WO2004054504A2 - Inhibiteurs d'aminocyanopyridine tricyclique de la proteine kinase 2 a activation par mitogene a activation par proteine kinase - Google Patents

Inhibiteurs d'aminocyanopyridine tricyclique de la proteine kinase 2 a activation par mitogene a activation par proteine kinase Download PDF

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WO2004054504A2
WO2004054504A2 PCT/US2003/039122 US0339122W WO2004054504A2 WO 2004054504 A2 WO2004054504 A2 WO 2004054504A2 US 0339122 W US0339122 W US 0339122W WO 2004054504 A2 WO2004054504 A2 WO 2004054504A2
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chromeno
pyridine
carbonitrile
diamino
alkoxy
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PCT/US2003/039122
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WO2004054504A3 (fr
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David R. Anderson
William F. Vernier
Len F. Lee
Emily J. Reinhard
Shridhar G. Hegde
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Pharmacia Corporation
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Priority to BR0317228-7A priority Critical patent/BR0317228A/pt
Priority to EP03813362A priority patent/EP1569942A2/fr
Priority to MXPA05006369A priority patent/MXPA05006369A/es
Priority to JP2004560741A priority patent/JP2006511551A/ja
Priority to AU2003296406A priority patent/AU2003296406A1/en
Priority to CA002509665A priority patent/CA2509665A1/fr
Publication of WO2004054504A2 publication Critical patent/WO2004054504A2/fr
Publication of WO2004054504A3 publication Critical patent/WO2004054504A3/fr

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Definitions

  • the present invention relates to aminocyanopyridine compounds, and in particular, to tricyclic aminocyanopyridine compounds which inhibit mitogen-activated protein kinase-activated protein kinase-2
  • MAPKs Mitogen-activated protein kinases
  • MAPKs are members of conserved signal transduction pathways that activate transcription factors, translation factors and other target molecules in response to a variety of extracellular signals.
  • MAPKs are activated by phosphorylation at a dual phosphorylation motif with the sequence Thr-X-Tyr by mitogen-activated protein kinase kinases (MAPKKs).
  • MAPKKs mitogen-activated protein kinase kinases
  • the physiological role of MAPK signaling has been correlated with cellular events such as proliferation, oncogenesis, development and differentiation. Accordingly, the ability to regulate signal transduction via these pathways could lead to the development of treatments and preventive therapies for human diseases associated with MAPK signaling, such as inflammatory diseases, autoimmune diseases and cancer.
  • the p38 MAPK pathway is potentially activated by a wide variety of stresses and cellular insults. These stresses and cellular insults include heat shock, UV irradiation, inflammatory cytokines (such as TNF and IL-1), tunicamycin, chemotherapeutic drugs (i.e., cisplatinum), anisomycin, sorbitol/hyperosmolarity, gamma irradiation, sodium arsenite, and ischaemia. See, Ono, K., etal, Cellular Signalling 12, 1 - 13 (2000).
  • stresses and cellular insults include heat shock, UV irradiation, inflammatory cytokines (such as TNF and IL-1), tunicamycin, chemotherapeutic drugs (i.e., cisplatinum), anisomycin, sorbitol/hyperosmolarity, gamma irradiation, sodium arsenite, and ischaemia. See, Ono, K., etal, Cell
  • Activation of the p38 pathway is involved in (1) production of proinflammatory cytokines, such as TNF- ⁇ ; (2) induction of enzymes, such as Cox-2; (3) expression of an intracellular enzyme, such as iNOS, which plays an important role in the regulation of oxidation; (4) induction of adherent proteins, such as VCAM-1 and many other inflammatory-related molecules.
  • the p38 pathway functions as a regulator in the proliferation and differentiation of cells of the immune system. See, Ono, [0006]
  • the p38 kinase is an upstream kinase of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP kinase-2 or MK-2). (See, Freshney, N.
  • MK-2 is a protein that appears to be predominantly regulated by p38 in cells. Indeed, MK-2 was the first substrate of p38 ⁇ to be identified. For example, in vitro phosphorylation of MK-2 by p38 ⁇ activates MK-2.
  • the substrates that MK-2 acts upon, in turn, include heat shock protein 27, lymphocyte-specific protein 1 (LAP1), cAMP response element-binding protein (CREB), ATF1 , serum response factor (SRF), and tyrosine hydroxylase.
  • LAP1 lymphocyte-specific protein 1
  • CREB cAMP response element-binding protein
  • SRF serum response factor
  • tyrosine hydroxylase tyrosine hydroxylase
  • the role of the p38 pathway in inflammatory-related diseases has been studied in several animal models.
  • the pyridinyl imidazole compound SB203580 has been shown to be a specific inhibitor of p38 in vivo, and also has been shown to inhibit activation of MK-2, (See, Rouse, J., et al, Cell, 75:1027-1037 (1994); Cuenda, A., et al, Biochem. J., 333:11-15 (1998)), as well as a MAP kinase homologue termed reactivating kinase (RK).
  • RK MAP kinase homologue
  • mice lacking MK-2 possessed increased stress resistance and survived LPS-induced endotoxic shock better than MK-2 + mice.
  • MK-2 was an essential component in the inflammatory response that regulates biosynthesis of TNF ⁇ at a post-transcriptional level. More recently,
  • MK-2-deficient mice showed increased susceptibility to Listeria monocytogenes infection, and concluded that MK-2 had an essential role in host defense against intracellular bacteria, probably via regulation of TNF and IFN-gamma production required for activation of antibacterial effector mechanisms.
  • MK-2 in the p38 signaling pathway at a point that is downstream of p38 offers the potential that MK-2 could act as a focal point for modulating the pathway without affecting as many substrates as would the regulation of an enzyme further upstream in the signaling cascade -- such as p38 MAP kinase.
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 each is independently selected from the group consisting of hydrogen, hydroxy, amino, halo, nitro, branched or unbranched CrC ⁇ alkyl, C 2 -d alkenyl, d-d alkynyl, C ⁇ -C 6 alkoxy, hydroxy d-d alkyl, hydroxy d- alkoxy, d-d alkoxy Ci- C ⁇ alkoxy, d-d alkoxy CrC ⁇ alkyl, d-C 6 alkenoxy, branched or unbranched amino d-d alkyl, diamino C 2 -C 6 alkyl, d- C 6 alkylamino d-d alkyl, CrC ⁇ alkylamino, di-( d-d alkyl)amino, d-d alkoxyarylamino, d-d alkoxyalkylamino, amino Crd al
  • C 3 -C 6 heterocyclyl ring contains O, S, or N, branched or unbranched CrC ⁇ alkoxycarbonyl Crd alkoxy, and carboxy, carboxy CrC ⁇ alkoxy, carboxy d-d alkyl, hydroxy d-d alkoxycarbonyl, d-d alkoxycarbonyl, where R 6 and R 7 are such that they optionally join to form a ring system of the type selected from
  • G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, R 9 and R 0 are absent; when G is sulfur, each of R 9 and R 10 is optionally absent, or is oxo; when G is nitrogen, R 4 is -H, R 9 is absent, and R 10 is d-d-alkyl.
  • the present invention is also directed to a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and an aminocyanopyridine MK-2 inhibiting compound having the structure:
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 each is independently selected from the group consisting of hydrogen, hydroxy, amino, halo, nitro, branched or unbranched d- alkyl, C 2 -C 6 alkenyl, d-d alkynyl, d-d alkoxy, hydroxy d-d alkyl, hydroxy Crd alkoxy, d-d alkoxy d- C 6 alkoxy, CrC ⁇ alkoxy d-d alkyl, d-d alkenoxy, branched or unbranched amino CrC ⁇ alkyl, diamino C 2 -d alkyl, Cr C 6 alkylamino d-d alkyl, d-d alkylamino, di-( d-d alkyl)amino, Crd alkoxyarylamino, d- alkoxyaikylamino, amino d-d alkoxy, di
  • G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, R 9 and R 10 are absent; when G is sulfur, each of R 9 and R 10 is optionally absent, or is oxo; when G is nitrogen, R 9 is absent, and R 10 is d-d-alkyl.
  • the present invention is also directed to a novel kit comprising a dosage form containing an aminocyanopyridine MK-2 inhibiting compound having the structure:
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 each is independently selected from the group ' consisting of hydrogen, hydroxy, amino, halo, nitro, branched or unbranched d-d alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Crd alkoxy, hydroxy Crd alkyl, hydroxy CrC ⁇ alkoxy, d-d alkoxy d- Ce alkoxy, d-d alkoxy d-d alkyl, d-d alkenoxy, branched or unbranched amino d-d alkyl, diamino C 2 -C 6 alkyl, d- Ce alkylamino d- alkyl, Crd alkylamino, di-( Crd alkyl)amino, d- alkoxyarylamino, d-dalkoxyalkylamino, amino CrC ⁇ alkoxy, di
  • G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, R 9 and R 10 are absent; when G is sulfur, each of R 9 and R 10 is optionally absent, or is oxo; when G is nitrogen, R 9 is absent, and R 10 is d-C 4 -alkyl.
  • aminocyanopyridine compounds can inhibit the activity of MAPKAP kinase-2. Many of these compounds exhibit their inhibitory effect at low concentrations - having in vitro MK-2 inhibition I o values of under 1.0 ⁇ M, and with some having Ido values of under about 0.5 ⁇ M, and even as low as about 0.2 ⁇ M. Accordingly, these compounds can be potent and effective drugs for use in methods to prevent or treat diseases and disorders that are mediated by TNF ⁇ . For example, they can be used for the prevention or treatment of arthritis.
  • Aminocyanopyridine compounds that are useful in the present method include those aminocyanopyridine compounds having the structure shown in formula I:
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 each is independently selected from the group consisting of hydrogen, hydroxy, amino, halo, nitro, branched or unbranched d-d alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, d-d alkoxy, hydroxy d-d alkyl, hydroxy d-d alkoxy, d-d alkoxy d- d alkoxy, d-d alkoxy CrC ⁇ alkyl, CrC ⁇ alkenoxy, branched or unbranched amino d-d alkyl, diamino C 2 -d alkyl, d- d alkylamino d-d alkyl, d-d alkylamino, di-( d-d alkyl)amino, d-d alkoxyarylamino, d- alkoxyalkylamino, amino
  • C 3 -d heterocyclyl ring contains O, S, or N, branched or unbranched d-d alkoxycarbonyl d-d alkoxy, and carboxy, carboxy d-d alkoxy, carboxy d-d alkyl, hydroxy Crd alkoxycarbonyl, Crd alkoxycarbonyl, where R 6 and R 7 are such that they optionally join to form a ring system of the type selected from
  • ring substituent groups that join to form additional ring structures adjacent the substituted ring can be described with reference to chemical formulas that show wavy lines to indicate that a partial molecule is shown.
  • the wavy lines cut through the ring to which the substituents are joined (in this case, the phenyl ring of formula I), rather than across the bond joining the substituent group to the ring.
  • the partial ring that is shown is the ring to which the substituent groups are shown as being bonded in the general formula.
  • G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, R 9 and R 0 are absent; when G is sulfur, each of R 9 and R 10 is optionally absent, or is oxo; when G is nitrogen, R 4 is -H, R 9 is absent, and R 10 is d-d-alkyl.
  • R 6 is other than cyano.
  • alkyl alone or in combination, means an acyclic alkyl radical, linear or branched, which, unless otherwise noted, preferably contains from 1 to about 10 carbon atoms and more preferably contains from 1 to about 6 carbon atoms.
  • Alkyl also encompasses cyclic alkyl radicals containing from 3 to about 7 carbon atoms, preferably from 3 to 5 carbon atoms.
  • the alkyl radicals can be optionally substituted with groups as defined below. Examples of such alkyl radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl, and the like.
  • alkenyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond. Unless otherwise noted, such radicals preferably contain from 2 to about 6 carbon atoms, preferably from 2 to about 4 carbon atoms, more preferably from 2 to about 3 carbon atoms.
  • the alkenyl radicals may be optionally substituted with groups as defined below.
  • alkenyl radicals examples include propenyl, 2- chloropropylenyl, buten-1yl, isobutenyl, penten-1yl, 2-methylbuten-1-yl, 3- methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1 -yl, octen-1-yl, and the like.
  • alkynyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds, such radicals preferably containing 2 to about 6 carbon atoms, more preferably from 2 to about 3 carbon atoms.
  • alkynyl radicals may be optionally substituted with groups as described below.
  • suitable alkynyl radicals include ethynyl, proynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4- methoxypentyn-2-yl, 3-methylbutyn-1 -yl, hexyl-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1 -yl radicals, and the like.
  • alkoxy includes linear or branched oxy-containing radicals, each of which has, unless otherwise noted, alkyl portions of 1 to about 6 carbon atoms, preferably 1 to about 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, isobutoxy radicals, and the like.
  • alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • radicals examples include methoxyalkyls, ethoxyalkyls, propoxyalkyls, isopropoxyalkyls, butoxyalkyls, tert-butoxyalkyls, and the like.
  • the "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide "haloalkoxy” radicals.
  • halo atoms such as fluoro, chloro, or bromo
  • examples of such radicals included fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, fluoropropoxy, and the like.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, preferably, unless otherwise noted, of from 1 to about 6 carbon atoms, attached to a divalent sulfur atom.
  • alkylthioalkyl embraces alkylthio radicals, attached to an alkyl group. An example of such radicals is methylthiomethyl.
  • halo means radicals comprising halogens, such as fluorine, chlorine, bromine, or iodine.
  • heterocyclyl means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms is replaced by N, S, P, or O. This includes, for example, structures such as:
  • Z, Z ⁇ Z 2 , or Z 3 is C, S, P, O, or N, with the proviso that one of Z, Z 1 , Z 2 , or Z 3 is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom.
  • the optional substituents are understood to be attached to Z, Z 1 , Z 2 , or Z 3 only when each is C.
  • heterocycle also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others.
  • heteroaryl means a fully unsaturated heterocycle, which can include, but is not limited to, furyl, thenyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, thiazolyl, quinolinyl, isoquinoiinyl, benzothienyl, and indolyl.
  • heterocyclyl or “heteroaryl”
  • the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
  • cycloalkyi means a mono- or multi-ringed carbocycle wherein each ring contains three to about seven carbon atoms, preferably three to about six carbon atoms, and more preferably three to about five carbon atoms. Examples include radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl.
  • radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl.
  • cycloalkyi additionally encompasses spiro systems wherein the cycloalkyi ring has a carbon ring atom in common with the seven-membered heterocyclic ring of the benzothiepine.
  • oxo means a doubly-bonded oxygen.
  • aryl means a fully unsaturated mono- or multi-ring carbocycle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl.
  • the present aminocyanopyridine compounds inhibit the activity of the MK-2 enzyme.
  • a subject compound inhibits MK- 2
  • MK-2 enzymatic activity is lower in the presence of the compound than it is under the same conditions in the absence of such compound.
  • One method of expressing the potency of a compound as an MK-2 inhibitor is to measure the "IC 50 " value of the compound.
  • the Ido value of an MK-2 inhibitor is the concentration of the compound that is required to decrease the MK-2 enzymatic activity by one-half.
  • aminocyanopyridine compounds that inhibit MK-2 can be referred to as aminocyanopyridine MK-2 inhibitors, or aminocyanopyridine MK-2 inhibiting compounds or MK-2 inhibiting agents.
  • the tricyclic aminocyanopyridine compounds that are useful in the present invention include benzonapthyridines, pyridochromanes, and pyridothiochromanes.
  • a The aminocyanopyridine compound may be shown with a solvent, such as, for example, trifluoroacetate, with which it can form a salt. Both the salt and acid forms of the aminocyanopyridine compound are included in the present invention.
  • b Compound names generated by ACD/Name software.
  • the present aminocyanopyridine compound has the structure shown in formula I, where:
  • R 1 is selected from the group consisting of hydrogen, branched or unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy, carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl, alkylamino, halo, alkylaminoalkyl, alkoxy, alkoxyalkyl, monocyclyl, bicyclyl, polycyclyl, and heterocyclyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl;
  • R 3 is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties
  • R 4 is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
  • R 5 is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkylyl, arylalkyl, or alkylaryl
  • R 6 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy; where the R ⁇ and R 7 groups optionally join to form a six membered heterocyclic ring;
  • R 8 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl; and
  • G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, R 9 and R 10 are absent; when G is sulfur, each of R 9 and R 10 is optionally absent, or is oxo; when G is nitrogen, R 9 is absent, and R 10 is d-d-alkyl.
  • the present aminocyanopyridine compound can have the structure shown in formula I, where: R 1 is selected from the group consisting of hydrogen, ethyl, dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl;
  • R 2 is selected from the group consisting of hydrogen, hydroxyethyl, propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl, phenylmethyl, dimethylaminoethyl, phthaloaminoethyl, butyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl;
  • R 3 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl.
  • R 4 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
  • R 5 is selected from the group consisting of hydrogen, hydroxy, methoxy, bromo, and 2-pyridomethyl
  • R 6 is selected from the group consisting of hydrogen, hydroxy, methoxy, amino, carboxy, diaminoethoxy, bromo, propoxy, isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro, pyridylmethyl, and fluoro;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy, morpholinoethoxy, carboxymethoxy, ⁇ /-pyrrolidylethoxy, dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and isobutylcarboxymethoxy, where the R 6 and R 7 groups optionally join to form a six membered heterocyclic ring;
  • R 8 is selected from the group consisting of hydrogen, hydroxy, fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl, hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy, dimethylaminoethoxy, carboxy, bromo, and pyrridylmethyl; and G is selected from the group consisting of oxygen, sulfur, and
  • R 1 is selected from the group consisting of hydrogen, and d-C 2 alky
  • R 2 is selected from the group consisting of hydrogen, d-d alkyl, hydroxy d-d alkyl, Crd alkoxyphenyl, d-C 2 alkoxy d-d alkyl, amino d-d alkyl, phenyl Crd alkyl, and di d-d alkylamino d-d alkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, dicyano d-d alkyl, and halophenyl;
  • R 5 is selected from the group consisting of hydrogen, and hydroxy
  • R b is selected from the group consisting of hydrogen, hydroxy, C
  • R 7 is selected from the group consisting of hydrogen, hydroxy, Ci -
  • R 6 and R 7 groups optionally join to form a six membered heterocyclic ring;
  • R 8 is selected from the group consisting of hydrogen, hydroxy, halo, C -C2 alkyl, C r C 2 alkoxy, nitro, amino, pyrrolidyl d-d alkoxy, carboxy d- C 2 alkoxy, hydroxy d-C 2 alkoxy, and amino C
  • G is selected from the group consisting of oxygen and sulfur; when G is sulfur, each of R 9 and R 10 is optionally absent, or is oxo; when G is oxygen, R 9 and R 10 are absent.
  • the present aminocyanopyridine compound can provide an Ido of less than about 100 ⁇ M, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula I, where:
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of hydrogen, Ci - C 3 alkyl, hydroxy C - C 2 alkyl, Ci - C 2 alkoxyphenyl, Ci - C 2 alkoxy C - C 2 alkyl, amino Ci - C 2 alkyl, phenyl Ci - C 2 alkyl, and di Ci - C 2 alkylamino Ci - d alkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, and dicyano Ci - d alkyl.
  • R 5 is selected from the group consisting of hydrogen, and hydroxy
  • R 6 is selected from the group consisting of hydrogen, hydroxy, d- C 2 alkoxy, amino, carboxy, nitro, diamino Crd alkoxy, halo, 2-propenoxy, iso C 3 -C 4 alkylcarboxy Crd alkoxy, di d-C 2 alkylamino, and phenyl;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, C - C 2 alkoxy, hydroxy d-d alkoxy, d-d alkoxy d-C 2 alkoxy, amino d-C 2 alkoxy, morpholino d-C 2 alkoxy, carboxyl Crd alkoxy, pyrrolidyl d-d alkoxy, di d-d alkylamino d-C 2 alkoxy, pyrrolidyl d-d alkyl. is ° C 3 -C 4 alkylcarboxy d-d alkoxy, and 2-propenoxy; wherein the R 6 and R 7 groups optionally join to form a six membered heterocyclic ring;
  • R 8 is selected from the group consisting of hydrogen, hydroxy, halo, d-d alkoxy, nitro, amino, pyrrolidyl d-d alkoxy, and carboxy d-C 2 alkoxy;
  • G is selected from the group consisting of oxygen and sulfur; when G is sulfur, each of R 9 and R 0 is optionally absent, or is oxo; when G is oxygen, R 9 and R 10 are absent.
  • the present aminocyanopyridine compound can provide an Ido of less than about 50 ⁇ M, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula I, where:
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of hydrogen, d-d alkyl, hydroxy Crd alkyl, d-d alkoxyphenyl, d-d alkoxy d-d alkyl, amino d-d alkyl, and phenyl d-d alkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, and dicyano d-d alkyl.
  • R 5 is selected from the group consisting of hydrogen, and hydroxy
  • R 6 is selected from the group consisting of hydrogen, hydroxy, d- C 2 alkoxy, amino, carboxy, diamino d-C 2 alkoxy, halo, 2-propenoxy, iso d-d alkylcarboxy d-C 2 alkoxy, and di d-d alkylamino;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, d- d alkoxy, hydroxy d-d alkoxy, Crd alkoxy d-d alkoxy, amino Crd alkoxy, morpholino d-d alkoxy, carboxyl d-d alkoxy, pyrrolidyl Crd alkoxy, di d-C 2 alkylamino Crd alkoxy, pyrrolidyl d-d alkyl, iso C 3 -C 4 alkylcarboxy d-d alkoxy, and 2-propenoxy; where the R 6 and R 7 groups optionally join to form a six membered heterocyclic ring;
  • R 8 is selected from the group consisting of hydrogen, hydroxy, halo, d-d alkoxy, nitro, amino, and pyrrolidyl d-d alkoxy;
  • G is selected from the group consisting of oxygen and sulfur; when G is sulfur, each of R 9 and R 10 is optionally absent, or is oxo; when G is oxygen, there R 9 and R 10 are absent.
  • the present aminocyanopyridine compound can provide an Ido of less than about 20 ⁇ M, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula I, where: R 1 is hydrogen;
  • R 2 is selected from the group consisting of hydrogen, d-d alkyl, hydroxy d-d alkyl, d-d alkoxyphenyl, d-d alkoxy d-d alkyl, and amino Crd alkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, and dicyanoethyl
  • R 5 is selected from the group consisting of hydrogen, and hydroxy
  • R 3 6 is selected from the group consisting of hydrogen, hydroxy, C
  • R 7 is selected from the group consisting of hydrogen, hydroxy, d- C 2 alkoxy, hydroxy Crd alkoxy, d-C 2 alkoxy d-d alkoxy, amino d-C 2 alkoxy, morpholino d-d alkoxy, carboxyl d-C 2 alkoxy, pyrrolidyl d-C 2 alkoxy, di d-d alkylamino Crd alkoxy, pyrrolidyl d-C 2 alkyl, iso C 3 -d alkylcarboxy d-d alkoxy, and 2-propenoxy; where the R 6 and R 7 groups optionally join to form a six membered heterocyclic ring;
  • R 8 is selected from the group consisting of hydrogen, hydroxy, halo, methoxy, nitro, and amino; and G is selected from the group consisting of oxygen and sulfur; when G is sulfur, each of R 9 and R 10 is optionally absent, or is oxo; when G is oxygen, R 9 and R 10 are absent.
  • Examples of aminocyanopyridine MK-2 inhibitor compounds of the present invention include, without limitation, the following: 2,4-diamino-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
  • Aminocyanopyridine MK-2 inhibiting compounds of the type shown in formula I, above include tricyclic aminocyanopyridine MK-2 inhibiting compounds, such as benzonapthyridines, pyridochromanes, and pyridothiochromanes.
  • tricyclic aminocyanopyridine MK-2 inhibiting compounds such as benzonapthyridines, pyridochromanes, and pyridothiochromanes.
  • a general method for the synthesis of these tricyclic aminocyanopyridines is shown in Scheme 1 , below: Scheme 1 :
  • a substituted benzaldehyde is reacted with a tricarbonitrile, preferably 2-amino-1 -propene-1 ,1 ,3-tricarbonitrile.
  • the reaction can be carried out by heating the reactants to reflux in a solution of acetic acid and ethanol.
  • the reaction product can be concentrated in vacuo and dissolved in trifluoroacetic acid.
  • Triethylsilane is added and the mixture is stirred. In a preferred method, the mixture is stirred for about 1 hour at 0°C.
  • Dichloromethane is then added and solids are collected. The solids can be collected by filtration, and can be washed with dichloromethane and ether.
  • the solids comprise the desired tricyclic aminocyanopiyridine MK-2 inhibiting compound of the type including benzonapthyridines, pyridochromanes, and pyridothiochromanes.
  • Z can be OH, SH, or NR a Y, where Y is a protecting group for nitrogen.
  • the Y group can be benzyl, allyl, an alkyl carbamate, or a benzyl carbamate.
  • Other nitrogen protecting groups are know to persons having skill in the art of organic synthesis.
  • a perferred protecting group is tert- butylcarbamate.
  • R a can be an alkyl group, an aryl group, or a heteroaryl group.
  • the benzene ring of the benzaldehyde can be further substituted by one, two, three, or four additional R groups at carbons 3, 4, 5, or 6.
  • Each R can independently be hydrogen; alkyl; aryl; a heteroatom, such as O, N, or S, substituted with hydrogen, d-d alkyl, CrC ⁇ branched alkyl, aryl, heteroaryl (wherein the heteroaryl can include, but is not limited to, pyrazolyl, inidizolyl, pyrryl, pyridyl, thiophyl, furyl and pyrimidyl), ester and amido.
  • Advantages of this method include that it is a general method that can be used to produce various types of the tricyclic compounds of formula I depending upon the types of reactants used. It is also an easy and straightforward synthesis method that can be carried out in a single vessel.
  • a tricyclic aminocyanopyridine MK-2 inhibiting compound can be prepared by reacting a substituted benzaldehyde having the structure:
  • Z is selected from the group consisting of -OH, -SH, and -NR a Y;
  • R a is selected from the group consisting of alkyl, aryl, and heteroaryl;
  • Y is a protecting group for nitrogen.
  • nitrogen protecting groups include benzyl, allyl, alkyl carbamates and benzyl carbamates.
  • G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, it has no substituent groups; when G is sulfur, it is either unsubstituted, or is substitutued with one or two oxo groups; when G is nitrogen, it is substituted with d-d alkyl;
  • R b is selected from the group consisting of furyl and -NH-R 2 ;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, halo, alkyl, alkenyl, alkylyl, arylalkyl, alkylaryl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylamino, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, alkylcarboxyalkoxy, pyrrolidylethoxy, hydroxyalkoxy, and alkylcarboxy, where R 6 and R 7 are such that they optionally join to form a six membered heterocyclic ring.
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
  • R 5 is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkylyl, arylalkyl, or alkylaryl;
  • R 6 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy; where the R 6 and R 7 groups optionally join to form a six membered heterocyclic ring; and
  • R 8 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl.
  • the substituted benzaldehyde comprises salicaldehyde and the tricarbonitrile comprises 2- amino-1 -propene-1 ,1 ,3-tricarbonitrile.
  • the nitrogen protecting group "Y" comprises tert-butylcarbamate.
  • Z is selected from the group consisting of -OH, -SH, and -NR a Y;
  • R a is selected from the group consisting of alkyl, aryl, and heteroaryl
  • Y is a protecting group for nitrogen that is selected from the group consisting of benzyl, allyl, alkyl carbamates and benzyl carbamate
  • G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, it has no substituent groups; when G is sulfur, it is either unsubstituted, or is substitutued with one or two oxo groups; when G is nitrogen, it is substituted with d-d alkyl;
  • R b is selected from the group consisting of furyl and -NH-R 2 ;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of: hydrogen, hydroxy, amino, halo, nitro, branched or unbranched d-d alkyl, C 2 -C 6 alkenyl, C 2 -d alkynyl, CrC 6 alkoxy, hydroxy d-d alkyl, hydroxy d-d alkoxy, d-d alkoxy d- d alkoxy, d-d alkoxy d-d alkyl, C 2 -C 6 alkenoxy, branched or unbranched amino d-d alkyl, diamino d-d alkyl, d- d alkylamino Crd alkyl, d-d alkylamino, di-( d-d alkyl)amino, d-d alkoxyarylamino, d- alkoxyalkylamino, amino CrC ⁇ alkoxy, di-(d-d alkylamin
  • alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkoxy, halo, alkylthio, alkylthioalkyl, heterocyclyl, cyclyl, aryl, heteroaryl, cycloaryl, and oxo have the same meanings as described above.
  • a pharmaceutical composition can be provided.
  • the pharmaceutical composition contains one or more of the tricyclic aminocyanopyridine MK- 2 inhibitors that are described herein and a pharmaceutically acceptable carrier.
  • kits can be produced that comprises a dosage form comprising a tricyclic aminocyanopyridine MK-2 inhibitor in an amount which comprises a therapeutically effective amount. If desirable, the kit can also contain one or more other materials that are well known for use in medicaments.
  • an "effective amount” means the dose or effective amount to be administered to a patient and the frequency of administration to the subject which is readily determined by one of ordinary skill in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • the dose or effective amount to be administered to a patient and the frequency of administration to the subject can be readily determined by one of ordinary skill in the art by the use of known techniques and by observing results obtained under analogous circumstances.
  • a number of factors are considered by the attending diagnostician, including but not limited to, the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances.
  • the phrase "therapeutically-effective" indicates the capability of an agent to prevent, or improve the severity of, the disorder, while avoiding adverse side effects typically associated with alternative therapies.
  • terapéuticaally-effective is to be understood to be equivalent to the phrase “effective for the treatment, prevention, or inhibition”, and both are intended to qualify the amount of the each of the subject compounds for use in therapy which will achieve the goal of improvement in the severity of pain and inflammation and the frequency of incidence, while avoiding adverse side effects typically associated with alternative therapies.
  • dosages may also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.
  • the frequency of dose will depend upon the half-life of the active components of the composition. If the active molecules have a short half life (e.g.
  • a preferred dosage rate is to administer the dosage amounts described above to a subject once per day.
  • compositions may also include stabilizers, anti-oxidants, colorants, and diluents.
  • Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not canceled or inhibited to such an extent that treatment is ineffective.
  • pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician. This amount can be a therapeutically effective amount.
  • compositions include metallic ions and organic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences.
  • Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, ⁇ /,/V-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (/V-methylglucamine) and procaine.
  • Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
  • isomeric forms and tautomers and the pharmaceutically-acceptable salts of the aminocyanopyridine MK-2 inhibitors are also included in the invention.
  • Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, ⁇ -hydroxybutyric, galactaric and galacturonic acids.
  • Suitable pharmaceutically-acceptable base addition salts of compounds of the present invention include metallic ion salts and organic ion salts. More preferred metallic ion salts include, but are not limited to, appropriate alkali metal (Group la) salts, alkaline earth metal (Group lla) salts and other physiological acceptable metal ions. Such salts can be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trifluoroacetate, trimethylamine, diethylamine, ⁇ /,/V-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.
  • the tricyclic aminocyanopyridine compouds of the present invention are useful for, but not limited to, the prevention and treatment of diseases and disorders that are mediated by TNF ⁇ .
  • the aminocyanopyridine MK-2 inhibitors of the invention would be useful to treat arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • aminocyanopyridine MK-2 inhibitor compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, and skin related conditions such as psoriasis, eczema, burns and dermatitis.
  • tricyclic aminocyanopyridine MK-2 inhibitor compounds that are useful in the method of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention or treatment of cancer, such as colorectal cancer.
  • Such aminocyanopyridine MK-2 inhibiting compounds would be useful in treating inflammation in diseases and conditions such as herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like.
  • diseases and conditions such as herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vagin
  • the tricyclic aminocyanopyridine MK-2 inhibitors would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and of acute injury to the eye tissue. These compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders such as cortical dementias including Alzheimer's disease. [00074] As used herein, the terms "TNF ⁇ mediated disease or disorder" are meant to include, without limitation, each of the symptoms or diseases that is mentioned above.
  • treating or “to treat” mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms.
  • treatment includes alleviation, elimination of causation of or prevention of pain and/or inflammation associated with, but not limited to, any of the diseases or disorders described herein.
  • the present compounds are also useful for treatment of mammals, including horses, dogs, cats, rats, mice, sheep, pigs, etc.
  • subject for purposes of treatment includes any human or animal subject who is in need of the prevention of or treatment of any one of the TNF ⁇ mediated diseases or disorders. The subject is typically a mammal.
  • the mammal refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc., Preferably, the mammal is a human.
  • the subject is any human or animal subject, and preferably is a subject that is in need of prevention and/or treatment of a TNF ⁇ mediated diseases or disorders.
  • the subject may be a human subject who is at risk of obtaining a TNF ⁇ mediated disease or disorder, such as those described above.
  • the subject may be at risk due to genetic predisposition, sedentary lifestyle, diet, exposure to disorder- causing agents, exposure to pathogenic agents and the like.
  • the subject pharmaceutical compositions may be administered enterally and parenterally.
  • Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art.
  • Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups.
  • the pharmaceutical composition may be at or near body temperature.
  • the pharmaceutical compositions of the present invention can be administered orally, for example, as tablets, coated tablets, dragees, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions can be produced that contain the aminocyanopyridine MK-2 inhibitors in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an
  • the aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives.
  • a dispersing or wetting agent and suspending agents are exemplified by those already mentioned above.
  • Additional excipients for example sweetening, flavoring and coloring agents, may also be present.
  • Syrups and elixirs containing the novel MK-2 inhibitors may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • compositions can also be administered parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or olagenous suspensions.
  • sterile injectable aqueous or olagenous suspensions Such suspensions may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above, or other acceptable 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 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 di-, glycerides.
  • n-3 polyunsaturated fatty acids may find use in the preparation of injectables.
  • compositions can also be administered by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and poly-ethylene glycols.
  • the novel compositions can also be administered topically, in the form of creams, ointments, jellies, collyriums, solutions or suspensions.
  • Daily dosages can vary within wide limits and will be adjusted to the individual requirements in each particular case.
  • a daily dosage for administration to adults, an appropriate daily dosage has been described above, although the limits that were identified as being preferred may be exceeded if expedient.
  • the daily dosage can be administered as a single dosage or in divided dosages.
  • Various delivery systems include capsules, tablets, and gelatin capsules, for example.
  • Tetramethylsilane was used as an internal standard for proton spectra and the solvent peak was used as the reference peak for carbon spectra.
  • Mass spectra were obtained on a Perkin Elmer Sciex 100 atmospheric pressure ionization (APCI) mass spectrometer, a Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) mass spectrometer, a
  • Preferred aminocyanopyridine MK-2 inhibiting compounds of the present invention provide Ido values for MK-2 inhibition of below 200 ⁇ M.
  • One method that can be used for determining the MK-2 inhibition Ido value is that described just above.
  • More preferred aminocyanopyridine MK-2 inhibiting compounds have the capability of providing MK-2 inhibition Ido values of below 100 ⁇ M, yet more preferred of below 50 ⁇ M, even more preferred of below 20 ⁇ M, yet more preferred of below 10 ⁇ M, and even more preferred of below 1 ⁇ M.
  • U937 Cell TNF ⁇ release assay [000101] The human monocyte-like cell line, U937 (ATCC #CRL-1593.2), is cultured in RPMI1640 media with 10% heat-inactivated fetal calf serum
  • U937 to monocytic/macrophage-like cells is induced by the addition of phorbol12-myristate 13-acetate (Sigma) at final concentration of 20 ng/ml to a culture of U937 cells at -0.5 million cells/ml and incubated for 24 hrs. The cells are centrifuged, washed with PBS and resuspended in fresh media without PMA and incubated for 24 hrs.
  • phorbol12-myristate 13-acetate Sigma
  • Cells adherent to the culture flask are harvested by scraping, centrifugation, and resuspended in fresh media to 2 million cells/ml, and 0.2 ml is aliquoted to each of 96 wells in flat-bottom plate. Cells are then incubated for an additional 24 hrs to allow for recovery. The media is removed from the cells, and 0.1 ml of fresh media is added per well. 0.05 ml of serially diluted compound or control vehicle (Media with DMSO) is added to the cells. The final DMSO concentration does not exceed 1%.
  • ELISA plates NUNC-lmmunoTM Plate MaxisorbTM Surface
  • purified mouse monoclonal lgG1 anti-human TNF ⁇ antibody R&D Systems #MAB610; 1.25 ug/ml in sodium bicarbonate pH
  • TNF levels were quantitated from a recombinant human TNF ⁇ (R&D Systems #210-TA- 010) standard curve using a quadratic parameter fit generated by SoftMaxPRO software.
  • ELISA sensitivity was approximately 30 pg TNF/ml.
  • IC 50 values for compounds were generated using BioAssay Solver.
  • Preferred aminocyanopyridine MK-2 inhibiting compounds of the present invention provide TNF ⁇ release Ido values of below 200 ⁇ M in an in vitro cell assay.
  • One method that can be used for determining TNF ⁇ release Ido values of below 200 ⁇ M One method that can be used for determining TNF ⁇ release Ido values of below 200 ⁇ M.
  • TNF ⁇ release IC 5 o in an in vitro cell assay is that described just above. More preferred aminocyanopyridine MK-2 inhibiting compounds have the capability of providing TNF ⁇ release Ido values of below 50 ⁇ M, yet more preferred of below 10, and even more preferred of below 1.0 ⁇ M.
  • LPS Lipopolvsaccharide
  • Rats were prepared as a suspension in a vehicle consisting of 0.5% methylcellulose, 0.025% Tween-20 in PBS. Compounds or vehicle were orally administered in a volume of 1 ml using an 18 gauge gavage needle. LPS (E. coli serotype 0111 :B4, Lot #39H4103, Cat. # L-2630, Sigma) was administered 1-4 hr later by injection into the penile vein at a dose of 1 mg/kg in 0.5 ml sterile saline.
  • LPS E. coli serotype 0111 :B4, Lot #39H4103, Cat. # L-2630, Sigma
  • ELISA plates (NUNC-lmmunoTM Plate MaxisorbTM Surface) were coated with 0.1 ml per well of an Protein G purified fraction of a 2.5 ug/ml of hamster anti-mouse/rat TNF ⁇ monoclonal antibody TN19.12 (2.5 ug/ml in PBS, 0.1 ml/well).
  • the hybridoma cell line was kindly provided by Dr. Robert Schreiber, Washington University. Wells were blocked the following day with 1 mg/ml gelatin in PBS.
  • Serum samples were diluted in a buffer consisting of 5 mg/ml bovine ⁇ -globulin, 1 mg/ml gelatin, 1 ml/I Tween-20, 1 mg/ml thimerasol in PBS, and 0.1 ml of diluted serum was added wells in duplicate and allowed to incubate for 2 hr at 37°C. Plates were washed with PBS-Tween, and 0.1 ml per well of a 1 :300 dilution of rabbit anti-mouse/rat TNF ⁇ antibody (BioSource International, Cat.
  • TNF levels in serum were quantitated from a recombinant rat TNF ⁇ (BioSource International, Cat. #PRC3014.) standard curve using a quadratic parameter fit generated by SoftMaxPRO software.
  • ELISA sensitivity was approximately 30 pg TNF/ml. Results are expressed in percent inhibition of the production of TNF ⁇ as compared to blood collected from control animals dosed only with vehicle.
  • Preferred aminocyanopyridine MK-2 inhibiting compounds of the present invention are capable of providing some degree of inhibition of
  • TNF ⁇ in animals that is, the degree of inhibition of TNF ⁇ in animals is over 0%.
  • One method for determining the degree of inhibition of TNF ⁇ is the rat LPS assay that is described just above. More preferred aminocyanopyridine MK-2 inhibiting compounds have the capability of providing rat LPS TNF ⁇ inhibition values of at least about 25%, even more preferred of above 50%, yet more preferred of above 70%, and even more preferred of above 80%.
  • EXAMPLE 2 [000113] This illustrates the production of 2,4-diamino-10-methyl-5,10- dihydrobenzo[b]-1 ,8-naphthyridine-3-carbonitrile trifluoroacetate.
  • Step A (synthesis of f-Butyl 2-bromophenyl(methyl)carbamate) 2-bromoaniline (25 mmol, 1.0 equiv. 4.3g) was dissolved in tetrahydrofuran (THF) (150 mL). Sodium hydride (60% in mineral oil, 1.1g) was added and the mixture heated to reflux for 1 hour. After cooling to room temperature, a solution of di-f-butyl-dicarbonate in THF (1.0M, 30 mmol, 1.2 equiv., 30 mL) was added followed by sodium hydride (1.1g). The resulting mixture was heated to reflux for 14 hours.
  • THF tetrahydrofuran
  • Step B (synthesis of 2,4-diamino-10-methyi-5,10- dihydrobenzo[b]-1 ,8-naphthyridine-3-carbonitrile trifluoroacetate)f-Butyl 2- bromophenyl(methyl)carbamate (2.65 mmol, 1.0 equiv., 759 mg) was dissolved in THF (20 mL). The solution was cooled in a dry ice acetone bath and a solution of n-BuLi in hexane (1.6M, 1.1 equiv. 1.8 mL) was added dropwise. After 15 minutes, dimethylformamide (DMF) (1 mL) was added and the reaction allowed to warm to room temperature.
  • DMF dimethylformamide
  • reaction mixture was quenched with sat. aq. NH 4 CI, and partitioned between ether and water. The organic layer was washed with water and dried over MgS0 4 , filtered and evaporated to get 820 mg of a yellow oil.
  • EXAMPLE 3 This illustrates the production of 2,4-diamino-8 ⁇ ethoxy-7- hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
  • EXAMPLE 7 [000122] This illustrates the production of 2,4-diamino-7,8-dihydroxy-5H- chromeno[2,3-b]pyridine-3-carbonitrile.
  • EXAMPLE 8 This illustrates the production of 2,4-diamino-8-hydroxy-5H- chromeno[2,3-b]pyridine-3-carbonitrile.
  • 2,4-Dihydroxy-benzaldehyde (43.4mmol, 6.0g), 2-amino-1- propene-1 , 1 ,3-tricarbonitrile (43.4mmol, 5.74g), acetic acid (13.0mL), and ethanol (125.0mL) were combined and heated to reflux for 2 hours.
  • the reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (160.0mL) at 0°C.
  • Triethylsilane (0.28mol, 32.76g,
  • EXAMPLE 9 This illustrates the production of 8,10-diamino-2,3-dihydro-11 H- [1 ,4]dioxino[2 ⁇ 3':6,7]chromeno[2,3-b]pyridine-9-carbonitrile.
  • EXAMPLE 11 This illustrates the production of 2,4-diamino-8-(2-pyrrolidin-1 - ylethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile .
  • 2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3- b]pyridine-3-carbonitrile was prepared from 2,4-diamino ⁇ 8-hydroxy-5H- chromeno[2,3-b]pyridine-3-carbonitrilein the same manner as described in Example 10, using 1 -(2-chloroethyl)pyridine in lieu of 2-bromoethyl- ethylether.
  • EXAMPLE 12 [000132] This illustrates the production of 2,4-diamino-8-(2- aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
  • TNF ⁇ release assay IC 50 6.9 ⁇ M; Rat LPS Assay 88% inhibition at 20 mpk (IP).
  • EXAMPLE 13 This illustrates the production of [(2,4-diamino-3-cyano-5H- chromeno[2,3-b]pyridin-8-yl)oxy]acetic acid.
  • [(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-8- yl)oxy]acetic acid was prepared from 2,4-diamino-8-hydroxy-5H- chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in Example 10 using bromoacetic acid in lieu of 2-bromoethyl-ethylether. The product was isolated as a tan solid (110.6mg, 31% yield). 1 H NMR
  • EXAMPLE 14 [000136] This illustrates the production of 2,4-diamino-8-(2- hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
  • EXAMPLE 23 This illustrates the production of 2,4-diamino-9-methoxy-5H- chromeno[2,3-b]pyridine-3-carbonitrile bis(trifluoroacetate).
  • 3-Methoxysalicyaldehyde (10 mmol, 1.52 g), 2-amino-1- propene-1 , 1 ,3-tricarbonitrile (10 mmol, 1.32 g) acetic acid (2.5 mL), and ethanol (40 L) were combined and heated to reflux overnight. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (15 mL) at 0°C.
  • Triethylsilane (62 mmol, 7.2 g, 10 mL) was added via syringe. The reaction stirred for one hour at room temperature. Dichloromethane (100 mL) was added to the reaction and the solid formed was collected via filtration and washed with dichloromethane (2x). The product was isolated as a white solid (2.5 g, 50% yield).
  • EXAMPLE 24 This illustrates the production of 2,4-diamino-7-hydroxy-5H- chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
  • 2,4-diamino-7-hydroxy-5H-chromeno[2,3-b]pyridine-3- carbonitrile was prepared in the same manner as described in Example 23, except that 5-hydroxysalicyaldehyde was used in place of methoxysalicyaldehyde. The product was isolated as a pink solid (951 mg, 30% yield).
  • EXAMPLE 27 [000150] This illustrates the production of 2,4-diamino-9-hydroxy-8- methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
  • EXAMPLE 28 This illustrates the production of 2,4-diamino-9-hydroxy-5H- chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
  • 2,3-dihydroxybenzaldehyde (5 mmol, 691 mg), 2-amino-1- propene-1 , 1,3-tricarbonitrile (5 mmol, 661 mg), acetic acid (1.2 mL), and ethanol (20 mL) were combined and heated to reflux overnight. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (20 mL) at 0°C.
  • Step A Preparation of 2,4-diamino-7-nitro-5H-chromeno[2,3- b]pyridine-3-carbonitrile: 5-nitrosalicylaldehyde (132 mmol, 22.00 g), 2- amino-1 -propene-1 , ,3-tricarbonitrile (132 mmol, 17.39 g), acetic acid (31 mL), and ethanol (500 mL) were combined and heated to reflux overnight. The resulting slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (350 mL) at 0°C. Triethylsilane (1.40 mol, 162 g, 225 mL) was added.
  • Step B A mixture of 2,4-diamino-7-nitro-5H-chromeno[2,3- b]pyridine-3-carb ⁇ nitrile, produced as described above, (0.55 mmol, 155 mg) and palladium over carbon (Pd/C) (35 mg, 10% on activated carbon) in dimethylformamide (DMF) (15 mL) was stirred under an atmosphere of hydrogen (balloon) for 3.5 hours. The catalyst was removed by filtration using a plug of celite.
  • DMF dimethylformamide
  • EXAMPLE 30 This illustrates the production of 2,4-diamino-9-fluoro-5H- chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
  • 3-Fluoro-2-hydroxybenzaldehyde (3.45 mmol, 484 mg)
  • 2- amino-1 -propene-1, 1 ,3-tricarbonitrile (3.50 mmol, 463 mg)
  • acetic acid 0.9 mL
  • ethanol 27 mL
  • Triethylsilane (43mmol, 4.97 g, 6.9 L) was added via syringe. The reaction was heated to reflux for 5 hours. Dichloromethane (50 mL) was added to the reaction and the solid formed was collected via filtration and washed with methanol. The product was isolated as a white solid (377 mg, 30% yield).
  • 1 H NMR 500 MHz, DMSO- d 6 ): ⁇ 7.25-7.19 (m, 1 H), 7.15-7.08 (m, 1 H), 7.00-6.96 (m, 1 H), 6.70 (bs, 2H), 6.51 (bs, 2H), 3.75 (S, 2H); m/z 257 (M+H).
  • EXAMPLE 31 This illustrates the production of 2,4-diamino-3-cyano-5H- chromeno[2,3-b]pyridine-7-carboxylic acid Bis(trifluoroacetate).
  • 5-Carboxysaiicyaldehyde (3 mmol, 500 mg)
  • 2-amino-1- propene-1 , 1 ,3-tricarbonitrile 3 mmol, 396 mg
  • acetic acid 1.2 mL
  • ethanol 15 mL
  • Triethylsilane (62 mmol, 7.2g, 10 mL) was added via syringe. The reaction was stirred for 4 hours at 50 °C and then was stirred overnight at room temperature. Dichloromethane (20 mL) was added to the reaction and the solid formed was collected via filtration and washed with dichloromethane (2x). The product was isolated as a yellow solid (560 mg, 36% yield).
  • EXAMPLE 52 [000165] This illustrates the production of 2,4-diamino-7-nitro-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile.
  • Step 1 Production of 5-Nitrothiosalicylaldehyde: A mixture of 2- chloro-5-nitrobenzaldehyde (2g, 11 mmol) and lithium sulfide (0.54 g, 11.7 mmol) in 30 mL of anhydrous DMSO was stirred under nitrogen at room temperature overnight. The solution was then added to a mixture of ice- water, acidified with 2N HCl and extracted with ether three times.
  • Step 2 A solution of the crude 5-nitro-2-thiosalicylaldehyde (1.3g, 7.1 mmol), 2-amino-1 -propene-1, 1 ,3-tricarbonitrile (7.6 mmol, 1 g), acetic acid (2.5 mL) in 70 L of ethanol was heated at 76°C under nitrogen overnight. The reaction mixture was cooled to room temperature and filtered.
  • Step 3 A reaction mixture of the aforementioned tricyclic intermediate (1.2 g, 4 mmol) and triethylsilane (15 mL) in 100 mL of trifluoroacetic acid was heated at between 60-65°C under nitrogen for 2 hours. After that, the solution was cooled to room temperature and concentrated in vacuo. Ether was added to the residue. The solid was filtered, washed with additional ether to give 2,4-diamino-7-nitro-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile as an orange powder (0.9 g, 75% yield).
  • EXAMPLE 53 This illustrates the production of 2,4,7-triamino-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
  • EXAMPLE 54 This illustrates the production of 2,4-diamino-7-nitro-5H- thiochromeno[2,3-b]pyridine-3-carbonitriie 10, 10-dioxide.
  • [000172] To a solution of 2,4-diamino-7-nitro-5H-thiochromeno[2,3- b]pyridine-3-carbonitrile, produced as described in Example 52, (3 g, 10 mmol) in 125 mL of trifluoroacetic acid cooled with a water bath was added dropwise 30% hydrogen peroxide (8 g). After addition was completed, the water bath was removed. After 4 hours, additional 30% hydrogen peroxide (2 g) was added and stirring at room temperature was continued for additional 2 hours.
  • EXAMPLE 56 [000175] This illustrates the production of 2,4-diamino-7-fluoro-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile.
  • EXAMPLE 57 This illustrates the production of 2,4-diamino-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile Bis(trifluoroacetate).
  • EXAMPLE 58 This illustrates the production of 2,4-diamino-7-methoxy-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile.
  • 2,4-diamino-7-methoxy-5H-thiochromeno[2,3-b]pyridine-3- carbonitrile was prepared in the same manner as described in Example 52, except that 2-fluoro-5-methoxybenzaldehyde was used as the starting material. The product was isolated as a beige solid (0.5 g, 49% yield).
  • Example 58 and 0.6 mL of boron tribromide (6.4 mmol) in 30 mL of methylene chloride was stirred at room temperature for 18 h. After that, the solid was filtered, washed with methylene chloride, water and methanol. The methanol filtrate was concentrated to give a solid, which was washed with water, acetonitrile and ether to give the desired product as a red solid (54 mg, 33.6% yield).
  • 1 H NMR 400 MHz, DMSO + D 2 0) ⁇ 9.520 (s, 1H), 8.111 (d, 1 H), 7.561 (d, 1H), 7.522 (s, 2H); m/z 271 (M+H).
  • EXAMPLE 60 This illustrates the production of 2,4-diamino-7-nitro-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile 10, 10-dioxide (an alternative procedure).
  • EXAMPLE 62 [000187] This illustrates the production of 2,4-diamino-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile 10, 10-dioxide.
  • EXAMPLE 63 This illustrates the production of 2,4-diamino-7-methoxy-5H- thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide.
  • Example 69 2-amino-4- ⁇ [2-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2- yl)ethyl]amino ⁇ -7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile
  • Example 70 2-amino-7,8-dimethoxy-4-[(2-pyrrolidin-1 -ylethyl)amino]-5H- chromeno[2,3-b]pyridine-3-carbonitrile
  • Example 71 7,8-dimethoxy-2,4-bis[(2-pyrrolidin-1-ylethyl)amino]-5H- chromeno[2,3-b]pyridine-3-carbonitrile,
  • Example 72 2, 4-bis(glycinyl)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-
  • Example 73 ⁇ /-(2-amino-3-cyano-7,8-dimethoxy-5H-chromeno[2,3- b]pyridin-4-yl)glycine,
  • Example 77 2-amino-4-(butylamino)-7,8-dimethoxy-5H-chromeno[2,3- b]pyridine-3-carbonitrile
  • Example 78 7,8-dimethoxy-2,4-bis(propylamino)-5H-chromeno[2,3- b]pyridine-3-carbonitrile
  • Example 80 2,4-bis(ethylamino)-7,8-dimethoxy ⁇ 5H-chromeno[2,3- b]pyridine-3-carbonitrile, and
  • Example 81 2-amino-4-(ethylamino)-7,8-dimethoxy-5H-chromeno[2,3- b]pyridine-3-carbonitrile.
  • EXAMPLE 83 This illustrates the production of 2-amino-7,8-dihydroxy-4- (propylamino)-5H-chromeno[2,3-b pyridine-3-carbonitrile.
  • 2-amino-7,8-dihydroxy-4-(propylamino)-5H-chromeno[2,3- b]pyridine-3-carbonitrile is prepared using the demethylation procedure described above for Examples 66 - 81 starting with 2-amino-7,8- dimethoxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
  • EXAMPLE 84 This illustrates the production of 2-amino-7,8-dihydroxy-4-[(2- hydroxyethyl)amino]-5H-chromeno[2,3-b]pyridine-3-carbonitriIe.
  • 2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl)amino]-5H- chromeno[2,3-b]pyridine-3-carbonitrile was prepared using the demethylation procedure described above for Examples 66 - 81, starting with 2-amino-7,8-dimethoxy-4-[(2-methoxyethyl)amino]-5H ⁇ chromeno[2,3- b]pyridine-3-carbonitrile.
  • Example 87 (2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-9- yl)oxy]acetic acid
  • Example 88 2,4-diamino-9-(2-hydroxyethoxy)-5H-chromeno[2,3- b]pyridine-3-carbonitrile
  • Example 92 2,4-diamino-9-hydroxy-6,8-bis(piperidin-1 -ylmethyl)-5H- chromeno[2,3-b]pyridine-3-carbonitrile
  • Example 93 2,4-diamino-9-hydroxy-8-(piperidin-1 -ylmethyl)-5H- chromeno[2,3-b]pyridine-3-carbonitrile, were produced starting with 2,4- diamino-9-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile, produced as described in Examples 66 - 81 , and
  • Example 94 2,4-diamino-8-hydroxy-7,9-bis(piperidin-1 -y!methyl)-5H- chromeno[2,3-b]pyridine-3-carbonitrile, was produced starting with 2,4- diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile, produced as described in Example 8.
  • aminocyanopyridine compounds of the present invention can be produced by the same general method, and are shown in the table below along with NMR parameters, which were determined as described above.
  • EXAMPLE 121 This illustrates the production of 2,4-diamino-7,8-dimethoxy-5H- chromeno[2,3-b]pyridine-3-carbonitrile.
  • EXAMPLE 122 This illustrates the production of 2(2,4-diamino-3-cyano-8- methoxy-5H-chromeno[2,3-b]pyridin-5-yl)malononitrile.
  • 1 H NMR 400 MHz, DMSO) ⁇ 7.274(d, 1 H), 6.999 (s, 2H), 6.817 (dd, 1 H), 6.733 (d, 1 H), 6.619
  • EXAMPLE 123 This illustrates the production of 2(2,4-diamino-3-cyano-7- bromo-5H-chromeno[2,3-b]pyridin-5-yl)malononitrile.
  • EXAMPLE 124 This illustrates the production of 2(2,4-diamino-3-cyano-7- methoxy-5H-chromeno[2,3-b]pyridin-5-yl)malononitrile.
  • 2-hydroxy-5-methoxybenzaldehyde (1 Ommol, 1.52g) and malononitrile (40mmol, 2.64g) in ethanol (350mL) was added six drops of piperidine and the mixture was stirred at room temperature for 18 hours. The resultant precipitate was collected by filtration, successively washed with ethanol and ether and and and air-dried to give the product as a grey solid (1.42g, 43% yield).
  • EXAMPLE 125 This illustrates the production of 2(2,4-diamino-3-cyano ⁇ 8- hydroxy-5H-chromeno[2,3-b]pyridin-5-yl)malononitrile.
  • EXAMPLE 126 - 135 This illustrates the production of certain aminocyanopyridine compounds of the present invention.

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Abstract

L'invention concerne des composés d'aminocyanopyridine qui sont capables d'inhiber la protéine kinase 2 à activation par mitogène à activation par protéine kinase. L'invention décrit aussi des compositions pharmaceutiques et des kits qui comprennent un composé MK-2 à inhibition d'aminocyanopyridine.
PCT/US2003/039122 2002-12-12 2003-12-09 Inhibiteurs d'aminocyanopyridine tricyclique de la proteine kinase 2 a activation par mitogene a activation par proteine kinase WO2004054504A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR0317228-7A BR0317228A (pt) 2002-12-12 2003-12-09 Inibidores de aminocianopiridina tricìclicos de proteìna quinase-2 ativada por proteìna quinase ativada por mitógeno
EP03813362A EP1569942A2 (fr) 2002-12-12 2003-12-09 Inhibiteurs d'aminocyanopyridine tricyclique de la proteine kinase 2 a activation par mitogene a activation par proteine kinase
MXPA05006369A MXPA05006369A (es) 2002-12-12 2003-12-09 Inhibidores triciclicos de aminocianopiridina de laproteina cinasa-2 activada por la proteina cinasa activada por mitogeno.
JP2004560741A JP2006511551A (ja) 2002-12-12 2003-12-09 マイトジェン活性化プロテインキナーゼ活性化プロテインキナーゼ−２の三環系アミノシアノピリジン阻害剤
AU2003296406A AU2003296406A1 (en) 2002-12-12 2003-12-09 Tricyclic aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase-2
CA002509665A CA2509665A1 (fr) 2002-12-12 2003-12-09 Inhibiteurs d'aminocyanopyridine tricyclique de la proteine kinase 2 a activation par mitogene a activation par proteine kinase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43284402P 2002-12-12 2002-12-12
US60/432,844 2002-12-12

Publications (2)

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WO2004054504A2 true WO2004054504A2 (fr) 2004-07-01
WO2004054504A3 WO2004054504A3 (fr) 2004-08-12

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PCT/US2003/039122 WO2004054504A2 (fr) 2002-12-12 2003-12-09 Inhibiteurs d'aminocyanopyridine tricyclique de la proteine kinase 2 a activation par mitogene a activation par proteine kinase

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EP (1) EP1569942A2 (fr)
JP (1) JP2006511551A (fr)
AU (1) AU2003296406A1 (fr)
BR (1) BR0317228A (fr)
CA (1) CA2509665A1 (fr)
MX (1) MXPA05006369A (fr)
WO (1) WO2004054504A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7417053B2 (en) 2005-04-07 2008-08-26 Teijin Pharma Limited Pyrazolo[1,5-a]pyridine derivatives or pharmaceutically acceptable salts thereof
US7473694B2 (en) 2005-03-17 2009-01-06 Teijin Pharma Limited Pyrazolopyrimidine derivatives or pharmaceutically acceptable salts thereof
JP2009519318A (ja) * 2005-12-13 2009-05-14 スプラテック ファーマ インク アザキサントンを用いる腫瘍の治療方法
US9593113B2 (en) 2013-08-22 2017-03-14 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
US9796720B2 (en) 2013-08-22 2017-10-24 Bristol-Myers Squibb Company Imidazole-derived modulators of the glucocorticoid receptor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [Online] O'CALLAGHAN ET AL: 'Synthetic reactions of 2-(2-amino-3-cyano-4H-[1Übenzopyran-4-yl)pr opane-1,3-dintrile with reactive methylene compounds', XP002978277 Retrieved from STN Database accession no. 1995:39637 & JOURNAL OF CHEMICAL SOCIETY vol. 4, 1995, pages 417 - 420 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7473694B2 (en) 2005-03-17 2009-01-06 Teijin Pharma Limited Pyrazolopyrimidine derivatives or pharmaceutically acceptable salts thereof
US7417053B2 (en) 2005-04-07 2008-08-26 Teijin Pharma Limited Pyrazolo[1,5-a]pyridine derivatives or pharmaceutically acceptable salts thereof
JP2009519318A (ja) * 2005-12-13 2009-05-14 スプラテック ファーマ インク アザキサントンを用いる腫瘍の治療方法
US9593113B2 (en) 2013-08-22 2017-03-14 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
US9796720B2 (en) 2013-08-22 2017-10-24 Bristol-Myers Squibb Company Imidazole-derived modulators of the glucocorticoid receptor

Also Published As

Publication number Publication date
EP1569942A2 (fr) 2005-09-07
CA2509665A1 (fr) 2004-07-01
WO2004054504A3 (fr) 2004-08-12
JP2006511551A (ja) 2006-04-06
AU2003296406A8 (en) 2004-07-09
MXPA05006369A (es) 2005-08-29
BR0317228A (pt) 2005-11-01
AU2003296406A1 (en) 2004-07-09

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