KR20000010580A - Urea derivatives as inhibitors of impdh enzyme - Google Patents

Abstract

PURPOSE: Methods for inhibiting the activity of IMPDH using the compounds of urea derivatives and related compounds are provided which relates to pharmaceutical compositions, are particularly well suited for inhibiting IMPDH enzyme activity and consequentially, and may be advantageously used as therapeutic agents for IMPDH mediated processes. CONSTITUTION: A compound of formula I is described: A is selected from:(C1 -C6)-straight or branched alkyl, or (C2 -C6)-straight or branched alkenyl or alkynyl; and A optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from R1 or R3, and the second of the substituents, if present, is R1; B is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, O, or S.

Description

Urea Derivatives as Inhibitors of IMDPH Enzymes

Nucleotide synthesis of organisms requires cell division and replication of these organisms. Nucleotide synthesis in mammals can be carried out via one of two pathways: the de novo synthesis pathway or the salvage pathway. Different types of cells use these pathways to different degrees.

Inosine-5'-monophosphate dehydrogenase (IMPDH; EC 1.1.1 205) is an enzyme associated with de novo synthesis of guanosine nucleotides. IMPDH promotes NAD-dependent oxidation of inosine-5'-monophosphate (IMP) to xanthosine-5'-monophosphate (XMP) [Jackson R. C. Et al., Nature, 256, p 331-333, (1975).

IMPDH is ubiquitous in eukaryotes, bacteria and protists [Wy. Natsumeda & S.F. Kar, Ann. N. Y. Acad., 696, p 88-93 (1993)]. Prokaryotic forms share 30% -40% sequence identity with human enzymes. Regardless of species, the enzyme follows a sequential Bi-Bi reaction sequence of substrate and cofactor binding and product release. First, IMP binds to IMPDH. Then join with the joiner NAD. The reduced cofactor NADH is then released from the product to yield the product XMP [S. F. Carr et al., J. Biol. Chem., 268, p27286-90 (1993); this. W. Holmes et al., Biochim. Biophys. Acta, 364, p209-217 (1974). This mechanism differs from most known NAD-dependent dehydrogenases and requires the addition of a substrate in random order or requires NAD before binding to the substrate.

Two isoforms of human IMPDH, termed type I and type II, have been identified and sequenced [F. R. Kolat and E. Huberman, J. Biol. Chem., 263, p15769-15772, (1988); Why. Natsumeda et al., J. Biol. Chem., 265, p5292-5295, (1990)]. Each is 514 amino acids and has 84% sequence identity. IMPDH Forms I and II form active tetramers in solution and the molecular weight of the subunits is 56 kDa [W. Yamada et al., Biochemistry, 27, p 2737-2745 (1988).

De novo synthesis of guanosine nucleotides and thereby the activity of IMPDH are particularly important for B-lymphocytes and T-lymphocytes. These cells rely on the de novo pathway rather than the recovery pathway to produce a sufficient amount of nucleotides necessary to initiate a proliferative response to a cleavage promoter or antigen [A. C. Alison et al., Lancet II, 1179, (1975) and Ciba Alison et al., Ciba Found. Symp., 48, 207, (1977). Thus, IMPDH is an effective target for selectively inhibiting the immune system without inhibiting the proliferation of other cells.

Immunosuppression, such as phosphatase calcineurin (inhibited by cyclosporin and FK-506); Dihydroorotate dehydrogenase, an enzyme associated with pyrimidine biosynthesis (inhibited by leflunomide and brequinar); Kinase FRAP (inhibited by rapamycin); And various enzymes, including heat shock protein hsp70 (inhibited by deoxysperguarine). [Reference; B.D.Kaan, Immunological Reviews, 136, p29-49 (1993); R. E. Morris, The Journal of Heart and Lung Transplantation, 12 (6), p S275-S286 (1993)].

Inhibitors of IMPDH are also known. U.S. Pat.Nos. 5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184 disclose effective, noncompetitive and reversible inhibitors of human IMPDH type I (K _i = 33 nM) and type II (K _i = 9 nM). Mycophenolic acid (MPA) and some derivatives thereof are disclosed. MPA has been demonstrated to block the response of B-lymphocytes and T-lymphocytes to cleavage promoters or antigens [A. C. Alison et al., Ann. NY Acad. Sci., 696, 63, (1993)].

Immune inhibitors such as MPA are useful drugs for the treatment of transplant rejection and autoimmune diseases. R. Morris, Kidney Intl., 49, Suppl. 53, S-26, (1996). However, MPA is characterized by having undesirable pharmacological properties such as gastrointestinal toxicity and poor bioavailability. L. M. Shaw et al., Therapeutic Drug Monitoring, 17, p 690-699, (1995).

In addition, nucleoside analogs such as thiazopurin, ribavirin and myzoribin inhibit IMPDH. L. Hedstrom et al., Biochemistry, 29, p 849-854 (1990). These compounds, which are competitive inhibitors of IMPDH, lack specificity for this enzyme.

Recently, mycophenolate mofetil, a prodrug that rapidly releases free MPA in vivo, has been recognized to prevent acute renal autograft rejection after kidney transplantation. L. M. Shaw et al., Therapeutic Drug Monitoring, 17, p 690-699, (1995); H. double U. Solinger, Transplantation, 60, p225-232 (1995)]. However, some clinical observations limit the therapeutic efficacy of this drug. L. M. Shaw et al., Therapeutic Drug Monitoring, 17, p690-699, (1995). MPA rapidly metabolizes inactive glucuronide in vivo [A.C. Alison and E. M. Organic, Immunological Reviews, 136, p 5-28 (1993)]. The glucuronide then undergoes recirculation of the intestines, causing the accumulation of MPA in the gastrointestinal pathway that is unable to exert IMPDH inhibitory activity in the immune system. This actually reduces the in vivo efficacy of the drug while increasing undesirable gastrointestinal side effects.

IMPDH is known to play an important role in other metabolism. Increased activity of IMPDH was found when rapidly proliferating human leukemia cell lines and other tumor cell lines, indicating that IMPDH is a target of immunosuppressive chemotherapy as well as anticancer [M. Nagai et al., Cancer Res., 51, p 3886-3890, (1991). IMPDH also appears to play an important role in the proliferation of smooth muscle cells, suggesting that inhibitors of IMPDH, such as MPA or rapamycin, may be useful in preventing restenosis or other hyperproliferative vascular diseases. . Gregory et al., Transplantation, 59, p 655-61 (1995); PCT publication WO 94/12184; And PCT publication WO 94/01105.

IMPDH also appears to play an important role in viral replication in some viral cell lines. S.F.Carr, J. Biol. Chem., 268, p 27286-27290 (1993)]. Similar to lymphocyte and tumor cell lines, viral replication processes are involved in the de novo pathway rather than the recovery pathway.

Ribavirin, an IMPDH inhibitor, is currently useful for treating hepatitis C virus (HCV) and hepatitis B virus (HBV) infections and diseases. Ribavirin increases the sustained effect of interferon in the treatment of HBV and HCV. However, the therapeutic efficacy of ribavirin is limited by the lack of sustained response and widespread cytotoxicity in monotherapy.

Thus, there is a need for an effective IMPDH inhibitor with improved pharmacological properties. These inhibitors have therapeutic efficacy as immunosuppressants, anticancer agents, vascular hyperproliferation inhibitors, anti-inflammatory agents, antifungal agents, psoriasis agents and antiviral agents.

The present invention relates to a new class of compounds that inhibit IMPDH. The present invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of the present invention are particularly suitable for inhibiting IMPDH enzyme activity and consequently can be advantageously used as therapeutic agents for inhibiting the process mediated by IMPDH. The invention also relates to methods of inhibiting the activity of IMPDH using the compounds of the invention and related compounds.

Summary of the Invention

It is a first object of the present invention to provide a compound useful as an inhibitor of IMPDH, a pharmaceutically acceptable derivative thereof. These compounds may be used alone or in combination with therapeutic or prophylactic agents such as antiviral agents, anti-inflammatory agents, antibiotics and immunosuppressants to treat or prevent transplant rejection and autoimmune diseases. In addition, these compounds, alone or in combination with other agents, are useful as antiviral agents, antitumor agents, anticancer agents, anti-inflammatory agents, antifungal agents, psoriasis treatment immunosuppressive chemotherapy and relapse stenosis therapies and prophylactic agents.

It is a second object of the present invention to provide a multicomponent composition further comprising an IMPDH compound together with an immunosuppressive agent as well as a pharmaceutical composition comprising the compound of the present invention. The present invention also provides a method of using the compounds of the present invention and other related compounds to inhibit IMPDH.

Compounds of the invention and compounds used in the methods of the invention exhibit different metabolic profiles than MPA and derivatives thereof. Because of this difference, the methods of the present invention and the compounds used herein may provide utility as therapeutic agents for IMPDH mediated diseases. These advantages increase the overall therapeutic benefit and reduce harmful side effects.

Detailed description of the invention

In order to understand the disclosed invention in more detail, it is described in detail below. In this description, the following abbreviations are used.

Name Reagent or Fragment

Ac acetyl

Me methyl

Et ethyl

Bn benzyl

CDI carbonyldiimidazole

DIEA diisopropylethylamine

DMAP dimethylaminopyridine

DMF Dimethylformamide

DMSO Dimethylsulfoxide

EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

Hydrochloride

EtOAc ethyl acetate

THF tetrahydrofuran

The following terms are used herein.

Unless otherwise stated, "-SO _2- " and "-S (O) ₂ -as used herein refer to sulfones or sulfone derivatives (ie, addition groups bonded to S), but not to sulfinate esters.

"Halo" or "halogen" means a radical of fluorine, chlorine or iodine.

"Immunosuppressant" means a compound or drug that possesses immune response inhibitory activity. Examples of this agent are cyclosporin A, FK506, rapamycin, leflunoamide, deoxysperguarine, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and myzoribin.

"Interferon" refers to all forms of interferon, including but not limited to forms α, β and γ.

IMPDH mediated disease refers to any disease state in which IMDPH enzymes play a regulatory role in disease metabolic pathways. Examples of IMDPH mediated diseases include transplant rejection and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, childhood diabetes, asthma and inflammatory bowel disease, as well as inflammatory, cancer, viral replication and vascular diseases.

For example, the compounds, compositions, and methods of using the present invention can be used for transplant rejection (eg, kidney, liver, heart, lung, pancreatic (pancreatic islet cells), bone marrow, cornea, small intestine, and skin graft and heart plate xenografts). ) And autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, childhood diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitis), lupus, diabetes mellitus, myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea , Pulmonary inflammation, ocular uveitis, hepatitis, Graves' disease, Hashimoto's thyroiditis, Besett's or Sjogren's syndrome (dry eye / oral), malignant or immunohemolytic anemia, idiopathic adrenal insufficiency, polymorphic autoimmune syndrome and glomerulonephritis, scleroderma, Squamous gland, viteligo (pigmentation of the skin), autoimmune thyroiditis and alveolitis, inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma and adult respiratory distress syndrome It can be used for the treatment of cancer and tumors such as solid tumors, lymphomas and leukemias, vascular diseases such as restenosis, stenosis and atherosclerosis, and DNA and RNA viral replication diseases such as retroviral diseases, and herpes.

In addition, IMPDH enzymes are known to be present in bacteria and can regulate bacterial growth. Accordingly, the IMPDH inhibitory compounds, compositions and methods disclosed herein can be used alone or in combination with other antibiotics to treat or prevent bacterial infections.

"Treatment" as used herein means to alleviate the symptoms of a particular disorder in a patient or to improve a detectable test associated with a particular disorder. As used herein, "patient" refers to a mammal, including humans.

"Tiocarbamate" means a compound containing a functional group N-SO ₂ -O.

"HBV", "HCV" and "HGV" mean hepatitis B virus, hepatitis C virus and hepatitis G virus, respectively.

In one aspect of the invention, the invention provides a method of inhibiting IMPDH activity of a mammal, comprising administering to the mammal a compound of formula (I):

Where

A is selected from (C ₁ -C ₆ )-straight or branched chain alkyl or (C ₂ -C ₆ )-straight or branched chain alkenyl or alkynyl, A optionally comprises up to 2 substituents,

Wherein the first substituent, when present, is selected from R ¹ or R ³ ,

The second substituent, if present, is R ¹ ;

B is a saturated, unsaturated or partially saturated monocyclic ring or bicyclic ring optionally comprising up to 4 heteroatoms selected from N, O or S and is selected from:

or

Wherein each X is the number of hydrogen atoms needed to complete the proper valences;

B optionally contains 3 or fewer substituents,

Wherein the first substituent, when present, is selected from R ¹ , R ² , R ⁴ or R ⁵ ,

The second substituent, when present, is selected from R ¹ or R ⁴ ,

The third substituent, if present, is R ¹ ;

D is selected from C (O), C (S) or S (O) ₂ ;

Wherein each R ¹ is each selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R ⁶ or (CH ₂ ) _n -Y

N is 0, 1 or 2;

Y is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, SR ⁶ , S (O) R ⁶ , SO ₂ R ⁶ , NH ₂ , NHR ⁶ , N (R ⁶ ) ₂ , NR ⁶ R ⁸ , COOH, COOR ⁶ or OR ⁶ ;

Each R ² is selected from (C ₁ -C ₄ )-straight or branched chain alkyl, or (C ₂ -C ₄ )-straight or branched chain alkenyl or alkynyl; Each R ² optionally contains 2 or fewer substituents,

Wherein the first substituent, if present, is selected from R ¹ , R ⁴ and R ⁵

The second substituent, if present, is R ¹ ;

R ³ is selected from a monocyclic or bicyclic ring system comprising 5 to 6 members per ring, the ring system optionally comprises up to 4 heteroatoms selected from N, O or S, CH ₂ adjacent to any of the above N, O or S heteroatoms is optionally substituted with C (O); Each R ³ optionally contains up to 3 substituents,

In this case, the first substituent, when present, is selected from R ¹ , R ² , R ⁴ or R ⁵ ,

The second substituent, when present, is selected from R ¹ or R ⁴ ,

The third substituent, if present, is R ¹ ;

Each R ⁴ is OR ⁵ , OC (O) R ⁶ , OC (O) R ⁵ , OC (O) OR ⁶ , OC (O) OR ⁵ , OC (O) N (R ⁶ ) ₂ , OP (O) (OR ⁶ ) ₂ , SR ⁶ , SR ⁵ , S (O) R ⁶ , S (O) R ⁵ , SO ₂ R ⁶ , SO ₂ R ⁵ , SO ₂ N (R ⁶ ) ₂ , SO ₂ NR ⁵ R ⁶ , SO ₃ R ⁶ , C (O) R ⁵ , C (O) OR ⁵ , C (O) R ⁶ , C (O) OR ⁶ , NC (O) C (O) R ⁶ , NC (O) C (O) R ⁵ , NC (O) C (O) OR ⁶ , NC (O) C (O) N (R ⁶ ) ₂ , C (O) N (R ⁶ ) ₂ , C (O) N ( OR ⁶ ) R ⁶ , C (O) N (OR ⁶ ) R ⁵ , C (NOR ⁶ ) R ⁶ , C (NOR ⁶ ) R ⁵ , N (R ⁶ ) ₂ , NR ⁶ C (O) R ¹ , NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ⁵ , NR ⁶ C (O) OR ⁶ , NR ⁶ C (O) OR ⁵ , NR ⁶ C (O) N (R ⁶ ) ₂ , NR ⁶ C (O) NR ⁵ R ⁶ , NR ⁶ SO ₂ R ⁶ , NR ⁶ SO ₂ R ⁵ , NR ⁶ SO ₂ N (R ⁶ ) ₂ , NR ⁶ SO ₂ NR ⁵ R ⁶ , N (OR ⁶ ) R ⁶ , N (OR ⁶ ) R ⁵ , P (O) (OR ⁶ ) N (R ⁶ ) ₂ and P (O) (OR ⁶ ) ₂ , respectively;

Each R ⁵ is a monocyclic or bicyclic ring system consisting of 5 to 6 members per ring, said ring system optionally comprising up to 4 heteroatoms selected from N, O or S, CH ₂ adjacent to O or S may be substituted with C (O); Each R ⁵ optionally contains up to 3 substituents, each of which, if present, is R ¹ ;

Each R ⁶ is each selected from H, (C ₁ -C ₄ ) straight or branched alkyl, or (C ₂ -C ₄ ) straight or branched alkenyl; Each R ⁶ optionally comprises a R ⁷ substituent;

R ⁷ is a monocyclic or bicyclic ring system consisting of 5 to 6 members per ring, said ring system optionally comprising up to 4 heteroatoms selected from N, O or S, and N, O Or CH ₂ adjacent to S may be substituted with C (O); Each R ⁷ is optionally H, (C ₁ -C ₄ ) straight or branched alkyl, or (C ₂ -C ₄ ) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedi Oxy, or up to two substituents each selected from (CH ₂ ) _n -Z;

N is 0, 1 or 2;

Z is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, S (C ₁ -C ₄ ) -alkyl, SO (C ₁ -C ₄ ) -alkyl, SO ₂ (C ₁ -C ₄ ) -alkyl , NH ₂ , NH (C ₁ -C ₄ ) -alkyl, N [(C ₁ -C ₄ ) -alkyl] ₂ , N [(C ₁ -C ₄ ) -alkyl] R ⁸ , COOH, C (O) O (C ₁ -C ₄ ) -alkyl or O (C ₁ -C ₄ ) -alkyl;

R ⁸ is an amino protecting group;

The carbon atom of any A, R ² or R ⁶ is optionally substituted with O, S, SO, SO ₂ , NH or N (C ₁ -C ₄ ) -alkyl.

The term "substituted" means replacing one or more hydrogen radicals of a given structure with a radical selected from a specific group. When one or more hydrogen radicals are substituted with substituents selected from the same specific group, the substituents can be the same or different at all positions.

"Monocyclic or bicyclic ring system consisting of 5 to 6 members per ring" means a 5 to 6 membered monocyclic ring structure and an 8, 9 and 10 membered bicyclic ring structure, of which each ring Each bond may have a chemically possible degree of saturation. Where this structure includes substituents, these substituents may be present at any position in the ring system unless otherwise noted.

In certain cases, the ring system can optionally include up to four heteroatoms selected from N, O or S. These heteroatoms can replace any carbon atom of these ring systems as long as the product is chemically stable.

"Each X is the number of hydrogen atoms needed to complete the proper valence" means that X is 0, 1 or 2 hydrogen atoms, which means the presence of a ring atom to which X is bonded (C, N, O or S) , The presence of two neighboring ring atoms, and the bonding properties (single bond, double bond or triple bond) between the ring atom to which X is bonded and the two adjacent ring atoms. In practice, this definition means that X excludes any substituent other than hydrogen.

"Amino protecting group" means a suitable chemical group capable of bonding to a nitrogen atom. "Protection" means when a designated functional group is bound to a suitable chemical group (protecting group). Examples of suitable amino protecting groups and protecting groups are described in T. Double U. Green and P. G. M. a. Wortz, Protective Groups in Organic Synthesis, 2d, Ed., John Wiley and Sons (1991); L. Fisher and M. Fisher; Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquet Edit, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), illustrating certain chemicals used in the present invention.

In another embodiment, the present invention provides a method of inhibiting IMPDH in a mammal by administering a compound of Formula II.

Wherein B and D are as described above.

In the process using the compounds of formula (I) or (II), component B more preferably comprises 0 to 2 substituents. In an alternative embodiment, the invention provides a method of inhibiting IMPDH in a mammal using a compound of Formula I or II, wherein B comprises at least a single substituent selected from the group defined by R ⁵ . In this embodiment, B is preferably a monocyclic aromatic ring containing at least one substituent which is a monocyclic aromatic ring.

The present invention also provides compounds useful for inhibiting IMPDH. In one embodiment, the IMPDH inhibitory compound comprises a compound of Formula III:

Where

A, B and D are as described above;

E is oxygen or sulfur;

G and G 'are each selected from R ¹ or hydrogen.

In an alternative embodiment, the present invention provides a compound of formula IV.

Where

B, D, E, G and G 'are as described above and B' is a saturated, unsaturated or partially saturated monocyclic ring optionally containing up to 4 heteroatoms selected from N, O or S or Bicyclic rings and are selected from:

or

Wherein each X is the number of hydrogen atoms needed to complete the proper valences;

B 'optionally includes 3 or fewer substituents,

Wherein the first substituent, when present, is selected from R ¹ , R ² , R ⁴ or R ⁵ ,

The second substituent, when present, is selected from R ¹ or R ⁴ ,

The third substituent, if present, is R ¹ ; X, R ¹ , R ² , R ⁴ and R ⁵ are as described above.

Compounds of formula IV wherein B and B 'are simultaneously unsubstituted phenyl and compounds of formula IV wherein B is unsubstituted phenyl and B' is trichlorophenyl, tribromophenyl or triiodophenyl are excluded from the invention.

In the compound of formula IV, B and B 'are preferably phenyl groups containing one or more substituents. These compounds are represented by the following general formula (V).

Wherein K is selected from R ¹ or R ⁴ ; J is selected from R ¹ , R ² or R ⁴ .

Preferred compounds represented by the formula (V) are those wherein D is -C (O)-; A compound in which E is oxygen; J is NR ⁶ C (O) R ⁵ or NR ⁶ C (O) R ⁶ , preferably NR ⁶ C (O) R ⁶ , more preferably N (CH ₃ ) C (O) R ⁶ and even more Preferably a compound that is N (CH ₃ ) C (O) CH ₃ ; K is (CH ₂ ) _n -Y, preferably OCH ₃ (ie, n is 0, Y is OR ⁶ and R ⁶ is CH ₃ ); And G is hydrogen. More preferred compounds of formula (V)

E is oxygen;

J is NR ⁶ C (O) R ⁵ or NR ⁶ C (O) R ⁶ ;

K is (CH ₂ ) _n -Y; And

G is a compound that is hydrogen.

Even more preferred compounds of formula V are

D is -C (O)-;

E is oxygen;

J is NR ⁶ C (O) R ⁶ ;

K is OCH ₃ ; And

G is a compound that is hydrogen.

Most preferred of these compounds are those wherein J is N (CH ₃ ) C (O) R ⁶ .

Alternative preferred compounds of formula (V) J is R ² of the compound, D is -C (O) - is NR ⁶ A compound, E is oxygen, the compounds, J is an R ² (preferably R ⁴ is substituted by R ⁴ C (O) OR ⁵ or NR ⁶ C (O) OR ⁶ , more preferably R ⁴ is NR ⁶ C (O) OR ⁵ , more preferably R ⁴ is NHC (O) OR ⁵ and even more preferably Is a compound in which R ⁴ is NHC (O) -O-3-tetrahydrofuranyl), a compound in which K is (CH ₂ ) _n -Y, preferably K is OCH ₃ , a compound in which G is hydrogen, and

D is -C (O)-;

E is oxygen;

K is OCH ₃ ; And

G is a compound that is hydrogen.

Alternatively, other preferred compounds include compounds represented by the following formula (VI): compounds of formula (VI) wherein K is OCH ₃ and compounds of formula (VI) wherein G is hydrogen.

Another aspect of the invention is that K is selected from R ¹ or R ⁴ ; J is a compound of Formula V selected from R ¹ , R ² , R ⁴ and R ⁹ , wherein R ¹ , R ² and R ⁴ are as described above and R ⁹ is each (C ₁ -C ₄ ) straight chain Or branched alkyl, or (C ₂ -C ₄ ) straight or branched alkenyl or alkynyl; each R ⁹ optionally comprises up to 2 substituents selected from NR ⁶ C (O) OR ¹⁰ and Where R ⁶ is as described above and R ¹⁰ is selected from NR ⁶ R ⁸ , SR ⁶ , SO ₂ R ⁶ ,-(CH ₂ ) _n -SR ⁶ ,-(CH ₂ ) _n -OR ⁶ and OR ⁶ And (C ₁ -C ₅ ) straight or branched chain alkyl optionally comprising up to 2 substituents, wherein n, R ⁶ and R ⁸ are as described above).

In another embodiment, preferred compounds are those represented by Formula VII.

Where

K is selected from R ¹ and R ⁴ ;

A, D, R ¹ and R ⁴ are each as defined in claim 1.

More preferred compounds represented by formula (VII) are those wherein D is -C (O)-, A is NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ⁵ , CH ₂ NR ⁶ C (O) OR ⁶ And CH ₂ NR ⁶ C (O) OR ⁵ , wherein the compound is a monocyclic aromatic ring substituted with one to two substituents selected from the group consisting of: A is CH ₂ NR ⁶ C (O) OR ⁶ and CH ₂ NR ⁶ A compound that is a monocyclic aromatic ring substituted with one to two substituents selected from the group consisting of C (O) OR ⁵ , A is a monocyclic aromatic ring substituted with CH ₂ NR ⁶ C (O) OR ⁵ A compound wherein A is a monocyclic aromatic ring substituted with CH ₂ NHC (O) OR ⁵ , A compound is a monocyclic aromatic ring substituted with CH ₂ NHC (O) O-3-tetrahydrofuryl, and K is (CH ₂ ) _n- Y compound, K is OCH ₃ , and

A is a monocyclic aromatic ring substituted with CH ₂ NHC (O) O-3-tetrahydrofuryl;

X is a compound that is OCH ₃ .

Alternatively, other preferred compounds of the present invention include compounds represented by the following formula (VIII).

Wherein D and K are as defined in claim 1.

Another embodiment is a compound represented by the following formula (IX).

Where

D is selected from C (O), C (S) and S (O) ₂ ;

K is selected from R ¹ and R ⁴ ;

J is selected from R ¹ , R ² and R ⁴ .

More preferred compounds represented by formula (IX) include compounds wherein D is -C (O)-, J is NR ⁶ C (O) R ⁵ or NR ⁶ C (O) R ⁶ , J is NR ⁶ C (O ) R ⁶ compound, J is N (CH ₃ ) C (O) R ⁶ compound, J is N (CH ₃ ) C (O) CH ₃ compound, K is (CH ₂ ) nY compound, K is OCH ₃ phosphorus compound, and

K is OCH ₃ ;

J is N (CH ₃ ) C (O) CH ₃ .

Tables IA, IB and IIB disclose preferred individual compounds of the invention and the preferred compounds used in the compositions and methods of the invention. Table IIA discloses preferred compounds used in the methods of the present invention.

number G K A One H H benzyl

number G K B ' 2 H H 3-methoxyphenyl 3 H H 3-thienyl 4 H H 3,4-difluorophenyl 5 H H 2,5-dimethoxyphenyl 6 H H 3-methylthiophenyl 7 H H 3-bromophenyl 8 H H 3-cyanophenyl 9 H H 3-trifluoromethyl-4-chlorophenyl 10 H H 2-methyl-3-chlorophenyl 11 H H 2-methoxy-5-methylphenyl 12 H H 2-methoxyphenyl 13 H H 3-methoxyphenyl 14 H H 2,5-dimethoxyphenyl 15 H H 3-nitrophenyl 16 H H 4-nitrophenyl 17 H H 3-methylphenyl 18 H H 3-trifluoromethylphenyl

number G K B ' 19 H H 2-trifluoromethylphenyl 20 H H 3-fluorophenyl 21 H H 4-phenoxyphenyl 22 H H 3-chlorophenyl 23 H H 3-chloro-4-fluorophenyl 24 H H 3-aminophenyl 25 H H 3- (hydroxymethyl) phenyl 26 H H 3-acetylenylphenyl 27 H H 3-hydroxyphenyl 29 H H 3-pyridinyl 30 H H 4-pyridinyl 31 H H 2- (5-methyl) thiazolyl 39 H H 3,4-ethylenedioxyphenyl 40 H H 3-methyl-4-nitrophenyl 41 H H 3-trifluoromethyl-4-nitrophenyl 42 H 3-chloro Phenyl 43 H 3-chloro 3-methylphenyl 44 - - - 45 H 3-fluoro Phenyl 46 H 3-fluoro 3-methylphenyl 47 H H 3-carbomethoxymethylphenyl 48 H H 3-carboxyethylphenyl 49 H H 3-dimethylaminophenyl 50 H H 3- [2- (2-methyl) dioxoranyl] phenyl 51 H H 3-aminocarbonylphenyl 53 H H 3- (3-furanyl) -phenyl 54 H H 3-carboxymethylphenyl 55 H 3-methoxy 3-methylphenyl

number G K B ' 56 H 3-methoxy 3-nitrophenyl 57 H 3-chloro 3-carbomethoxymethylphenyl 58 H H 3-amino-5-methylphenyl 59 H 3-methoxy 3-aminophenyl 60 H 3-bromo 3-methylphenyl 61 H 3-chloro 3-chloro-4- (5-oxazolyl) phenyl 62 H 3-chloro 4- (2-methylpyridyl) 63 H 3-chloro 3-carboxymethylphenyl 64 H 3-bromo 3-nitrophenyl 65 H 3-bromo 3-aminophenyl 66 H H 3- [5- (2-methylpyrimidinyl)] phenyl 67 H H 3- (5-oxazolyl) phenyl 68 H 3-chloro 2-thienyl 69 H 3-chloro 3-thienyl 71 H 3-chloro 3-methoxycarbamoyl-phenyl 72 H 3-chloro 3-acetamidophenyl 73 H 3-chloro 3-iodophenyl 74 H 3-methyl Phenyl 75 H 3-methyl 3-methylphenyl 76 methyl 3-chloro 3-methylphenyl 77 methyl H 3-methylphenyl 78 H 3-chloro 3-nitrophenyl 79 H 3-chloro 3-aminophenyl 80 H H 3- (cyclohexylsulfamoyl) phenyl 81 H H 3- (methylsulfamoyl) phenyl 82 H H 3- (phenylsulfamoyl) phenyl 83 H 3-methoxy 3-benzyloxycarbamoyl-phenyl 84 H 3-methoxy 3-acetamidophenyl 85 H 3-chloro 4- (2-methyl) furanyl

number G K B ' 86 H 3-chloro 5- (2-methyl) thienyl 88 H 3-carbomethoxy 3-methylphenyl 89 H 3-carbomethoxy 3-nitrophenyl 91 H 3-chloro 4- (2-nitro) thienyl 92 H 3-chloro 4- (2-hydroxyamino) thienyl 93 H 3-chloro 3- (N-methyl) trifluoroacet amidophenyl 94 H 3-chloro 3- (methylamino) phenyl 95 H 3-chloro 4- (2-amino) thienyl 96 H 3-methoxy 3-trifluoroacetamidophenyl 97 H 3-methoxy 3- (N-methyl) trifluoroacet amidophenyl 98 H 3-methoxy 3- (3'-picolyloxycarbamoyl) phenyl 99 H 3-methoxy 3- (phenoxycarbamoyl) phenyl 100 H 3-methoxy 3-difluoroacetamidophenyl 101 H 3-acetoxymethyl 3-methylphenyl 102 H 3-hydroxymethyl 3-methylphenyl 104 H H 3-nitro-4-fluorophenyl 105 H 3-methoxy 3- (aminomethyl) phenyl [* TFA] 106 H 3-methoxy 5- (N-acetoxy) indolinyl 107 H 3-methoxy 3- (N-methyl) acetamidophenyl 108 H 3-methoxy 3-[(2-oxo-2- (3,4,5-trimethoxyphenyl) acetyl) amino] phenyl 109 H 3-amino 3-methylphenyl 110 H 3-methoxy 3-benzamidophenyl 111 H 3-methoxy 3-phenylacetamidophenyl 112 H 3-methoxy 3-phenylureidophenyl 113 H 3-methoxy 3- (t-butoxycarbamoylmethyl) phenyl 114 H 3-methoxy 3- (cyclopentylacetamido) phenyl 115 H 3-methoxy 3-methylphenyl

compound L 116 NHC (O) -O-t-butyl 117 NCH ₃ C (O) Ot-Butyl 118 NHC (O) O-methyl 119 NHC (O) O-phenyl 120 NHC (O) O- (S) -3-tetrahydrofuranyl 121 NHC (O) O-2-picolinyl 122 NHC (O) O- (S) -5-oxazolidinonylmethyl 123 NHC (O) O-4-carbomethoxyphenyl 124 NHC (O) O-isobutyl 125 NHC (O) O-allyl 126 NHC (O) O-5- (1,3-dioxanyl) 127 NHC (O) O-4-acetamidophenyl 128 NHC (O) O-2-furfuryl 129 NHC (O) O-2-thiofurfuryl 130 NHC (O) O-2-methoxyethyl 131 NHC (O) O-4-tetrahydropyranyl 132 NHC (O) O-cyclohexyl 133 NHC (O) O-cyclopentyl 134 NHC (O) O-2-hydroxyethyl 135 NHC (O) O-cyclohexylmethyl 136 NHC (O) O- (R, S) -3-tetrahydrofuranyl 137 NHC (O) O-3-pyridyl

compound L 138 NHC (O) O-benzyl 139 NHC (O) O-3- (tBOC-amino) propyl 140 NHC (O) O-4-hydroxybutyl 141 NHC (O) O-5-hydroxypentyl 142 NHC (O) O- (R, S) -2-pyranyl 143 NHC (O) O-3- (N-tBOC) -piperidinyl 144 NHC (O) O- (R) -3- (2-oxo-4,4-dimethyl) furanyl 145 NHC (O) O-3-methylthiopropyl 146 NHC (O) O-4-[(2,2-dimethyl) -1,3-dioxanyl] methyl 147 NHC (O) O-2-di- (hydroxymethyl) ethyl 148 NHC (O) O-4- (N-tBOC) -piperidinylmethyl 149 NHC (O) O-3- (N-tBOC) -piperidinylmethyl 150 NHC (O) O- (dibenzyloxymethyl) methyl 151 NHC (O) O-di- (hydroxymethyl) methyl 152 NHC (O) O-2- (N-tBOC) -piperidinylmethyl 153 NHC (O) O-3-piperidinyl-TFA 154 NHC (O) O- (R, S)-(2-tetrahydropyranyl) methyl 155 NHC (O) O-4-piperidinylmethyl-TFA 156 NHC (O) O- (R, S) -tetrahydrofuranylmethyl 157 NHC (O) O-3-methylsulfonylpropyl 158 NHC (O) O-3-piperidinylmethyl-TFA 159 NHC (O) O-2-piperidinylmethyl-TFA 160 NHC (O) O- (R, S) -3-tetrahydrothiophenyl 161 NHC (O) O- (R, S) -3-tetrahydrothiopyranyl 162 NHC (O) O-3-methoxypropyl

number Q ¹ Q ² B 28 3-methoxy 4-methoxy 3-methylphenyl 32 3-nitro H 3-methylphenyl 33 4-cyano H 3-methylphenyl 34 3-methoxy 4-methoxy 3-bromophenyl 35 3-methoxy 4-methoxy 2-methoxy-5-chlorophenyl 36 3-methoxy 4-methoxy 3-fluorophenyl 37 3-methoxy 4-methoxy 3-ethylphenyl 38 3-methoxy 4-methoxy 3-methylthiophenyl 52 3-chloro 4-methoxy 3-nitrophenyl 70 4-cyano 3-chloro 3-methylphenyl 87 1-imidazolyl H 3-methylphenyl 90 3-hydroxymethyl 4-methoxy 3-methylphenyl 103 3- (t-butoxycarbamoylmethyl) H 3- (t-butoxycarbamoylmethyl) phenyl

number Q ₁ Q ₃ 163 Cl N (Me) (Ac) 164 OMe N (Me) (Ac) 165 SMe CH ₂ NHC (O) O- (3s) -tetrahydrofuranyl 166 S (O) ₂ Me N (Me) (Ac) 167 OMe N (Me) (Ac) 168 SMe CH ₂ NHC (O) O- (3s) -tetrahydrofuranyl

Compounds of Table IIA correspond to compounds of formula II wherein one of the B components is phenyl substituted with two substituents, Q ¹ and Q ² . According to formula (II)

Q ¹ is selected from R ¹ , R ² , R ⁴ or R ⁵ ;

Q ² is selected from R ¹ or R ⁴ .

The compounds of the present invention may comprise one or more asymmetric carbon atoms and may therefore occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereoisomers. It is evident that all isomeric forms of these compounds are included in the present invention. Each conformational carbon may be of R or S structure.

Combinations of substituents and variants in the context of the present invention are those which form stable compounds. As used herein, “stable” refers to a compound that has sufficient stability to make and that is capable of preserving the compound for a sufficient time to be useful for use for the purposes described herein (eg, to administer or prophylactically administer to a mammal or Use in the application of chemotherapy). Typically, this compound is stable for at least one week at temperatures below 40 ° C. in the absence of moisture or other chemically reactive conditions.

As used herein, compounds of the present invention, including compounds of Formulas I-IX, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. "Pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salts, esters, salts of esters, or compounds of the invention that can provide (directly or indirectly) a compound of the invention when administered to a recipient It means other derivatives of. Particularly preferred derivatives and prodrugs may be used in parental species to increase the bioavailability of the compound when it is administered to a mammal (e.g., to allow the orally administered compound to be more readily absorbed into the blood). Compared to biological compartments (eg brain or lymphatic system). Preferred prodrugs include derivatives in which groups which increase aqueous solubility or active transport through the digestive tract membrane are added to the structure of the compounds of formulas (I) to (IX).

Pharmaceutically acceptable salts of the compounds of this invention include pharmaceutically acceptable inorganic and organic acids, inorganic bases and organic bases. Examples of suitable acid salts are acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dode Silsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydride Oxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, Phosphate, Picrate, Pivalate, Propionate, Salicylate, Succinate, Sulfate, Tar A rate, thiocyanate, tosylate and undecanoate. Although not per se pharmaceutically acceptable, other acids such as oxalic acid can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from suitable bases include alkali metals (eg sodium), alkaline earth metals (eg magnesium), ammonium and N- (C _1-4 alkyl) ₄ ⁺ salts. The present invention also quaternizes any basic nitrogen containing groups of the compounds disclosed herein. Quaternization may yield a water soluble or fat soluble or dispersible product.

The compounds of the present invention can be synthesized using conventional techniques. It is advantageous for these compounds to be conveniently synthesized from readily available starting materials.

In general, compounds of formulas (I) to (IX) are conveniently obtained by the methods illustrated in the following general synthetic schemes (1 to 3).

In Scheme 1, X-substituted aniline is reacted with Y-substituted phenylisocyanate under standard conditions to form the desired urea. In this process, X and Y may be one or more independent substituents (or suitably protected variants) as exemplified by the ring substituents listed for the compounds of Formulas I-IX described above at any position of the aromatic ring. Can be.

In Scheme 2, the substituted benzaldehyde (here, 2-methoxy-4-nitro-substituted benzaldehyde) is successively treated with tosylmethyl isocyanide to obtain oxazole, and then reduced by catalytic hydrogenation to reduce the desired aniline. Get Under standard conditions the reaction of this aniline with an isocyanate (here m-tosyl isocyanate) gives the desired urea.

Alternative synthetic routes are illustrated in Scheme 3 above. The substituted benzaldehyde (here 4-nit substituted benzaldehyde) is converted to the corresponding oxazolyl aniline, as shown in Scheme 2. This aniline is treated under standard reaction conditions with substituted benzoic acid (here 3-methyl-substituted benzoic acid) and a carboxylic acid activator such as diphenylphosphoryl azide to form the desired urea.

As will be appreciated by those skilled in the art, the foregoing synthetic schemes are not intended to be an exhaustive list of all methods for synthesizing the compounds disclosed and claimed herein. Other methods will be apparent to those skilled in the art. In addition, the various synthetic steps described above may be performed in alternating order or order to provide the desired compound.

Compounds of the present invention can increase selective biological properties with modifications that add appropriate functional groups. These modifications are known in the art and increase biological penetration into a given biological compartment (e.g., blood, lymphatic, central nervous system), increase oral availability, increase solubility for injection, and metabolism This includes changing the product and changing the rate of excretion.

The novel compounds of the present invention are excellent ligands for IMPDH. Thus, these compounds can target and inhibit IMPDH enzymes. Inhibition can be measured by a variety of methods, including, for example, IMP dehydrogenase HPLC analysis (measuring enzyme production of XMP and NADH from IMP and NAD) and IMP dehydrogenase spectrophotometry (measuring enzymatic production of NADH from NAD). [Note: Mr. Montero et al., Clinica Chimica Acta, 238, p 169-178 (1995)].

The pharmaceutical composition of the present invention may be a compound of formula (I), (II) or (VII) or a pharmaceutically acceptable salt thereof; Additional agents selected from immunosuppressive, anticancer, antiviral, anti-inflammatory, antifungal, antibiotic or vascular hyperproliferative compounds; And any pharmaceutically acceptable carrier, adjuvant or excipient. Another composition of the invention is a compound of Formula III-IX or a pharmaceutically acceptable salt thereof; And pharmaceutically acceptable carriers, adjuvants or excipients. The composition may optionally comprise an immunosuppressive agent, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic or an anti-vascular hyperproliferative compound.

"Pharmaceutically acceptable carrier or adjuvant" means a non-toxic carrier or adjuvant when administered with a compound of the present invention to a patient and administered in an amount sufficient to deliver a therapeutic amount of the compound without destroying its pharmacological activity. .

Pharmaceutically acceptable carriers, adjuvants and excipients that may be used in the pharmaceutical compositions of the invention include self-emulsifying drug delivery systems (SEDDS) such as ion exchangers, alumina, aluminum stearate, lecithin, dα-tocopherol polyethyleneglycol 1000 succinate. Surfactant, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, saturated glyceride mixtures, used in pharmaceutical dosage forms such as tween or other similar polymer delivery matrices , Water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based materials, polyethylene glycol, sodium carboxymethylcellulose, poly Acrylate, wax, poly Alkylene-polyoxyalkylene, but this propylene block polymer, polyethylene glycol and wool fat, and the like. chemicals such as hydroxyalkylcyclodextrins, including cyclodextrins such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, or 2-hydroxypropyl-βcyclodextrin and 3-hydroxypropyl-βcyclodextrin It may be advantageous to use modified or other solubilized derivatives to increase delivery of the compounds of formulas (I) to (IX).

The pharmaceutical compositions of the present invention may be administered via oral, parenteral, inhalational injection, topical, rectal, nasal, nasal, vaginal or implanted reservoir. Oral or injection administration is preferred. The pharmaceutical composition of the present invention may comprise any conventional nontoxic pharmaceutically acceptable carrier, adjuvant or excipient. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to increase the stability of the formulated compound or its delivery form. Parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intramuscular, intrasternal, endocardial, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of sterile injectable preparations, such as sterile injectable aqueous suspensions or oily suspensions. This suspension may be formulated by techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. Sterile injection preparations can be sterile injection solutions or suspensions in nontoxic parenterally acceptable diluents or solvents such as 1,3-butanediol. Acceptable excipients and solvents that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fatty oils are conventionally employed as a solvent or suspending medium. For this purpose, any less toxic fatty oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for injectable preparations, and pharmaceutically acceptable natural oils such as olive oil or castor oil, especially their polyoxyethylated forms, are also useful. These oil solutions or suspensions may be prepared as long chain alcohol diluents or dispersants, such as Pharmacopeia Helvetica, Ph. Helv., Or similar dispersants generally used in the formulation of pharmaceutically acceptable dosage forms, such as similar alcohols, carboxycellulose, or emulsions and / or suspensions. Other commonly used surfactants such as tween or span and / or other similar emulsifiers or bioavailability enhancers widely used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can be used for formulation.

The pharmaceutical compositions of the present invention may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. For oral tablets, carriers commonly used include lactose and corn starch. In addition, lubricants such as magnesium stearate are generally added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. In the case of oral administration of an aqueous suspension and / or emulsion, the active ingredient may be suspended or dissolved in an oil phase mixed with the emulsifier and / or suspending agent. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

The pharmaceutical composition of the present invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients, which are dissolved at the rectum and liberate the active ingredient because they are solid at room temperature but liquid at rectum. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

If the desired treatment includes a site or organ that is easily affected by topical administration, topical administration of the pharmaceutical compositions of the invention is particularly useful. When administered topically to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in the carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, polypropylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream containing the active ingredient and the appropriate emulsifier suspended or dissolved in the carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the invention may be applied topically to the lower intestinal route in the form of rectal suppository formulations or suitable enema formulations. Topical transdermal patches are also included in the present invention.

The pharmaceutical composition of the present invention may be administered by nasal spray or inhalation. The composition is prepared according to techniques known in the art of pharmaceutical formulations and comprises benzyl alcohol or other suitable preservatives, absorption accelerators for increasing bioavailability, fluorocarbons and / or solubilizers or dispersants known in the art, It can be prepared in the form of a solution in brine.

An amount of about 0.01 mg to about 100 mg, preferably about 0.5 mg to about 75 mg per kg body weight per day of the IMDPH inhibitory compounds disclosed herein is monotherapy and / or combination therapy for the prevention and treatment of IMPDH mediated diseases. Useful for Usually, the pharmaceutical composition of the present invention is administered about 1 to about 5 times daily, and may alternatively be administered continuously. Such administration may be used for chronic or acute therapy. The amount of active ingredient which can be combined with a carrier material to form a single dosage form depends on the subject treated and the mode of administration. Typical formulations comprise from about 5% to about 95% active ingredient (w / w). Such formulations preferably comprise from about 20% to about 80% active compound.

Compositions of the present invention may comprise a combination of an IMPDH inhibitor of a compound of Formulas (I) -IX and one or more therapeutic or prophylactic agents, both inhibitors and additives being generally about 10% to 100%, more commonly administered in monotherapy. Preferably it should be present in an amount of about 10% to 80%. Additional formulations may be administered separately from the compounds of the present invention as part of multiple uses. Alternatively, these agents may be part of a single dosage form mixed with a compound of the present invention in a single composition.

In a first embodiment, the pharmaceutical composition of the present invention comprises an additional immunosuppressive agent. Examples of additional immunosuppressants include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxysperguarine, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon, and myzoribin It doesn't happen.

In a second embodiment, the pharmaceutical composition of the present invention may further comprise an anticancer agent. Examples of anticancer agents include cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipside, taxol, colchicine, cyclosporin A, phenothiazine , Interferon and thioxanthere, but are not limited thereto.

In a third embodiment, the pharmaceutical composition of the present invention may further comprise an antiviral agent. Examples of antiviral agents include, but are not limited to, cytobin, gangcyclovir, trisodium phosphonoformate, ribavirin, d4T, ddI, AZT and acyclovir.

In a fourth embodiment, the pharmaceutical composition of the present invention may further comprise an inhibitor of vascular hyperproliferation. Vascular hyperproliferation inhibitors include HMG Co-A reductase inhibitors such as lovastatin, thrombolic acid A2 synthase inhibitors, eicosaptannoic acid, cyprostene, trapidyl, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin and 5- (3'-pyridinylmethyl) benzofuran-2-carboxylate, but is not limited thereto.

If the symptoms of the patient are ameliorated, the amount of the compound, composition or combination of the present invention may be maintained as needed. The dosage or frequency, or both, may then be reduced as a function of the symptoms such that the symptoms are alleviated to the desired level and the improved symptoms are retained when treatment should be discontinued. However, patients may require intermittent treatment for a long time upon recurrence of disease symptoms.

As will be appreciated by those skilled in the art, dosages above or below the recited ranges may be required. Specific dosages and treatments for any particular patient may include the specific compound used, age, weight, general state of health, sex, diet, time of administration, rate of excretion, combination of drugs, the severity and progression of infection, and the predisposition of the patient to infection. And the judgment of the treating physician, and may vary depending on various factors.

In another aspect, the present invention provides a method of treating or preventing an IMPDH mediated disease in a mammal, comprising administering to the mammal any of the pharmaceutical compositions and combinations described above. If the pharmaceutical composition comprises only the IMPDH inhibitor of the invention as an active ingredient, the method may further comprise administering to the mammal an agent selected from an anti-inflammatory agent, an immunosuppressive agent, an anticancer agent, an antiviral agent or an anti-vascular hyperproliferative compound. . Additional agents may be administered to the mammal prior to, concurrent with, or after administration of the IMPDH inhibitory composition.

In one preferred embodiment, these methods are useful for inhibiting the immune response of a mammal. This method involves graft rejection (eg, kidney, liver, heart, lung, pancreas (pancreatic islet cells), bone marrow, cornea, small intestine and skin grafts and heart xenografts), graft-versus-host disease and autoimmune diseases such as rheumatoid Arthritis, multiple sclerosis, childhood diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitis), lupus, diabetes mellitus, myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, lung inflammation, ocular uveitis, hepatitis , Graves' disease, Hashimoto's thyroiditis, Besett's or Sjogren's syndrome (dry eye / oral), malignant or immunohemolytic anemia, idiopathic adrenal insufficiency, polymorphic autoimmune syndrome, glomerulonephritis, scleroderma, squamous gland, vitiligo (Pigmentation of the skin), autoimmune thyroiditis and alveolitis, are useful for the treatment or prevention of diseases.

These methods include administering to a mammal a composition comprising any compound of Formulas I-IX and a pharmaceutically acceptable adjuvant. In a preferred embodiment, this particular method further comprises administering to the mammal a composition comprising an additional immunosuppressive agent and a pharmaceutically acceptable adjuvant.

Alternatively, the process may comprise a compound represented by formulas (I) to (IX); Administering to the mammal a composition comprising an additional immunosuppressant and a pharmaceutically acceptable adjuvant.

In another preferred embodiment, these methods are useful for inhibiting viral replication in mammals. This method includes, for example, HTLV-1 and HTLV-2, HIV-1 and HIV-2, parapharyngeal cancer virus, HBV, HCV, HGV, yellow fever virus, dengue virus, Japanese encephalitis virus, human papillose virus, rhinovirus and It is useful for preventing or treating DNA and RNA viral diseases caused by herpes viruses such as Epstein-Barr virus, cytomegalovirus and herpes simplex type 1 and 2 or 6. [Reference, US Patent 5,380,879].

These methods include administering to a mammal a composition comprising any compound of Formulas I-IX and a pharmaceutically acceptable adjuvant. In one preferred embodiment, the method comprises the additional step of administering to the mammal a pharmaceutical composition further comprising an antiviral agent and a pharmaceutically acceptable adjuvant.

Alternatively, the present invention provides a compound of formula I to IX; Administering to the mammal a composition comprising an additional antiviral agent and a pharmaceutically acceptable adjuvant.

In another preferred embodiment, these methods are useful for inhibiting vascular cell hyperproliferation in mammals. This method is useful for treating or preventing diseases, including restenosis, stenosis, arteriosclerosis, and other hyperproliferative vascular diseases.

These methods include administering to a mammal a composition comprising a compound of Formula I-IX and a pharmaceutically acceptable adjuvant. In one preferred embodiment, the method further comprises administering to the mammal a composition comprising a further vascular hyperproliferation inhibitor and a pharmaceutically acceptable carrier.

Alternatively, the method may comprise a compound represented by formulas (I) to (IX); Administering to the mammal a composition comprising an additional vascular hyperproliferation inhibitor and a pharmaceutically acceptable adjuvant.

In another preferred embodiment, these methods are useful for inhibiting tumors and cancers of a mammal. This method is useful for treating or preventing diseases, including tumors and drugs, such as lymphomas, leukemias and other types of cancer.

These methods include administering to a mammal a composition comprising any compound of Formulas I-IX and a pharmaceutically acceptable adjuvant. In one preferred embodiment, the method comprises the further step of administering to the mammal a composition comprising an additional antitumor or anticancer agent and a pharmaceutically acceptable adjuvant.

Alternatively, the method may comprise a compound of Formulas I-IX; Administering to the mammal a composition comprising an additional antitumor or anticancer agent and a pharmaceutically acceptable adjuvant.

In another preferred embodiment, these methods are useful for inhibiting inflammation and inflammatory diseases in mammals. This method is useful for the prevention or treatment of diseases including osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma and adult respiratory distress syndrome.

These methods include administering to a mammal a composition comprising a compound of Formulas I-IX and a pharmaceutically acceptable adjuvant. In one preferred embodiment, the method further comprises administering to the mammal a composition comprising an anti-inflammatory agent and a pharmaceutically acceptable adjuvant.

In order to understand the present invention in more detail, the following examples are disclosed. These examples are illustrative only and are not intended to limit the scope of the invention.

Common Materials and Methods

Record all temperatures in degrees Celsius. Thin layer chromatography (TLC) was performed by eluting with a designated solvent system using an _E. Merck silica gel 60 F ₂₅₄ plate of 0.25 mm thickness. The plate was treated with a suitable visualizer such as a 10% phosphomolybic acid solution in ethanol or 0.1% ninhydrin solution in ethanol and then heated and / or exposed to ultraviolet or iodine vapor at appropriate times to detect the compound. Analytical HPLC using Rainin Mycrosorb-MV, 5 μ cyano reverse phase column, 3.9 mm × 150 mm, flow rate of 1.0 mL / min and 5-100% acetonitrile in water (0.1%) TFA) solvent gradient. HPLC retention time was recorded in minutes. NMR spectral data were obtained using Bruker AMX500 in the designated solvent.

IMP dehydrogenase HPLC analysis followed standard conditions for the enzymatic production of XMP and NADH from IMP and NAD, but using high pressure liquid chromatography on a C18 column with ion pair reagents to separate all four components. . The reaction range was then determined by product peak area. This assay is particularly useful for determining the inhibition profile of compounds that exhibit significant absorbance in the UV-visible region of 290 nM to 340 nM.

The reaction mixture is usually 0.1 M KPi; pH 8.0, 0.1 M KCl, 0.5 mM EDTA, 2 mM DTT and 0.2 mM of IMP and NAD, respectively. This solution was incubated at 37 ° C. for 10 minutes. The enzyme is added to initiate the reaction so that the final concentration is between 20 nM and 100 nM and the reaction is allowed to proceed for 10 minutes. After the allotted time, the reaction is terminated by adding mycophenolic acid to a final concentration of 0.01 mM.

The degree of conversion was 0-30% for 15 minutes using a solvent system comprising a Linin microsolve ODS column C18-200 with dimensions 4.6 mm x 10 mm and tetrabutylammonium sulfate (5 mM) in 0.1 M KPi pH 6.0. Monitored by methanol gradient HPLC. Similar solvent systems have already been used to purify halo-IMP derivatives. [L.C. Antiion and Jay C. Wu, Biochemistry, 33, 1753-1759 (1994)]. Four components are detected using a UV monitor set at 254 nM and the product peak is integrated to determine the conversion of the substrate.

For inhibition assays, the compound is dissolved in DMSO to a final concentration of 20 mM and added to the initial assay mixture at the desired concentration of 2% by volume to 5% by volume (v / v). The reaction is initiated by addition of the enzyme and terminated as described above after 10 minutes. After HPLC analysis, the production area is used to determine the conversion for a control containing only DMSO and no test compound. IC50 or Ki values are determined by substituting nonlinear least squares for Henderson's close coupling equation of the conversion versus concentration curve. [PJ.F. Henderson, Biochem. J., 127, 321 (1972).

We applied the method first reported by Magasani to determine the inhibition constant of each compound for IMPDH. [B.Magasanik, H. s. Moide and L. B. Gering, J. Biol. Chem., 226, p 339 (1957).

As long as the compounds of Formulas (I) to (IX) inhibit IMPDH, there is obvious clinical utility for the treatment of IMPDH mediated diseases. These tests anticipate the compound's ability to inhibit IMPDH in vivo.

Representative Examples of Synthesis

Example 1

Synthesis of Compound 1

50 μl (400 μmol) benzyl isocyanate was added to a 25 mg (156 μmol) 4- (5-oxazolyl) -aniline solution in 250 μl CH ₂ Cl ₂ at room temperature. After stirring overnight, the compound of 1 was isolated in pure form by filtration with a 3: 1 hexanes / CH ₂ Cl ₂ detergent to afford 21 mg (46%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86 (s), 7.55 (d), 7.38 (d), 7.22-7.35 (m), 6.39 (s), 5.0 (br s), 4.43 (s). R _f 0.30 (5% MeOH / CH ₂ Cl ₂ ).

Example 2

Synthesis of Compound 43

Concentrated H ₂ SO ₄ (6.9 mL) was added dropwise to a solution of glacial acetic acid (46 mL), acetic anhydride (46 mL, 485 mmol) and 2-chloro-4-nitrotoluene (5 g, 29.1 mmol) at 0 ° C. At the end of the addition, CrO ₃ (8.08 g, 80.8 mmol) was added in portions for 60 minutes. After further stirring at 0 ° C. for 15 minutes, the reaction mixture was poured onto ice and the resulting precipitate was separated by filtration and washed with cold H ₂ O. Purification by flash chromatography eluting with a gradient of 15% -50% EtOAc in hexanes yielded 2.02 g (24%, 40% based on recovered starting material) B1 as a white solid. ¹ H NMR was consistent with that of the desired structure.

Compound B1 was dissolved in 1: 1 ethanol / water (20 mL), treated with concentrated H ₂ SO ₄ (2 mL) and refluxed for 1 h. After cooling to room temperature, the reaction was extracted three times with diethyl ether. The ethereal solution was washed twice with water, dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow solid. The purified product was obtained through two recrystallizations from hot Et ₂ O / hexanes to give 620 mg (47.6%) of B2 as a light yellow crystalline solid. ¹ H NMR was consistent with that of the desired structure.

A mixture of B2 (200 mg, 1.2 mmol), tosylmethyl isocyanide (236 mg, 1.2 mmol) and powder K ₂ CO ₃ (172 mg, 1.2 mmol) in methanol (13 mL) was heated at reflux for 90 minutes and Stir overnight at room temperature. Upon concentration to dryness, the mixture was partitioned between CH ₂ Cl ₂ and water. The organics were separated, washed with 0.5N HCl, water and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo to yield a crude yellow solid. Purified product B3 is CH ₂ Cl ₂ from 0% ~2.5% CH ₃ OH with flash chromatography and recrystallized (CH ₂ Cl ₂ / hexanes) eluted with a gradient of a light yellow crystalline solid to give the 3.3 g (68%) . ¹ H NMR was consistent with the results of the desired structure.

A solution of B3 (150 mg, 0.67 mmol) in ethanol (7.5 mL) was treated with SnCl ₂ · 2H ₂ O (excess; about 5 equivalents) and heated at reflux for 30 minutes. The mixture was cooled to room temperature, diluted with diethyl ether and partitioned with 2N NaOH. The organics were separated, washed with water and brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. Purified product B4 was obtained by flash chromatography eluting with a gradient of 0% to 0.5% CH ₃ OH in CH ₂ Cl ₂ to give 54 mg (41.5%) as a light yellow crystalline oil. ¹ H NMR was consistent with the results of the desired structure.

20 μl of m-tosyl isocyanate was added to a 20 mg (103 μmol) B4 solution in 1 mL of CH ₂ Cl ₂ at room temperature. After stirring overnight, 43 was purified by filtration with EtOAc / hexane cleaners to give 25 mg (74%). ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.06 (s), 8.73 (s), 8.50 (s), 7.89 (s), 7.73 (d), 7.67 (s), 7.42 (d), 7.31 ( s), 7.23 (d), 7.18 (t), 6.82 (d), 2.27 (s). R _f 0.28 (5% MeOH / CH ₂ Cl ₂ ).

Example 3

Synthesis of Compound 56

C1 (8.14 g, 51%) was prepared from 2-methyl-5-nitroanizol (10.0 g, 60 mmol) in a similar manner to the preparation of B1 as described above. ¹ H NMR was consistent with the results of the desired structure.

A stirred suspension of C1 (81.94 g, 307 mmol) in dioxane (100 mL) was treated with concentrated HCl (20 mL) and heated at reflux overnight. Upon cooling to room temperature, the product C2 precipitated as a light yellow crystalline solid, yielding 40.65 g (73.1%). The filtrate was concentrated to a volume of about 80 mL and the second product of the product crystals was derived from the solution by addition of hexane to give 8.91 g (16.0%). Both batches were identical by ¹ H NMR and TLC analysis and were consistent with those of the desired material. The total yield of C2 was 49.56 g (89.1%).

A solution of C2 (456 mg, 2.51 mmol), tosylmethyl isocyanide (490 mg, 2.51 mmol) and K ₂ CO ₃ (347 mg, 251 mmol) was dissolved in methanol and heated at reflux for 1.5 hours. The resulting mixture was then concentrated in vacuo, redissolved in CH ₂ Cl ₂ , washed with water and brine, dried over Na ₂ SO ₄ and then concentrated in vacuo again. Purified product C3 gave 375 mg (68%) through recrystallization (Et ₂ O / hexane). ¹ H NMR was consistent with the results of the desired structure.

C3 (4.214 g, 19.1 mmol) solution in EtOAc (150 mL) was treated with 10% Pd / C (1.05 g, 25 wt% of C3) and overnight at 40 psi H ₂ (g) (Parr hydrogenation unit ) Was added. The reaction mixture was filtered and concentrated in vacuo. Pure product C4 gave 3.4 g (93%) by flash chromatography eluting with a 30% -40% EtOAc / hexanes gradient. ¹ H NMR was consistent with the results of the desired structure.

Tolyl isocyanate (25 μl, 0.197 mmol) was added to a solution of C4 (25 mg, 0.131 mmol) in CH ₂ Cl ₂ (1 mL) at room temperature. After stirring overnight, the mixture was filtered through CH ₂ Cl ₂ detergent to separate 56 in pure form to give 42 mg (74%). ¹ H NMR (500 MHz, d ₆ -DMSO) δ 8.87 (s), 8.64 (s), 8.37 (s), 7.60 (d), 7.46 (d), 7.42 (s), 7.33 (s), 7.23 ( d), 7.16-7.19 (t), 7.05 (dd), 6.80 (d), 3.92 (s), 2.28 (s). R _f 0.46 (5% MeOH / CH ₂ Cl ₂ ).

Example 4

Synthesis of Compound 59

To a solution of C4 (75 mg, 0.394 mmol) in dichloroethane (5 mL) at room temperature was added 3-nitrophenyl isocyanate (97 mg, 0.591 mmol). After stirring overnight, the mixture was filtered with CH ₂ Cl ₂ detergent to give 110.3 mg (79%) of D1 in pure form. ¹ H NMR was consistent with the results of the desired structure.

To a stirred suspension of D1 (95 mg, 0.268 mmol) in EtOH (20 mL) was added SnCl ₂ · 2H ₂ O (302 mg, 1.34 mmol). The reaction mixture is refluxed for 1.5 hours, at which time dissolution occurs. The solution was cooled to room temperature, diluted with EtOAc, washed with 2N NaOH and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification product 59 was subjected to flash chromatography eluted with a gradient of 2.5% to 5% MeOH in CH ₂ Cl ₂ and then selectively crystallized the desired material from fractions with some impurities to give 15.7 mg (18%). ¹ NMR (500 MHz, d ₆ -DMSO) δ 8.83 (s), 8.44 (s), 8.35 (s), 7.59 (d), 7.48 (d), 7.40 (s), 6.97-7.04 (dd), 6.86 -6.92 (t), 6.83 (d), 6.54 (dd), 6.20 (dd), 5.05 (br s), 3.92 (s). R _f 0.20 (5% MeOH / CH ₂ Cl ₂ ).

Example 5

Synthesis of Compound 113

Treatment of 3-aminobenzylamine (826 mg, 6.87 mmol) and triethylamine (2.39 mL, 17.18 mmol) with di-t-butyldicarbonate (1.50 g, 6.87 mmol) and the mixture at room temperature for 2 hours Stirred at. The reaction was then diluted with CH ₂ Cl ₂ , washed with NaHCO ₃ (aq), water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Flash chromatography eluted with 25% EtOAc in hexanes to give 200 mg (46%) of pure E1. ¹ H NMR was consistent with the results of the desired structure.

A solution of C4 (150 mg, 0.789 mmol) and 1,1-dicarbonylamidazole (160 mg, 0.986 mmol) was mixed in TFH (5 mL) and stirred at room temperature for 6 hours. Imidazole precipitated out. Then E1 (351 mg, 1.58 mmol) and N, N-dimethylaminopyridine (97 mg, 0.789 mmol) were added thereto, and the mixture was refluxed overnight to obtain a homogeneous solution. Upon cooling to room temperature, the reaction was diluted with EtOAc (20 mL), washed with KHSO ₄ (aq), water and brine, dried (MgSO ₄ ) and concentrated. Flash chromatography eluted with a 20-30-35% acetone gradient in hexanes to give 164 mg (47%) of pure 113. ¹ NMR (500 MHz, d ₆ -DMSO) δ 8.90 (s), 8.75 (s), 8.38 (s), 7.60 (d), 7.51 (d), 7.3-7.46 (m), 7.21-7.27 (t) , 7.05 (dd), 6.87 (d), 4.12 (d), 3.93 (s), 1.44 (s). R _f 0.21 (5% MeOH / CH ₂ Cl ₂ ).

Example 6

Synthesis of Compound 70

A solution of 3-chloro-4-cyanoaniline (500 mg, 7.76 mmol) and m-tolylisocyanate (1.0 mL, 3.17 mmol) in CH ₂ Cl ₂ (3 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and MPLC eluted with 1% MeOH in CH ₂ Cl ₂ gave 285 mg (31%) of pure compound 70. ¹ NMR (500 MHz, d ₆ -DMSO) δ 9.36 (s), 8.88 (s), 7.94 (s), 7.83 (d), 7.44 (d), 7.30 (s), 7.24 (d), 7.15-7.20 (t), 6.82 (d), 2.29 (s). R _f 0.36 (5% MeOH / CH ₂ Cl ₂ ).

Example 7

Synthesis of Compound 108

To a solution of 3,4,5-trimethoxyacetophenone (9.2 g, 43.4 mmol) in pyridine (35 mL) was added selenium dioxide (6.3 g, 56.7 mmol) and the resulting solution was heated at reflux overnight. The reaction mixture was cooled to room temperature, filtered through celite and concentrated to give a dark brown oil, which was dissolved in ethyl acetate, washed with 1.0N HCl and washed with saturated NaHCO ₃ . The basic aqueous layer was diluted with ether and acidified with concentrated HCl. The layers were separated and the organic phase was washed with brine and dried (Na ₂ SO ₄ ) to give 8.4 g of a dark brown solid. This material was recrystallized from ethyl acetate-hexane to give G1 (6.8 g) as a light yellow solid. ¹ H NMR was consistent with the results of the desired structure.

A mixture of 59 (64 mg, 0.20 mmol), G1 (300 mg, 1.20 mmol) and EDC (300 mg, 1.6 mmol) in THF (5 mL) was stirred overnight at room temperature. The reaction was diluted with EtOAc (150 mL), washed with water, dried (MgSO ₄ ) and concentrated in vacuo. 37.4 mg (35%) of pure 108 was obtained via MPLC eluted with a gradient system of 0-1% MeOH in CH ₂ Cl ₂ . ¹ NMR (500 MHz, d ₆ -DMSO) δ 9.83 (s), 8.23 (s), 8.18 (s), 7.65 (s), 7.61 (s), 7.35 (d), 7.33 (s), 7.29 (s ), 7.27 (s), 7.11 (s), 7.06-7.10 (t), 6.94-6.99 (t), 6.52 (d), 3.68 (s), 3.63 (s), 3.61 (s). R _f 0.26 (5% MeOH / CH ₂ Cl ₂ ).

Example 8

Synthesis of Compound 115

A solution of 59 (300 mg, 1.58 mmol) and m-tolyl isocyanate (2.0 mL, 14.7 mmol) in CH ₂ Cl ₂ (5 mL) was stirred overnight at room temperature. To terminate the reaction, additional m-tolyl isocyanate (1.0 mL, 7.4 mmol) was added and the mixture was heated at reflux for 3 hours. The reaction was concentrated in vacuo and 210 mg (39%) of 115 in pure form was obtained via MPLC eluted with 0-5% EtOAc in CH ₂ Cl ₂ . ¹ NMR (500 MHz, d ₆ -DMSO) δ 7.90 (s), 7.89 (s), 7.82 (s), 7.75 (d), 7.64 (s), 7.44 (s), 7.32-7.37 (t), 7.27 (s), 7.13-7.21 (m), 6.91 (dd), 3.98 (s), 2.40 (s). R _f 0.36 (5% MeOH / CH ₂ Cl ₂ ).

Example 9

Synthesis of Compound 97

A solution of nitroaniline (1.0 g, 7.13 mmol) in CH ₂ Cl ₂ (25 mL) was treated with pyridine (2.9 mL, 36 mmol) and trifluoroacetic anhydride (5 mL, 36 mmol) and kept at room temperature for 3 hours. Stirred. The reaction was further diluted with CH ₂ Cl ₂ , washed with 1N HCl and brine, dried (MgSO ₄ ) and concentrated in vacuo to give I1 (1.61 g, 95%) as a white solid. ¹ H NMR was consistent with the results of the desired structure.

To a slurry of NaH (60% oil dispersion; 34 mg, 1.42 mmol) in THF (10 mL) at 0 ° C. was added a solution of I1 (200 mg, 0.85 mmol) in THF (10 mL) and the mixture was stirred for 1 h. It was. To this was added methyl iodide (100 μl, 1.7 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with EtOAc. The organics were separated, dried (MgSO ₄ ) and concentrated in vacuo. Flash chromatography eluted with 5% EtOAc in hexanes to give 163 mg (66%) of pure I2 as a yellow solid. ¹ H NMR was consistent with the results of the desired structure.

A solution of I2 (163 mg, 0.66 mmol) in ethanol (5 mL) was treated with Pd / C (20 mg) and H ₂ (1 atm) was added for 3 hours. The reaction was filtered and concentrated in vacuo to give I3 (120 mg, 84%) as a waxy solid. ¹ H NMR was consistent with the results of the desired structure.

To a solution of triphosgen (31 mg, 0.104 mmol) in dichloroethane (1 mL) was added dropwise a solution of B4 (50 mg, 0.260 mmol) and diisopropylethylamine (67 mg, 518 mmol) in dichloroethane (5 mL). . The reaction mixture was stirred for another 1 h at room temperature, treated with I3 (50 mg, 0.230 mmol) and stirred overnight. The entire reaction mixture was subjected to flash chromatography eluting with 1% MeOH in CH ₂ Cl ₂ to give 8 mg (7%) of pure 97. ¹ NMR (500 MHz, d ₆ -DMSO) δ 9.20 (s), 8.98 (s), 8.39 (s), 7.67 (s), 7.63 (d), 7.48 (s), 7.38-7.45 (m), 7.04 -7.10 (t), 3.95 (s), 3.31 (s). R _f 0.37 (5% MeOH / CH ₂ Cl ₂ ).

Example 10

Synthesis of Compound 111

A solution of 59 (50 mg, 0.154 mmol) and triethylamine (31 mg, 0.308 mmol) in DMF (0.5 mL) was added dropwise with phenylacetyl chloride (25 mg, 0.169 mmol) and the reaction stirred at room temperature overnight. The mixture was diluted with CH ₂ Cl ₂ , washed with NaHCO ₃ (aq) and water, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography eluted with 2% MeOH in CH ₂ Cl ₂ gave 42 mg (62%) of pure 111. ¹ NMR (500 MHz, d ₆ -DMSO) δ 10.20 (s), 8.90 (s), 8.79 (s), 8.39 (s), 7.88 (s), 7.63 (d), 7.53 (d), 7.44 (s ), 7.25-7.40 (m), 7.22 (t), 7.14 (d), 7.05 (dd), 3.96 (s), 3.66 (s). R _f 0.31 (5% MeOH / CH ₂ Cl ₂ ).

Example 11

Synthesis of Compound 102

A solution of 2-methyl-5-nitrobenzoic acid (15 g, 82.8 mmol) in DMF (75 mL) was treated with methyl iodide (6.7 mL, 107.64 mmol) followed by powder K ₂ CO ₃ (17.2 g, 124.2 mmol). Treated (excessive exotherm) and the suspension was stirred overnight at room temperature. The reaction mixture was partitioned between EtOAc and water, the organics separated and washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give K1 (15.86 g, 98%) in pure form as an off-white solid. Got. ¹ H NMR was consistent with the results of the desired structure.

K2 (4.09 g, 16.2%) was prepared from K1 (15.86 g, 81.3 mmol) in a similar manner to the preparation of B1 as described above. ¹ H NMR was consistent with the results of the desired structure.

A solution of K2 (2.5 g. 8.03 mmol) in dioxane (10 mL) was treated with concentrated hydrochloric acid (0.5 mL) and the mixture was heated at reflux for 2 hours. Additional concentrated HCl (0.5 mL) was added and the reaction was refluxed for another 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Flash chromatography eluted with a 20-30-50% Et ₂ O gradient in hexanes yielded 1.14 g (68%) of pure K3. In addition, 215 mg (11.8%) of hydrated aldehyde was isolated. ¹ H NMR was consistent with the results of the desired structure.

A solution of K3 (300 mg, 1.43 mmol) in benzene (5 mL) was treated with 1,3-propanediol (114 μl, 1.573 mmol) and p-TsOH.H ₂ O (27 mg, 0.14 mmol) and 4.5 hours The mixture was refluxed while Dean-Stark was removed while water. The reaction was cooled to room temperature and partitioned between EtOAc and dilute NaHCO ₃ , the organics separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Flash chromatography eluted with a gradient of 20% to 25% Et ₂ O in hexanes gave 324 mg (84.5%) of pure K4 as an off-white crystalline solid. ¹ H NMR was consistent with the results of the desired structure.

A solution of K4 (289 mg, 1.08 mmol) in THF (5 mL) at 0 ° C. was added dropwise with DIBAL (1.0 M in CH ₂ Cl ₂ ; 2.7 mL, 2.7 mmol) solution and stirred for 40 minutes. Saturated Rochelle's salt solution (10 mL) was added to terminate the reaction, diluted with EtOAc and stirred for 30 minutes. The organics were recovered, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 250 mg (97%) of K5 as a white crystalline solid. ¹ H NMR was consistent with the results of the desired structure.

A solution of K5 (250 mg, 1.05 mmol) in CH ₂ Cl ₂ (4 mL) at 0 ° C. was treated with pyridine (110 μl, 1.37 mmol), benzoyl chloride (146 μl, 1.26 mmol) and 4-DMAP (catalyst amount) , Was stirred at room temperature overnight. The reaction mixture was diluted with CH ₂ Cl ₂ , washed with 0.5 N HCl, brine and water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Flash chromatography eluted with 10% EtOAc in hexanes gave 340 mg (99%) of pure K6 as a white solid. ¹ H NMR was consistent with the results of the desired structure.

A solution of K6 (326 mg, 0.99 mmol) in dioxane (7 mL) was treated with 2.0 N HCl (5 mL) and the mixture was heated at 80 ° C. overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO ₃ (aq), water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Flash chromatography eluted with 30% Et ₂ O in hexanes gave 208 mg (77.5%) of pure K7 as a white solid. ¹ H NMR was consistent with the results of the desired structure.

A solution of K7 (208 mg, 0.729 mmol) in MeOH (6 mL) was treated with K ₂ CO ₃ (101 mg, 0.765 mmol) and TosMIC (149 mg, 0.765 mmol) and the solution was heated at 60 ° C. for 1 h. The reaction is concentrated in vacuo, redissolved in CH ₂ Cl ₂ and washed with 1.0N NaOH (diluted with saturated NaHCO ₃ ). The aqueous portion was back extracted with CH ₂ Cl ₂ , the organics were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Flash chromatography, eluting with a 10% to 50% acetone gradient in hexane, gave 70 mg (44%) of pure K8. ¹ H NMR was consistent with the results of the desired structure.

A solution of K8 (70 mg, 0.318 mmol) in acetic anhydride (1.5 mL) and pyridine (1.0 mL) was treated with 4-DMAP (catalyst amount) and stirred at room temperature for 3 hours. The mixture was diluted with CH ₂ Cl ₂ , washed with 1.0 N HCl, water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 82 mg (98%) of K9 as a pale yellow solid. ¹ H NMR was consistent with the results of the desired structure.

A solution of K9 (80 mg, 0.305 mmol) in anhydrous EtOH (4 mL) was treated with SnCl ₂ · 2H ₂ O (241 mg, 1.07 mmol) and the mixture was heated at 60 ° C. for 50 minutes. The reaction was diluted with EtOAc, washed with saturated NaHCO ₃ , water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Flash chromatography eluted with a gradient of 20% to 30% acetone in hexane to give 52 mg (73.4%) of pure K10 as light yellow oil. ¹ H NMR was consistent with the results of the desired structure.

A solution of K10 (52 mg, 0.224 mmol) in dichloroethane (2 mL) was treated with m-tolyl isocyanate (43 μl, 0.336 mmol) and stirred at room temperature overnight. The mixture was diluted with CH ₂ Cl ₂ : hexanes (2: 1), filtered and washed with the same solvent system to give K11 (67 mg, 82%) as a white solid. ¹ H NMR was consistent with the results of the desired structure.

A K11 (33 mg, 0.09 mmol) solution in MeOH (2 mL) was treated with 1.0 N NaOH (135 μl, 0.135 mmol) and stirred at room temperature for 1.5 hours. 1.0 N HCl (135 μl) was added to neutralize the reaction and concentrated in vacuo. The white solid was washed with water and CH ₂ Cl ₂ : hexanes (2: 1) and dried in vacuo to give 102 (20 mg, 68%) as a white solid. ¹ NMR (500 MHz, d ₆ -DMSO) δ 9.29 (s), 9.00 (s), 8.42 (s), 7.69 (s), 7.55 (m), 7.37 (s), 7.33 (s), 7.27 (d ), 7.16 (t), 6.80 (d), 5.39 (t), 4.58 (s), 2.28 (s). R _f 0.13 (1: 1 hexanes / acetone).

Example 12

Synthesis of Compound 106

C4 (50 mg, 0.263 mmol) solution in THF (2 mL) was treated with CDI (53 mg, 0.330 mmol) and stirred at room temperature for 4 hours. To this was added 1-acetyl-6-aminoindole (93 mg, 0.526 mmol, Sigma Chemical Company) and 4-DMAP (35 mg, 0.289 mmol) and the mixture was refluxed overnight. Diluted with EtOAc (100 mL), washed with 5% KHSO ₄ , water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Redissolved in EtOAc and filtered to remove insoluble material and reconcentrated in vacuo. Flash chromatography eluted with a gradient of 50% to 60% acetone in hexane to give 37 mg (36%) of pure Compound 106 as a white solid. ¹ NMR (500 MHz, d ₆ -DMSO) δ 8.79 (s), 8.74 (s), 8.37 (s), 8.11 (s), 7.62 (d), 7.47 (s), 7.43 (s), 7.30 (d ), 7.13 (d), 7.14 (d), 4.11 (t), 3.94 (s), 3.07 (t), 2.17 (s). R _f 0.14 (1: 1 hexanes / acetone).

Example 13

To a suspension of 113 (obtained in Example 5) (250 mg, 5.76 mmol) in CH ₂ Cl ₂ (1 mL) was added dropwise addition of trifluoroacetic acid and stirred for 90 minutes. The resulting solution was stripped in vacuo and triturated with CH ₂ Cl ₂ and methanol. Isolation by filtration gave 258 mg (99%) of pure product 168. ¹ H NMR was consistent with the results of the desired structure.

A suspension of 168 (250 mg, 0.55 mmol) in 21 mL of CH ₂ Cl ₂ / DMF (20: 1 by volume) was treated with triethylamine (193 μl, 1.38 mmol) and room temperature until a homogenate was obtained. Stirred at. The solution was cooled to 0 ° C. and treated with (S) 3-tetrahydrofuranyl-N-oxysuccinimidyl carbonate (635 mg, 0.608 mmol) and stirred overnight while warming to room temperature. The mixture was poured into ethyl acetate (500 mL), washed with NaHCO ₃ (aq) (twice), water (twice) and brine (once), dried (Na ₂ SO ₄ ) and stripped in vacuo. Isolation by trituration (30 mL CH ₂ Cl ₂ , 100 mL ether) gave 212 mg (85%) of pure product 120. ¹ H NMR was consistent with the results of the desired structure.

Example 14

IMPDH activity inhibition assay

We determined the inhibition constants of the compounds listed in Table 3 using the following protocol.

IMP dehydrogenase activity was analyzed by applying the method first reported by Magasnick. [Magasanik Rain. Moide, H. S and Gering El. ratio. (1957) J. Biol. Chem. 226, 339]. Enzyme activity was measured spectrophotometrically by monitoring the increase in absorbance at 340 nm due to the formation of NADH (ε340 is 6220 M ^-1 cm ^-1 ). The reaction mixture contained 0.1 M Tris pH 8.0, 0.1 M KCl, 3 mM EDTA, 2 mM DTT, 0.1 M IMP and enzyme (IMPDH human type 2) at a concentration of 15 nM-50 nM. This solution was incubated at 37 ° C. for 10 minutes. The reaction was initiated by the addition of NAD to a final concentration of 0.1 M and the initial rate was measured as the linear increase in absorbance at 340 nm for 10 minutes. Reading on a standard spectrophotometer (path length 1 cm) gave a final volume of 1.0 ml in the cuvette. The analytes were also applied to the 96 well microtiter plate form; In this case the concentrations of all reagents remain the same and the final volume is reduced to 200 μl.

For inhibitor analysis, the compound of interest is dissolved in DMSO to a final concentration of 20 mM, which is added to the initial assay mixture for preincubation with enzymes at a final volume of 2% -5% (v / v). The reaction is initiated by addition of NAD and the initial rate is measured as described above. The amount of inhibitor was varied and Henderson's tight coupling equation [Henderson P. J. F. (1972) Biochem. J. 127, 321] was used to determine the Ki by measuring the initial velocity by substituting data.

These results are shown in Table III. Ki values are expressed in nM units. Group "A" has activity of 0.01 nm to 50 nm, Group "B" has activity of 51 nm to 1000 nm, Group "C" has activity of 1001 nm to 10,000 nm, and Group "D" has activity of 10,000 nm or more. Indicates. "ND" is used when the given compound has not been tested.

Compound number Ki (nM) Compound number Ki (nM) Compound number Ki (nM) One C 35 C 69 B 2 C 36 C 70 C 3 B 37 C 71 C 4 D 38 D 72 C 5 C 39 D 73 B 6 C 40 C 74 B 7 B 41 C 75 B 8 C 42 B 76 C 9 C 43 B 77 B 10 C 44 - 78 B 11 C 45 C 79 B 12 C 46 B 80 C 13 C 47 B 81 C 14 C 48 C 82 C 15 C 49 C 83 B 16 C 50 D 84 B 17 B 51 D 85 B 18 C 52 C 86 C 19 C 53 C 87 D 20 C 54 C 88 C 21 C 55 A 89 C 22 C 56 B 90 C 23 C 57 B 91 C 24 B 58 C 92 C 25 C 59 A 93 A 26 C 60 B 94 B 27 C 61 D 95 C 28 C 62 C 96 B 29 D 63 C 97 A 30 C 64 B 98 B 31 D 65 B 99 A 32 D 66 C 100 B 33 D 67 C 101 C 34 C 68 B 102 C

Compound number Ki (nM) Compound number Ki (nM) Compound number Ki (nM) 103 C 125 A 147 A 104 C 126 A 148 A 105 B 127 A 149 A 106 B 128 A 150 A 107 A 129 A 151 B 108 B 130 A 152 B 109 B 131 A 153 A 110 B 132 A 154 A 111 A 133 A 155 A 112 B 134 A 156 A 113 A 135 A 157 B 114 B 136 A 158 B 115 B 137 B 159 A 116 A 138 A 160 A 117 B 139 B 161 A 118 C 140 A 162 A 119 A 141 A 163 B 120 A 142 A 164 B 121 A 143 B 165 A 122 A 144 B 166 D 123 A 145 A 167 B 124 A 146 A 168 B

Example 15

Antiviral analysis

The antiviral effects of the compounds can be assessed by various in vitro and in vivo assays. For example, compounds can be tested in an in vitro virus replication assay. In vitro assays may use whole cells or isolated cellular components. In vivo assays include animal models for viral diseases. Examples of animal models include, but are not limited to, rodent models for HBV or HCV infection, Woodchuck models for HBV infection, and champan models for HCV infection.

While many aspects of the invention have been described, it is evident that the basic configuration may be modified to provide other aspects using the products and methods of the invention. Accordingly, it should be understood that the scope of the present invention is limited by the claims rather than the specific aspects shown in the examples.

Claims (53)

A method of inhibiting IMPDH activity of a mammal, comprising administering to the mammal a compound of Formula I: Formula I Where A is selected from (C ₁ -C ₆ )-straight or branched chain alkyl, or (C ₂ -C ₆ )-straight or branched chain alkenyl or alkynyl, and A optionally comprises up to 2 substituents , Wherein, if present, the first substituent is selected from R ¹ or R ³ , The second substituent, if present, is R ¹ ; B is a saturated, unsaturated or partially saturated monocyclic ring or bicyclic ring optionally comprising up to 4 heteroatoms selected from N, O or S and is selected from: or Wherein each X is the number of hydrogen atoms needed to complete the proper valences; B optionally contains 3 or fewer substituents, Wherein the first substituent, when present, is selected from R ¹ , R ² , R ⁴ or R ⁵ , The second substituent, if present, is selected from R ¹ or R ⁴ , The third substituent, if present, is R ¹ ; D is selected from C (O), C (S) or S (O) ₂ ; Wherein each R ¹ is each selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R ⁶ or (CH ₂ ) _n -Y, N is 0, 1 or 2; Y is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, SR ⁶ , S (O) R ⁶ , SO ₂ R ⁶ , NH ₂ , NHR ⁶ , N (R ⁶ ) ₂ , NR ⁶ R ⁸ , COOH, COOR ⁶ or OR ⁶ ; Each R ² is selected from (C ₁ -C ₄ )-straight or branched chain alkyl, or (C ₂ -C ₄ )-straight or branched chain alkenyl or alkynyl; Each R ² optionally comprises up to 2 substituents, Wherein the first substituent, when present, is selected from R ¹ , R ⁴ and R ⁵ , The second substituent, if present, is R ¹ ; R ³ is selected from a monocyclic or bicyclic ring system containing 5 to 6 members per ring, the ring system optionally comprising up to 4 heteroatoms selected from N, O or S, CH ₂ adjacent to any of the above N, O or S heteroatoms is optionally substituted with C (O); Each R ³ optionally contains up to 3 substituents, In this case, the first substituent, when present, is selected from R ¹ , R ² , R ⁴ or R ⁵ , The second substituent, if present, is selected from R ¹ or R ⁴ , The third substituent, if present, is R ¹ ; Each R ⁴ is OR ⁵ , OC (O) R ⁶ , OC (O) R ⁵ , OC (O) OR ⁶ , OC (O) OR ⁵ , OC (O) N (R ⁶ ) ₂ , OP (O) (OR ⁶ ) ₂ , SR ⁶ , SR ⁵ , S (O) R ⁶ , S (O) R ⁵ , SO ₂ R ⁶ , SO ₂ R ⁵ , SO ₂ N (R ⁶ ) ₂ , SO ₂ NR ⁵ R ⁶ , SO ₃ R ⁶ , C (O) R ⁵ , C (O) OR ⁵ , C (O) R ⁶ , C (O) OR ⁶ , NC (O) C (O) R ⁶ , NC (O) C (O) R ⁵ , NC (O) C (O) OR ⁶ , NC (O) C (O) N (R ⁶ ) ₂ , C (O) N (R ⁶ ) ₂ , C (O) N ( OR ⁶ ) R ⁶ , C (O) N (OR ⁶ ) R ⁵ , C (NOR ⁶ ) R ⁶ , C (NOR ⁶ ) R ⁵ , N (R ⁶ ) ₂ , NR ⁶ C (O) R ¹ , NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ⁵ , NR ⁶ C (O) OR ⁶ , NR ⁶ C (O) OR ⁵ , NR ⁶ C (O) N (R ⁶ ) ₂ , NR ⁶ C (O) NR ⁵ R ⁶ , NR ⁶ SO ₂ R ⁶ , NR ⁶ SO ₂ R ⁵ , NR ⁶ SO ₂ N (R ⁶ ) ₂ , NR ⁶ SO ₂ NR ⁵ R ⁶ , N (OR ⁶ ) R ⁶ , N (OR ⁶ ) R ⁵ , P (O) (OR ⁶ ) N (R ⁶ ) ₂ and P (O) (OR ⁶ ) ₂ , respectively; Each R ⁵ is a monocyclic or bicyclic ring system consisting of 5 to 6 members per ring, said ring system optionally comprising up to 4 heteroatoms selected from N, O or S, and N, CH ₂ adjacent to O or S may be substituted with C (O); Each R ⁵ optionally contains up to 3 substituents, each of which, if present, is R ¹ ; Each R ⁶ is each selected from H, (C ₁ -C ₄ ) straight or branched alkyl or (C ₂ -C ₄ ) straight or branched alkenyl; Each R ⁶ optionally includes substituents that are R ⁷ ; R ⁷ is a monocyclic or bicyclic ring system consisting of 5 to 6 members per ring, said ring system optionally comprising up to 4 heteroatoms selected from N, O or S, and N, O Or CH ₂ adjacent to S may be substituted with C (O); Each R ⁷ is optionally H, (C ₁ -C ₄ ) straight or branched alkyl, or (C ₂ -C ₄ ) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedi Oxy, or up to two substituents each selected from (CH ₂ ) _n -Z; N is 0, 1 or 2; Z is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, S (C ₁ -C ₄ ) -alkyl, SO (C ₁ -C ₄ ) -alkyl, SO ₂ (C ₁ -C ₄ ) -alkyl , NH ₂ , NH (C ₁ -C ₄ ) -alkyl, N [(C ₁ -C ₄ ) -alkyl] ₂ , N [(C ₁ -C ₄ ) -alkyl] R ⁸ , COOH, C (O) O (C ₁ -C ₄ ) -alkyl or O (C ₁ -C ₄ ) -alkyl; R ⁸ is an amino protecting group; Any carbon atom of any A, R ² or R ⁶ is optionally substituted with O, S, SO, SO ₂ , NH or N (C ₁ -C ₄ ) -alkyl. The method of claim 1, wherein B of said compound inhibits IMPDH activity in a mammal having 0 to 2 substituents. The method of claim 1 or 2, wherein B of the compound comprises at least a first substituent and the first substituent is R ⁵ . 4. The method of claim 3, wherein B of the compound is a monocyclic aromatic ring and the first substituent of B is a monocyclic aromatic ring. A method of inhibiting IMPDH activity in a mammal, comprising administering a compound of Formula II to the mammal. Formula II Where D and each B are as described in Claim 1. 6. The method of claim 5, wherein at least one B of said compound inhibits IMPDH activity in a mammal having 0 to 2 substituents. 7. The method of claim 5 or 6, wherein in said compound one B comprises at least a first substituent and the first substituent is R ⁵ . 8. The method of claim 7, wherein B of the compound is a monocyclic aromatic ring and the first substituent of B is a monocyclic aromatic ring. A compound of formula III Formula III A, D and B are as described in claim 1; E is O or S; G and G 'are each selected from R ¹ or H. A compound of formula IV: Formula IV Where B and D are as described in claim 5; E, G and G 'are as described in claim 9; B 'is a saturated, unsaturated or partially saturated monocyclic ring or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, O or S and is selected from: or B 'optionally includes 3 or fewer substituents, Wherein the first substituent, when present, is selected from R ¹ , R ² , R ⁴ or R ⁵ , The second substituent, when present, is selected from R ¹ or R ⁴ , The third substituent, if present, is R ¹ ; X, R ¹ , R ² , R ⁴ and R ⁵ are as described in claim 5; When B is unsubstituted phenyl, all substituents on B 'are R ¹ , and at least one of these R ¹ substituents is not chloro, bromo or iodo; B and B 'are not unsubstituted phenyl at the same time. The compound of claim 10, represented by the following general formula (V). Formula V Where K is selected from R ¹ and R ⁴ ; J is selected from R ¹ , R ² and R ⁴ . The compound of claim 11, wherein D is —C (O) —. The compound of claim 11, wherein E is oxygen. The compound of claim 11, wherein J is NR ⁶ C (O) R ⁵ or NR ⁶ C (O) R ⁶ . The compound of claim 14, wherein J is NR ⁶ C (O) R ⁶ . The compound of claim 15, wherein J is N (CH ₃ ) C (O) R ⁶ . The compound of claim 11, wherein K is (CH ₂ ) _n -Y. 18. The compound of claim 17, wherein K is OCH ₃ . The compound of claim 11, wherein G is hydrogen. The method of claim 16, D is -C (O)-; E is oxygen; K is OCH ₃ ; G is hydrogen. The compound of claim 11, wherein J is R ² . The compound of claim 21, wherein E is oxygen. The compound of claim 21, wherein J is R ² substituted with R ⁴ . The compound of claim 23, wherein R ⁴ is NR ⁶ C (O) OR ⁵ or NR ⁶ C (O) OR ⁶ . The compound of claim 21, wherein K is (CH ₂ ) _n -Y. The compound of claim 25, wherein K is OCH ₃ . The method of claim 21, D is -C (O)-; E is oxygen; K is OCH ₃ ; G is hydrogen. A compound of formula VII Formula VII Where K is selected from R ¹ and R ⁴ ; A, D, R ¹ and R ⁴ are each as described in claim 1. 29. The compound of claim 28, wherein D is -C (O)-. The group of claim 28, wherein A is composed of NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ⁵ , CH ₂ NR ⁶ C (O) OR ⁶ and CH ₂ NR ⁶ C (O) OR ⁵ A monocyclic aromatic ring substituted with 1 to 2 substituents selected from. 31. The compound of claim 30, wherein A is a monocyclic aromatic ring substituted with one to two substituents selected from the group consisting of CH ₂ NR ⁶ C (O) OR ⁶ and CH ₂ NR ⁶ C (O) OR ⁵ . The compound of claim 28, wherein K is (CH ₂ ) _n -Y. 33. The compound of claim 32, wherein K is OCH ₃ . A compound of formula IX Formula IX Where D is selected from C (O), C (S) and S (O) ₂ ; K is selected from R ¹ and R ⁴ ; J is selected from R ¹ , R ² and R ⁴ . The compound of claim 34, wherein D is -C (O)-. The compound of claim 34, wherein J is NR ⁶ C (O) R ⁵ or NR ⁶ C (O) R ⁶ . The compound of claim 34, wherein K is (CH ₂ ) _n -Y. 38. The compound of claim 37, wherein K is OCH ₃ . 11. A group according to claim 10 comprising compounds 1-27, 29-31, 39-51, 53-69, 71-86, 88-89, 91-102 and 104-162 of Tables IA, IB and IC. Compound selected from. The compound of claim 28 selected from the group consisting of Compounds 163-168 of Table IIB. a. An effective amount of a compound of Formula I or Formula II to inhibit IMPDH activity; b. Additional agents selected from immunosuppressive agents, anticancer agents, antiviral agents, anti-inflammatory agents, antifungal agents, antibiotics or vascular hyperproliferation inhibitors; c. A pharmaceutical composition comprising a pharmaceutically acceptable adjuvant. Formula I Formula II Wherein A, B and D are as defined in claim 1. The compound of claim 41, wherein one or more B of the compound comprises at least a first substituent and the first substituent is R ⁵ . a. 41. A compound according to any one of claims 9-40 for inhibiting IMPDH activity; And b. A pharmaceutical composition comprising a pharmaceutically acceptable adjuvant. The pharmaceutical composition of claim 43, further comprising an additional agent selected from an immunosuppressant, anticancer, antiviral, anti-inflammatory, antifungal, antibiotic or vascular hyperproliferative inhibitor. 42. A method of treating or preventing an IMPDH mediated disease in a mammal, comprising administering the composition of claim 41 to the mammal. The method of treating or preventing an IMPDH mediated disease comprising administering to a mammal the composition of claim 43. 47. The method of claim 46, wherein said composition further comprises an additional agent selected from an immunosuppressive agent, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic or an vascular hyperproliferative inhibitor. 48. The method of any one of claims 45-47, wherein the method is used to suppress an immune response and is an immunosuppressant when the additional agent is present. 49. The method of claim 48, wherein said IMPDH mediated disease is an autoimmune disease. 48. The method of any one of claims 45-47, wherein the IMPDH mediated disease is a viral disease and an antiviral agent when the additional agent is present. 48. The method of any one of claims 45-47, wherein the IMPDH mediated disease is a vascular disease and an vascular hyperproliferation inhibitor when the additional agent is present. 48. The method of any one of claims 45-47, wherein the IMPDH mediated disease is cancer and the additional agent is an anticancer agent when present. 48. The method of any one of claims 45-47, wherein the IMPDH mediated disease is an inflammatory disease and is an anti-inflammatory agent when the additional agent is present.