Amino-substituted compounds useful as inhibitors of IMPDH...

Details Amino-substituted compounds useful as inhibitors of IMPDH... Amino-substituted compounds useful as inhibitors of IMPDH...

2002-05-23

2003-09-09

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254020, C514S326000, C514S340000, C514S374000, C544S138000, C544S369000, C546S208000, C546S271400, C548S236000

Reexamination Certificate

active

06617323

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds that inhibit IMPDH. The invention also encompasses pharmaceutical compositions comprising these compounds and to methods for inhibiting the activity of IMPDH using the compounds of this invention and related compounds.
BACKGROUND OF THE INVENTION
Inosine monophosphate dehydrogenase (IMPDH) has been shown to be a key enzyme in the regulation of cell proliferation and differentiation. Nucleotides are required for cells to divide and replicate. In mammals, nucleotides may be synthesized through one of two pathways: the de novo synthesis pathway or the salvage pathway. The extent of utilization of each pathway is dependent on cell type. This selectivity has ramifications with regard to therapeutic utility as described below.
IMPDH is involved in the de novo synthesis of guanosine nucleotides. IMPDH catalyzes the irreversible NAD-dependent oxidation of inosine-5′-monophosphate (“IMP”) to xanthosine-5′-monophosphate (“XMP”). Jackson et al.,
Nature,
256:331-333 (1975).
IMPDH is ubiquitous in eukaryotes, bacteria and protozoa. The prokaryotic forms share 30-40% sequence identity with the human enzyme.
Two distinct cDNA's encoding IMPDH have been identified and isolated. These transcripts are labeled type I and type II and are of identical size (514 amino acids). Collart et al.,
J. Biol. Chem.,
263:15769-15772 (1988); Natsumeda et al.,
J. Biol. Chem.,
265:5292-5295 (1990); and U.S. Pat. No. 5,665,583 to Collart et al. These isoforms share 84% sequence identity. IMPDH type I and type II form tetramers in solution, the enzymatically active unit.
B and T-lymphocytes depend on the de novo pathway, rather than the salvage pathway, to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen. Due to the B and T cell's unique reliance on the de novo pathway, IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
Immunosuppression has been achieved by inhibiting a variety of enzymes. Examples include: phosphatase calcineurin (inhibited by cyclosporin and FK-506); dihydroorotate dehydrogenase (DHODase), an enzyme involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar); the kinase FRAP (inhibited by rapamycin); and the heat shock protein hsp70 (inhibited by deoxyspergualin).
Inhibitors of IMPDH have also been described in the art. WO 97/40028, U.S. Pat. Nos. 5,807,876, and 6,344,465 B1 describe a class of urea derivatives that possess a common urea backbone. A large number of compounds are described in WO 97/40028 and U.S. Pat. No. 5,807,876, but several of the compounds suffer from drawbacks such as inferior solubility. A recent publication, WO 98/40381, describes a series of heterocyclic substituted anilines as inhibitors of IMPDH.
U.S. Pat. Nos. 5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184 describe mycophenolic acid (“MPA”) and some of its derivatives as potent, uncompetitive, reversible inhibitors of human IMPDH type I and type II. MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen. Immunosuppressants, such as MPA and derivatives of MPA, are useful drugs in the treatment of transplant rejection, autoimmune disorders, psoriasis, inflammatory diseases including rheumatoid arthritis, tumors, and allograft rejection. These are described in U.S. Pat. Nos. 4,686234, 4,725622, 4,727,069, 4,753,935, 4,786,637, 4,808,592, 4,861,776, 4,868,153, 4,948,793, 4,952,579, 4,959,387, 4,992,467, 5.247,083; and U.S. patent application Ser. No. 07/927,260, filed Aug. 7, 1992. However, MPA displays undesirable pharmacological properties, such as gastrointestinal toxicity and poor bioavailability.
Tiazofurin, ribavirin and mizoribine also inhibit IMPDH. Although these nucleoside analogs are competitive inhibitors of IMPDH, they also inhibit other NAD dependent enzymes. This low level of selectivity for IMPDH limits the therapeutic application of tiazofurin, ribavirin and mizoribine. Thus, new agents having improved selectivity for IMPDH would represent a significant improvement over the nucleoside analogs.
Mycophenolate mofetil, sold under the trade name CELLCEPT, is a prodrug which liberates MPA in vivo. It is approved for use in preventing acute renal allograft rejection following kidney transplantation. The side effect profile limits the therapeutic potential of this drug. MPA is rapidly metabolized to the inactive glucuronide in vivo. In humans, the blood levels of glucuronide exceed that of MPA. The glucuronide undergoes enterohepatic recycling causing accumulation of MPA in the bile and subsequently in the gastrointestinal tract. This together with the production of the inactive glucuronide effectively lowers the drug's in vivo potency, while increasing its undesirable gastrointestinal side effects.
Unlike type I, type II mRNA is preferentially upregulated in human leukemic cell lines K562 and HL-60. Weber,
J. Biol. Chem.,
266: 506-509 (1991). In addition, cells from human ovarian tumors and leukemic cells from patients with chronic granulocytic, lymphocytic and acute myeloid leukemias also display an up regulation type II mRNA. This disproportionate increase in IMPDH activity in malignant cells may be addressed through the use of an appropriate IMPDH inhibitor. IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases.
IMPDH has been shown to play a role in viral replication in some viral cell lines. Carr,
J. Biol. Chem.,
268:27286-27290 (1993). The IMPDH inhibitor VX-497 is being evaluated for the treatment of hepatitis C virus in humans. Ribavirin has also been used in the treatment of hepatitis C and B viruses and when used in combination with interferon, an enhancement in activity was observed. The IMPDH inhibitor ribavirin is limited by its lack of a sustained response in monotherapy and broad cellular toxicity.
There remains a need for potent selective inhibitors of IMPDH with improved pharmacological properties, physical properties and fewer side effects. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-vascular hyperproliferative agents, antuinflammatory agents, antifungal agents, antipsoriatic agents, and anti-viral agents. The compounds of the present invention differ from those taught by the prior art and are effective inhibitors of IMPDH. All references cited herein are incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
The present invention provides compounds of the following Formula I, and salts thereof, for use as inhibitors of IMPDH enzyme:
wherein:
X is selected from the group consisting of —C(O)—, —C(S)—, and —S(O)
2
—;
A is a saturated or unsaturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, O, or S, and wherein a CH
2
adjacent to any of said N, O, or S heteroatoms is optionally substituted with oxo (═O); and each ring is optionally substituted with up to 3 substituents, wherein:
the first of said substituents, if present, is a group U, wherein U is selected from the group consisting of R
1
, R
2
, and R
3
;
the second of said substituents, if present, is selected from a group U
1
, wherein U
1
is selected from the group consisting of R
1
and R
2
; and
the third of said substituents, if present, is selected from the group U
1
;
R
1
is a saturated or unsaturated monocyclic ring having 4 to 6 members in the ring and wherein said ring optionally comprises up to 4 heteroatoms selected from N, O, and S, and wherein a CH
2
adjacent to any of said N, O, or S heteroatoms is optionally substituted with oxo (═O); and each R
1
optionally comprises up to 3 substituents selected from R
2
and R
3
;
R
2
is selected from halogen, CN, NO
2
, CF
3
, —(C
0
-C
4
alkyl)OR
3
, OCF
3
, OC(O)R
3
, OC(O)OR
3

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