substituents, and includes
multiple degrees of substitution.
[0161] As used herein, the terms "contain" or "containing" with
reference to alkyl, alkenyl, alkynyl or cycloalkyl substituents
indicates in-line substitution(s) with one or more substituents at
any position along the alkyl, alkenyl, alkynyl or cycloalkyl
substituents, such as one or more of any of O, S, SO, SO.sub.2, N,
or N-alkyl, including, for example, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--SO.sub.2--CH.sub.2--, --CH.sub.2--NH--CH.sub.3 and so
forth.
[0162] As used herein, the term "solvate" is a complex of variable
stoichiometry formed by a solute (in this invention, a compound of
formula (I)) and a solvent. Such solvents for the purpose of the
invention may not interfere with the biological activity of the
solute. Solvents may be, by way of example, water, ethanol, or
acetic acid.
[0163] The compounds of the present invention have the ability to
crystallize in more than one form, a characteristic that is known
as polymorphism, and such polymorphic forms ("polymorphs") are
within the scope of the present invention. Polymorphism generally
can occur as a response to changes in temperature or pressure or
both and can also result from variations in the crystallization
process. Polymorphs can be distinguished by various physical
characteristics known in the art such as x-ray diffraction
patterns, solubility, and melting point.
[0164] As used herein, the term "physiologically functional
derivative" refers to any pharmaceutically acceptable derivative of
a compound of the present invention, for example, an ester or an
amide, which upon administration to a mammal is capable of
providing (directly or indirectly) a compound of the present
invention or an active metabolite thereof. Such derivatives are
clear to those skilled in the art, without undue experimentation,
and with reference to the teaching of Burger's Medicinal Chemistry
And Drug Discovery, 5.sup.th Edition, Vol 1: Principles and
Practice, which is incorporated herein by reference to the extent
that it teaches physiologically functional derivatives. Including
within the scope of the term are the terms "biohydrolyzable
carbonate", "biohydrolyzable ureide", "biohydrolyzable carbamate",
"biohydrolyzable ester", and "biohydrolyzable amide".
[0165] As used herein, the terms "biohydrolyzable carbonate",
"biohydrolyzable ureide" and "biohydrolyzable carbamate" include
carbonates, ureides, and carbamates, respectively, of a compound of
the general formula (I) which carbonates, ureides, and carbamates,
do not completely diminish the biological activity of the parent
substance. Such carbonates, ureides, and carbamates may confer on
the parent compound of the general formula (I) advantageous
properties in vivo, such as improved duration of action, onset of
action, and the like. Also included are compounds which are
relatively biologically inactive but which are converted in vivo by
the subject to the biologically active principle. An advantage of
such biohydrolyzable forms is that, for example, they facilitate
improved oral administration because the carbonates, ureides, and
carbamates are more readily absorbed from the gut and are then
transformed to a compound of formula (I) in plasma. Many examples
of such biohydrolyzable compounds are known in the art and include,
by way of example, lower alkyl carbamates.
[0166] As used herein, the term "biohydrolyzable ester" is an ester
of a compound of general formula, which does not completely
diminish the biological activity of the parent substance. Such
esters may confer on the parent compound of the general formula (I)
advantageous properties in vivo, such as improved duration of
action, onset of action, and the like. Also included are esters
which are relatively biologically inactive but which are converted
in vivo by the subject to the biologically active principle. An
advantage of such biohydrolyzable forms is that, for example, they
facilitate improved oral administration because they are more
readily absorbed from the gut and are then transformed to a
compound of formula (I) in plasma. Many examples of such
biohydrolyzable esters are known in the art and include, by way of
example, lower alkyl esters, lower acyloxy-alkyl esters, lower
alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino
alkyl esters and choline esters.
[0167] As used herein, the term "biohydrolyzable amide" is an amide
of a compound of general formula, which does not completely
diminish the biological activity of the parent substance. Such
amides may confer on the parent compound of the general formula (I)
advantageous properties in vivo, such as improved duration of
action, onset of action, and the like. Also included are amides
which are relatively biologically inactive but which are converted
in vivo by the subject to the biologically active principle. An
advantage of such biohydrolyzable forms is that, for example, they
facilitate improved oral administration because they are more
readily absorbed from the gut and are then transformed to a
compound of formula (I) in plasma. Many examples of such
biohydrolyzable are known in the art and include, by way of
example, lower alkyl amides, .alpha.-amino acid amides, alkoxyacyl
amides and alkylaminoalkylcarbonyl amides.
[0168] As used herein, the term "prodrug" includes compounds, which
are hydrolyzable in vivo to yield an active compound of formula
(I), including for example, biohydrolyzable amides, biohydrolyzable
esters and biohydrolyzable carbamates. The term "prodrug" also
includes compounds in which the biohydrolyzable functionality is
encompassed in the compound of formula (I): for example, a lactam
formed by a carboxylic group in R.sub.1 and an amine in R.sub.2,
and compounds which may be oxidized or reduced biologically at a
given functional group to yield drug substances of formula (I).
Examples of such functional groups are, but are not limited to,
1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine,
1,4-cyclohexadiene, tert-butyl, and the like.
[0169] As used herein, the term "affinity reagent" means a group
attached to the compound of formula (I) which does not affect its
in vitro biological activity, allowing the compound to bind to a
target, yet such a group binds strongly to a third component
allowing a) characterization of the target as to localization
within a cell or other organism component, perhaps by visualization
by fluorescence or radiography, or b) facile separation of the
target from an unknown mixture of targets, whether proteinaceous or
not proteinaceous. An Example of an affinity reagent according to
b) would be biotin either directly attached to (I) or linked with a
spacer of one to 50 atoms selected from the group consisting of: C,
H, O, N, S, or P in any combination. An Example of an affinity
reagent according to a) above would be fluorescein, either directly
attached to (I) or linked with a spacer of one to 50 atoms selected
from the group consisting of: C, H, O, N, S, or P in any
combination.
[0170] The term "effective amount" means that amount of a drug or
pharmaceutical agent that will elicit the biological or medical
response of a issue, system, animal or human that is being sought
by a researcher or clinician. The term "therapeutically effective
amount" means any amount which, as compared to a corresponding
subject who has not received such amount, results in improved
treatment, healing, prevention, or amelioration of a disease or
disorder, or a decrease in the rate of advancement of a disease or
disorder, and also includes amounts effective to enhance normal
physiological function.
[0171] Whenever the terms "aliphatic" or "aryl" or either of their
prefixes appear in a name of a substituent (e.g. arylalkoxyaryloxy)
they include those characteristics given above for "aliphatic" and
"aryl". Aliphatic or cycloalkyl substituents are term equivalents
to those having one or more degrees of unsaturation. Designated
numbers of carbon atoms (e.g. C.sub.1-10) refer independently to
the number of carbon atoms in an aliphatic or cyclic aliphatic
moiety or to the aliphatic portion of a larger substituent in which
the term "aliphatic" appears as a prefix (e.g. "al-").
[0172] As used herein, the term "disubstituted amine" or
"disubstituted amino-" includes either one or two substitutions on
that particular nitrogen atom.
[0173] As used herein, the term "oxo" refers to the substituent
.dbd.O.
[0174] As used herein, the term "halogen" or "halo" shall include
iodine, bromine, chlorine and fluorine.
[0175] As used herein, the term "mercapto" refers to the
substituent --SH.
[0176] As used herein, the term "carboxy" refers to the substituent
--COOH.
[0177] As used herein, the term "cyano" refers to the substituent
--CN.
[0178] As used herein, the term "aminosulfonyl" refer to the
substituent --SO.sub.2NH.sub.2.
[0179] As used herein, the term "carbamoyl" refers to the
substituent --C(O)NH.sub.2.
[0180] As used herein, the term "sulfanyl" refers to the
substituent --S--.
[0181] As used herein, the term "sulfenyl" refers to the
substituent --S(O)--.
[0182] As used herein, the term "sulfonyl" refers to the
substituent --S(O).sub.2--.
Pharmaceutical Formulation and Doses
[0183] While it is possible that, for use in therapy,
therapeutically effective amounts of a compound of formula I, as
well as salts, solvates and physiological functional derivatives
thereof, may be administered as the raw chemical, it is possible to
present the active ingredient as a pharmaceutical composition.
Accordingly, the invention further provides pharmaceutical
compositions which include therapeutically effective amounts of
compounds of the formula I and salts, solvates and physiological
functional derivatives thereof, and one or more pharmaceutically
acceptable carriers, diluents, or excipients. The compounds of the
formula I and salts, solvates and physiological functional
derivatives thereof, are as described above. The carrier(s),
diluent(s) or excipient(s) must be acceptable in the sense of being
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof. In accordance with another
aspect of the invention there is also provided a process for the
preparation of a pharmaceutical formulation including admixing a
compound of the formula I, or salts, solvates and physiological
functional derivatives thereof, with one or more pharmaceutically
acceptable carriers, diluents or excipients.
[0184] The compounds of the present invention can be administered
in such oral (including buccal and sublingual) dosage forms as
tablets, capsules (each including timed release and sustained
release formulations), pills, powders, granules, elixirs,
tinctures, suspensions, syrups and emulsions. Likewise, they may
also be administered in nasal, ophthalmic, otic, rectal, topical,
intravenous (both bolus and infusion), intraperitoneal,
intraarticular, subcutaneous or intramuscular inhalation or
insufflation form, all using forms well known to those of ordinary
skill in the pharmaceutical arts.
[0185] The dosage regimen utilizing the compounds of the present
invention is selected in accordance with a variety of factors
including type, species, age, weight, sex and medical condition of
the patient; the severity of the condition to be treated; the route
of administration; the renal and hepatic function of the patient;
and the particular compound or salt thereof employed. An ordinarily
skilled physician or veterinarian can readily determine and
prescribe the effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0186] Oral dosages of the present invention, when used for the
indicated effects, will range between about 0.1 to about 100 mg/kg
of body weight per day, and particularly about 1 to 10 mg/kg of
body weight per day. Oral dosage units will generally be
administered in the range of from 1 to about 250 mg and more
preferably from about 25 to about 250 mg. The daily dosage for a 70
kg mammal will generally be in the range of about 70 mg to 7 grams
of a compound of formula I or II.
[0187] The dosage to be administered is based on the usual
conditions such as the physical condition of the patient, age, body
weight, past medical history, route of administrations, severity of
the conditions and the like. Oral administration is generally
preferred for administration to a human. In some cases, a
relatively lower dose is sufficient and, in some cases, a
relatively higher dose or increased number of doses may be
necessary. Topical application similarly may be once or more than
once per day depending upon the usual medical considerations.
Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
The compounds of the invention can be prepared in a range of
concentrations for topical use of about 0.5 to about 5 mg/ml of
suitable solvent. A preferred volume for application to the scalp
is about 2 ml, resulting in an effective dosage delivered to the
patient of about 1 to about 10 mg.
[0188] In the methods of the present invention, the compounds
herein described in detail can form the active ingredient and are
typically administered in admixture with suitable pharmaceutical
diluents, excipients or carriers (collectively referred to herein
as "carrier" materials) suitably selected with respect to the
intended form of administration, that is, oral tablets, capsules,
elixirs, syrups and the like, and consistent with conventional
pharmaceutical practices.
[0189] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Powders are prepared by
comminuting the compound to a suitable fine size and mixing with a
similarly comminuted pharmaceutical carrier such as an edible
carbohydrate, as, for example, starch or mannitol. Flavoring,
preservative, dispersing and coloring agent can also be
present.
[0190] Capsules are made by preparing a powder mixture as described
above, and filling formed gelatin sheaths. Glidants and lubricants
such as colloidal silica, talc, magnesium stearate, calcium
stearate or solid polyethylene glycol can be added to the powder
mixture before the filling operation. A disintegrating or
solubilizing agent such as agar-agar, calcium carbonate or sodium
carbonate can also be added to improve the availability of the
medicament when the capsule is ingested.
[0191] Moreover, when desired or necessary, suitable binders,
lubricants, disintegrating agents and coloring agents can also be
incorporated into the mixture. Suitable binders include starch,
gelatin, natural sugars such as glucose or beta-lactose, corn
sweeteners, natural and synthetic gums such as acacia, tragacanth
or sodium alginate, carboxymethylcellulose, polyethylene glycol,
waxes and the like. Lubricants used in these dosage forms include
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like. Tablets are
formulated, for example, by preparing a powder mixture, granulating
or slugging, adding a lubricant and disintegrant and pressing into
tablets. A powder mixture is prepared by mixing the compound,
suitably comminuted, with a diluent or base as described above, and
optionally, with a binder such as carboxymethylcellulose, an
aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant
such as paraffin, a resorption accelerator such as a quaternary
salt and/or an absorption agent such as bentonite, kaolin or
dicalcium phosphate. The powder mixture can be granulated by
wetting with a binder such as syrup, starch paste, acadia mucilage
or solutions of cellulosic or polymeric materials and forcing
through a screen. As an alternative to granulating, the powder
mixture can be run through the tablet machine and the result is
imperfectly formed slugs broken into granules. The granules can be
lubricated to prevent sticking to the tablet forming dies by means
of the addition of stearic acid, a stearate salt, talc or mineral
oil. The lubricated mixture is then compressed into tablets. The
compounds of the present invention can also be combined with free
flowing inert carrier and compressed into tablets directly without
going through the granulating or slugging steps. A clear or opaque
protective coating consisting of a sealing coat of shellac, a
coating of sugar or polymeric material and a polish coating of wax
can be provided. Dyestuffs can be added to these coatings to
distinguish different unit dosages.
[0192] Oral fluids such as solution, syrups and elixirs can be
prepared in dosage unit form so that a given quantity contains a
predetermined amount of the compound. Syrups can be prepared by
dissolving the compound in a suitably flavored aqueous solution,
while elixirs are prepared through the use of a non-toxic alcoholic
vehicle. Suspensions can be formulated by dispersing the compound
in a non-toxic vehicle. Solubilizers and emulsifiers such as
ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol
ethers, preservatives, flavor additive such as peppermint oil or
saccharin, and the like can also be added.
[0193] Where appropriate, dosage unit formulations for oral
administration can be microencapsulated. The formulation can also
be prepared to prolong or sustain the release as for Example by
coating or embedding particulate material in polymers, wax or the
like.
[0194] The compounds of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
[0195] Compounds of the present invention may also be delivered by
the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol- , or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polepsilon caprolactone, polyhydroxy
butyric acid, polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers
of hydrogels.
[0196] The present invention includes pharmaceutical compositions
containing about 0.01 to about 99.5%, more particularly, about 0.5
to about 90% of a compound of the formula (II) in combination with
a pharmaceutically acceptable carrier.
[0197] Parenteral administration can be effected by utilizing
liquid dosage unit forms such as sterile solutions and suspensions
intended for subcutaneous, intramuscular or intravenous injection.
These are prepared by suspending or dissolving a measured amount of
the compound in a non-toxic liquid vehicle suitable for injection
such as aqueous oleaginous medium and sterilizing the suspension or
solution.
[0198] Alternatively, a measured amount of the compound is placed
in a vial and the vial and its contents are sterilized and sealed.
An accompanying vial or vehicle can be provided for mixing prior to
administration. Non-toxic salts and salt solutions can be added to
render the injection isotonic. Stabilizers, preservations and
emulsifiers can also be added.
[0199] Rectal administration can be effected utilizing
suppositories in which the compound is admixed with low-melting
water-soluble or insoluble solids such as polyethylene glycol,
cocoa butter, higher ester as for Example flavored aqueous
solution, while elixirs are prepared through myristyl palmitate or
mixtures thereof.
[0200] Topical formulations of the present invention may be
presented as, for instance, ointments, creams or lotions, eye
ointments and eye or ear drops, impregnated dressings and aerosols,
and may contain appropriate conventional additives such as
preservatives, solvents to assist drug penetration and emollients
in ointments and creams. The formulations may also contain
compatible conventional carriers, such as cream or ointment bases
and ethanol or oleyl alcohol for lotions. Such carriers may be
present as from about 1% up to about 98% of the formulation. More
usually they will form up to about 80% of the formulation.
[0201] For administration by inhalation the compounds according to
the invention are conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebulizer, with the
use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane,
tetrafluoroethane, heptafluoropropane, carbon dioxide or other
suitable gas. In the case of a pressurized aerosol the dosage unit
may be determined by providing a valve to deliver a metered amount.
Capsules and cartridges of e.g. gelatin for use in an inhaler or
insufflator may be formulated containing a powder mix of a compound
of the invention and a suitable powder base such as lactose or
starch.
[0202] The preferred pharmaceutical compositions are those in a
form suitable for oral administration, such as tablets and liquids
and the like and topical formulations.
[0203] The compounds of formula (I) can be prepared readily
according to the following reaction General Synthesis Schemes (in
which all variables are as defined before) and Examples or
modifications thereof using readily available starting materials,
reagents and conventional synthesis procedures. In these reactions,
it is also possible to make use of variants, which are themselves
known to those of ordinary skill in this art, but are not mentioned
in greater detail.
[0204] General Synthesis Schemes 1415161718
[0205] The most preferred compounds of the invention are any or all
of those specifically set forth in these examples. These compounds
are not, however, to be construed as forming the only genus that is
considered as the invention, and any combination of the compounds
or their moieties may itself form a genus. The following examples
further illustrate details for the preparation of the compounds of
the present invention. Those skilled in the art will readily
understand that known variations of the conditions and processes of
the following preparative procedures can be used to prepare these
compounds. All temperatures are degrees Celsius unless noted
otherwise.
[0206] Abbreviations used in the Examples are as follows:
[0207] g=grams
[0208] mg=milligrams
[0209] L=liters
[0210] mL=milliliters
[0211] M=molar
[0212] N=normal
[0213] mM=millimolar
[0214] i.v.=intravenous
[0215] p.o.=per oral
[0216] s.c.=subcutaneous
[0217] Hz=hertz
[0218] mol=moles
[0219] mmol=millimoles
[0220] bar=millibar
[0221] psi=pounds per square inch
[0222] rt=room temperature
[0223] min=minutes
[0224] h=hours
[0225] mp=melting point
[0226] LC=thin layer chromatography
[0227] R.sub.f=relative TLC mobility
[0228] MS=mass spectrometry
[0229] NMR=nuclear magnetic resonance spectroscopy
[0230] PCI=atmospheric pressure chemical ionization
[0231] ESI=electrospray ionization
[0232] m/z=mass to charge ratio
[0233] t.sub.r=retention time
[0234] Pd/C=palladium on activated carbon
[0235] ether=diethyl ether
[0236] MeOH=methanol
[0237] EtOAc=ethyl acetate
[0238] EA=triethylamine
[0239] DIEA=diisopropylethylamine
[0240] THF=tetrahydrofuran
[0241] DMF=N,N-dimethylformamide
[0242] DMSO=dimethylsulfoxide
[0243] DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone
[0244] LAH=lithium aluminum hydride
[0245] TFA=trifluoroacetic acid
[0246] LDA=lithium diisopropylamide
[0247] THP=tetrahydropyranyl
[0248] NMM=N-methylmorpholine, 4-methylmorpholine
[0249] HMPA=hexamethylphosphoric triamide
[0250] DMPU=1,3-dimethypropylene urea
[0251] d=days
[0252] ppm=parts per million
[0253] kD=kiloDalton
[0254] LPS=lipopolysaccharide
[0255] PMA=phorbol myristate acetate
[0256] SPA=scintillation proximity assay
[0257] EDTA=ethylenediamine tetraacetic acid
[0258] FBS=fetal bovine serum
[0259] PBS=phosphate buffered saline solution
[0260] BrdU=bromodeoxyuridine
[0261] BSA=bovine serum albumin
[0262] FCS=fetal calf serum
[0263] DMEM=Dulbeccois modified Eagleis medium
[0264] pfu=plaque forming units
[0265] MOI=multiplicity of infection
[0266] Reagents are commercially available or are prepared
according to procedures in the literature. The physical data given
for the compounds exemplified is consistent with the assigned
structure of those compounds. .sup.1H NMR spectra were obtained on
VARIAN Unity Plus NMR spectrophotometers at 300 or 400 Mhz. Mass
spectra were obtained on Micromass Platform II mass spectrometers
from Micromass Ltd. Altrincham, UK, using either Atmospheric
Chemical Ionization (APCI) or Electrospray Ionization (ESI).
Analytical thin layer chromatography (TLC) was used to verify the
purity of some intermediates which could not be isolated or which
were too unstable for full characterisation, and to follow the
progress of reactions. Unless otherwise stated, this was done using
silica gel (Merck Silica Gel 60 F254). Unless otherwise stated,
column chromatography for the purification of some compounds, used
Merck Silica gel 60 (230-400 mesh), and the stated solvent system
under pressure.
EXAMPLE 1
Preparation of
5-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}-
-1,3-dihydro-2H-benzimidazol-2-one
[0267] 19
[0268] A solution of 161 mg (1.00 mMol) of
3-(hydroxymethylene)-1,3-dihydr- o-2H-indol-2-one, 149 mg (1.00
mMol) of 5-aminobenzimidazolone, and 5 ml of ethanol was heated at
550C for 1.5 hr. The resulting solid was isolated by filtration and
recrystallized from DMSO/methanol to yield 150 mg (51%) of a yellow
solid, .sup.1H NMR (DMSO-d.sub.6): .delta. 6.80 (d, J=7.7 Hz, 1H),
6.85-6.98 (m, 4H), 7.00 (s, 1H), 7.54 (d, J=7.4 Hz, 1H), 8.50 (d,
J=12.7 Hz, 1H), 10.39 (s, 1H), 10.56 (s, 1H), 10.72 (d, J=12.7 Hz,
1H), 10.74 (s, 1H); APCI-MS m/z 291 (M-H).sup.-.
EXAMPLE 2
Preparation of
(3Z)-3-{[4-(1H-1,2,4-triazol-1-yl)anilino]-methylene}-1,3-d-
ihydro-2H-indol-2-one
[0269] 20
[0270] Prepared in an analogous manner to Example 1 using 1
equivalent of 4-(1H-1,2,4-triazol-1-yl)aniline in place of
5-aminobenzimidazolone. .sup.1H NMR (DMSO-d.sub.6): .delta. 10.80
(m, 1H); 10.52 (s, 1H); 9.26 (s, 1H); 8.62 (m, 1H); 8.22 (s, 1H);
7.86 (m, 2H); 7.60 (m, 3H); 7.02 (m, 1H); 6.94 (m, 1H); 6.85 (m,
1H). APCI MS (+ve) 304. APCI MS (-ve) 302.
EXAMPLE 3
Preparation of
3-ethyl-3-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)me-
thyl]amino}phenyl)-2,6-piperidinedione
[0271] 21
[0272] Prepared in an analogous manner to Example 1 using one
equivalent of 3-ethyl-3-(4-(aminophenyl)-2,6-piperidinedione in
place of 5-aminobenzimidazolone. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 10.91 (s,1H), 10.73 (d, 1H, J=12.5 Hz), 10.52
(s, 1H), 8.58 (d,1H, J=12.5 Hz), 7.59 (d,1H, J=7.4 Hz), 7.43 (d,2H,
J=8.6 Hz), 7.31 (d,2H,J=8.6 Hz), 7.1-6.85 (m,3H), 2.48-2.4 (m,2H),
2.2-2.1 (m,2H), 2.0-1.8 (m,2H), 0.795 (t,2H, J=7.3 Hz), MS
(AP+,m/z) 376 (M+H).
EXAMPLE 4
Preparation of
(8Z)-8-{[3-(5-amino-1,3,4-oxadiazol-2-yl)anilino]methylene}-
-6,8-dihydro[1,2,3]triazolo[4,5-e]indol-7(3H)-one
[0273] 22
[0274] Prepared in an analogous manner to Example 1 using 1
equivalent of
8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazo-
lo[4,5-e]indol-7-one and 3-(2-(5-amino)-oxadiazoyl)-aniline. APCI
MS (-ve) 359.
Preparation of
8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydr-
o[1,2,3]triazolo[4,5-e]indol-7-one
[0275] 5-Aminobenzotriazole (Lancaster Chemical, 10.14 g, 75 mmol)
was dissolved in 200 ml of anhydrous DMF under nitrogen and 3.00 g
(75 mmol) of sodium hydride (60% oil dispersion) was added in one
portion. Hydrogen evolution and mild exothermicity was observed.
The reaction was stirred at room temperature for 20 minutes and
then cooled in an ice bath. A solution of di-tert-butyldicarbonate
(16.4 g, 75 mmol) in 100 ml of anhydrous DMF was added via siphon.
Stirring was continued for 2 hrs at ice bath temperature. The
solvent was removed by rotary evaporation under high vacuum at
50.degree. C. to give 32 g of viscous liquid. The crude product was
dissolved in a minimum volume of chloroform and filtered through a
short column of 600 ml silica gel, eluting with 10% methanol in
chloroform. The collected product was evaporated to dryness,
redissolved in 400 ml of diethyl ether, and washed three times with
water and once with saturated sodium chloride solution. The ether
solution was dried over magnesium sulfate and the solvent was
removed to give 17.7 g of a mixture of 1- and
3-tert-butyloxycarbonyl-5-aminobenzotriazole contaminated with
approx. 1 g of residual mineral oil. This material was then
cyclized to the corresponding 3-methylthio-oxindole by the method
of Procedure (Gassman). The resultant product (9.6 g of gray solid)
was shown to be partially deprotected by NMR. This material was
dissolved 200 ml of THF and treated with 50 g of zinc dust
(activated by stirring for 10 min in 150 ml of 1 M HCl, followed by
washing with three 100 ml portions of water). Saturated aqueous
ammonium chloride (150 ml) was added and the reaction was stirred
overnight at room temperature. The solution was filtered through
Celite, washing with THF and ethyl acetate to give 4.0 g of gray
solid which was primarily 1-tert-butyloxycarbonyl-1-
,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one. This material (2.04 g,
7.4 mmol) was suspended in 10 ml of anhydrous DMF under nitrogen,
cooled in an ice bath, and treated with 4.0 ml (3.4 g, 2.2 equiv)
of dimethylformamide di-tert-butyl acetal. The reaction was allowed
to warm to room temperature and was stirred overnight. The solvent
was removed by rotary evaporation under high vacuum. The residue
was filtered through a short column of 100 ml silica gel with 30%
ethanol in dichloromethane. Evaporation of solvent provided 1.74 g
of yellow solid which was primarily
8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,-
2,3]triazolo[4,5-e]indol-7-one containing some product lacking the
tert-butyloxycarbonyl protecting group.
EXAMPLE 5
Preparation of
2-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]ami-
no}phenyl)acetamide
[0276] 23
[0277] A mixture of 0.214 g (1.33 mmol) of
(3Z)-3-(hydroxymethylene)-1,3-d- ihydro-2H-indol-2-one.sup.1,2 and
0.200 g (1.33 mmol) of 4-aminophenylacetamide.sup.3 in 5 ml of ETOH
was heated to 80.degree. C. for 1 hr. After cooling to ambient
temperature, the solid was collected by vacuum filtration and dried
in a vacuum oven at 60.degree. C. to afford
2-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phen-
yl)acetamide (0.15 g, 37%). mp>250.degree. C.; .sup.1H NMR
(DMSO-d.sub.6): .delta. 3.36 (s, 2H), 6.81-7.08 (m, 4H), 7.27 (d,
J=8.6 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.47 (s, 1H), 7.60 (d, J=7.3
Hz, 1H), 8.59 (d, J=12.5 Hz, 1H), 10.51 (s, 1H), 10.73 (d, J=12.5
Hz, 1H); APCI-MS: m/z 292 (m-H).sup.-. Anal. Calcd for
C.sub.17H.sub.15N.sub.3O.su- b.3: C, 69.61; H, 5.15; N, 14.33;
Found: C, 69.54; H, 5.20; N, 14.37.
[0278] (1) Wolfbeis, Otto S.; Junek, Hans. Diacylenamines and
-enoles, III. Formylation of CH2-acidic compounds via the
anilinomethylene derivatives. Z. Naturforsch., B: Anorg. Chem.,
Org. Chem. (1979), 34B(2), 283-9. (2) Winn, Martin; Kyncl, John J.
Aminomethylene oxindoles. U.S. (1979), 6 pp (3) Clark, C. Randall;
Davenport, Timothy W. Anticonvulsant activity of some
4-aminophenylacetamides. J. Pharm. Sci. (1987), 76(1), 18-20.
EXAMPLE 6
Preparation of
(3Z)-3-{[4-(1H-1,2,4-triazol-3-yl)anilino]methylene}-1,3-di-
hydro-2H-indol-2-one
[0279] 24
[0280] Prepared in an analogous manner to Example 1 using one
equivalent of 4-(1H-1,2,4-triazol-3-yl)aniline in place of
5-aminobenzimidazolone. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
14.32 (s, 1H, exchangeable); 14.05 (s, 1H, exchangeable); 10.82 (m,
1H); 10.54 (m, 1H); 8.64 (m, 1H); 8.60 (s, 1H, exchangeable); 8.00
(m, 2H); 7.63 (m, 1H); 7.47 (m, 1H); 7.03 (m, 1H); 6.94 (m, 1H);
6.85 (m, 1H). APCI MS (-ve) 302.
Biological Data
[0281] The compounds of the present invention have valuable
pharmacologic properties. Different compounds from this class are
particularly effective at inhibiting the trkA kinase enzyme at
concentrations that range from 0.0001 to 1 .mu.M and additionally
show specificity relative to other kinases. Substrate
phosphorylation assays were carried out as follows:
[0282] Screening format: Tyrosine kinase activity is being measured
using a synthetic peptide substrate. The enzyme is a GST-fusion of
the intracellular domain expressed in SF9 cells. The enzyme is
expressed and purified by Regeneron. The enzyme is preincubated
with cold ATP and Mg to allow autophosphorylation prior to running
the screen. This increases the initial rate of catalysis
approximately 3 fold. The assay is performed in 96 well microtitre
plates, and reaction products are detected following filtration
through millipore p81 phosphocellulose plates.
[0283] Assay Conditions
3 Peptide Src peptide, NH2-RRRAAAEEIYGEI-NH2 substrate Peptide Km
60 uM ATP Km 30 uM Kcat/Km 1 .times. 10.sup.4 (peptide): Assay
20-40 nM TrkA, 30 uM ATP, 50 uM Src peptide, 50 mM conditions MOPS
pH 7.5, 10 mM MgCl.sup.2, 0.6 uCi .sup.33P.quadrature.ATP
Incubation RT for 120' Termination Add 100 ul of 0.5% Phosphoric
acid. Spot 100 ul onto millipore p81 96 well filter plate. Filter,
wash 3x with 200 ul 0.5% phosphoric acid. Add 50 ul scintillation
cocktail. Count in Packard Topcount
[0284] Representative results are shown in Table 1 for the TrkA
tyrosine kinase inhibition
4 TABLE 1 Substrate Phosphorylation Example TrkA 1 +++ 2 +++ 3 +++
4 +++ 5 ++ 6 ++
[0285]
5 IC.sub.50 values Symbol <0.010 uM +++ 0.010-0.10 uM ++
0.10-1.0 uM + >1.0 uM - Not determined ND
Utility of Invention
[0286] Inhibitors of Trk tyrosine kinase have utility as agents in
the treatment of a wide variety of disorders. These include, for
example, cancers and chronic pain.
[0287] While the invention has been described and illustrated with
reference to certain preferred embodiments thereof, those skilled
in the art will appreciate that various changes, modifications and
substitutions can be made therein without departing from the spirit
and scope of the invention. For example, effective dosages other
than the preferred dosages as set forth herein above may be
applicable as a consequence of variations in the responsiveness of
the mammal being treated for cancer conditions, or for other
indications for the compounds of the invention as indicated above.
Likewise, the specific pharmacologic responses observed may vary
according to and depending upon the particular active compound
selected or whether there are present certain pharmaceutical
carriers, as well as the type of formulation and mode of
administration employed, and such expected variations or
differences in the results are contemplated in accordance with the
objects and practices of the present invention. It is intended,
therefore, that the invention be limited only by the scope of the
claims, which follow, and that such claims be interpreted as
broadly as is reasonable.
[0288] The application of which this description and claim(s) forms
part may be used as a basis for priority in respect of any
subsequent application. The claims of such subsequent application
may be directed to any feature or combination of features described
herein. They may take the form of product, formulation, process or
use claims and may include, by way of example and without
limitation, one or more of the following claim(s):
* * * * *