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Definitions

• the present invention generally relates to cytokine inhibitors. More specifically, the invention is directed to inhibitors of macrophage migration inhibitory factor.
• MIF macrophage migration inhibitory factor
• MIF was one of the first soluble, non-immunoglobulin factors that was amenable to study in vitro.
• MIF produced by numerous cell types, including immune and endocrine cells, is now recognized as a pro-inflammatory counter-regulator of the anti-inflammatory activities of the glucocorticoids.
• MIF expression abrogates the anti-inflammatory and immunosuppressive effect of glucocorticoid production on pro-inflammatory cytokines (TNF- ⁇ , IL-I , IL-2, IL-6, and IL-8) (Calandra and Bucala, 1997; Donnelly et al., 1997).
• MIF is critically involved in the pathogenesis of a variety of inflammatory diseases.
• animal models of Gram- positive, Gram-negative, and polymicrobial sepsis, as well as MIF knockout models indicate a critical role of MIF " in sepsis (Calandra et al., 2000; Bozza et a!., 1999; Bernhagen et al., 1993).
• MIF is an important late-acting mediator of systemic inflammation. Deletion of the MIF gene in mice conferred protection against lethal endotoxemia staphylococcal toxic shock (Bozza et al., 1999). In addition, administration of neutralizing MIF- antibody protected mice from: (a) LPS-induced lethality; (b) lethal peritonitis and septic shock induced by E. coli peritonitis and (c) fulminant septic shock induced by cecal ligation and puncture (CLP) in TNF- ⁇ deficient mice (Calandra, 2001; Bernhagen et al., 1993).
• CLP cecal ligation and puncture
• anti-MIF therapies are potentially more beneficial than anti-TNF- ⁇ and anti-IL-1 therapies, which have demonstrated limited benefits for patients with severe sepsis (Abraham, 1999).
• administration of anti-MIF antibody 8 hours post-induction of sepsis confers significant protection in a murine CLP model of sepsis versus animals receiving control IgG.
• Human studies also support a role for MIF in septic shock (Beishuizen et al., 2001 ; Calandra et al., 2000).
• MIF appears as a homotrimer (Suzuki et al., 1994; Taylor et al., 1999; Sugimoto et al., 1995; Kato et al., 1996; Lolis and Bucala, 1996; Sugimoto et al., 1996; Sun et al., 1996; Suzuki et al., 1996; Lubetsky et al., 1999; Orita et al., 2001 ; Lubetsky et al., 2002).
• MIF possesses the unusual ability to catalyze the tautomerization of D,L-dopachrome methyl esters into their corresponding indole derivatives (Rosengren et al., 1996). More recently, phenylpyruvic acid and /7-hydroxyphenylpyruvic acid were found to be MIF substrates (Matsunaga et al., 1999a; Rosengren et al., 1997; Matsunaga et al., 1999b). The crystal structures of MIF complexed withp-hydroxyphenylpyruvic acid has identified an active site which lies in a hydrophobic cavity that forms between two adjacent subunits of the homotrimer (Lubetsky et al., 1999).
• Proline Pro-1 of the active site appears to be the critical residue for enzymatic activity, since site-directed mutagenesis that substitutes a serine (Pl-s) or glycine (Pl-g) for Pro-1 results in mutants devoid of D-dopachrome and /7-hydroxy- phenylpyruvic acid tautomerase activity (Lubetsky et al., 1999; Bendrat et al., 1997; Swope et al., 1998).
• Bm MIF mutant Pl-g is 10-fold less active in inducing production of TNF- ⁇ and chemotactic activity of human macrophages compared to the parent Bm MIF and human MIF (Zang et al., 2002).
• Pl-g mutant is greatly impaired in its ability to stimulate superoxide generation in activated ' neutrophils (Swope et al., 199S).
• a Pl -a mutant of MIF which loses the tautomerase activity, loses its ability to enhance matrix metalloproteinase (MMP) mRNA levels (Onodera et al., 2000).
• MMP matrix metalloproteinase
• MIF pro-inflammatory cytokines
• mice (a) from LPS-induced lethality; (b) against lethal peritonitis and septic shock induced by E. coli peritonitis and (c) against lethal sepsis induced by cecal ligation (CLP) and puncture in TNF- ⁇ deficient mice.
• CLP cecal ligation
• the compound (5,/2)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-I) was recently designed as an inhibitor of MIF activity (PCT Publication WO 02/100332).
• the crystal structure of MIF complexed to ISO-I revealed that it binds to a hydrophobic pocket.
• ISO-I inhibits 60% of TNF release by LPS-treated macrophages.
• intraperitoneal administration of ISO-I at 40 mg/kg increased the survival rate in endotoxemia and sepsis (Al-Abed et al., 2005). These results are comparable with monoclonal anti-MIF antibodies for the treatment of septic animals.
• the ISO-I structure incorporates the structure of Schiff base inhibitors of MIF enzyme activity that were designed originally to mimic the structure of dopachrome tautomerization intermediates of MIF catalysis. While ISO-I has moderate anti-inflammatory activity, synthesis of a focused library around the ISO-I structure alone did not significantly improve MIF inhibitor activity. Thus, new molecular scaffolds are required to identify additional MIF inhibitors. The present invention addresses that need.
• Ri is a single or multiple substitution independently H, OH, R 5 , N(Rs), SR 5 , or a halogen;
• R 2 comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R 3 ; and
• R 4 is H, R5, or a halogen, where
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -Ce alkoxy.
• the invention is also directed to pharmaceutical compositions comprising above compounds, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable excipient.
• the invention is additionally directed to a compound of formula I:
• Ri is a single or multiple substitution independently H, OH, R 5 , N(Rs), SR 5 , or a halogen, wherein at least one substitution is a halogen;
• R 2 comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R3;
• R 3 is O, C(Rs) 2 , or S;
• R 4 is H, R 5 , or a halogen, wherein
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -C 6 alkoxy.
• the invention also encompasses pharmaceutical compositions comprising any of these compounds.
• R] is a single or multiple substitution independently H, OH, R 5 , N(R 5 ), SR 5 , or a halogen;
• R 2 is/ram-hydroxymethylphenyl;
• R 3 is O, C(Rs) 2 , or S; and
• R 4 is H, R 5 , or a halogen, wherein R 5 is independently H, a straight or branched Cj-C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -C 6 alkoxy;
• the invention is further directed to a compound of formula IH
• Ri comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R 2 ;
• R 2 and R 3 are independently O, C(R 5 ) 2 , or S;
• R 4 is a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -C 6 alkoxy;
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -C 6 alkoxy.
• the invention also encompasses pharmaceutical compositions comprising any of these compounds.
• the invention is directed to methods of inhibiting macrophage migration inhibitory factor (MIF) activity in a mammal.
• the methods comprise administering any of the above- identified pharmaceutical compositions to the mammal in an amount effective to inhibit MIF activity in the mammal.
• MIF macrophage migration inhibitory factor
• the invention is directed to other methods of inhibiting macrophage migration inhibitory factor (MIF) activity in a mammal.
• the methods comprise administering a pharmaceutical composition to the mammal in an amount effective to inhibit MIF activity in the mammal.
• the pharmaceutical composition comprises a compound of formula I or formula II, or a pharmaceutically acceptable salt, ester, or taut ⁇ mer thereof, in a pharmaceutically acceptable excipient, where formula I and formula II are
• Ri is a single or multiple substitution independently H, OH, R 5 , N(R 5 ), SR 5 , or a halogen;
• R 2 comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R3;
• R 4 is H, R 5 , or a halogen, where
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C2-C6 alkoxy.
• the invention is directed to methods of treating or preventing inflammation in a mammal.
• the methods comprise administering any of the above-identified the pharmaceutical compositions to the mammal in an amount effective to treat or prevent the inflammation in the mammal.
• the invention is also directed to other methods of treating or preventing inflammation in a mammal.
• the methods comprise administering a pharmaceutical composition to the mammal in an amount effective to treat or prevent the inflammation in the mammal, where the pharmaceutical composition comprises a compound of formula I or formula II, or a pharmaceutically acceptable salt, ester, or tautomer thereof, in a pharmaceutically acceptable excipient.
• Formula I and formula II are examples of compounds of formula I or formula II, or a pharmaceutically acceptable salt, ester, or tautomer thereof, in a pharmaceutically acceptable excipient.
• R 1 is a single or multiple substitution independently H, OH, R 5 , N(R 5 ), SR 5 , or a halogen;
• R 2 comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R 3 ;
• R 3 Is O 1 C(Rs) 25 Or S;
• R 4 is H, R 5 , or a halogen
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -C 6 alkoxy.
• the invention is directed to methods of treating a mammal having sepsis, septicemia, and/or endotoxic shock.
• the methods comprise administering any of the above- identified pharmaceutical compositions to the mammal in an amount sufficient to treat the sepsis, septicemia and/or endotoxic shock.
• the invention is further directed to additional methods of treating a mammal having sepsis, septicemia, and/or endotoxic shock.
• the methods comprise administering a compound to the mammal in an amount sufficient to treat the sepsis, septicemia and/or endotoxic shock, where the compound is
• FIG. 1 shows the rationale for the synthesis of the Cyc-Oxi oxime compounds.
• FIG. 2 shows three inhibitors of macrophage migration inhibitory factor (MIF).
• MIF macrophage migration inhibitory factor
• FFG. 3 is a graph of experimental results establishing that Cyc-Oxi- 11 suppresses the ability of MIF to regulate glucocorticoids in LPS-treated macrophages.
• monocyte- derived macrophages from human peripheral blood were preincubated with dexamethasone (10 "9 ) or dexamethasone plus MIF (3 nM purified native MIF) and various concentrations of Cyc-Oxi- 1 1 (0, 0.01, 0.1 and 1 mM) before the addition of 0.5 ⁇ g/ml lipopolysaccharide (LPS). TNF- ⁇ production was then measured. The data shown are mean ⁇ SD of triplicate wells in experiments that were repeated twice. FlG.
• FIG. 4 is a graph of experimental results establishing that Cyc-Oxi-11 inhibits MIF induction of TNF release from LPS-stimulated macrophages. Briefly, monocyte-derived macrophages from human peripheral blood were pre-treated with various concentrations of Cyc- Oxi-11 10 minutes prior to the addition of 0.5 ⁇ g/ml (LPS). TNF- ⁇ production was then measured. The data shown are mean ⁇ SD of triplicate wells in experiments that were repeated twice.
• FIG. 5 is a graph of the kinetics of MIF appearance in the serum post CLP surgery.
• FlG. 6 is a graph showing that Cyc-Oxi-11 is protective even when given 24 h after the induction of sepsis.
• FIG. 7 shows the synthesis and activity of compounds 3a-3h.
• IC 50 represents the inhibition of MIF tautomerase activity.
• FIG. 8 shows the synthesis and activity of compounds 4-5.
• IC50 represents the inhibition of MIF tautomerase activity.
• Ri is a single or multiple substitution independently H, OH, R 5 , N(R 5 ), SR 5 , or a halogen;
• R 2 comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R 3 ;
• R 3 is O, C(Rs) 2 , or S; and R 4 is H, R 5 , or a halogen, where R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -Ce alkoxy.
• Ri is H, OH or a halogen. More preferably, Ri is OH. In the most preferred embodiments where Rj a single substitution, R 1 is OH in the para position.
• Ri is multiple substitutions
• one R 1 is preferably OH, most preferably in the para position
• the second substitution is preferably a halogen, more preferably fluorine. Most preferably this second substitution is a fluorine in the meta position.
• R 2 comprises a 3-, 4-, 5- or 6-membered alicyclic, heterocyclic or aromatic ring.
• the most preferred rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexy 1-2,3 -ene, or 1-adamantyl.
• R 2 is a heterocyclic ring, the most preferred rings are pyrimidine, pyridazine, pyrazine, pyridine, pyrazole, imidazole, pyrrole, pyran or furan rings.
• the most preferred rings are cyclobenzyl, 4- pyrimidyl, 3-pyrimidyl, or/j ⁇ r ⁇ hydroxymethylphenyl (the latter as in compounds 4 and 5 of FIG.
• the ring structure OfR 2 can comprise more than one ring, and/or be substituted or unsubstituted. When the ring structure is substituted, it is preferably substituted with at least one straight or branched Ci-C 6 alky], straight or branched Ci-C 6 alkenyl, straight or branched Ci-C 6 alkanoyl, straight or branched C r C 6 alkoxy, keto, carboxy, nitro, amino, hydroxy, halogen, cyano, diazo, thio, or hydroxyamino. More preferred substitutions on R 2 are at least one nitro, amino, hydroxyl or halogen.
• R 3 is O. It is also preferred that R 4 is H. In the most preferred compounds, R3 is O and R 4 is H. Within those most preferred compounds, Ri is preferably OH, most preferably in the para position. Also within the most preferred compounds where R 3 is O and R 4 is H, R 2 most preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-2,3-ene, cyclobenzyl, 4- pyrimidyl, 3-pyrimidyl, 1-adamantyl, or methoxyphenyl. Specific preferred compounds comprise
• the compound comprises, or consists of
• Still other preferred compounds of the present invention comprise, or consist of
• Additional preferred compounds comprise, or consist of
• Still additional preferred compounds comprise, or consist of
• Still further additional preferred compounds comprise, or consist of
• Additional preferred compounds comprise, or consist of
• the above-described compounds are useful as inhibitors of macrophage migration inhibitory factor (MIF).
• MIF macrophage migration inhibitory factor
• the invention is also directed to pharmaceutical compositions comprising any of the above compounds, or a pharmaceutically acceptable salt, ester, or tautomer thereof, in a pharmaceutically acceptable excipient.
• pharmaceutically acceptable it is meant a material that (i) is compatible with the other ingredients of the composition without rendering the composition unsuitable for its intended purpose, and (ii) is suitable for use with subjects as provided herein without undue adverse side effects (such as toxicity, irritation, and allergic response). Side effects are “undue” when their risk outweighs the benefit provided by the composition.
• pharmaceutically acceptable carriers include, without limitation, any of the standard pharmaceutical carriers such as phosphate buffered saline solutions, water, emulsions such as oil/water emulsions, microemulsions, and the like.
• compositions designed for oral, lingual, sublingual, buccal and intrabuccal administration can be made without undue experimentation by means well known in the art, for example with an inert diluent or with an edible carrier.
• the compositions may be enclosed in gelatin capsules or compressed into tablets.
• compositions of the present invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
• Tablets, pills, capsules, troches and the like may also contain binders, recipients, disintegrating agent, lubricants, sweetening agents, and flavoring agents.
• binders include microcrystalline cellulose, gum tragacanth or gelatin.
• excipients include starch or lactose.
• disintegrating agents include alginic acid, cornstarch and the like.
• lubricants include magnesium stearate or potassium stearate.
• An example of a glidant is colloidal silicon dioxide.
• sweetening agents include sucrose, saccharin and the like.
• flavoring agents include peppermint, methyl salicylate, orange flavoring and the like. Materials used in preparing these various compositions should be pharmaceutically pure and nontoxic in the amounts used.
• the compounds can easily be administered parenterally such as for example, by intravenous, intramuscular, intrathecal or subcutaneous injection.
• Parenteral administration can be accomplished by incorporating the compounds into a solution or suspension.
• solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
• Parenteral formulations may also include antibacterial agents such as for example, benzyl alcohol or methyl parabens, antioxidants such as for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA.
• Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added.
• the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
• Rectal administration includes administering the compound, in a pharmaceutical composition, into the rectum or large intestine. This can be accomplished using suppositories or enemas.
• Suppository formulations can easily be made by methods known in the art. For example, suppository formulations can be prepared by heating glycerin to about 120° C, dissolving the composition in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.
• Transdermal administration includes percutaneous absorption of the composition through the skin.
• Transdermal formulations include patches (such as the well-known nicotine patch), ointments, creams, gels, salves and the like.
• the present invention includes nasally administering to the mammal a therapeutically effective amount of the compound.
• nasally administering or nasal administration includes administering the compound to the mucous membranes of the nasal passage or nasal cavity of the patient.
• pharmaceutical compositions for nasal administration of the compound include therapeutically effective amounts of the compound prepared by well-known methods to be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the compound may also take place using a nasal tampon or nasal sponge.
• the compound is preferably formulated in a pharmaceutical composition that enhances the ability of the compound to cross the blood-brain barrier of the mammal.
• a pharmaceutical composition that enhances the ability of the compound to cross the blood-brain barrier of the mammal.
• Such formulations are known in the art and include lipophilic compounds to promote absorption. Uptake of non- lipophilic compounds can be enhanced by combination with a lipophilic substance.
• Lipophilic substances that can enhance delivery of the compound across the nasal mucus include but are not limited to fatty acids (e.g., palmitic acid), gangliosides (e.g., GM-I), phospholipids (e.g., phosphatidylserine), and emulsifiers (e.g., polysorbate 80), bile salts such as sodium deoxycholate, and detergent-like substances including, for example, polysorbate 80 such as TweenTM, octoxynol such as TritonTM X-IOO, and sodium tauro-24,25-dihydrofusidate (STDHF). See Lee et al., Biopharm., April 1988 issue:3037.
• fatty acids e.g., palmitic acid
• gangliosides e.g., GM-I
• phospholipids e.g., phosphatidylserine
• emulsifiers e.g.
• the compound is combined with micelles comprised of lipophilic substances.
• micelles can modify the permeability of the nasal membrane to enhance absorption of the compound.
• Suitable lipophilic micelles include without limitation gangliosides (e.g., GM-I ganglioside), and phospholipids (e.g., phosphatidylserine).
• Bile salts and their derivatives and detergent-like substances can also be included in the micelle formulation.
• the compound can be combined with one or several types of micelles, and can further be contained within the micelles or associated with their surface.
• the compound can be combined with liposomes (lipid vesicles) to enhance absorption.
• the compound can be contained or dissolved within the liposome and/or associated with its surface.
• Suitable liposomes include phospholipids (e.g., phosphatidylserine) and/or gangliosides (e.g., GM-I).
• phospholipids e.g., phosphatidylserine
• gangliosides e.g., GM-I
• Bile salts and their derivatives and detergent-like substances can also be included in the liposome formulation.
• the invention is additionally directed to a compound of formula I:
• is a single or multiple substitution independently H, OH, R 5 , N(R 5 ), SR 5 , or a halogen, wherein at least one substitution is a halogen;
• R2 comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R3;
• R 3 is O, C(R 5 ) 2 , or S; and R» is H, Rs, or a halogen, wherein
• R 5 is independently H, a straight or branched C 2 -Ce alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -Cs alkanoyl, or a straight or branched C 2 -C O alkoxy.
• the invention also encompasses pharmaceutical compositions comprising any of these compounds.
• Ri is a multiple substitution comprising OH and a halogen. More preferably Ri comprises OH in the para position. It is also preferred that the halogen substitution is a fluorine. More preferably, the fluorine is in the meta position.
• R 2 comprises a 3-, 4-, 5- or 6-membered alicyclic, heterocyclic or aromatic ring. More preferably, the ring of R 2 is alicyclic. Most preferred alicyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-2,3-ene, and 1-adamantyl. Some of the preferred rings OfR 2 are heterocyclic. A preferred heterocyclic ring is para- hydroxymethylphenyl. Other preferred heterocyclic rings are pyrimidine, pyridazine, pyrazine, pyridine, pyrazole, imidazole, pyrrole, pyran and furan.
• aromatic rings OfR 2 are aromatic. Most preferably the aromatic ring is cyclobenzyl, 4-pyrimidyl, or 3-pyrimidyI.
• the ring structure of R 2 comprises more than one ring. Additionally, the ring structure of R 2 may be unsubstituted. Alternatively, the ring structure of R 2 is substituted with at least one straight or branched Ci-C 6 alkyl, straight or branched Ci-Ce alkenyl, straight or branched Ci-C 6 alkanoyl, straight or branched C 1 -C 6 alkoxy, keto, carboxy, nitro, amino, hydroxy, halogen, cyano, diazo, thio, or hydroxyamino. Other preferred substitutions of the ring structure of R 2 is at least one nitro, amino, hydroxyl or halogen.
• R3 is O. It is also preferred that R 4 is H. Most preferably R 3 is O and R 4 is H.
• Ri comprises an OH substitution and a halogen substitution.
• the OH is in the para position.
• R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-2,3-ene, cyclobenzyl, 4-pyrimidyl, 3-pyrimidyl, 1-adamantyl, or methoxyphenyl.
• the compound comprises, or consists of
• the invention is further directed to a compound of formula I:
• Ri is a single or multiple substitution independently H, OH, R 5 , N(Rs), SR 5 , or a halogen; R ⁇ is/? ⁇ r ⁇ -hydroxymethylphenyl;
• R 3 is O, C(R 5 ) 2 , or S; and R 4 is H, R5, or a halogen, wherein
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoy], or a straight or branched C 2 -C 6 alkoxy.
• Ri is a multiple substitution comprising OH and a halogen. More preferably, OH in the para position and fluorine in the meta position. Most preferably, the compound comprises, or consists of
• Another most preferred compound comprises, or consists of
• the invention is also directed to a pharmaceutical composition
• a pharmaceutical composition comprising any the above compounds, or a pharmaceutically acceptable salt, ester, or tautomer thereof, in a pharmaceutically acceptable excipient.
• the invention is further directed to a compound of formula HI
• Ri comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R 2 ;
• R 2 and R 3 are independently O, C(R 5 ) 2 , or S;
• R 4 is a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -C 6 alkoxy;
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -C 6 alkoxy.
• the invention also encompasses pharmaceutical compositions comprising any of these compounds.
• R 2 and R 3 are both O.
• R 4 is tert-butyl.
• R moieties are cyclopropyl, cyclobutyl, cyclopemyl, cyclohexyl, cyclobenzyl, and a substituted cyclobenzyl.
• Ri is a substituted cyclobenzyl, it is preferably a/ ⁇ ar ⁇ -substituted cyclobenzyl.
• The/? ⁇ r ⁇ -substituted cyclobenzyl is most preferably Even more preferably, the compound comprises
• the compound consists of
• the compound most preferably comprises, or consists of
• the compound can also most preferably comprise, or consist of
• the compound can additionally most preferably comprise, or consist of
• the. compound can most preferably comprise, or consist of
• the compound can most preferably comprise, or consist of
• the compound can still further most preferably comprise, or consist of
• the compound can also most preferably comprise, or consist of
• the compound can additionally preferably comprise, or consist of
• the compound can most preferably comprise, or consist of
• the compound can most preferably comprise, or consist of
• the invention also encompasses pharmaceutical composition
• pharmaceutical composition comprising any of the above compounds, or a pharmaceutically acceptable salt, ester, or tautomer thereof,, in a pharmaceutically acceptable excipient.
• the invention is also directed to methods of inhibiting macrophage migration inhibitory factor (MlF) activity in a mammal.
• the methods comprise administering any of the above- identified pharmaceutical compositions to the mammal in an amount effective to inhibit MIF activity in the mammal.
• MlF macrophage migration inhibitory factor
• the invention is directed to other methods of inhibiting macrophage migration inhibitory factor (MIF) activity in a mammal.
• the methods comprise administering a pharmaceutical composition to the mammal in an amount effective to inhibit MIF activity in the mammal.
• the pharmaceutical composition comprises a compound of formula I or formula II, or a pharmaceutically acceptable salt, ester, or tautomer thereof, in a pharmaceutically acceptable excipient, where formula I and formula II are
• R is a single or multiple substitution independently H, OH, R 5 , N(R 5 ), SR 5 , or a halogen;
• R 2 comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R 3 ;
• R 4 is H, Rs, or a halogen, where
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -Cg alkanoyl, or a straight or branched C 2 -C 6 alkoxy.
• the compound utilized in these methods is of formula I. It is also preferred if R
• R 2 preferably comprises a 3-, A-, 5- or 6-membered alicyclic, heterocyclic or aromatic ring.
• R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-2,3-ene, cyclobenzyl, 4-pyrimidyl, 3-pyrimidyl, 1 -adamantyl, or methoxyphenyl.
• Preferred specific compounds for the present methods include
• the mammal in these methods is preferably a human.
• the mammal also preferably has or is at risk for a condition that comprises an inflammatory cytokine cascade that is at least partially mediated by an MIF.
• Preferred examples of such conditions include cancer, acute respiratory distress syndrome, cytokine-mediated toxicity, psoriasis, interleukin-2 toxicity, appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, inflammatory bowel disease, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cache
• the condition is sepsis, septicemia, and/or endotoxic shock.
• the invention is also directed to methods of treating or preventing inflammation in a mammal.
• the methods comprise administering any of the above-identified pharmaceutical compositions to the mammal in an amount effective to treat or prevent the inflammation in the mammal.
• the invention is additionally directed to other methods of treating or preventing inflammation in a mammal.
• the methods comprise administering a pharmaceutical composition to the mammal in an amount effective to treat or prevent the inflammation in the mammal, where the pharmaceutical composition comprises a compound of formula I or formula II, or a pharmaceutically acceptable salt, ester, or tautomer thereof, in a pharmaceutically acceptable excipient.
• formula I and formula II are examples of formula I and formula II.
• Ri is a single or multiple substitution independently H, OH, R5, N(Rs), SR 5 , or a halogen;
• R 2 comprises a ring structure in which an atom in the ring structure is bound to the carbon that is bound to R3;
• R 4 is H, R 5 , or a halogen, where
• R 5 is independently H, a straight or branched C 2 -C 6 alkyl, a straight or branched C 2 -C 6 alkenyl, a straight or branched C 2 -C 6 alkanoyl, or a straight or branched C 2 -Ce alkoxy.
• the compounds in these methods are preferably of formula I. It is also preferred if Ri of the compounds is OH in the para position.
• R 2 preferably comprises a 3-, 4-, 5- or 6-membered alicyclic, heterocyclic or aromatic ring.
• R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-2,3-ene, cyclobenzyl, 4-pyrimidyl, 3-pyrimidyl, 1-adamantyl, or methoxyphenyl.
• Preferred specific compounds for these methods are
• the mammal in these methods is preferably a human.
• the mammal also preferably has a condition that comprises an inflammatory cytokine cascade that is at least partially mediated by an MIF.
• Preferred examples of such conditions include cancer, acute respiratory distress syndrome, cytokine-mediated toxicity, psoriasis, interleukin-2 toxicity, appendicitis, peptic, gastric and duodenal ulcers, peritonitis, .pancreatitis, ulcerative, pseudomembranous, acute and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, inflammatory bowel disease, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyper
• These methods can further comprise administering a second anti-inflammatory agent to the mammal.
• the second anti-inflammatory agent is an NSAID, a salicylate, a COX inhibitor, a COX-2 inhibitor, or a steroid.
• the mammal has or is at risk for sepsis, septicemia, and/or endotoxic shock and the second treatment is administration of a muscarinic agonist, an adrenomedullin, an adrenomedullin binding protein, a milk fat globule epidermal growth factor factor VIII, an activated protein C, or an ⁇ 2A -adrenergic antagonist.
• the invention is also directed to a method of treating a mammal having sepsis, septicemia, and/or endotoxic shock.
• the method comprises administering any of the above pharmaceutical compositions to the mammal in an amount sufficient to treat the sepsis, septicemia and/or endotoxic shock.
• the invention is further directed to other methods of treating a mammal having sepsis, septicemia, and/or endotoxic shock.
• the methods comprise administering a compound to the mammal in an amount sufficient to treat the sepsis, septicemia and/or endotoxic shock, where the compound is
• Example 1 Oxime inhibitors of macrophage migration inhibitory factor.
• NAPQI N-acetyl-/?-benzoquinone imine
• Cyc-Oxi-11 is one of 29 oxime derivatives that were synthesized around the scaffold and is 30-fold more potent inhibitor of MIF proinflammatory activity in vitro than ISO-I.
• Representative structures of the novel oxime scaffold are presented in Table 1, with their IC 5O of inhibiting MIF dopachrome tautomerase activity. Since toxicity is a concern with respect to the proposed therapeutic use of any novel compound, preliminary acute toxicity screening of Cyc-Oxi-11 was conducted. No evidence of toxicity in intraperitoneal injection was found with doses up to 100 mg/Kg (data not shown). In preliminary studies, the antibacterial effect of Cyc- Oxi-1 1 was also tested and was found to be negative.
• Cyc-Oxi- 1 1 binding to the MIF active site down-regulates MIF glucocorticoid-regulating activity on LPS-activated monocytes.
• the more potent neutralization of MlF proinflammatory activity in vitro is associated with enhanced inhibitory effect on MIF tautomerase activity. This association is further borne out in the new class of Cyc- Oxi agents. As shown in FIG.
• Cyc-Oxi- 11 significantly inhibited MIF-dependent interference with glucocorticoids from LPS-stimulated macrophages and Cyc-Oxi- 11 is one of the most potent inhibitor of MIF tautomerase and proinflammatory activity with an IC 50 of ⁇ 1.3 ⁇ M in both assays (30-fold more potent than ISO-I). Cyc-Oxi- 11 inhibits TNF release in vitro. Cvc-Oxi-11 inhibits MIF proinflammatory activity in vitro. It has been shown that the macrophage is an abundant source of MIF (Calandra et al., 1994), which is released after LPS stimulation. This led to an examination of the autocrine and paracrine activity of secreted MIF in vitro.
• Cyc-Oxi-11 neutralization of secreted MIF from LPS-stimulated human macrophages is able to inhibit MIF activity to mediate TNF release.
• Cyc-Oxi-1 1 in a dose-dependent manner, inhibits TNF release by LPS-stimulated human macrophages similarly to anti-MIF antibody treatment.
• Macrophage migration inhibitory factor is a pro-inflammatory cytokine that plays a critical role in the pathogenesis of inflammatory diseases.
• MIF a homotrimer (Sun et al., 1996; Sugimoto et al., 1996), possesses the unique ability to catalyze the tautomerization of non- physiological substrates such as D or L-dopachrome methyl ester into their corresponding indole derivatives (Rosengren et al., 1996).
• This Example describes the influence of ortho-halogenation in respect to the hydroxy 1 group on the potency to inhibit MIF tautomerase activity.
• E halogenated 4-hydroxybenzaldehyde O-cyclohexanecarbonyloxime
• OXIM-1 1, 3a a potent and specific inhibitor of the MIF tautomerase activity.
• the mono-fluorination ortho to the hydroxyl improves the inhibition of MIF bioactivity up to 63%.
• the halogenated 4-hydroxybenzaldehydes Ib-Ih were either commercially available or prepared according to the procedure described in literature (Lawrence et al., 2003).
• the o ⁇ imes 2a-2h (FIG.7) were synthesized in excellent yields by condensation of hydroxylamine with the aldehydes Ia-Ih in basic alcoholic solvent.
• the final compounds 3a-3h (FIG. 7) were synthesized in good yields by condensation of oximes 2a-2h with cyclohexanecarboxylic acid chloride in dry dichloromethane in present of pyridine from 0 °C to room temperature overnight (Scheme 1) (See Supplemental Material below).
• Compound 4 and 5 were prepared as the similar method as the compound 3 (FIG. 8).
• the final compounds 3a-3h, 4 and 5 reported here were fully characterized by 1 H NMR, 13 C NMR and ESI-MS (See Supplemental Material below).
• the crystal structure of MIF complexed to ISO-I or OXIM-1 1 revealed that the phenolic group has a critical role in binding within the active site of MIF in both substrate and inhibitors. Compounds bearing halogens in an ortho position of the phenolic group were thus evaluated to determine whether the halogen enhances the hydrogen bond of the phenol for the additional binding within the active site of MIF.
• the candidate compounds 3a-3h were synthesized, and the inhibition of MIF dopachrome tautomerase activity is presented in FIG. 7.
• the (£)-4-hydroxybenzaldehyde O-cyclohexanecarbonyloxime (OXIM-11, 3a), inhibits MIF dopachrome tautomerase activity with an IC 50 of 1.3 ⁇ M.
• Mono-fluorination on the ortho position of the phenolic group, compound 3b improves the inhibition of the dopachrome tautomerase activity by 35%, to an IC 50 of 0.9 ⁇ M.
• the strong electronegativity of the fluorine substituent polarizes the phenolic ring and enhances the OH hydrogen bond accepting ability that corresponds to the observed the most potency of compound 3b.
• Difluoro analogue 3c and tetrafluoro analogue 3d were considerably less potent than 3b because of the electrostatic repulsion of the fluorine groups (Malamas et al., 2004).
• the 2,6-difluoro analogue 3c is most likely to have repulsion with the amide group of Asn-97.
• the other halogenated compounds bearing chlorine or bromine or iodine, compound 3e- 3h have reduced activity (FIG. 7). This finding is not surprising because the hydrogen bonds between the side-chain of Asn-97 and hydroxyl group are the key interaction within the MIF active site (Lubetsky et al., 1999).
• halogens such as chlorine, bromine and iodine ortho to the hydroxyl group significantly alter the size of the molecule, and result in noticeably decreased ligand binding.
• the intramolecular hydrogen bonds between OH and the halogens reduce the OH hydrogen bond donating ability as evidenced by increasing the acidity of OH in proton NMR analysis (FIG. 7) (Himo et al., 2000). Therefore, fluorine on the ortho position of the phenolic group on compound 3b has a critical and specific role for additional binding within the active site of MIF.
• MIF tautomerase activity was measured by UV- Visible recording spectrophotometry (SHIMADZU, UV 1600U).
• a fresh stock solution of L-dopachrome methyl ester was prepared at 2.4 mM through oxidation of L-3,4-dihydroxyphenylalanine methyl ester with sodium periodate.
• 1 ⁇ L of MIF solution (800-900 ng/mL) and 1 ⁇ L of a DMSO solution with various concentrations of the enzymatic inhibitor were added into a plastic cuvette (10 mm, 1.5 mL) containing 0.7 mL assay buffer (IX potassium phosphate, pH 7.2).
• the L-dopachrome methyl ester solution (0.3 mL) was added to the assay buffer mixture.
• the coupling constants (J) are measured in Hertz (Hz) and assigned as s (singlet), d (doublet), t (triplet), m (multiplet) and br (broad). Low-resolution mass spectra were acquired using Thermofinnigan LCQ DecaXPplus quadrupole ion trap MS with negative-ion mode.
• Example 3 Additional compounds inhibiting MIF. Additional compounds were produced and tested for MIF inhibitory activity in vitro by the methods described in the above examples. Table 2 provides the results of those experiments.
• Cerami A, Bucala R: MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365:756-759, 1993
• Calandra T, Bucala R Macrophage migration inhibitory factor (MIF): a glucocorticoid counter-regulator within the immune system. Crit Rev Immunol 17:77-88, 1997 Calandra T, Bernhagen J, Mitchell RA, Bucala R: The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 179:1895- 1902, 1994
• Calandra T, Spiegel LA, Metz CN, Bucala R Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria.
• Proc Natl Acad Sci USA 95:1 1383-11388, 1998 Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN 3 Hultner L, Heumann D, Mannel D, Bucala R, Glauser MP: Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6: 164-170, 2000
• Lolis E, Bucala R Crystal structure of macrophage migration inhibitory factor (MIF), a glucocorticoid-induced regulator of cytokine production, reveals a unique architecture.
• MIF macrophage migration inhibitory factor
• Onodera S Kaneda K, Mizue Y, Koyama Y, Fujinaga M, Nishihira J: Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. J Biol Chem 275:444-450, 2000 Orita M, Yamamoto S, Katayama N, Aoki M, Takayama K, Yamagiwa Y, Seki N, Suzuki
• MIF macrophage migration inhibitory factor

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• 2007
  • 2007-06-04 EP EP07777387A patent/EP2023732A4/en not_active Withdrawn
  • 2007-06-04 CA CA002653646A patent/CA2653646A1/en not_active Abandoned
  • 2007-06-04 US US12/227,777 patent/US20090318509A1/en not_active Abandoned
  • 2007-06-04 JP JP2009514326A patent/JP2009539838A/ja active Pending
  • 2007-06-04 AU AU2007258731A patent/AU2007258731B2/en not_active Ceased
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