Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-19
2002-12-24
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S227500, C514S227800, C514S236800, C514S438000, C514S473000, C514S522000, C544S058200, C544S058500, C544S059000, C544S060000, C544S137000, C544S163000, C548S236000, C548S567000, C549S475000, C558S417000
Reexamination Certificate
active
06498178
ABSTRACT:
The present invention relates to compounds which inhibit IMPDH. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMPDH enzyme activity and consequently, may be advantageously used as therapeutic agents for IMPDH ediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention a nd related compounds.
BACKGROUND OF THE INVENTION
The synthesis of nucleotides in organisms is required for the cells in those organisms to divide and re plicate. Nucleotide synthesis in mammals may be achiev ed through one of two pathways: the de novo synthesis pathway or the salvage pathway. Different cell types use these pathways to a different extent.
Inosine-5′-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) is an enzyme involved in the de novo synthesis of guanine nucleotides. IMPDH catalyzes the NAD-dependent oxidation of inosine-5′-monophosphate (IMP) to xanthosine-5′-monophosphate (XMP) [Jackson R. C. et. al.,
Nature
, 256, pp. 331-333, (1975)].
IMPDH is ubiquitous in eukaryotes, bacteria and protozoa [Y. 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. Two isoforms of human IMPDH, designated type I and type II, have been identified and sequenced [F. 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 [Y. Yamada et. al.,
Biochemistry
, 27, pp. 2737-2745 (1988)].
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 sufficient 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 selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
Immunosuppression has been achieved by inhibiting a variety of enzymes including for example, the phosphatase calcineurin (inhibited by cyclosporin and FK-506); dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar); the kinase FRAP (inhibited by rapamycin); and the heat shock protein hsp7o (inhibited by deoxyspergualin). [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)].
Inhibitors of IMPDH are also known. U.S. Pat. No. 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 (K
i
=33 nM) and type II (K
i
=9 nM). MPA has been demonstrated to block the response of B and T-cells 10 to mitogen or antigen [A. C. Allison et. al.,
Ann. N. Y. Acad. Sci
., 696, 63, (1993).
Immunosuppressants, such as MPA, are useful drugs in the treatment of transplant rejection and autoimmune diseases. [R. E. Morris,
Kidney Intl
., 49, Suppl. 53, S-26, (1996)]. However, MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity. [L. M. Shaw, et. al.,
Therapeutic Drug Monitoring
, 17, pp. 690-699, (1995)].
Nucleoside analogs such as tiazofurin, ribavirin and mizoribine also inhibit IMPDH [L. Hedstrom, et. al.
Biochemistry
, 29, pp. 849-854 (1990)]. These compounds, however, suffer from lack of specificity to IMPDH.
Mycophenolate mofetil, a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute renal allograft rejection following kidney transplantation. [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 Reviews
, 136, pp. 5-28 (1993)]. The glucuronide then undergoes 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.
More recently, IMPDH inhibitors of different classes have been described in PCT publications WO 97/40028 and WO 98/40381.
It is also known that IMPDH plays a role in other metabolic events. Increased IMPDH activity has been 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 proliferation of smooth muscle cells, indicating that inhibitors of 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 publication WO 94/01105].
Additionally, IMPDH has been shown to play a role in viral replication in some virus-infected cell lines. [S. F. Carr,
J. Biol. Chem
., 268, pp. 27286-27290 (1993)]. Analogous to lymphocytes and lymphocytic and tumor cell lines, the implication is that the de novo, rather than the salvage, pathway is critical in the process of viral replication.
Thus, there remains a need for potent IMPDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-vascular hyperproliferative agents, anti-inflammatory agents, antifungal agents, antipsoriatic and anti-viral agents.
SUMMARY OF THE INVENTION
The present invention provides compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of IMPDH. The compounds of this invention can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antibiotics, and immunosuppressants for the treatment or prophylaxis of transplant rejection and autoimmune disease.
Additionally, these compounds are useful, alone or in combination with other agents, as therapeutic and prophylactic agents for antiviral, anti-tumor, anti-cancer, anti-inflammatory agents, antifungal agents, antipsoriatic immunosuppressive chemotherapy and restenosis therapy regimens.
The invention also provides pharmaceutical compositions comprising the compounds of this invention, as well as multi-component compositions comprising additional IMPDH compounds together with an immunosuppressant. The invention also provides methods of using the compounds of this invention, as well as other related compounds, for the inhibition of IMPDH.
DETAILED DESCRIPTION OF THE INVENTION
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:
Designation
Reagent or Fragment
Ac
acetyl
Me
methyl
Et
ethyl
Bn
benzyl
CDI
carbonyldiimidazole
DBU
1,8-diazabicyclo[5.4.0]undec-7-ene
DIEA
diisopropylethylamine
DMAP
dimethylaminopyridine
DMF
dimethylformamide
DMSO
dimethylsulfoxide
DPPA
dip
Badia Michael
Bethiel Scott
Ronkin Steven
Saunders Jeffrey
Stamos Dean
Raymond Richard L.
Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals, Incorporated Nandakumar Govindaswamy
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