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  • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
  • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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  • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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  • C07C235/66—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
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  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Definitions

• the present invention relates to compounds which inhibit IMPDH.
• This invention also relates to pharmaceutical compositions comprising these compounds.
• the compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMPDH enzyme activity and consequently, may be advantageously used as therapeutic agents for IMPDH mediated processes.
• This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention and related compounds.
• nucleotide synthesis in organisms is required for the cells in those organisms to divide and replicate. Nucleotide synthesis in mammals may be achieved through one of two pathways : the de novo synthesis pathway or the salvage pathway. Different cell types use these pathways to a different extent.
• Inosine-5 ' -monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) is an enzyme involved in the de novo synthesis of guanosine nucleotides.
• IMPDH catalyzes the NAD-dependent oxidation of inosine-5 ' -monophosphate (IMP) to xanthosine-5 ' -monophosphate (XMP) [Jackson R.C. et. al., Nature, 256, pp. 331-333, (1975)].
• IMPDH inosine-5 ' -monophosphate
• XMP xanthosine-5 ' -monophosphate
• IMPDH is ubiquitous in eukaryotes, bacteria and protozoa [Y. Natsumeda & S.F. Carr, Ann. N. Y. Acad. , 696, pp. 88-93 (1993)].
• the prokaryotic forms share 30-40% sequence identity with the human enzyme. Regardless of species, the enzyme follows an ordered Bi-Bi reaction sequence of substrate and cofactor binding and product release. First, IMP binds to IMPDH. This is followed by the binding of the cofactor NAD. The reduced cofactor, NADH, is then released from the product, followed by the product, XMP [S.F. Carr et al . , J. Biol. Chem., 268, pp. 27286-90 (1993); E.W.
• guanosine nucleotides and thus the activity of IMPDH, is particularly important in B and T-lymphocytes. These cells depend on the de novo, rather than salvage pathway to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen [A.C. Allison et. al . , Lancet II, 1179, (1975) and A.C. Allison - 3 -
• IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
• Immunosuppression has been achieved by inhibiting a variety of enzymes including for example, the phosphatase calcineurin (inhibited by cyclosporin and FK-506); dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar) ; the kinase FRAP (inhibited by rapamycin) ; and the heat shock protein hsp70 (inhibited by deoxyspergualin) .
• the phosphatase calcineurin inhibited by cyclosporin and FK-506
• dihydroorotate dehydrogenase an enzyme involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar)
• the kinase FRAP inhibited by rapamycin
• Inhibitors of IMPDH are also known.
• United States patents 5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184 describe mycophenolic acid (MPA) and some of its derivatives as potent, uncompetitive, reversible inhibitors of human
• MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen [A. C. Allison et. al., Ann . N. Y. Acad. Sci., 696, 63, (1993). Immunosuppressants, such as MPA, are useful drugs in the treatment of transplant rejection and autoimmune diseases. [R. E. Morris, Kidney Intl . , 49, Suppl. 53, S-26, (1996)]. However, MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity and poor bioavailability. [L. M. Shaw, et. al . , Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)]. - 4 -
• Nucleoside analogs such as tiazofurin, ribavirin and mizoribine also inhibit IMPDH [L. Hedstrom, et. al. Biochemistry, 29, pp. 849-854 (1990)]. These compounds, which are competitive inhibitors of IMPDH, suffer from lack of specificity to this enzyme.
• Mycophenolate mofetil a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute renal allograft rejection following kidney transplantation. [L. M. Shaw, et. al . , Therapeutic Drug Monitoring, 17, pp. 690-699, (1995); H. W. Sollinger, Transplantation, 60, pp. 225-232 (1995)]. Several clinical observations, however, limit the therapeutic potential of this drug. [L. M. Shaw, et. al . , Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)]. MPA is rapidly metabolized to the inactive glucuronide in vivo . [A.C. Allison and E.M. Eugui, Immunological Reviews, 136, pp.
• IMPDH inhibitors of a different class have been described in PCT publication WO 97/40028. It is also known that IMPDH plays a role in other metabolic events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumor cell lines, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy [M. Nagai et . al . , Cancer Res . , 51, pp.
• IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH, such as MPA or rapamycin, may be useful in preventing restenosis or other hyperproliferative vascular diseases [C. R. Gregory et al., Transplantation, 59, pp. 655-61 (1995); PCT publication WO 94/12184; and PCT publication WO 94/01105] .
• IMPDH has been shown to play a role in viral replication in some viral cell lines. [S.F. Carr, J. Biol. Chem., 268, pp. 27286-27290 (1993)]. Analogous to lymphocyte and tumor cell lines, the implication is that the de novo, rather than the salvage, pathway is critical in the process of viral replication.
• inhibitors with improved pharmacological properties.
• Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-vascular hyperproliferative agents, anti-inflammatory agents, antifungal agents, antipsoriatic and anti-viral agents.
• the present invention provides compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of IMPDH. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti- inflammatory agents, antibiotics, and immunosuppressants for the treatment or prophylaxis of transplant rejection and autoimmune disease.
• therapeutic or prophylactic agents such as anti-virals, anti- inflammatory agents, antibiotics, and immunosuppressants for the treatment or prophylaxis of transplant rejection and autoimmune disease.
• these compounds are useful, alone or in combination with other agents, as therapeutic and prophylactic agents for antiviral, anti-tumor, anti- cancer, anti-inflammatory agents, antifungal agents, 6 -
• the invention also provides pharmaceutical compositions comprising the compounds of this invention, as well as multi-component compositions comprising additional IMPDH compounds together with an immunosuppressant .
• the invention also provides methods of using the compounds of this invention, as well as other related compounds, for the inhibition of IMPDH.
• -SO2- and “-S(0)2-" ss used herein refer to a sulfone or sulfone derivative (i.e., both appended groups linked to the S) , and not a sulfinate ester.
• halo or “halogen” refer to a radical of fluorine, chlorine, bromine or iodine.
• immunosuppressant refers to a compound or drug which possesses immune response inhibitory activity.
• agents include cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, 0KT3 , ATAG, interferon and mizoribine.
• interferon refers to all forms of interferons, including but not limited to alpha, beta and gamma forms.
• IMPDH-mediated disease refers to any disease state in which the IMPDH enzyme plays a regulatory role in the metabolic pathway of that disease.
• IMPDH-mediated disease include transplant rejection and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory diseases, cancer, viral replication diseases and vascular diseases .
• the compounds, compositions and methods of using them of this invention may be used in the treatment of transplant rejection (e.g., kidney, liver, heart, lung, pancreas (islet cells) , bone marrow, cornea, small bowel and skin allografts and heart valve xenografts), rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitis), lupus, diabetes, mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, pulmonary inflammation, eye uveiti ⁇ , hepatitis, Grave's disease, Hashimoto's thyroiditi ⁇ , Behcet's or Sjorgen's syndrome (dry eyes/mouth) , pernicious or immunohaemolytic anaemia, idiopathic adrenal insufficiency, polyglandular autoimmune syndrome, and glomerulonep
• IMPDH enzymes are also known to be present in bacteria and thus may regulate bacterial growth.
• the IMPDH-inhibitor compounds, compositions and methods described herein may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents.
• treating refers to the alleviation of symptoms of a particular disorder in a patient or the improvement of an ascertainable measurement associated with a particular disorder.
• patient refers to a mammal, including a human.
• HBV hepatitis-B virus
• HCV hepatitis-C virus
• HGV hepatitis-G virus
• the invention provides compounds of formula I : R2
• X is selected from -C (0) -N (R 6 ) - , -N (R 6 ) -C (0) - , -CH 2 - N(R 6 )-, -N(R 6 )-CH 2 -, -N(R 6 )-S(0) 2 -, -S (0) 2 -N (R 6 ) - ,
• each R 6 is independently selected from hydrogen, d- C 4 straight or branched alkyl, C -C 4 straight or branched alkenyl or alkynyl, Ar-substituted-C ⁇ -C 4 straight or branched alkyl, or Ar-substituted-C-C 4 straight or branched alkenyl or alkynyl ; wherein
• Re is optionally substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino; each R 12 is independently selected from R 6 , W- [C 1 -C 4 straight or branched alkyl], W-[C 2 -C 4 straight or branched alkenyl or alkynyl], Ar-substituted- [W- [C 1 -C 4 straight or branched alkyl]], Ar-substituted- [W- [C 2 -C straight or branched alkenyl or alkynyl]], 0-Ar, N(R 6 )-Ar, S-Ar, S(0)- Ar, S(0) 2 -Ar, S-C(0)H, N(R 6 )-C(0)H, or 0-C(0)H; wherein
• W is 0-, 0-C(0)-, S-, S(0)-, S(0) 2 -, S-C(0)-, N(R 6 )-, or N(R 6 )-C(0)-; and wherein each R 12 is optionally and independently substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino. - 10 -
• Q is selected from 0, -0-C(0)-, -C(0)-0-, -N(H)-C(0)-0-, -0-N(H)-C(0)-, -N(H)-C(0)-, -C(0)-N(H)-, -0-C(0)-N(H)-, or -C(0)-N(H)-0-;
• Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1, 2
• R ⁇ is selected from [C ⁇ -C ⁇ straight or branched alkyl] or, [C 2 -C ⁇ 2 straight or branched alkenyl or alkynyl] ; wherein R i3 is optionally substituted with 1 to 4 substituents independently selected from R ⁇ 4 or R 15 , wherein each Ri 4 is a monocyclic or a bicyclic ring system consisting of 3 to 7 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S; wherein a CH 2 adjacent to said N, O or S maybe substituted with C(O); and wherein R i4 optionally comprises up to 2 substituents independently selected from (Ci-C 4 ) -straight or branched alkyl, (C 2 -C 4 ) straight or branched alkenyl, 1 , 2-methylenedioxy, 1,2- ethylenedioxy, (CH 2 ) n -R 16 , -S- (CH 2 ) n -
• Ri 6 is selected from halogen, -CN, -N0 2 , -CF 3 , -0CF 3 , -OH, -S-(Ci-C 4 ) -alkyl, -S (0) - (C ⁇ -C 4 ) -alkyl , -S (0) 2 - (C ⁇ C - alkyl, -NH 2 , -NH- (C ⁇ -C 4 ) -alkyl , N ( (Ci-C 4 ) -alkyl ) 2 , COOH, C(0)-0-(Cj . -C 4 ) -alkyl or 0- (C ⁇ -C 4 ) -alkyl ; and - 12 -
• each R 15 is independently selected from -ORj .7 , or -N(R ⁇ 8 ) 2 ;
• R17 is selected from hydrogen, - (C ⁇ -C 6 ) -straight alkyl, - (C ⁇ -C 6 ) -straight alkyl-Ar, -C (0) - (C ⁇ -C 6 ) -straight or branched alkyl, -C(0)-Ar, or - (C ⁇ -C 6 ) -straight alkyl - CN; and each Rig is independently selected from -(C ⁇ -C 6 )- straight or branched alkyl, - (C ⁇ -C 6 ) -straight or branched alkyl-Ar, - (C ⁇ -C 6 ) -straight alkyl-CN, - (C ⁇ -C 6 ) -straight alkyl-OH, - (C ⁇ -C 6 ) -straight alkyl-0R 17 , -C (0) - (C ⁇ -C 6 ) - straight or branched alkyl, -C(0)-Ar,
• R 2 , R 3 , R , or R 5 is hydrogen; no more than two of Ri, R 2 , R 3 , R 4 , or R 5 comprises Ar; at least two of R 7 , R e , R 9 , Rio or R u is hydrogen; and no more than two of R 7 , R 8 , R 9 ⁇ R 10 or R comprises
• the compounds of this invention specifically exclude those wherein X is -NH-S(0) 2 - or -S (0) 2 -N(H) - , one of Ri, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , Rg, Rio or Rn is 0-(d-C 4 )- straight or branched alkyl, seven of Ri , R2, R 3 , R , Rs, R7, R 8 , R 9 , Rio or Rn is hydrogen and the remaining two of Ri, R2, R 3 , R , R5, R7, R 8 - R9, Rio or Rn are bound together to form a 5 to 6-membered aromatic carbocyclic or heterocyclic ring.
• X is -NH-S(0) 2 - or -S (0) 2 -N (H) - , two of R x , R 2
• R 8 , Rg, Rio or Rn are 0- (C ⁇ -C 4 ) -straight or branched alkyl, seven of R ⁇ , R 2 , R 3 , R 4 , R5, R7, Rs, R9, Rio or Rn is hydrogen and the remaining one of Ri, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , Rio or Rn is -N0 2 , -CN or -Ar.
• Another set of compounds excluded from the present invention are those wherein X is -NH-S(0) 2 - or - S(0) 2 -N(H)-, two of Ri, R 2 , R 3 , R 4 , R5, R7, Rs , Rg, Rio or Rn are 0- (C ⁇ -C 4 ) -straight or branched alkyl, six of Ri, R 2 , R 3 , R 4 , R5, R7, Rs , R9, Rio or Rn is hydrogen and the remaining two of Ri, R 2 , R 3 , R 4 , R5, R 7 , Rs, R9, Rio or Rn are both halo.
• Yet another set of compounds excluded are those wherein X is -NH-S(0) 2 - or -S (0) 2 -N(H) - , one of R ⁇ , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , Rio or Rn is Ar and the remaining 9 of Ri, R 2 , R 3 , R 4 , R 5 , R , R 8 , Rg, Rio or Rn are each hydrogen.
• Another set of excluded compounds are those wherein X is -N(H) -C (0) -S- or -S-C (0) -N(H) - , one of R l t R2, R 3 , R 4 , R5, R 7 , Rs, Rg, Rio or Rn is -OH, eight of R l t R 2 , R 3 , R 4 , R 5 , R7, Rs, Rg, Rio or Rn are hydrogen and the remaining one of Ri , R 2 , R 3 , R 4 , R5, R7, Rs , Rg, Rio or Rn is halo; and those wherein X is - (H) -C (0) -S- or -S-C(O)- N(H)-, one of R l t R 2 , R 3 , R 4 , R 5 , R 7 , Rs, Rg, Rio or R ⁇ is - 14 -
• R lr R 2 , R 3 , R 4 , R 5 , R 7 , Rs, Rg, Rio or Rn are hydrogen, one of Ri, R 2 , R3 , R 4 , R5 , R7 , Rs, Rg, Rio or Rn is 0- (C ⁇ C ) -straight or branched alkyl and the remaining one of Ri, R 2 R 3 , R 4 , R 5 , R 7 , R 8 , R 9, R 10 or R ⁇ is halo or (C ⁇ C 4 ) -straight or branched alkyl.
• heterocyclic ring refers to a ring which comprises 1 to 4 heteroatoms independently selected from N, O or S .
• Ar-substituted- (C1-C4) -straight or branched alkyl and “Ar-substituted- (C 2 -C 4 ) -straight or branched alkenyl or alkynyl” denote that one or more Ar groups may be attached to the alkyl, alkenyl or alkynyl chain at any chemically feasible position on the chain, including the termini .
• references to "[branched alkyl, alkenyl or alkynyl] -Ar” or "[branched alkyl, alkenyl or alkynyl] -Q- Ar” denote that an “Ar” or "Q-Ar” moiety is attached to one or more terminal ends of the branched alkyl, alkenyl or alkynyl chain.
• X is selected from -C(0)-N(R 6 ) -, -N (R 6 ) -C (0) - , -CH 2 -N(R 6 )-, or -N(R 6 )-CH 2 - or -N(R 6 ) -C(O) -Y . More preferably, X is - 15 -
• R is selected from H, (C ⁇ -C 4 ) -straight or branched alkyl, OH, 0- (C ⁇ -C 4 ) -straight or branched alkyl, 0-Ar, 0CF 3 , halo, cyano or S- (C ⁇ -C 4 ) -straight or branched alkyl.
• Ri is H when R 2 is not H.
• R 2 is preferably selected from H, (C 1 -C 4 )- straight or branched alkyl, Ar, 0- (C 1 -C 4 ) -straight or branched alkyl, 0-Ar, 0CF 3 , halo, cyano, C(0)NH 2 or S(0) 2 -
• R 2 is H.
• R 3 is preferably selected from H, Ar, cyano, O-
• R 4 is selected from H, (C1-C4) -straight or branched alkyl, OH, 0-(C ⁇ -C 4 )- straight or branched alkyl, 0-Ar, OCF 3 , halo, cyano or S-
• R 5 is preferably selected from H, (C 1 -C 4 )- ⁇ traight or branched alkyl, Ar, 0- (C 1 -C 4 ) -straight or branched alkyl, O-Ar, 0CF 3 , halo, cyano, C(0)NH 2 or S(0) 2 -
• R 7 is selected from H, OH, OC (0) - (C 1 -C 4 ) -straight or branched alkyl, 0- (C ⁇ -C ) -straight or branched alkyl, O-Ar, amino, or N(H)C(0) - (C 1 -C 4 ) -straight or branched alkyl. Even more preferred is when R 7 is OH.
• R 8 is preferably H, (C ⁇ -C 4 ) -straight or branched alkyl, 0- (C ⁇ -C 4 ) -straight or branched alkyl, or (C 1 -C 4 )- straight or branched alkyl-N (H) C (0) 0-Ar . - 16 -
• R 9 is selected from H, (C 1 -C 4 ) -straight or branched alkyl, 0- (C ⁇ -C 4 ) -straight or branched alkyl, or R 9 is taken together with Rio and the carbon atoms to which they are bound to form a fused benzene ring. More preferred is when Rg and Rio are taken together with the carbon atoms to which they are bound to form a fused benzene ring.
• R 10 is selected from H, (C 1 -C 4 ) -straight or branched alkyl, 0- (C1-C4) -straight or branched alkyl, or Rio is taken together with R 9 and the carbon atoms to which they are bound to form a fused benzene ring.
• Rn is selected from H, OH, OC (0) - (C 1 -C 4 ) -straight or branched alkyl, 0- (C1-C4) -straight or branched alkyl, O-Ar, amino, or N(H)C(0) - (C 1 -C 4 ) -straight or branched alkyl. More preferably, R X1 is H.
• Q is -N(H)-C(0)-0-.
• preferred compounds of the invention are listed in the table below.
• the compounds of this invention may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers . All such isomeric forms of these compounds are expressly included in the present invention.
• Each stereogenic carbon may be of the R or S configuration.
• stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a mammal or for use in affinity chromatography applications) .
• such compounds are stable at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
• the compounds of this invention are defined to include pharmaceutically acceptable derivatives or prodrugs thereof .
• a "pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention.
• Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally - 40 -
• prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of the compounds of this invention.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
• suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-pheny
• Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dieyelohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth.
• the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, - 41 -
• dialkyl sulfates such as dimethyl, diethyl, dibutyl and dia yl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
• the compounds of this invention may be synthesized using conventional techniques.
• these compounds are conveniently synthesized from readily available starting materials.
• a in the initial step was -N(H)R 6 and B was -C(0)OH or -C(0)C1.
• the coupling was performed in the presence of EDC, HOAt and CH 3 CN.
• a in the initial step was -N(H)R 6 and B was -Y-C(0)OH or -Y-C(0)C1.
• the coupling was performed in the presence of EDC, CH 2 Cl 2 and DMAP.
• a in the initial step was N(H)R 6 and B was S(0) 2 C1.
• the coupling was performed in the presence of TEA and CH 2 C1 2 .
• a in the initial step was N(H)R 6 and B was 0C(0)C1.
• the coupling was performed in the presence of TEA and CH 2 C1 2 .
• a in the initial step was NC(0) and B was SH.
• the coupling was performed in the presence of DMAP and CH 2 C1 2 .
• the procedure is as follows :
• Event Volume Flow rate condition sorbent 1.5 ml 3 mL/min load and collect 0.9 ml 3 mL/min elute 1.5 ml 1 mL/min
• the collected solution contained product at >95% purity (HPLC: 210 nm) with traces of O-acylated impurity. Yields were typically 8-12 mg.
• the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
• modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system) , increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
• novel compounds of the present invention are excellent ligands for IMPDH. Accordingly, these compounds are capable of targeting and inhibiting IMPDH - 44 -
• Inhibition can be measured by various methods, including, for example, IMP dehydrogenase HPLC assays (measuring enzymatic production of XMP and NADH from IMP and NAD) and IMP dehydrogenase spectrophotometric assays (measuring enzymatic production of NADH from NAD) .
• IMP dehydrogenase HPLC assays measuring enzymatic production of XMP and NADH from IMP and NAD
• IMP dehydrogenase spectrophotometric assays measuring enzymatic production of NADH from NAD
• compositions of this invention comprise a compound of this invention or a salt thereof; an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, anti-inflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
• Alternate compositions of this invention comprise a compound of this invention or a salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
• Such composition may optionally comprise an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, anti-inflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound.
• the compositions of this invention are pharmaceutical compositions .
• pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
• compositions that may be used in the pharmaceutical - 45 -
• compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d ⁇ -tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates , waxes, polyethylene-polyoxypropylene-block polymers , polyethylene glycol and wool
• Cyclodextrins such as cc-, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of this invention.
• the pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or administration by injection.
• the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically - 46 -
• parenteral as used herein includes subcutaneous, intracutaneous , intravenous, intramuscular, intra-articular, intraarterial , intrasynovial , intrasternal , intrathecal, intralesional and intracranial injection or infusion techniques.
• compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
• This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 , 3-butanediol .
• suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides .
• Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as those described in Pharmacopeia Helvetica, Ph. Helv. , or a similar alcohol, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the - 47 -
• compositions such as emulsions and or suspensions
• Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• compositions of this 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.
• carriers which are commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried corn starch.
• compositions of this invention may also be administered in the form of suppositories for rectal administration.
• These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
• suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols . - 48 -
• Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
• the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
• Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
• the pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, - 49 -
• fluorocarbons and/or other solubilizing or dispersing agents known in the art .
• Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the IMPDH inhibitory compounds described herein are useful in a monotherapy and/or in combination therapy for the prevention and treatment of IMPDH mediated disease.
• the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w) .
• compositions of this invention comprise a combination of an IMPDH inhibitor of this invention and one or more additional therapeutic or prophylactic agents
• both the IMPDH inhibitor and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 to 80% of the dosage normally administered in a monotherapy regimen.
• the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. - 50 -
• the pharmaceutical compositions of this invention comprise an additional immunosuppression agent.
• additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3 , ATAG, interferon and mizoribine.
• the pharmaceutical compositions of this invention may additionally comprise an anti-cancer agent.
• anti-cancer agents include, but are not limited to, cis- platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines , interferon and thioxantheres .
• compositions of this invention may additionally comprise an anti-viral agent.
• anti-viral agents include, but are not limited to, Cytovene, Ganciclovir, trisodium phosphonoformate,
• Ribavirin, d4T, ddl, AZT, and acyclovir Ribavirin, d4T, ddl, AZT, and acyclovir.
• the pharmaceutical compositions of this invention may additionally comprise an anti-vascular hyperproliferative agent.
• anti-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin and 5-(3'- pyridinylmethyl)benzofuran-2-carboxylate. - 51 -
• a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
• this invention provides methods of treating or preventing IMPDH mediated disease in a mammal comprising the step of administrating to said mammal any of the pharmaceutical compositions and combinations described above. If the pharmaceutical composition only comprises the IMPDH inhibitor of this invention as the active component, such methods may additionally comprise the step of administering to said mammal an agent selected from an anti-inflammatory agent, immunosuppressant, an anti-cancer agent, an anti-viral agent, or an anti-vascular hyperproliferation compound. Such additional agent may be administered to the mammal - 52 -
• these methods are useful in suppressing an immune response in a mammal.
• Such methods are useful in treating or preventing diseases, including, transplant rejection (e.g., kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small bowel and skin allografts and heart valve xenografts) , graft versus host disease, and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitus), lupus, diabetes, mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, pulmonary inflammation, eye uveitis, Grave's disease, Hashimoto's thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes /mout ) , pernicious or immunohaemolytic anaemia,
• transplant rejection
• these methods comprise the step of administering to the mammal a composition comprising a compound of this invention and a pharmaceutically acceptable adjuvant.
• this particular method comprises the additional step of administering to said mammal a composition comprising an additional immunosuppressant and a pharmaceutically acceptable adjuvant.
• this method comprises the step of administering to said mammal a composition comprising a compound of this invention; an additional - 53 -
• immunosuppressive agent and a pharmaceutically acceptable adjuvant .
• these methods are useful for inhibiting viral replication in a mammal.
• Such methods are useful in treating or preventing DNA and RNA viral diseases caused by infection for example, by orthomyxoviruses (influenza viruses types A and B) , paramyxoviruses (respiratory syncytial virus (RSV) , subacute sclerosing panencephalitis (SSPE) virus) measles and parainfluenza type 3), herpesviruses (HSV-1, HSV-2, HHV-6, HHV-7, HHV-8, Epstein Barr Virus (EBV) , cytomegalovirus (HCMV) and varicella zoster virus (VZV) ) , retroviruses (HIV-1, HIV-2, HTLV-1, HTLV-2), flavi- and pestiviruses (yellow fever virus (YFV) , hepatitis C virus (HCV) , dengue fever virus, bovine viral diarrhea virus
• RVFV sandfly fever Sicilian virus
• Hantaan virus Caraparu virus
• human papilloma viruses human papilloma viruses
• encephalitis viruses La Crosse virus
• arena viruses Junin and Tacaribe virus
• reovirus vesicular stomatitis virus
• rhinoviruses enteroviruses
• enteroviruses polio virus, coxsackie viruses, encephalomyocarditis virus (EMC)
• Lassa fever virus and togaviruses (Sindbis and Semlike forest viruses) and poxviruses (vaccinia virus), adenoviruses, rubiola, and rubella.
• These methods comprise the step of administering to the mammal a composition comprising a compound of this invention, and a pharmaceutically - 54 -
• this particular method comprises the additional step of administering to said mammal a composition comprising an additional anti-viral agent and a pharmaceutically acceptable adjuvant.
• this method comprises the step of administering to said mammal a composition comprising a compound of this invention; an additional anti-viral agent and a pharmaceutically acceptable adjuvant.
• these methods are useful for inhibiting vascular cellular hyperproliferation in a mammal. Such methods are useful in treating or preventing diseases, including, restenosis, stenosis, artherosclerosis and other hyperproliferative vascular disease.
• these methods comprise the step of administering to the mammal a composition comprising a compound of this invention, and a pharmaceutically acceptable adjuvant.
• this particular method comprises the additional step of administering to said mammal a composition comprising an additional anti-vascular hyperproliferative agent and a pharmaceutically acceptable adjuvant.
• this method comprises the step of administering to said mammal a composition comprising a compound of this invention; an additional anti-vascular hyperproliferative agent and a pharmaceutically acceptable adjuvant.
• these methods are useful for inhibiting tumors and cancer in a mammal .
• Such methods are useful in treating or - 55 -
• diseases including, tumors and malignancies, such as lymphoma, leukemia and other forms of cancer.
• these methods comprise the step of administering to the mammal a composition comprising a compound of this invention, and a pharmaceutically acceptable adjuvant.
• this particular method comprises the additional step of administering to said mammal a composition comprising an additional anti-tumor or anti-cancer agent and a pharmaceutically acceptable adjuvant.
• this method comprises the step of administering to said mammal a composition comprising a compound of this invention; an additional anti-tumor or anti-cancer agent and a pharmaceutically acceptable adjuvant.
• these methods are useful for inhibiting inflammation and inflammatory diseases in a mammal .
• Such methods are useful in treating or preventing diseases, including, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma and adult respiratory distress syndrome.
• these methods comprise the step of administering to the mammal a composition comprising a compound of this invention, and a pharmaceutically acceptable adjuvant.
• this particular method comprises the additional step of administering to said mammal a composition comprising an anti-inflammatory agent and a pharmaceutically acceptable adjuvant .
• IMP dehydrogenase activity was assayed following an adaptation of the method first reported by Magasanik. [B. Magasanik et al . , J. Biol. Chem. , 226, p. 339 (1957), the disclosure of which is herein incorporated by reference] . Enzyme activity was measured spectrophotometrically, by monitoring the increase in absorbance at 340 nm due to the formation of NADH ( ⁇ 340 is 6220 M -1 c ⁇ l) .
• 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 II) at a concentration of 15 to 50 nM. This solution is incubated at 37°C for 10 minutes. The reaction is started by adding NAD to a final concentration of 0. IM and the initial rate is measured by following the linear increase in absorbance at 340 nm for 10 minutes. For reading in a standard spectrophotometer (path length 1 cm) the final volume in the cuvette is 1.0 ml. The assay has also been adapted to a 96 well microtiter plate format; in this case the concentrations of all the reagents remain the same and the final volume is decreased to 200 ⁇ l .
• the compound in question is dissolved in DMSO to a final concentration of 20 mM and added to the initial assay mixture for preincubation with the enzyme at a final volume of 2- 5% (v/v) .
• the reaction is started by the addition of NAD, and the initial rates measured as above.
• K-j_ determinations are made by measuring the initial velocities in the presence of varying amounts of inhibitor and fitting the data using the tight-binding - 61 -
• Category "A” indicates a Ki of less than 10 ⁇ M
• category “B” indicates a K ⁇ of between 10 and 20 ⁇ M
• category “C” indicates a K ⁇ greater than 20 ⁇ M.
• the anti-viral efficacy of compounds may be evaluated in various _in vitro and _in vivo assays.
• compounds may be tested in _in vitro viral replication assays.
• Xn vitro assays may employ whole cells or isolated cellular components.
• Xn vivo assays include animal models for viral diseases. Examples of such animal models include, but are not limited to, rodent models for HBV or HCV infection, the Woodchuck model for HBV infection, and chimpanzee model for HCV infection.

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