Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/57—Nitriles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/30—Hetero atoms other than halogen
  • C07D333/34—Sulfur atoms

Definitions

• This invention relates generally to amino-thio- acrylonitriles as MEK inhibitors, pharmaceutical compositions containing the same, and methods of using the same as for treatment and prevention of inflammatory disorders, cancer or other proliferative diseases or as a radiosensitizing agents against cancer or other proliferative disorders.
• the mitogen activated protein kinase (MAPK) signaling pathways are involved in cellular events such as growth, differentiation and stress responses ( J. Biol . Chem . (1993) 268, 14553-14556).
• MAPK mitogen activated protein kinase
• Four parallel pathways have been identified to date ERK1/ERK2, JNK, p38 and ERK5. These pathways are linear kinase cascades in that MAPKKK phosphorylates and activates MAPKK that phosphorylates and activates MAPK.
• MAPKK homologs MEK1, MEK2, MKK3, MKK4/SEK, MEK5 , MKK6 , and MKK7
• MAPK families ERK1/2, JNK, p38, and ERK5
• the MAPKK family members are unique in that they are dual-specific kinases, phosphorylating MAPKs on threonine and tyrosine. Activation of these pathways regulates the activity of a number of substrates through phosphorylation.
• These substrates include transcription factors such as TCF, c-myc, ATF2 and the AP-1 components, fos and Jun; the cell surface components EGF-R; cytosolic components including PHAS-I, p90 rs ⁇ , cPLA2 and c-Raf-1; and the cytoskeleton components such as tau and MAP2.
• transcription factors such as TCF, c-myc, ATF2 and the AP-1 components, fos and Jun
• EGF-R cell surface components
• cytosolic components including PHAS-I, p90 rs ⁇ , cPLA2 and c-Raf-1
• the cytoskeleton components such as tau and MAP2.
• the prototypical mitogen activated protein kinase cascade is reflected by the ERK pathway (Biochem J. (1995) 309, 361-375).
• the ERK pathway is activated primarily in response to ligation of receptor tyrosine kinases (RTKs) (FEBS Lett . (1993) 334, 189-192).
• RTKs receptor tyrosine kinases
• Signal propagation from the RTKs occurs down the Ras pathway through sequential phosphorylation of Raf, MEK and ERK. This pathway has not been typically viewed of as an important contributor to the inflammatory response, but rather involved in growth and differentiation processes.
• Cytokines such as TNFa and IL-lb, the bacterial cell wall mitogen, LPS, and chemotactic factors such as fMLP, C5a, and IL-8 all activate the ERK pathway.
• the ERK pathway is activated as a result of T cell receptor ligation with antigen or agents such as PMA/ionomycin or anti-CD3 antibody, which mimic TCR ligation in T cells ( Proc . Natl . Acad. Sci . USA (1995) 92, 7686- 7689) .
• PD 098059 blocks thymidine incorporation into DNA in PDGF-stimulated Swiss 3T3 cells (J " . Biol . Chem . (1995) 46, 27498-27494).
• PD 098059 also prevents PDGF-BB-dependent SMC (Smooth Muscle Cell) chemotaxis at concentrations which inhibit ERK activation (Hypertension (1997) 29, 334-339) .
• U0126 prevents PDGF-dependent growth of serum starved SMC.
• T cell antigen receptor is a non-RTK receptor whose intracellular signaling pathways have been elucidated ( Proc . Natl . Acad. Sci . USA (1995) 92, 7686-7689).
• DeSilva et al . have generated a great deal of information with U0126 in T cell systems (J " . Immunol . (1998) 160, 4175-4181). Their data showed that U0126 prevents ERK activation in T cells in response to PMA/ionomycin, Con A stimulation, and antigen in the presence of costimulation.
• PD 098059 has also been shown to inhibit T cell proliferation in response to anti-CD3 antibody, which is reversed by IL-2 ( J. Immunol . (1998) 160, 2579-2589.). PD 098059 also blocked IL-2 production by T cells stimulated with anti-CD3 antibody in combination with either anti-CD28 or PMA. In addition, the MEK inhibitor blocked TNFa, IL-3 GM-CSF, IFN-g, IL-6 and IL-10 production. In contrast, PD 098059 enhanced production of IL-4, IL-5 and IL-13 in similarly stimulated T cell cultures. These differential T cells effects with MEK inhibition suggest that therapeutic manipulations may be possible.
• Neutrophils show ERK activation in response to the agonists N-formyl peptide (fMLP) , IL-8, C5a and LTB. , which is blocked by PD 098059 ( Biochem . Biophy. Res . Commun . (1997) 232, 474-477). Additionally, PD 098059 blocks neutrophil chemotaxis in response to all agents, but does not alter superoxide anion production. However, fMLP- stimulated superoxide generation was inhibited by PD098059 in HL-60 cells (J. Immunol . (1997) 159, 5070-5078), suggesting that this effect may be cell-type specific.
• fMLP N-formyl peptide
• U0126 blocks ERK activation in fMLP- and LTB 4 -stimulated neutrophils, but does not impair NADPH-oxidase activity or bacterial cell killing.
• U0126 at 10 mM blunts up regulation of b2 integrin on the cell surface by 50% and blocks chemotaxis through a fibrin gel >80% in response to IL-8 and LTB 4 .
• neutrophil mobility is affected by MEK inhibition although the acute functional responses of the cell remain intact.
• Eicosanoids are key mediators of the inflammatory response.
• the proximal event leading to prostaglandin and leukotriene biosynthesis is arachidonic acid release from membrane stores, which is mediated largely through the action of cytosolic phospholipase A2 (CPLA2).
• CPLA2 cytosolic phospholipase A2
• CP A2 requires Ca 2+ along with phosphorylation on a consensus
• MAP kinase site Ser505, which increases catalytic efficiency of the enzyme (J " . Biol . Chem . (1997) 272, 16709- 16712).
• PD 098059 blocks arachidonic acid release in response to opsonized zymosan, aggregation of the high affinity IgG receptor, or thrombin, respectively.
• ERK As the mediator of CPLA2 activation through phosphorylation ( FEBS Lett . (1996) 388, 180-184. Biochem J. (1997) 326, 867-876 and J. Biol . Chem . (1997) 272, 13397-
• U0126 is able to block arachidonic acid release along with prostaglandin and leukotriene synthesis in keratinocytes stimulated with a variety of agents.
• the effector target, CPLA2 is sensitive to MEK inhibition in a variety of cell types.
• MEK inhibitors also seem to affect eicosanoid production through means other than inhibition of arachidonic acid release.
• PD 098059 partially blocked LPS- induced Cox-2 expression in RAW 264.7 cells, indicating ERK activation alone may not be sufficient to induce expression of this key enzyme mediating inflammatory prostanoid production (Biochem J. (1998) 330, 1107-1114).
• U0126 inhibits Cox-2 induction in TPA-stimulated fibroblasts, although it does not impede serum induction of the Cox-2 transcript.
• PD 098059 also inhibits Cox-2 induction in lysophosphatidic acid (LPA) -stimulated rat mesangial cells, which further supports a role for ERK activation in production of prostaglandins (Biochem J. (1998) 330, 1107-1114). Finally, 5-lipoxygenase translocation from the cytosol to the nuclear membrane along with its activation as measured by 5-HETE production can be inhibited by PD 098059 in HL-60 cells (Arch . Biochem . Biophys . (1996) 331, 141-144) .
• Inflammatory cytokines such as TNFa and IL-lb are critical components of the inflammatory response. Cytokine production in response to cell activation by various stimuli as well as their activation of downstream signaling cascades represent novel targets for therapeutics . Although the primary effect of IL-lb and TNF-a is to up regulate the stress pathways (Nature (1994) 372, 729-746), published reports ( Proc . Natl . Acad. Sci . USA (1995) 92, 1614-1618. J. Immunol . (1995) 155, 1525-1533. J. Biol . Chem . (1995)
• Cytokines such as TNFa and IL- lb, the bacterial cell wall mitogen, LPS, and chemotactic factors such as fMLP, C5a, and IL-8 all activate the ERK pathway.
• the ERK pathway is activated as a result of T cell receptor ligation with antigen or agents such as PMA/ionomycin or anti-CD3 antibody, which mimic TCR ligation in T cells ( Proc . Natl . Acad. Sci . USA (1995) 92, 7686-7689) and clearly show that the ERK pathway is also affected.
• U0126 can block MMP induction by IL-lb and TNF-a in fibroblasts ( J. Biol . Chem . (1998) 29, 18623-18632), demonstrating that ERK activation is necessary for this proinflammatory function.
• lipopolysaccharide (LPS) treatment of monocytes results in cytokine production that has been shown to be MAP kinase-dependent being blocked by PD 098059 ( J. Immunnol . (1998) 160, 920-928).
• LPS lipopolysaccharide
• U0126 is able to impede the growth of RAS-transformed cells in soft agar even though these compounds show minimal effects on cell growth under normal culture conditions .
• PD 098059 has been shown to reduce urokinase secretion controlled by growth factors such as EGF, TGFa and
• Skin disease such as psoriasis provides another potential area where MEK inhibitors may prove useful since MEK inhibition prevents skin edema in mice in response to TPA. MEK inhibition also blocks keratinocyte responses to growth factor cocktails, which are known mediators in the psoriatic process.
• a MEK inhibitor in cancer can not be overlooked.
• Ionizing radiation initiates a process of apoptosis or cell death that is useful in the treatment solid tumors .
• This process involves a balance between pro- apoptotic and anti-apoptotic signal ( Science 239, 645-647), which include activation of MAP kinase cascades.
• Activation of the SAPK pathway delivers a pro-apoptotic signal (Radiotherapy and Oncology (1998) 47, 225-232.), whereas activation of the MAPK pathway is anti-apoptotic (Nature (1996) 328, 813-816.).
• the inhibitors include 2-(2- amino-3-methoxyphenyl) -4-OXO-4H- [l]benzopyran and a compound of the formula:
• one object of the present invention is to provide novel amino-thio-acrylonitriles which are useful as MEK inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
• It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
• It is another object of the present invention to provide a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof .
• la lb or pharmaceutically acceptable salt or prodrug forms thereof, wherein R and R are defined below, are effective MEK inhibitors .
• R and R are defined below, are effective MEK inhibitors .
• DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS thus, in a first embodiment, the present invention provides a novel compound of formula la or lb:
• R! is phenyl, naphthyl, 2 , 3-dihydroindol-5-yl or a 5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, and R ⁇ is substituted with 0-2
• R a is selected from H, Cl, F, Br, I, Ci-4 alkyl, C ⁇ _4 alkoxy, OH, CH2OH, H2 , (C1-3 alkyl )NH, (C1-3 alkyl) 2 , (H2NCH2C(0) )NH, (H2NCH (CH3 ) C (O) ) H, (CH3NHCH2C (O) ) H, ( (CH3)2NCH2C(0) )NH, CF3 , OCF3 , -CN, NO2 , C(0)NH2, and CH3C(0)NH;
• Y is selected from phenyl substituted with 0-5 R b , naphthyl substituted with 0-5 R b , and CHR 3 ;
• R b is selected from H, Cl, F, Br, I, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3 , OCF3 , -CN, NO2 , NH2 ,
• R 2 is selected from H, R a , C(0)R 2a , CH(OH)R 2a , CH2R 2a ,
• R 2a is selected from phenyl, naphthyl, and a 5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N,
• R 2a is substituted with 0-5 R b ;
• R 3 is phenyl substituted with 0-2 R c or naphthyl substituted with 0-2 R c ;
• R c is selected from H, Cl, F, Br, I, Ci-4 alkyl, OH, C1--4 alkoxy, CH2OH, CH(OH)CH3, CF3 , OCF3 , -CN, NO2 , NH2 , (C1-3 alkyl)NH, (C1-3 alkyl) 2N, and C(0)0-C ⁇ _4 alkoxy.
• the present invention provides a novel compound, wherein:
• R! is phenyl or a 5-6 membered heteroaryl ring with 1-2 heteroatoms selected from N, NH, 0, and S, and R! is substituted with 0-2 R a ;
• R a is selected from H, Cl, F, C ⁇ -4 alkyl, C1-4 alkoxy, OH, CH2OH, NH2, (C ⁇ _3 alkyl ) H, (C1-3 alkyl) 2N, (H2NCH2C(0) )NH, (H2NCH (CH3 ) C (O) ) NH, (CH3NHCH2C (O) ) NH, ( (CH3)2NCH2C(0) )NH, and CH3C(0)NH;
• Y is selected from phenyl substituted with 0-5 R b , naphthyl substituted with 0-5 R b , and CHR 3 ;
• R b is selected from H, Cl, F, Br, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3 , -CN, O2 , H2 , and (C1-3 alkyl )NH, (C1-3 alkyl) 2N;
• R 2 is selected from H, R 2a , C(0)R 2 , CH(OH)R 2 , CH2R 2a , and OR 2a ;
• R 2a is selected from phenyl, naphthyl, and a 5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N,
• R 2a is substituted with 0-5 R b ;
• R 3 is phenyl substituted with 0-2 R c or naphthyl substituted with 0-2 R c ;
• R c is selected from H, Cl, F, Br, I, C1-4 alkyl, OH, C1--4 alkoxy, CH2OH, CH(OH)CH3, CF3 , -CN, NO2 , NH2 , (C1-3 alkyl )NH, and (C1-3 alkyl )2N.
• the present invention provides a novel compound, wherein:
• R-- is phenyl or a 5-6 membered heteroaryl ring with 1-2 heteroatoms selected from N, NH, 0, and S, and R 1 is substituted with 0-2 R a ;
• R is selected from H, OH, and NH2 ;
• Y is selected from phenyl substituted with 0-2 R b , naphthyl substituted with 0-2 R b , and CHR 3 ;
• R b is selected from H, Cl, F, Br, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3 , -CN, NO2 , NH2 , and (C1-3 alkyl )NH, (C1-3 alkyl) 2N;
• R 2 is selected from H, R 2a , C(0)R 2a , CH(OH)R 2a , CH2R 2a , and OR 2a ;
• R 2a is selected from phenyl, naphthyl, and a 5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N,
• R a is substituted with 0-5 R b ;
• R 3 is phenyl substituted with 0-2 R c or naphthyl substituted with 0-2 R c ;
• R c is selected from H, Cl, F, Br, I, C ⁇ _4 alkyl, OH, Ci-4 alkoxy, CH2OH, CH(OH)CH3, CF3 , -CN, O2 , H2 , (C1-3 alkyl )NH, and (C1-3 alkyl )2 .
• the present invention provides a novel compound selected from:
• the present invention provides a novel compound selected from:
• the present invention provides a novel compound selected from:
• the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula la or lb or a pharmaceutically acceptable salt form thereof.
• the present invention provides a novel method for treating or preventing a disorder related to MEK, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula la or lb or a pharmaceutically acceptable salt form thereof .
• the present invention provides novel compounds of formula la or lb or a pharmaceutically acceptable salt form thereof for use in therapy.
• the present invention provides novel compounds of formula la or lb or a pharmaceutically acceptable salt form thereof for the manufacture of a medicament for the treatment of an inflammatory disease.
• the present invention provides novel compounds of formula la or lb or a pharmaceutically acceptable salt form thereof for the manufacture of a medicament for the treatment of cancer.
• the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis , periodontitis , gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
• the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof .
• the compounds herein described may have asymmetric centers .
• Substituted is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group (s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
• the present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include tritium and deuterium.
• Isotopes of carbon include C-13 and C-14.
• any variable e.g., R°
• its definition at each occurrence is independent of its definition at every other occurrence.
• R 6 at each occurrence is selected independently from the definition of R 6 .
• combinations of substituents and/or variables are permissible only if such combinations result in stable compounds .
• alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
• C. 4 alkyl is intended to include C. , C. , C . , and C, alkyl.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl , s-butyl, t-butyl, n-pentyl, and s-pentyl.
• Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
• alkoxy is intended to include C., C,, C., and C, alkoxy.
• alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
• aromatic heterocyclic system or “heteroaryl” is intended to mean a stable 5 or 6 membered monocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, 0 and S. It is to be noted that that the total number of S and 0 atoms in an aromatic heterocycle is not more than 1.
• heterocycles include, but are not limited to, 2H, 6H-1 , 5, 2-dithiazinyl, furanyl , imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1 , 2 , 3-oxadiazolyl, 1, 2 , 4-oxadiazolyl, 1 , 2 , 5-oxadiazolyl , 1 , 3 , 4-oxadiazolyl, oxazolidinyl, oxazolyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, 2H-pyrrolyl, pyrrolyl, tetrazolyl, 6H-1 , 2 , 5-thiadiazinyl, 1, 2 , 3-thiadiazolyl, 1, 2 , 4-thiadiazolyl, 1, 2 ,
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio .
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic , phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic , ethane disulfonic, oxalic, and isethionic.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tarta
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• Lists of suitable salts are found in Remington ' s Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
• Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to formula la or lb in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of a compound of formula la or lb are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
• Prodrugs include compounds of formula la or lb wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula la or lb is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
• Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula la or lb.
• “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
• “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit MEK or treat the symptoms of MEK over production in a host.
• the combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul . 22:27-55 (1984), occurs when the effect (in this case, MEK inhibition) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
• Synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds .
• Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
• radiation-induced cell death refers to a process whereby cells are made susceptible to radiation- induced cell death, or the cells that result from the process .
• the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis .
• the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
• the reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
• a thiol 1, such as a thiophenol, may be treated with a malononitrile such as malononitrile 2 in the presence of a base catalyst such as triethylamine, DBU, Hunig's base, or aqueous base
• the reaction medium can be degassed to eliminate the presence of oxygen which can facilitate disulfide formation via the dimerization of thiol 1.
• the vinylogous cyanamide is frequently isolated as a mixture of Z- and E-isomers and the melting point varies significantly with isomer composition. A crystalline single isomer or material enriched in one isomer may sometimes be obtained by spontaneous crystallization of one isomer, recrystallization, or stirring solid in a solvent which dissolves only part of the material. Alternatively, isomers may sometimes be separated by chromatography.
• aryl or heterocyclic anions may be quenched with sulfur to yield thiols ( Chem. Pharm . Bull . 1989, 37 (1), 36). Displacement of aryldiazonium salts with EtOCS2K leads to aryl thiols
• the malononitrile precursors (2 . ) to the compounds of this invention may be prepared by one of the three routes shown in Scheme 2.
• aryl iodides 4 may be treated with malononitrile in the presence of a copper catalyst to yield arylmalononitriles 2 (J. Org. Chem. 1993 (58) 7606-7).
• aryl iodides needed for these methods are commercially available or prepared by methods familiar to one skilled in the art.
• aryl iodides may be prepared by iodination with a source of electrophilic iodine, such as iodine monochloride, or by diazotization of anilines.
• Arylmalononitriles may also be prepared from aryl acetonitriles as shown the second route in Scheme 2.
• Aryl acetonitriles 5 may be deprotonated with a base, such as LDA, and quenched with a electrophilic source of cyanide, such as cyanogen chloride ( J. Org. Chem . 1966, 21, 919) or 2-chlorobenzylthiocyanate ( J. Org. Chem . 1983, 48, 2774-5) to yield malononitrile 2 .
• acetonitrile 5 can also be acylated in the presence of NaOMe with dimethyl carbonate to form the methyl cyanoacetate (not shown in Scheme 2) .
• arylmalononitriles 2 may also be synthesized from simpler bromo- or iodoarylmalononitriles . These bromo- or iodo- substituted arylmalononitriles may be prepared by either of the first two routes indicated in Scheme 2 for the preparation of malononitriles .
• This process may be carried out in an ethereal solvent such as THF at a temperature of -78 to 0
• the dianion may be quenched in si tu with one equivalent of an electrophile, such as an aldehyde, alkyl halide, disulfide, ester, or ketone, to yield a substituted malononitrile 2 with a new R2 group attached to the former site of the bromine or iodine atom.
• an electrophile such as an aldehyde, alkyl halide, disulfide, ester, or ketone
• the dianion may be treated in si tu with an aldehyde to produce hydroxy-phenylmalononitriles 8 .
• Hydroxy-phenyl alononitriles 8. may be oxidized to the corresponding keto-phenylmalononitrile 9. using Mn ⁇ 2 or a variety of other oxidizing agents familiar to one skilled in the art.
• Compounds 8 . and 9 may be reduced to the corresponding CH2R2 -substituted phenylmalononitriles 10 using hydrogen and a noble metal catalyst, NaBH4 and TFA ( Synthesis 1978, 763-5), or other procedures familiar to one skilled in the art.
• Malononitriles 8 , 9, and 10 may be treated with thiols 1 to yield the compounds of this invention. It must be noted that although only the meta- bro o isomer of 6. is pictured in Scheme 3 , one trained in the art may apply this methodology using other aryl halides and electrophiles to prepare isomers and compounds with different Y groups .
• malononitrile precursors useful for preparation of the compounds of this invention have structure 2a and may be prepared as shown in Scheme 4.
• Knoevenagel condensation Organic Reactions 15, 204-509
• alkylidene malononitriles .12 or 14 may be used to produce alkylidene malononitriles .12 or 14.
• Conjugate addition of a Grignard or organolithium reagent to 12 affords the malononitrile prescursors 2 . used in Scheme 1.
• alkylidene malononitriles 2 ⁇ may be reduced to malononitriles 2a with sodium borohydride, catalytic hydrogenation or other reducing agents familiar to one skilled in the art.
• Cuprous iodide (0.81 g, 0.082 mmol) and tris[2-(2- methoxyethoxy) ethyl] amine (1.5 mL, 4.1 mmol) were added and the reaction was refluxed overnight.
• the solution was decanted from the solid.
• Additional cuprous iodide (0.81 g, 0.082 mmol) and tris [2- (2 -methoxyethoxy) ethyl] amine (1.5 mL, 4.1 mmol) were added to the solution and the reaction was refluxed overnight with mechanical stirring.
• the reaction mixture was absorbed onto silica gel and eluted with hexane to afford the title compound (1.4 g) .
• GC-MS Calcd, 199;
• the presently claimed MEK inhibitors are also expected to have utility as radiosensitizers for the treatment of solid tumors.
• the presently claimed compounds are expected to have utility for the treatment of chronic pain or for inhibiting memory acquisition.
• Assays for chronic pain are found Science and Medicine (1996), Nov. /Dec, 22-31.
• Assays for mammalian associative learning are found in Nature Neuroscience (1998) 1 (1) 602-609.
• the ERK signal transduction pathway includes two very similar forms of MEK, MEKl and MEK2 , and two similar forms of ERK, ERKl and ERK2.
• MEK pathway a MEK inhibitor must prevent ERKl and/or ERK2 from being phosphorylated (and thereby activated) by the kinases MEKl or MEK2.
• the different roles played by MEKl and MEK2 and by ERKl and ERK2 are not currently understood well understood and they may be redundant under some or all circumstances.
• MEKl and MEK2 are phosphorylated (and thereby activated) by an upstream kinase, RAF.
• MEKl or MEK2 have little ability to phosphorylate ERKl and ERK2 until they have been phosphorylated and since they are usually isolated in their unphosphorylated state, it is difficult to obtain adequate quantities of phosphorylated MEKl or MEK2 suitable for assaying many compounds.
• a constitutively active mutant of MEKl e.g., 2X-MEKl
• This mutant enzyme has negatively- charged residues at the residues which are normally phosphorylated by RAF.
• Selected inhibitors of 2X-MEK1 disclosed herein have been shown to be inhibitors of phosphorylated (i.e., active) wild-type MEKl and MEK2. Furthermore, many of the MEK inhibitors of this invention have been shown to be capable of blocking phosphorylation of ERK induced by treatment of Jurkat cells with TPA (see J. Biol . Chem . (1998) 29, 18623-18632). Selected MEK inhibitors from this invention have also been shown to block the upregulation of AP-1 expression in Cos-7 cells induced by stimulation with TPA (see J. Biol . Chem . (1998) 29, 18623-18632) . AP-1 in turn regulates the expression of a number of pro-inflammatory and growth- stimulating genes including. These experiments prove that inhibitors of 2X-MEK1 function as inhibitors of MEK and ERK signal transduction in cell culture.
• the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations) , pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion) , intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
• the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
• a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
• the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day.
• the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
• Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
• Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches.
• suitable intranasal vehicles or via transdermal routes, using transdermal skin patches.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
• suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
• the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, and sorbitol; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, and water.
• suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
• Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, and xanthan gum.
• the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines .
• Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
• Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
• the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels .
• a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels .
• Dosage forms may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
• Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, and stearic acid. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract .
• Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
• water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
• Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
• Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
• citric acid and its salts and sodium EDTA are also used.
• parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol .
• Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
• Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
• Capsules A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
• Soft Gelatin Capsules 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
• a mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient.
• the capsules should be washed and dried.
• Tablets Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
• a parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.
• An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mL of vanillin.
• a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight.
• the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.
• a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight .
• a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.
• two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
• one active ingredient may be enteric coated.
• enteric coating one of the active ingredients it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
• One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
• the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
• Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low- viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
• HPMC hydroxypropyl methylcellulose
• the polymer coating serves to form an additional barrier to interaction with the other component.

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