Jan 24, 2003 - RELATED U.S. APPLICATION DATA ... sis pathWay or the salvage pathWay. ... rather than salvage pathWay to
US 20030195202A1
(19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0195202 A1 (43) Pub. Date:
Armistead et al. (54) INHIBITORS OF IMPDH ENZYME
Oct. 16, 2003
noW Pat. No. 6,054,472, Which is a continuation-in
part of application No. 08/801,780, ?led on Feb. 14,
(75) Inventors: David M. Armistead, Sudbury, MA (US); Michael C. Badia, Bedford, MA
1997, noW Pat. No. 6,344,465, Which is a continua
tion-in-part of application No. 08/636,361, ?led on Apr. 23, 1996, noW Pat. No. 5,807,876.
(US); Guy W. Bemis, Arlington, MA (US); Randy S. Bethiel, Cambridge,
Publication Classi?cation
MA (US); Catharine A. Frank,
Langhorne, PA (US); Perry M. Novak, Milford, MA (US); Steven M. Ronkin, WatertoWn, MA (US); J e?'rey O. Saunders, Acton, MA (US)
(51)
A61K 31/445; A61K 31/495; A61K 31/426; A61K 31/421 (52)
Correspondence Address:
(73) Assignee: Vertex Pharmaceuticals Incorporated
us. Cl. ........... .. 514/227.5; 514/237.8; 514/255.01;
514/317; 514/370; 514/399; 514/374; 514/607; 514/580;
FISH & NEAVE 1251 AVENUE OF THE AMERICAS 50TH FLOOR
NEW YORK, NY 10020-1105 (US)
Int. C1.7 ..................... .. A61K 31/54; A61K 31/535;
514/595
(57)
ABSTRACT
The present invention relates to a novel class of compounds
(21) Appl. No.:
10/351,731
Which are IMPDH inhibitors. This invention also relates to
(22) Filed:
Jan. 24, 2003
The compounds and pharmaceutical compositions of this
Related US. Application Data
enZyme activity and consequently, may be advantageously
(60) Division of application No. 09/556,253, ?led on Apr.
used as therapeutic agents for IMPDH mediated processes. This invention also relates to methods for inhibiting the
pharmaceutical compositions comprising these compounds. invention are particularly Well suited for inhibiting IMPDH
24, 2000, noW Pat. No. 6,541,496, Which is a division
of application No. 08/832,165, ?led on Apr. 2, 1997,
activity of IMPDH using the compounds of this invention and related compounds.
Oct. 16, 2003
US 2003/0195202 A1
INHIBITORS OF IMPDH ENZYME RELATED U.S. APPLICATION DATA
[0001] This application is a divisional of application Ser. No. 09/556,253, ?led Apr. 24, 2000, Which is a divisional of
application Ser. No. 08/832,165, ?led Apr. 2, 1997 (now US. Pat. No. 6,054,472), Which is a Continuation-in-Part of
application Ser. No. 08/801,780, ?led Feb. 14, 1997 (now US. Pat. No. 6,344,465), Which is a Continuation-in-Part of
application Ser. No. 08/636,361, ?led Apr. 23, 1996 (now
[0007] The de novo synthesis of guanosine nucleotides, and thus the activity of IMPDH, is particularly important in B and T-lymphocytes. These cells depend on the de novo,
rather than salvage pathWay to generate suf?cient levels of nucleotides necessary to initiate a proliferative response to
mitogen or antigen [A. C. Allison et. al., Lancet II, 1179, (1975) and A. C. Allison et. al., Ciba Found. Symp., 48, 207,(1977)]. Thus, IMPDH is an attractive target for selec
tively inhibiting the immune system Without also inhibiting the proliferation of other cells.
[0008] Immunosuppression has been achieved by inhibit ing a variety of enZymes including for eXample, the phos
US. Pat. No. 5,807,876). TECHNICAL FIELD OF THE INVENTION
phatase calcineurin (inhibited by cyclosporin and FK-506);
[0002] The present invention relates to a novel class of compounds Which inhibit IMPDH. This invention also
biosynthesis of pyrimidines (inhibited by le?unomide and brequinar); the kinase FRAP (inhibited by rapamycin); and the heat shock protein hsp70 (inhibited by deoXyspergualin).
dihydroorotate dehydrogenase, an enZyme involved in the
relates to pharmaceutical compositions comprising these
compounds. The compounds and pharmaceutical composi tions of this invention are particularly Well suited for inhib
iting IMPDH enZyme activity and consequently, may be advantageously used as therapeutic agents for IMPDH medi
[See B. D. Kahan, Immunological Reviews, 136, pp. 29-49 (1993); R. E. Morris, The Journal of Heart and Lung
Transplantation, 12(6), pp. S275-S286 (1993)].
ated processes. This invention also relates to methods for
[0009]
inhibiting the activity of IMPDH using the compounds of
5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184 describe mycophenolic acid
this invention and related compounds.
Inhibitors of IMPDH are also knoWn. US. Pat. No.
(MPA) and some of its derivatives as potent, uncompetitive, BACKGROUND OF THE INVENTION
reversible inhibitors of human IMPDH type I (Ki=33 nM)
[0003] The synthesis of nucleotides in organisms is
and type II (Ki=9nM). MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen [A. C. Allison et. al., Ann. N. Y Acad. Sci, 696, 63,(1993).
required for the cells in those organisms to divide and replicate. Nucleotide synthesis in mammals may be achieved through one of tWo pathWays: the de novo synthe sis pathWay or the salvage pathWay. Different cell types use
[0004] Inosine-5‘-monophosphate
MPA OH
these pathWays to a different eXtent.
O
dehydrogenase
(IMPDH; EC 1.1.1.205) is an enZyme involved in the de novo synthesis of guanosine nucleotides. IMPDH catalyZes
/ O O
the NAD-dependent oxidation of inosine-5‘-monophosphate
OCH3
(IMP) to Xanthosine-‘5-monophosphate (XMP) [Jackson R. C. et. al., Nature, 256, pp. 331-333, (1975)]. [0005] IMPDH is ubiquitous in eukaryotes, bacteria and protoZoa Natsumeda & S. F. Carr,Ann. N.Y.Acad., 696, pp. 88-93 (1993)]. The prokaryotic forms share 30-40% sequence identity With the human enZyme. Regardless of species, the enZyme folloWs an ordered Bi-Bi reaction
sequence of substrate and cofactor binding and product release. First, IMP binds to IMPDH. This is folloWed by the binding of the cofactor NAD. The reduced cofactor, NADH, is then released from the product, folloWed by the product, XMP [S. F. Carr et al., J. Biol. Chem, 268, pp. 27286-90 (1993); E. W. Holmes et al., Biochim. Biophys. Acta, 364, pp. 209-217 (1974)]. This mechanism differs from that of most other knoWn NAD-dependent dehydrogenases, Which have either a random order of substrate addition or require NAD to bind before the substrate.
[0006] TWo isoforms of human IMPDH, designated type I and type II, have been identi?ed and sequenced R. Collart and E. Huberman, J. Biol. Chem, 263, pp. 15769-15772, (1988); Y. Natsumeda et. al., J. Biol. Chem, 265, pp. 5292-5295,(1990)]. Each is 514 amino acids, and they share 84% sequence identity. Both IMPDH type I and type II form active tetramers in solution, With subunit molecular Weights of 56 kDa Yamada et. al., Biochemistry, 27, pp. 2737
2745 (1988)].
OH
CH3
[0010]
Immunosuppressants, such as MPA, are useful
drugs in the treatment of transplant rejection and autoim mune diseases. [R. E. Morris, Kidney Intl., 49, Suppl. 53,S-26,(1996)]. HoWever, MPA is characteriZed by unde sirable pharmacological properties, such as gastrointestinal toxicity and poor bioavailability. [L. M. ShaW, et. al.,
Therapeutic Drug Monitoring, 17, pp. 690-699,(1995)]. [0011] Nucleoside analogs such as tiaZofurin, ribavirin and miZoribine also inhibit IMPDH [L. Hedstrom, et. al.
Biochemistry, 29, pp. 849-854 (1990)]. These compounds, Which are competitive inhibitors of IMPDH, suffer from lack of speci?city to this enZyme.
[0012] Mycophenolate mofetil, a prodrug Which quickly liberates free MPA in vivo, Was recently approved to prevent
acute renal allograft rejection folloWing kidney transplanta tion. [L. M. ShaW, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995); H. W. Sollinger, Transplantation, 60, pp. 225-232 (1995)]. Several clinical observations, hoWever, limit the therapeutic potential of this drug. [L. M. ShaW, et.
al., Therapeutic Drug Monitoring, 17, pp. 690-699,(1995)]. MPA is rapidly metaboliZed to the inactive glucuronide in
vivo. [A. C., Allison and E. M. Eugui, Immunological
Oct. 16, 2003
US 2003/0195202 A1
Reviews, 136, pp. 5-28 (1993)]. The glucuronide then under goes enterohepatic recycling causing accumulation of MPA in the gastrointestinal tract Where it cannot exert its IMPDH
inhibitory activity on the immune system. This effectively loWers the drug’s in vivo potency, While increasing its undesirable gastrointestinal side effects.
metabolic pro?le than MPA and its derivatives. Because of this difference, methods of this invention and the compounds used therein may offer advantages as therapeutics for IMPDH mediated disease. These advantages include increased overall therapeutic bene?t and reduction in del eterious side effects.
[0013] It is also knoWn that IMPDH plays a role in other metabolic events. Increased IMPDH activity has been
DETAILED DESCRIPTION OF THE INVENTION
observed in rapidly proliferating human leukemic cell lines and other tumor cell lines, indicating IMPDH as a target for anti-cancer as Well as immunosuppressive chemotherapy
[M. Nagai et. al., Cancer Res., 51, pp. 3886-3890, (1991)]. IMPDH has also been shoWn to play a role in the prolifera
tion of smooth muscle cells, indicating that inhibitors of
[0020]
In order that the invention herein described may be
more fully understood, the folloWing detailed description is set forth. In the description, the folloWing abbreviations are used:
IMPDH, such as MPA or rapamycin, may be useful in
preventing restenosis or other hyperproliferative vascular
diseases [C. R. Gregory et al., Transplantation, 59, pp. 655-61 (1995); PCT publication WO 94/12184; and PCT
Designation
Reagent or Fragment
[0014] Additionally, IMPDH has been shoWn to play a role in viral replication in some viral cell lines. [S. F. Carr, J. Biol. Chem, 268, pp. 27286-27290 (1993)]. Analogous to lymphocyte and tumor cell lines, the implication is that the de novo, rather than the salvage, pathWay is critical in the process of viral replication.
Ac Me Et Bn CDI DIEA DMAP DMF DMSO EDC
acetyl methyl ethyl benzyl carbonyldiimidazole diisopropylethylamine dimethylaminopyridine dimethylformamide dimethylsulfoxide 1-(3-dimethylaminopropyl)-3
[0015] The IMPDH inhibitor ribavirin is currently being
EtOAc
ethyl acetate
THF
tetrahydrofuran
publication WO 94/01105].
evaluated for the treatment of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and disease. Ribavirin enhances the sustained e?icacy of interferon in HBV and HCV treatment. HoWever, the therapeutic potential of rib avirin is limited by its lack of a sustained response in
monotherapy and broad cellular toxicity. [0016]
Thus, there remains a need for potent IMPDH
inhibitors With improved pharmacological properties. Such inhibitors Would have therapeutic potential as immunosup pressants, anti-cancer agents, anti-vascular hyperprolifera
tive agents, antiin?ammatory agents, antifungal agents, antipsoriatic and anti-viral agents. SUMMARY OF THE INVENTION
[0017] The present invention provides compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of IMPDH. These compounds can be used alone or in combination With other therapeutic or
ethylcarbodiimide hydrochloride
[0021]
The folloWing terms are employed herein:
[0022]
Unless expressly stated to the contrary, the terms
“—SO2—” and “—S(O)2—” as used herein refer to a
sulfone or sulfone derivative (i.e., both appended groups linked to the S), and not a sul?nate ester.
[0023]
The terms “halo” or “halogen” refer to a radical of
?uorine, chlorine, bromine or iodine. [0024]
The term “immunosuppressant” refers to a com
pound or drug Which possesses immune response inhibitory
activity. Examples of such agents include cyclosporin A,
FK506,rapamycin, le?unomide, deoxyspergualin, pred nisone, aZathioprine, mycophenolate mofetil, OKT3,ATAG, interferon and miZoribine.
prophylactic agents, such as anti-virals, antiin?ammatory agents, antibiotics, and immunosuppressants for the treat mentor prophylaxis of transplant rejection and autoimmune
[0025] The term “interferon” refers to all forms of inter ferons, including but not limited to alpha, beta and gamma forms.
disease. Additionally, these compounds are useful, alone or in combination With other agents, as therapeutic and pro
[0026] IMPDH-mediated disease refers to any disease state in Which the IMPDH enZyme plays a regulatory role in
phylactic agents for antiviral, anti-tumor, anti-cancer, anti in?ammatory agents, antifungal agents, antipsoriatic immu nosuppressive chemotherapy and restenosis therapy
regimens. [0018] The invention also provides pharmaceutical com positions comprising the compounds of this invention, as Well as multi-component compositions comprising addi tional IMPDH compounds together With an immunosup pressant. The invention also provides methods of using the compounds of this invention, as Well as other related com
the metabolic pathWay of that disease. Examples of IMPDH mediated disease include transplant rejection and autoim mune diseases, such as rheumatoid arthritis, multiple scle
rosis, juvenile diabetes, asthma, and in?ammatory boWel disease, as Well as in?ammatory diseases, cancer, viral
replication diseases and vascular diseases.
[0027] For example, the compounds, compositions and methods of using them of this invention may be used in the
treatment of transplant rejection (e.g., kidney, liver, heart,
The compounds of this invention, as Well as those
lung, pancreas (islet cells), bone marroW, cornea, small boWel and skin allografts and heart valve xenografts) and autoimmune diseases, such as rheumatoid arthritis, multiple
used in the methods of this invention demonstrate a different
sclerosis, juvenile diabetes, asthma, in?ammatory boWel
pounds, for the inhibition of IMPDH. [0019]
Oct. 16, 2003
US 2003/0195202 A1
disease (Crohn’s disease, ulcerative colitus), lupus, diabetes, mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhoea, pulmonary in?ammation, eye uveitis, hepatitis,
X
X
X
X
Grave’s disease, Hashimoto’s thyroiditis, Behcet’s or Sjor
gen’s syndrome (dry eyes/mouth), pernicious or immuno haemolytic anaemia, idiopathic adrenal insuf?ciency, polyglandular autoimmune syndrome, and glomerulonephri tis, scleroderma, lichen planus, viteligo (depigmentation of the skin), autoimmune thyroiditis, and alveolitis, in?amma tory diseases such as osteoarthritis, acute pancreatitis,
chronic pancreatitis, asthma and adult respiratory distress syndrome, as Well as in the treatment of cancer and tumors,
X
X
X
X
such as solid tumors, lymphomas and leukemia, vascular diseases, such as restenosis, stenosis and artherosclerosis, and DNA and RNA viral replication diseases, such as
retroviral diseases, and herpes. [0028] Additionally, IMPDH enZymes are also knoWn to be present in bacteria and thus may regulate bacterial
groWth. As such, the IMPDH-inhibitor compounds, compo sitions and methods described herein may be useful in treatment or prevention of bacterial infection, alone or in combination With other antibiotic agents.
[0039] Wherein each X is the number of hydrogen atoms necessary to complete proper valence; and B optionally comprises up to 3 substituents,
[0029] The term “treating” as used herein refers to the alleviation of symptoms of a particular disorder in a patient
[0040] Wherein: [0041] the ?rst of said substituents, if present, is
or the improvement of an ascertainable measurement asso
ciated With a particular disorder. As used herein, the term “patient” refers to a mammal, including a human.
[0030] The term “thiocarbamates” refers to compounds containing the functional group N—SO2—O. [0031]
The terms “HBV”, “HCV” and “HGV” refer to
hepatitis-B virus, hepatitis-C virus and hepatitis-G virus,
respectively.
selected from R1, R2, R4 or R5, [0042] the second of said substituents, if present, is selected from R1 or R4, and
[0043] the third of said substituents, if present, is R1; and
[0044] D is selected from C(O), C(S), or S(O)2;
[0045]
[0032] According to one embodiment, the invention pro vides methods of inhibiting IMPDH activity in a mammal comprising the step of administering to said mammal, a compound of formula I:
Wherein:
[0046] each R1 is independently selected from 1,2 methylenedioXy, 1,2-ethylenedioXy, R6 or (CH2)n—
Y;
[0047]
Wherein n is 0, 1 or 2; and
[0048] Y is selected from halogen, CN, NO2,CF3, (I) E
E
OCF3, OH, SR6,S(O)R6, SO2R6, NH2, NHR6, N(R6)2, NR6R8, COOH, cooR6 or 0R6; [0049] each R2 is independently selected from (Cl C 4)-straight or branched alkyl, or (C2-C4)-straight or
[0033] Wherein: [0034] A is selected from:
[0035] (C1-C6)-straight or branched alkyl, or (C2 C6)-straight or branched alkenyl or alkynyl; andA
optionally comprises up to 2 substituents, Wherein:
branched alkenyl or alkynyl; and each R2 optionally comprises up to 2 substituents, Wherein: [0050] the ?rst of said substituents, if present, is
selected from R1, R4 and R5, and
[0051 [0052]
[0036] the ?rst of said substituents, if present, is selected from R1 or R3, and
the second of said substituents, if present, is
R1;
R3 is selected from a monocyclic or a bicyclic
ring system consisting of 5 to 6 members per ring,
[0053] Wherein said ring system optionally comprises up [0037] the second of said substituents, if
present, is R1; [0038]
B is a saturated, unsaturated or partially satu
rated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, O, or S and selected from the formulae:
to 4 heteroatoms selected from N, O, or S, and Wherein a
CH2 adjacent to any of said N, O, or S heteroatoms is
optionally substituted With C(O); and each R3 optionally comprises up to 3 substituents, Wherein:
[0054] the ?rst of said substituents, if present, is
selected from R1, R2, R4 or R5,
Oct. 16, 2003
US 2003/0195202 A1
[0055] the second of said substituents, if present, is selected from R1 or R4, and
[0056] the third of said substituents, if present, is R1; [0057] each R4 is inde endently selected from ORS,
OC(O)R6, OC(O)R , OC(O)OR6, OC(O)OR5,
[0067] As speci?ed, such ring systems may optionally comprise up to 4 heteroatoms selected from N, O, or S. Those heteroatoms may replace any carbon atoms in these
ring systems as long as the resulting compound is chemi
cally stable. [0068]
The term “Wherein each X is the number of hydro
gen atoms necessary to complete proper valence” means that
X is 0, 1 or 2 hydrogen atoms, depending upon the identity of the ring atom to Which X is bound (C, N, O, or S), the identity of the tWo adjacent ring atoms, and the nature of the bonds betWeen the ring atom to Which X is bound and the
tWo adjacent ring atoms (single, double or triple bond). In essence, this de?nition is meant to eXclude from X any
substituents other than hydrogen. [0069]
[0058] each R5 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring,
The term “amino protecting group” refers to a
suitable chemical group Which may be attached to a nitrogen atom. The term “protected” refers to When the designated functional group is attached to a suitable chemical group
(protecting group). Examples of suitable amino protecting
Wherein said ring system optionally comprises up to
groups and protecting groups are described in T. W. Greene
4 heteroatoms selected from N, O, or S, and Wherein a CH2 adjacent to said N, O, or S maybe substituted
and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M.
With C(O); and each R5 optionally comprises up to 3 substituents, each of Which, if present, is R1;
Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed. Encyclopedia
[0059] each R6 is independently selected from H, (C1-C4)-straight or branched alkyl, or (C2-C4) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7; [0060] R7 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, Wherein said ring system optionally comprises up to 4 heteroat
of Reagents for Organic Synthesis, John Wiley and Sons (1995) and are exempli?ed in certain of the speci?c com pounds used in this invention.
[0070] According to another embodiment, the invention provides methods of inhibiting IMPDH in mammals by administering a compound of the formula (II):
oms selected from N, O, or S, and Wherein a CH2
(II)
adjacent to said N, O, or S maybe substituted With
\
C(O); and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C4)
N E
/
\
N E
/
straight or branched alkyl, (C2-C4) straight or
branched alkenyl, 1,2-methylenedioXy, 1,2-ethylene dioXy, or (CH2)n-Z; [0061]
Wherein n is 0, 1 or 2; and
[0062] Z is selected from halogen, CN, NO2, CB3,
OCF3, OH, S(C1-C4)-alkyl, SO(C1-C4)-alkyl,
SO2(C1-C4)-alkyl, NH2,NH(C1-C4)-a1kyl, N((C1 C4)-alkyl)2, N((C1-C4)-alkyl)R8, COOH, C(O)O(C1-C4)-alkyl or O(C1-C4)-alkyl; and
[0071]
Wherein B and D are as de?ned above.
[0072] More preferably, in methods employing the com pounds of formulae (I) or (II), component B comprises from 0 to 2 substituents. According to an alternate embodiment, the invention provides methods for inhibiting IMPDH in a
mammal employing compounds (I) or (II), Wherein B com prises at least a single substituent selected from the group
de?ned by RS. Preferably, in this embodiment, B is a monocyclic aromatic ring containing at least one substituent Which is also a monocyclic aromatic ring.
[0063]
R8 is an amino protecting group; and
[0064]
Wherein any carbon atom in any A, R2 or R6
[0073] The present invention also provides compounds
is optionally replaced by O, S, SO, SO2,NH, or
Which are useful in inhibiting IMPDH. According to one
N(C1-C4)-alkyl. [0065]
The term “substituted” refers to the replacement of
embodiment, the IMPDH inhibitory compound has the
formula (III):
one or more hydrogen radicals in a given structure With a radical selected from a speci?ed group. When more than one
(III)
hydrogen radical may be replaced With a substituent selected from the same speci?ed group, the substituents may be either the same or different at every position.
[0066] The term “monocyclic or bicyclic ring system consisting of 5 to 6 members per ring” refers to 5 or 6
member monocyclic rings and 8, 9 and 10 membered bicyclic ring structures, Wherein each bond in each ring may be possess any degree of saturation that is chemically feasible. When such structures contain substituents, those substituents may be at any position of the ring system, unless
otherWise speci?ed.
[0074]
[0075] [0076]
Wherein A, B and D are as de?ned above;
E is oXygen or sulfur; and G and G‘ are independently selected from R1 or
hydrogen.
Oct. 16, 2003
US 2003/0195202 A1
[0077] According to an alternate embodiment, the inven tion provides a compound of the formula (IV):
[0085] Wherein K is selected from R1 or R4; and J is selected from R‘, R2 or R4.
[0086] Preferred compounds of formula (V) are those Wherein D is —C(O)—, those Wherein E is oxygen; those B‘
D \
E
/ \
B
E
/
G
(IV)
1;»
Wherein J is NR6C(O)R5 or NR6C(O)R6, preferably NR6C(O)R6, more preferably N(CH3)C(O)R6, and more preferably N(CH3)C(O)CH3; those Wherein K is (CH2)n—Y, preferably OCH3 (i.e., n is 0, Y is 0R6, and R6 is CH3); and those Wherein G is hydrogen. More preferred compounds of formula (V) are those Wherein:
[0078] Wherein B, D, E, G and G‘ are de?ned as above and B‘ is a saturated, unsaturated or partially saturated monocy
clic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, O, or S and selected from the formulae:
X
+319 +90 99 9Q
[0087] E is oxygen [0088] [0089] [0090] G is hydrogen. [0091] Even more preferred compounds of formula (V) are those Wherein:
[0092] D is —C(O)—;
[0093]
E is oxygen;
[0094] J is NR6C(O)R6; [0095] K is OCH3; and [0096] G is hydrogen.
[0097] Most preferably in such compounds, J is
N(CH3)C(O)R6. [0098] Alternate preferred compounds are those of for mula V: Wherein J is R2, those Wherein D is —C(O)—, those-Wherein E is oxygen, those Wherein J is R2 substituted
With R4‘ preferably Wherein R4 is NR6C(O)OR5 or
NR6C(O)OR6, more preferably Wherein R4 is NR6C(O)OR5, [0079] Wherein each X is the number of hydrogen atoms necessary to complete proper valence; and B‘ optionally comprises up to 3 substituents, Wherein:
[0080] the ?rst of said substituents, if present, is
selected from R1, R2, R4 or R5,
more preferably Wherein R is NHC(O)OR5, and more pref
erably Wherein R is NHC(O) O—3-tetrahydrofuranyl, those Wherein K is (CH2)n—Y, preferably Wherein K is OCH3, those Wherein G is hydrogen, and those Wherein:
[0099] D is —C(O)—;
[0081] the second of said substituents, if present, is selected from R1 or R4, and
[0082] the third of said substituents, if present, is R‘; Wherein X, R1, R2, R4 and R5 are de?ned as above. [0083] Excluded from this invention are compounds of formula (IV) Wherein B and B‘ are simultaneously unsub stituted phenyl and compounds Wherein B is unsubstituted phenyl and B‘ is tri-chloro-, tri-bromo or tri-iodo phenyl.
[0100]
E is oxygen;
[0101] K is OCH3; and
[0102] G is hydrogen.
[0103] Alternatively, other preferred compounds include those of formula VI:
[0084] Preferably, in compounds of formula (IV), B and B‘
VI
are phenyl groups comprising at least one substituent each.
0
These compounds are represented by formula (V): K
H N
H N H
(V)
K
E/\N
(E\N / G
[0104] those compounds of formula VI Wherein K is OCH3, and those compounds of formula VI Wherein G is
hydrogen.
Oct. 16, 2003
US 2003/0195202 A1
[0105] An alternate embodiment of this invention is com pounds of formula V Wherein K is selected from R1 or R4;
[0113] Another embodiment is those compounds of for mula IX:
and J is selected from R1, R2, R4, and R9 Wherein, R1, R2, and R4, are as de?ned above and R9 is independently selected from (C1-C4)-straight or branched alkyl, or (C2 C4)-straight or branched alkenyl or alkynyl; and each R9 optionally comprises up to 2 substituents selected from NR6C(O)OR1O, Wherein R6 is as de?ned above and R10 is
CN
selected from (C1-C5)-straight or branched alkyl optionally comprising up to tWo substituents selected from NR6R8,
SR6, SOZRG, —(CH2 n—SR6, —(CH2)n—OR6, and CR6, Wherein n, R6 and R8, are as de?ned above.
[0114] Wherein:
[0106] In another embodiment, preferred compounds are
[0115] D is selected from C(O), C(S) and S(O)2;
those of formula VII:
[0116] K is selected from R1 and R4; and
[0117] J is selected from R1, R2, and R4.
VII
[0118] More preferred compounds of formula IX6 include those Wherein D is —C(O)—, those Wherein J is NR C(O)R5 or NR6C(O)R6, those Wherein J is NR6C(O)R6, those Wherein J is N(CH3)C(O)R6, those Wherein J is N(CH3)C(O)CH3, those Wherein K is (CH2)n—Y, those Wherein K is OCH3, and those Wherein:
CN
[0119] K is OCH3; and [0107] Wherein K is selected from R1 and R4; and A, D, R1
[0120] J is N(CH3)C(O)CH3.
and R4 are each independently as de?ned in claim 1.
[0121] Tables IA, IB and IIB list preferred individual
[0108] More preferred compounds of formula VII are
compounds of the invention and preferred compounds
those Wherein D is —C(O)—, those Wherein A is a mono
employed in the compositions and methods of this inven tion. Table IIA lists preferred compounds employed in the
cyclic aromatic ring substituted With 1-2 substituents selected from the group consisting of NR6C(O)R6,
methods of this invention.
NR6C(O)R5, CH2NR6C(O)OR6, and CH2NR6C(O)OR5,
TABLE IA
those Wherein A is a monocyclic aromatic ring substituted With 1-2 substituents selected from the group consisting of
K
CH2NR6C(O)OR6 and CH2NR6C(O)OR5, those A is a monocyclic aromatic ring substituted With
O’\\ \
N
O
CH2NR6C(O)OR5‘ those Wherein A is a monocyclic aro
A \N )L N
matic ring substituted With CH2NHC(O)OR5, those Wherein A is a monocyclic aromatic ring substituted With CH2NHC(O)O-3-tetrahydrofuryl, those Wherein K is
H
G
H
#
G
K
A
1
H
H
benzyl
(CH2)n—Y, those Wherein Kis OCH3, and those Wherein: [0109] A is a monocyclic aromatic ring substituted
With CH2NHC(O)O-3-tetrahydrofuryl; and
[0122]
[0110] K is 0on3.
TABLE IB
[0111] Alternatively, other preferred compounds of this invention include those compounds of formula VIII:
K
O”\\ \
0
K
N \ D/ N
N
i oQ0
H NC
[0112]
Wherein D and K are as de?ned in claim 1.
N
O
VIII
\N H
N
H
#
G
K
B‘
2 3 4 5
H H H H
H H H H
3-methoxyphenyl 3-thienyl 3,4-di?uorophenyl 2,5-dimethoXyphenyl
Oct. 16, 2003
US 2003/0195202 A1
[0123]
[0124] TABLE IC
MeO
TABLE IIA
H
H
Q1
H
H
l N
| N
\\ E
N
N\B
T O
//
O
R > R or R ; and
.
.
.
.
.
racemates and racemic mixtures, single enantiomers, dias tereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S con?guration. _
_
_
_
_
[0130] Combinations of substituents and variables env1 sioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used
herein, refers to compounds Which possess stability suf?
Oct. 16, 2003
US 2003/0195202 A1
cient to allow manufacture and Which maintains the integrity of the compound for a sufficient period of time to be useful
for the purposes detailed herein (e.g., therapeutic or prophy lactic administration to a mammal or for use in affinity
chromatography applications). Typically, such compounds are stable at a temperature of 40° C. or less, in the absence
of moisture or other chemically reactive conditions, for at least a Week.
[0131] As used herein, the compounds of this invention, including the compounds of formulae I-IX, are de?ned to
include pharmaceutically acceptable derivatives or prodrugs thereof. A “pharmaceutically acceptable derivative or pro
[0134] The compounds of this invention may be synthe siZed using conventional techniques. Advantageously, these compounds are conveniently synthesiZed from readily avail able starting materials.
[0135] In general, compounds of formula (I)-(IX) are conveniently obtained via methods illustrated in General Synthetic Schemes 1-3.
[0136] In General Synthetic Scheme 1 (see beloW), an X-substituted aniline is reacted With a Y-substituted phenyl
isocyanate under standard conditions to give the desired urea. In this process, X and Y may be one or more inde
of an ester, or other derivative of a compound of this
pendent substituents (or their suitably protected variants) as exempli?ed by the ring substituents listed for compounds of
invention Which, upon administration to a recipient, is
formulae I-IX above, at any position on the aromatic ring.
capable of providing (directly or indirectly) a compound of this invention. Particularly favored derivatives and prodrugs
General Synthetic Scheme 1:
drug” means any pharmaceutically acceptable salt, ester, salt
are those that increase the bioavailability of the compounds of this invention When such compounds are administered to a mammal (e.g., by alloWing an orally administered com pound to be more readily absorbed into the blood) or Which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to
NCO
HZN
X
CHClg/DMF Ambient temp. 12 hours
the parent species. Preferred prodrugs include derivatives Where a group Which enhances aqueous solubility or active
transport through the gut membrane is appended to the structure of formulae I-IX.
.ONTNUX
[0132] Pharmaceutically acceptable salts of the com pounds of this invention include those derived from phar
maceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adi
pate, alginate, aspartate, benZoate, benZenesulfonate, bisul
fate, butyrate, citrate, camphorate, camphorsulfonate, cyclo pentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glyc erophosphate, glycolate, hemisulfate, heptanoate, hex anoate, hydrochloride, hydrobromide, hydroiodide, 2-hy droxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenyl propionate, phosphate, picrate, pivalate, propionate, salicy
General Synthetic Scheme 2: MeO
N02
themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtain
ing the compounds of the invention and their pharmaceuti cally acceptable acid addition salts. [0133] Salts derived from appropriate bases include alkali
metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C1_4 alkyl)4+salts. This invention also envisions the quaterniZation of any basic nitrogen-contain ing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such
quaterniZation.
.
K2CO3, MeOH, reflux 2) H2, Pd/C, EtOAc
H
MeO
late, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, While not in
.
1) Tosylmethyl isocyanide
NHz
.
3) m-tolyl isocyanate dichloroethane —>
O
< l
ambient temp.
overnight
Oct. 16, 2003
US 2003/0195202 A1
General Synthetic Scheme 3: N02
.
.
1) Tosylmethyl isocyanide K2CO3, MeOH, reflux —> 2) H2, Pd/C, EtOAc
H
O
N
3) 2PN3 HO
triethylamine, toluene, reflux
forgrgor l
[0137] In General Synthetic Scheme 2 (see above), a
[0142] Pharmaceutical compositions of this invention
substituted benzaldehyde (here, 2-methoxy-4-nitro-substi
comprise a compound of formulae (I), (II) or (VII) or a
tuted) is treated sequentially With tosylmethylisocyanide, to
pharmaceutically acceptable salt thereof; an additional agent
give the resulting oxazole, then reduced by catalytic hydro
selected from an immunosuppressant, an anti-cancer agent,
genation to give the desired aniline. Reaction of this aniline
an anti-viral agent, antiin?ammatory agent, antifungal agent,
With an isocyanate (here, m-tolylisocyanate) under standard
antibiotic, or an anti-vascular hyperproliferation compound;
conditions gives the desired urea.
and any pharmaceutically acceptable carrier, adjuvant or
[0138] An alternate synthetic route is illustrated in General
vehicle. Alternate compositions of this invention comprise a compound of formulae (III)-(IX) or a pharmaceutically
Synthetic Scheme 3 (see above). Asubstituted benzaldehyde (here 4-nitro substituted) is converted to the corresponding oxazolyl aniline as shoWn in General Synthetic Scheme 2. This aniline is treated With a substituted benzoic acid (here,
acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. Such composition may option
3-methyl-substituted) and a carboxylic acid activating agent,
ally comprise an additional agent selected from an immu nosuppressant, an anti-cancer agent, an anti-viral agent,
such as diphenylphosphoryl azide, under standard reaction conditions, to give the desired urea.
anti-vascular hyperproliferation compound.
[0139] As can be appreciated by the skilled artisan, the
[0143]
above synthetic schemes are not intended to comprise a
comprehensive list of all means by Which the compounds described and claimed in this application may be synthe sized. Further methods Will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.
[0140] The compounds of this invention may be modi?ed by appending appropriate functionalities to enhance selec tive biological properties. Such modi?cations are knoWn in the art and include those Which increase biological penetra
antiin?ammatory agent, antifungal agent, antibiotic, or an The term “pharmaceutically acceptable carrier or
adjuvant” refers to a carrier or adjuvant that may be admin istered to a patient, together With a compound of this
invention, and Which does not destroy the pharmacological activity thereof and is nontoxic When administered in doses suf?cient to deliver a therapeutic amount of the compound.
[0144] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical com positions of this invention include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, self-emul sifying drug delivery systems (SEDDS) such as da-toco pherol polyethyleneglycol 1000 succinate, surfactants used
tion into a given biological compartment (e.g., blood, lym
in pharmaceutical dosage forms such as TWeens or other
phatic system, central nervous system), increase oral avail ability, increase solubility to alloW administration by injection, alter metabolism and alter rate of excretion.
human serum albumin, buffer substances such as phos
[0141] The novel compounds of the present invention are excellent ligands for IMPDH. Accordingly, these com
pounds are capable of targeting and inhibiting IMPDH enzyme. Inhibition can be measured by various methods,
including, for example, IMP dehydrogenase HPLC assays (measuring enzymatic production of XMP and NADH from IMP and NAD) and IMP dehydrogenase spectrophotometric assays (measuring enzymatic production of NADH from NAD). [See C. Montero et al., Clinica Chimica Acta, 238, pp. 169-178 (1995)].
similar polymeric delivery matrices, serum proteins, such as
phates, glycine, sorbic acid, potassium sorbate, partial glyc eride mixtures of saturated vegetable fatty acids, Water, salts or electrolytes, such as protamine sulfate, disodium hydro
gen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyeth
ylene glycol, sodium carboxymethylcellulose, polyacry lates, Waxes, polyethylene-polyoxypropylene-block poly mers, polyethylene glycol and Wool fat. Cyclodextrins such as (X-, [3-, and y-cyclodextrin, or chemically modi?ed deriva tives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-[3-cyclodextrins, or other solubilized
Oct. 16, 2003
US 2003/0195202 A1
derivatives may also be advantageously used to enhance
[0148] The pharmaceutical compositions of this invention
delivery of compounds of formulae I-IX.
may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention With a suitable non-irritating excipient Which is solid at room temperature but liquid at the rectal temperature and therefore Will melt in
[0145] The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or
administration by injection. The pharmaceutical composi
the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beesWax and
tions of this invention may contain any conventional non
polyethylene glycols.
toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be
adjusted With pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intra
muscular,
intraarticular,
intraarterial,
intrasynovial,
intrasternal, intrathecal, intralesional and intracranial injec tion or infusion techniques.
[0146] The pharmaceutical compositions may be in the
[0149] Topical administration of the pharmaceutical com positions of this invention is especially useful When the desired treatment involves areas or organs readily accessible
by topical application. For application topically to the skin, the pharmaceutical composition should be formulated With a suitable ointment containing the active components sus pended or dissolved in a carrier. Carriers for topical admin istration of the compounds of this invention include, but are
not limited to, mineral oil, liquid petroleum, White petro
leum, propylene glycol, polyoxyethylene polyoxypropylene
form of a sterile injectable preparation, for example, as a
compound, emulsifying Wax and Water. Alternatively, the
sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques knoWn in the art using suitable dispersing or Wetting agents
pharmaceutical composition can be formulated With a suit able lotion or cream containing the active compound sus pended or dissolved in a carrier With suitable emulsifying agents. Suitable carriers include, but are not limited to,
(such as, for example, TWeen 80) and suspending agents. The sterile injectable preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, Water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, ?xed oils are conventionally employed as a solvent or
suspending medium. For this purpose, any bland ?xed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor
oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as those described in Pharmacopeia Helvetica, Ph. Helix, or a similar alcohol, or
carboxymethyl celluose or similar dispersing agents Which are commonly used in the formulation of pharmaceutically
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters Wax, cetearyl alcohol, 2-octyldodecanol, benZyl alco hol and Water. The pharmaceutical compositions of this invention may also be topically applied to the loWer intes tinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
[0150] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such
compositions are prepared according to techniques Well knoWn in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benZyl alcohol or other suitable preservatives, absorption promoters to
enhance bioavailability, ?uorocarbons, and/or other solubi liZing or dispersing agents knoWn in the art.
[0151]
Dosage levels of betWeen about 0.01 and about 100
mg/kg body Weight per day, preferably betWeen about 0.5 and about 75 mg/kg body Weight per day of the IMPDH
acceptable dosage forms such as emulsions and or suspen sions Other commonly used surfactants such as TWeens or
inhibitory compounds described herein are useful in a mono
Spans and/or other similar emulsifying agents or bioavail
therapy and/or in combination therapy for the prevention
ability enhancers Which are commonly used in the manu
and treatment of IMPDH mediated disease. Typically, the
facture of pharmaceutically acceptable solid, liquid, or other
pharmaceutical compositions of this invention Will be
dosage forms may also be used for the purposes of formu lation.
administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration
[0147] The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emul sions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers Which are commonly
used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingre dient may be suspended or dissolved in an oily phase is
combined With emulsifying and/or suspending agents. If
desired, certain sWeetening and/or ?avoring and/or coloring agents may be added.
can be used as a chronic or acute therapy. The amount of
active ingredient that may be combined With the carrier materials to produce a single dosage form Will vary depend ing upon the host treated and the particular mode of admin istration. A typical preparation Will contain from about 5% to about 95% active compound (W/W). Preferably, such preparations contain from about 20% to about 80% active
compound. [0152] When the compositions of this invention comprise a combination of an IMPDH inhibitor of formulae (I)-(IX) and one or more additional therapeutic or prophylactic
agents, both the IMPDH inhibitor and the additional agent should be present at dosage levels of betWeen about 10 to 100%, and more preferably betWeen about 10 to 80% of the
Oct. 16, 2003
US 2003/0195202 A1
dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as
prise the step of administering to said mammal an agent selected from an antiin?ammatory agent, immunosuppres
part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single
vascular hyperproliferation compound. Such additional
dosage form, mixed together With the compounds of this invention in a single composition.
[0153] According to one embodiment, the pharmaceutical
sant, an anti-cancer agent, an anti-viral agent, or an anti
agent may be administered to the mammal prior to, concur rently With, or folloWing the administration of the IMPDH
inhibitor composition.
compositions of this invention comprise an additional
[0160]
immunosuppression agent. Examples of additional immu
useful in suppressing an immune response in a mammal.
In a preferred embodiment, these methods are
nosuppression agents include, but are not limited to,
Such methods are useful in treating or preventing diseases,
cyclosporin A, FK506,rapamycin, le?unomide, deoxysper gualin, prednisone, aZathioprine, mycophenolate mofetil,
including, transplant rejection (e.g., kidney, liver, heart,
OKT3,ATAG, interferon and miZoribine.
[0154] According to an alternate embodiment, the phar maceutical compositions of this invention may additionally comprise an anti-cancer agent. Examples of anti-cancer agents include, but are not limited to, cis-platin, actinomycin
D, doxorubicin, vincristine, vinblastine, etoposide, amsa
crine,
mitoxantrone,
tenipaside,
taxol,
colchicine,
cyclosporin A, phenothiaZines, interferon and thioxantheres. [0155] According to another alternate embodiment, the pharmaceutical compositions of this invention may addi tionally comprise an anti-viral agent. Examples of anti-viral agents include, but are not limited to, Cytovene, Ganciclovir,
trisodium phosphonoformate, Ribavirin, d4T, ddI, AZT, and
acyclovir. [0156] According to yet another alternate embodiment, the pharmaceutical compositions of this invention may addi
lung, pancreas (islet cells), bone marroW, cornea, small boWel and skin allografts and heart valve xenografts), graft versus host disease, and autoimmune diseases, such as
rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, in?ammatory boWel disease (Crohn’s disease, ulcer ative colitus), lupus, diabetes, mellitus myasthenia gravis, psoriasis, dermatitis, ecZema, seborrhoea, pulmonary in?ammation, eye uveitis, hepatitis, Grave’s disease, Hash imoto’s thyroiditis, Behcet’s or Sjorgen’s syndrome (dry eyes/mouth), pernicious or immunohaemolytic anaemia, idiopathic adrenal insufficiency, polyglandular autoimmune
syndrome, glomerulonephritis, scleroderma, lichen planus, viteligo (depigmentation of the skin), autoimmune thyroidi tis, and alveolitis.
[0161] These methods comprise the step of administering to the mammal a composition comprising a compound of any of formulae I-IX and a pharmaceutically acceptable
adjuvant. In a preferred embodiment, this particular method
tionally comprise an anti-vascular hyperproliferative agent. Examples of anti-vascular hyperproliferative agents include,
comprises the additional step of administering to said mam mal a composition comprising an additional immunosup
but are not limited to, HMG Co-A reductase inhibitors such
pressant and a pharmaceutically acceptable adjuvant.
as lovastatin, thromboxane A2 synthetase inhibitors, eicosa
pentanoic acid, ciprostene, trapidil, ACE inhibitors, loW molecular Weight heparin, mycophenolic acid, rapamycin and 5-(3‘-pyridinylmethyl)benZofuran-2-carboxylate. [0157] Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combi nation of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a
level at Which the improved condition is retained When the symptoms have been alleviated to the desired level, treat ment should cease. Patients may, hoWever, require intermit
[0162] Alternatively, this method comprises the step of administering to said mammal a composition comprising a
compound of formulae I-IX; an additional immunosuppres sive agent and a pharmaceutically acceptable adjuvant. [0163]
In an alternate preferred embodiment, these meth
ods are useful for inhibiting viral replication in a mammal. Such methods are useful in treating or preventing, DNA and
RNA viral diseases caused by, for example, HTLV-l and HTLV-2, HIV-1 and HIV-2, nasopharyngeal carcinoma
virus, HBV, HCV, HGV, yelloW fever virus, dengue fever virus, Japanese encephalitis virus, human papilloma virus,
tent treatment on a long-term basis upon any recurrence of
rhinoviruses and Herpes viruses, such as Epstein-Barr,
disease symptoms.
cytomegaloviruses and Herpes Simplex, Types 1 and 2,or Type 6. [See, US. Pat. No. 5,380,879].
[0158] As the skilled artisan Will appreciate, loWer or higher doses than those recited above may be required.
[0164] These methods comprise the step of administering
Speci?c dosage and treatment regimens for any particular patient Will depend upon a variety of factors, including the activity of the speci?c compound employed, the age, body Weight, general health status, sex, diet, time of administra tion, rate of excretion, drug combination, the severity and
comprises the additional step of administering to said mam mal a composition comprising an additional anti-viral agent
course of the infection, the patient’s disposition to the
and a pharmaceutically acceptable adjuvant.
to the mammal a composition comprising a compound of any of formulae I-IX, and a pharmaceutically acceptable
adjuvant. In a preferred embodiment, this particular method
infection and the judgment of the treating physician. [0159] In an alternate embodiment, this invention provides methods of treating or preventing IMPDH mediated disease in a a mammal comprising the step of administrating to said mammal any of the pharmaceutical compositions and com
[0165] Alternatively, this method comprises the step of administering to said mammal a composition comprising a compound of formulae I-IX; an additional anti-viral agent
and a pharmaceutically acceptable adjuvant.
binations described above. If the pharmaceutical composi
[0166] In another alternate preferred embodiment, these
tion only comprises the IMPDH inhibitor of this invention as the active component, such methods may additionally com
methods are useful for inhibiting vascular cellular hyper proliferation in a mammal. Such methods are useful in
Oct. 16, 2003
US 2003/0195202 A1
treating or preventing diseases, including, restenosis, steno sis, artherosclerosis and other hyperproliferative vascular disease.
[0167] These methods comprise the step of administering to the mammal a composition comprising a compound of any of formulae I-IX, and a pharmaceutically acceptable
adjuvant. In a preferred embodiment, this particular method comprises the additional step of administering to said mam mal a composition comprising an additional anti-vascular
hyperproliferative agent and a pharmaceutically acceptable
adjuvant. [0168] Alternatively, this method comprises the step of administering to said mammal a composition comprising a compound of formulae I-IX; an additional anti-vascular
ethanol, folloWed by heating, and/or by eXposure to UV light or iodine vapors When appropriate. Analytical HPLC Was
carried out using a Rainin Mycrosorb-MV, 5p Cyano reverse phase column, 3.9mm >
