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WO2004099127A1 - Composes utilises comme inhibiteurs de kinase - Google Patents

Composes utilises comme inhibiteurs de kinase Download PDF

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Publication number
WO2004099127A1
WO2004099127A1 PCT/DK2004/000301 DK2004000301W WO2004099127A1 WO 2004099127 A1 WO2004099127 A1 WO 2004099127A1 DK 2004000301 W DK2004000301 W DK 2004000301W WO 2004099127 A1 WO2004099127 A1 WO 2004099127A1
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fused
dipropylsulfamoyl
compound according
benzoylamino
carboxylic acid
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Preben Houlberg Olesen
Anders Robert SØRENSEN
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Novo Nordisk AS
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Novo Nordisk AS
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    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • 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
    • C07D333/38—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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention provides novel compounds, their preparation and use as MAPKAP kinase 2 inhibitors.
  • MAP kinase-activated protein kinase 2 (MAPKAP-K2 or MK2) is one of several kinases downstream to the stress-activated p38 MAP kinase ⁇ - and ⁇ -isoforms.
  • the p38 MAP kinase pathway is known to mediate stress responses and is activated by heat shock, UV light, bacterial lipopolysaccharide (LPS) and the pro-inflammatory cytokines TNF- or IL-1. Activation of this pathway affects cell division, apoptosis, invasiveness of cultured cells and the inflammatory response.
  • LPS bacterial lipopolysaccharide
  • MAPKAP-K2 is essential for the response to LPS as its absence causes a severe reduction in the biosynthesis of sev- eral cytokines, especially TNF- ⁇ .
  • MAPKAP kinase 2 is essential for LPS- induced TNF-alpha biosynthesis. Nat. Cell Biol 1:94-97.
  • TNF Tumour Necrosis Factor
  • TNF- ⁇ Tumour Necrosis Factor
  • various members of the interleukin family various members of the interleukin family.
  • the compounds of the invention will be useful in the treatment of diseases or medical conditions in which excessive production of cytokines occur, for example excessive production of TNF- ⁇ or interleukins.
  • cytokines are produced by a variety of cells such as monocytes and macrophages and that they give ride to a variety of physiological effects which are believed to be important in disease or medical conditions such as in- flammation and immunoregulation.
  • a massive release of TNF- ⁇ in the host produces severe damage to a range of tissues.
  • TNF- ⁇ inhibitors have application in disorders which involve an inflammatory response, but this cytokine has multiple inflammatory, metabolic and immunological activities (Jirillo, E. Pellegrino, MM. and Antonaci, S. Role of Tumor Necrosis Factor- ⁇ in Physiological and Pathological Conditions. Med. Sci. Res., 1995, 23, 75-79).
  • TNf- ⁇ Abnormal levels of TNf- ⁇ have been implicated in a large number of different diseases as mentioned in W099/32110.
  • the disease are arthritic conditions such as rheumatoid arthritis, acute rheumatoid fever, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthri- tis, psoriatic arthritis, Reiter's syndrome, osteoarthritis, traumatic arthritis, and rubella arthritis;
  • Bacterial and viral/parasitic infections such as in fever, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, systemic inflammatory response syndrome, tuberculosis, malaria including Plasmodium falciparum malarie and cerebral malaria, meningitis and infections by Helicobacter pylori during peptic ulcer disease, Chaga's disease, infections from E-coli, Trypanosome, Staphylococcus
  • Cardiovascular diseases such as congestive heart failure and damage following heart disease, cardiomyopathy, myocardi- tis, vasculitis, atherosclerosis, thrombosis and myalgias;
  • Diseases in the central nervous system such as stroke, acute encephalitis, Alzheimer's disease, Parkinson's disease, ischemia and prevention of neuronal damage following cerebral ischaemia , open and closed head trauma, central nervous system injury, cachexia, multiple sclerosis including demyelation and oligodendrocyte loss in multiple sclerosis;
  • Inflammatory bowel diseases such as Crohn's dis- ease, gastritis and ulcerative colitis;
  • Immune related conditions such as graft-versus-host rejection, allograft rejection such as those of the kidney, heart, liver, skin, lung and complications following hip replacement;
  • Ophthalmic diseases such as retinitis, retinopathies, uveitis, ocular photophobia, actue injury to the eye tissue, corneal graft rejection,
  • Pulmonary conditions such as asthma, adult respiratory distress syndrom, chronic and acute pulmonary inflammatory disease, chronic obstructive pulmonary disease, lung inflammation, pulmonary sarcosis, pneumonia, restenosis, silicosis, allergic respiratory diseases, alveolar injury; Skin related diases such as psoriasis, eczema, burns, dermatitis, contact dermatitis, keloid formation and scar tissue formation; Liver diseases such as hepatic failure, liver disease during acture inflammation, severe alcoholic hepatitis; glomerulonephri- tis, pyresis, pancreati tis including systemic complications in acute pancreatitis, myelodys- plastic syndromes, b liary cirrhosis, nephritis, (cardiac /renal) reperfusion injury, macular de- generation, uveitis, d sorders of the female reproductive system, endometriosis, acute syn
  • TNF- ⁇ inhibitors are useful in the treatment of diabetes (Argiles, J.M., Lopez-Soriano, J. and Lopez-Soriano, F.J. Cytokines and Diabetes: The Final Step. Involvement of TNF- ⁇ in both Type I and Type II Diabetes ellitus. Horm. Metab. Res., 1994, 26, 447 - 449).
  • MAPKAP kinase 2 Due to the pharmacological activity of the compounds of the present invention as inhibitors of MAPKAP kinase 2, which in mammalian cells is involved in stress-induced biosynthesis of several pro-inflammatory and inflammatory cytokines (Kotlyarov et. al, Nature cell biology, Vol. 1 (2) pp. 94-97 (1999) Jun) the inhibition of MAPKAP-K2 has potential in the treatment of, all diseases that relate to dysregulated cytokine production of which TNF- ⁇ is an important proinflammatory cytokine.
  • the invention provides novel compounds having of the formula (I)
  • each q is independently 0 or 1 ;
  • cycloalkylene is cycloalkylene, heterocyclylene, arylene, heteroarylene, fused cycloalkylarylene, fused aryl- cycloalkylene, fused heterocyclylarylene, fused arylheterocyclylene, fused cycloalkylhet- eroarylene, fused heteroarylcycloalkylene, fused heterocyclylheteroarylene, or fused het- eroarylheterocyclylene, optionally substituted with one or more substituents R 31 , R 32 , R 33 , and R 34 , wherein
  • R 31 , R 32 , R 33 , and R 34 independently of each other are alkyl, halogen, haloalkyl, hydroxyalkyl, cyano, -N0 2 , R 1 -0-, R 1 -S(0) m -, R 1 -0-C(0)-, R 1 -C(0)-0-, R 1 -C(0)-, N(R 1 )(R 2 )-C(0)-,
  • R 1 and R 2 independently of each other, are hydrogen, haloalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, or
  • R 1 and R 2 when attached to a nitrogen atom, together with said nitrogen atom form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more alkyl substituents; m is an integer of 0,1 , or 2; n is an integer of 1 , 2, or 3; and indicates a single bond, double bond or an aromatic bond;
  • R 3 and R 4 independently of each other, are hydrogen, halogen, haloalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyalkyl, cyano, N(R 7 )(R 8 )-, or N(R 7 )(R 8 )-(CH 2 ) a -, wherein
  • R 7 and R 8 independently of each other, are hydrogen, haloalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, or cycloalkyl; and a is an integer of 1 , 2, or 3, or
  • R 3 and R 4 when attached to a nitrogen atom, together with said nitrogen atom form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more alkyl sub- stituents;
  • R 5 and R 6 independently of each other, are hydrogen, halogen, haloalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, or
  • R 5 and R 6 when attached to a nitrogen atom, together with said nitrogen atom form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more alkyl substituents; v and s, independently of each other, are an integer of 0,1 , or 2; and w, r and t, independently of each other, are an integer of 0, 1 , 2, or 3;
  • B 1 and B 2 independently of each other, are a linker selected from the group consisting of -
  • X is O, S or H 2 ; and R 15 is hydrogen, haloalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the above together with one or more pharmaceuti- cally acceptable carriers or excipients.
  • the invention provides the use of the compounds as above as medicaments.
  • the invention also provides the use of the compounds as above for the manufacture of a medicament for the treatment of the treatment and/or prevention of disorders or diseases, wherein a MAPKAP kinase 2 interaction is beneficial.
  • the invention provides a method for the treatment and/or prevention of disorders or diseases, wherein a MAPKAP kinase 2 interaction is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the above or a pharmaceutical composition according to the above.
  • C x-y -alkyl, C x-y -haloalkyl, C x-y -alkenyl, C x-y -alkynyl, C x-y - cycloalkyl, C x-y -aryl, or C x-y -cycloalkyl-C x-y -alkenyl- designates a radical of the designated type having from x to y carbon atoms.
  • alkyl refers to a straight or branched chain saturated monovalent hydrocarbon radical having, for instance, from one to ten carbon atoms, for example C 1-8 -alkyl.
  • Typical C 1-8 -alkyl groups include, but are not limited to e.g.
  • C -8 -alkyl as used herein also includes secondary C 3-8 -alkyl and tertiary C -8 -alkyl.
  • alkenyl refers to a straight or branched chain monovalent hydrocarbon radical having, for instance, from two to ten carbon atoms and at least one carbon-carbon double bond, for example C 2-8 -alkenyl.
  • Typical C 2-8 -alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3- butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2,4-hexadienyl, 5- hexenyl and the like.
  • alkynyl refers to a straight or branched monovalent hydrocarbon group containing, for instance, from 2 to the specified number of carbon atoms and at least one triple carbon-carbon bond, for example C 2-8 -alkynyl.
  • Typical C 2-8 -alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
  • cycloalkyl refers to a non-aromatic car- bocyclic monovalent hydrocarbon radical having, for instance, from three to twelve carbon atoms, and optionally with one or more degrees of unsaturation, for example C 3-8 -cycloalkyl.
  • a ring may be optionally fused to one or more benzene rings or to one or more of other cycloalkyl ring(s).
  • Such a ring may also be bicyclic.
  • Typical C 3-8 -cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.
  • cycloalkylene refers to a non-aromatic carbocyclic divalent hydrocarbon radical having, for instance, from three to twelve carbon atoms and optionally possessing one or more degrees of unsaturation, for example C 3-8 - cycloalkylene. Such a ring may be optionally fused to one or more benzene rings or to one or more of other cycloalkyl ring(s). Such a ring may also be bicyclic.
  • Typical C 3-8 -cycIoalkylene groups include, but are not limited to, cyclopropyl-1 ,1-diyl, cyclopropyl-1 ,2-diyl, cyclobutyl- 1,2-diyl, cyclopentyl-1 ,3-diyl, cyclohexyl-1 ,2-diyl, cyclohexenyl-1 ,2-diyl, cycloheptyl-1 ,4-diyl, cycloheptenyl-1 ,4-diyl, or cyclooctyl-1 ,5-diyl, and the like.
  • heterocyclic ring or “heterocyclic” or “heterocyclyl” as used herein, alone or in combination, refers to a heterocyclic ring with for instance from 3 to 12 member atoms, such as C 3- ⁇ o-heteroaryl, for instance C 3-6 -heteroaryl, having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO 2 , O, or N, for example C 3-8 -heterocyclyl.
  • Such a ring may be optionally fused to one or more of another "heterocyclic" ring(s) or cycloalkyl ring(s).
  • Such a ring may also be bicyclic.
  • Typical C 3 . 8 - heterocyclyl groups include, but are not limited to, tetrahydrofuran, 1 ,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, piperazine, and the like.
  • heterocyclylene refers to a heterocyclic ring diradical with for instance from 3 to 12 member atoms, such as C 3-10 -heteroaryl, for in- stance C 3-6 -heteroaryl, optionally having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO 2 , O, or N.
  • a ring may be optionally fused to one or more benzene rings or to one or more of another "heterocyclic" rings or cycloalkyl rings.
  • Such a ring may also be bicyclic.
  • heterocyclylene examples include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1 ,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1 ,4-diyl, pyrrolidine-1 ,3-diyl, morpholine- 2,4-diyl, piperazine-1,4-dyil, and the like.
  • aryl refers to a carbocyclic aromatic ring radical or to a aromatic ring system radical such as for instance C 6- ⁇ 8 -aryl, for instance such as C 6- ⁇ -aryl.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems.
  • heteroaryl refers to a aromatic ring radical with for instance from 5 to 7 member atoms, or to a aromatic ring system radical with for instance from 7 to 18 member atoms, containing one or more heteroatoms selected from ni- trogen, oxygen, or sulfur heteroatoms, wherein N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions; such as e.g.
  • aryl and “heteroaryl” includes, but are not limited to phenyl, biphenyl, indenyl, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furanyl (2-furanyl, 3-furanyl), indolyl, oxadia- zolyl, isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolinyl, fluorenyl, xanthenyl, iso- indanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1
  • the present invention also relates to partly or fully saturated analogues of the ring systems mentioned above.
  • arylene refers to carbocyclic aromatic ring diradical or to a aromatic ring system diradical. Examples of “arylene” include, but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the like.
  • arylene alone or in combination also include other divalent radicals of the monovalent radicals mentioned in the definition of aryl.
  • aralkyl as used herein, alone or in combination, refers to aryl as defined above and alkyl as defined above.
  • heteroarylene refers to a five to seven membered aromatic ring diradical, or to a aromatic ring system diradical, containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms, wherein N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions.
  • heteroarylene used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4- oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1 ,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyri- dine-2,4-diyl, pyridine-2,3-diyI, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.
  • heteroarylene alone or in combination also include other divalent radicals of the monovalent radicals mentioned in the definition of heteroaryl.
  • fused cycloalkylaryl refers to a cycloalkyl group fused to an aryl group, the two having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused cycloalkylaryl” used herein include 5-indanyl, 5,6,7,8-tetrahydro- 2-naphthyl,
  • fused cycloalkylarylene refers to a fused cycloalkylaryl, wherein the aryl group is divalent.
  • fused cycloalkylarylene used herein include
  • fused arylcycloalkyl refers to an aryl group fused to a cycloalkyl group, the two having two atoms in common, and wherein the cycloalkyl group is the point of substitution
  • fused arylcycloalkyl used herein include 1-indanyl, 2-indanyl, 1- (1 ,2,3,4-tetrahydronaphthyl),
  • fused arylcycloalkylene refers to a fused arylcycloalkyl, wherein the cycloalkyl group is divalent.
  • fused arylcycloalkylene used herein include
  • fused heterocyclylaryl refers to a heterocyclyl group fused to ah aryl group, the two having two atoms in common, and wherein the aryl group is the point of substitution.
  • fused heterocyclylaryl used herein include 3,4-methylenedioxy-1- phenyl,
  • fused heterocyclylarylene refers to a fused heterocyclylaryl, wherein the aryl group is divalent.
  • fused heterocyclylarylene used herein include
  • fused arylheterocyclyl refers to an aryl group fused to a heterocyclyl group, the two having two atoms in common, and wherein the heterocyclyl group is the point of substitution.
  • fused arylheterocyclyl used herein include 2-(1 ,3-benzo- dioxolyl),
  • fused arylheterocyclylene refers to a fused arylheterocyclyl, wherein the heterocyclyl group is divalent.
  • fused arylheterocyclylene used herein include
  • fused cycloalkylheteroaryl refers to a cycloalkyl group fused to a heteroaryl group, the two having two atoms in common, and wherein the heteroaryl group is the point of substitution.
  • fused cycloalkylheteroaryl used herein include 5-aza- 6-indanyl
  • fused cycloalkylheteroarylene refers to a fused cycloalkylheteroaryl, wherein the heteroaryl group is divalent.
  • fused cycloalkylheteroarylene used herein include
  • fused heteroarylcycloalkyl refers to a heteroaryl group fused to a cycloalkyl group, the two having two atoms in common, and wherein the cycloalkyl group is the point of substitution.
  • fused heteroarylcycloalkyl used herein include 5-aza- 1-indanyl,
  • fused heteroarylcycloalkylene refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent.
  • fused heteroarylcycloalkylene used herein include
  • fused heterocyclylheteroaryl refers to a heterocyclyl group fused to a heteroaryl group, the two having two atoms in common, and wherein the heteroaryl group is the point of substitution.
  • fused heterocyclylheteroaryl used herein in- dude 1 ,2,3,4-tetrahydro-beta-carbolin-8-yI,
  • fused heterocyclylheteroarylene refers to a fused heterocyclylheteroaryl, wherein the heteroaryl group is divalent.
  • fused heterocyclylheteroarylene examples include
  • fused heteroarylheterocyclyl refers to a heteroaryl group fused to a heterocyclyl group, the two having two atoms in common, and wherein the heterocyclyl group is the point of substitution.
  • fused heteroarylheterocyclyl used herein include
  • fused heteroarylheterocyclylene refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl group is divalent.
  • fused heteroarylheterocyclylene used herein include
  • halogen or “halo” means fluorine, chlorine, bromine or iodine.
  • haloalkyl as used herein means an alkyl substituted with one or more halogen atoms, such as for instance chloromethyl, fluoromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 2,2-difluoroethyl, or 1 ,2- dichloropropyl.
  • hydroxyalkyl as used herein means an alkyl substituted with one or more hydroxy groups, such as for instance 2-hydroxyethyl or 3,3-dihydroxypropyl.
  • cyano shall refer to the substituent -CN.
  • the terms “contain” or “containing” can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, S0 2 , N, or N-alkyl, including, for example, -CH 2 -0-CH 2 -, -CH 2 -S0 2 - CH 2 -, -CH 2 -NH-CH 3 and so forth.
  • solvate is a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula (I)) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • Solvents may be, by way of example, water, ethanol, or acetic acid.
  • biohydrolyzable ester is an ester of a drug substance (in this in- vention, a compound of Formula (I) ) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • the biohydrolyzable ester is orally absorbed from the gut and is trans- formed to (I) in plasma.
  • lower alkyl esters e.g., C 1-4
  • lower acyloxyalkyl esters e.g., C 1-4
  • lower alkoxyacyloxyalkyl esters e.g., C 1-4
  • alkoxyacyloxy esters e.g., C 1-4
  • alkyl acylamino alkyl esters e.g., C 1-4
  • choline esters e.g., choline esters.
  • biohydrolyzable amide is an amide of a drug substance (in this invention, a compound of general Formula (I)) which either a) does not interfere with the bio- logical activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • the advantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) in plasma.
  • Many examples of such are known in the art and include by way of example lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoal- kylcarbonyl amides.
  • prodrug includes biohydrolyzable amides and biohydrolyzable esters and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound of Formula (I) and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of For- mula (I).
  • these functional groups include, but are not limited to, 1,4- dihydropyridine, N-alkylcarbonyl-1 ,4-dihydropyridine, 1 ,4-cyclohexadiene, tert-butyl, and the like.
  • therapeutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the therapeutic response of an animal or human that is being sought.
  • treatment and “treating” as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the full spectrum of treatments for a given disorder from which the patient is suffering, such as the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disor- der or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • cycloalkylene is cycloalkylene, arylene, fused arylcycloalkylene, fused cycloalkylarylene, optionally substituted with one or more substituents R 31 , R 32 , R 33 , and R 34 as defined above.
  • heteroarylene is heteroarylene, heterocyclylene, fused heterocyclylarylene, fused arylheterocyclylene, fused cycloalkylheteroarylene, fused heteroarylcycloalkylene, fused heterocyclylheteroary- lene, or fused heteroarylheterocyclylene optionally substited with one or more substituents R 31 , R 32 , R 33 , and R 34 as defined above.
  • R 31 , R 32 , R 33 , and R 34 are substituents R 31 , R 32 , R 33 , and R 34 as defined above.
  • fused arylcycloalkylene is fused arylcycloalkylene, fused cycloalkylarylene, fused heterocyclylarylene, fused arylheterocyclylene, fused cycloalkylheteroarylene, fused heteroarylcycloalkylene, fused heterocy- clylheteroarylene, or fused heteroarylheterocyclylene optionally substited with one or more substituents R 31 , R 32 , R 33 , and R 34 as defined above.
  • phenyl are selected from phenyl, naphtyl, thienyl, thiazolyl or pyridyl;
  • R 35 , R 36 , R 37 , and R 38 independently of each other, are alkyl, halogen, aralkyl, haloalkyl, hydroxyalkyl, cyano, -N0 2 , R 3 -O-(CH 2 ) w -, R 3 -S(0) v -, N(R 3 )(R 4 )-S(0) v -, -R 3 -0-C(0)-, R 3 -C(O)-0-, R 3 -C(0)-, wherein R 3 and R 4 , v and w are as defined above.
  • R 3 and R 4 are independently selected from hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, or R 3 and R 4 , when attached to a nitrogen atom, together with said nitrogen atom form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more alkyl substituents;
  • R 3 and R 4 are hydrogen or alkyl
  • R 35 , R 36 , R 37 , and R 38 independently of each other, are N(R 3 )(R 4 )-C(0)-, R 3 -C(0)-N(R 4 )-(CH 2 ) w , B(OR 3 )(OR 4 )-, N(R 3 )(R 4 )-(CH 2 ) W -, or phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyalkyl, cyano, -N0 2l R 5 -O-, R 5 -S(O) s -, R 5 -O-C(O)-, R 5 -C(O)-0-, R 5 -C(0)-, N(R 5 )(R 6 )-C(O)-, N(R 5 )(R 6 )-, R 5 -C(0)-N(R 5 )-(CH 2 )
  • B 1 and B 2 independently of each other, are a linker selected from the group consisting of -C(X)-, -O-C(X)-, -C(X)-0-, -N(R 15 )-C(X)-, -C(X)-N(R 15 )-, wherein X is O, S and R 15 is as defined above.
  • B 1 and B 2 independently of each other, are selected from -C(O)-, - O-C(O)-, -C(0)-0-, -N(R 15 )-C(O)- or -C(0)-N(R 15 )-, wherein R 15 is as defined above.
  • R 15 is hydrogen, hydroxyalkyl, alkyl, alkenyl or alkynyl;
  • R 15 is hydrogen or alkyl
  • the invention provides compounds such as 3-(4-DipropyIsulfamoyl-benzoyloxy)-naphthalene-2-carboxylic acid methyl ester
  • the present invention provides compounds of the general formula (I)
  • the present compounds may have one or more asymmetric centres and it is intended that stereoisomers (optical isomers), as separated, pure or partially purified stereoisomers or ra- cemic mixtures thereof, are included in the scope of the present invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane- sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, di- methylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethyl- ammonium, butylammonium, tetramethylammonium salts and the like.
  • pharmaceutically acceptable acid addition salts are the hydrates which the present compounds are able to form. The compound may also be administered to a patient in need thereof in combination with one or more further active substances in any suitable ratios.
  • the present invention also provides pharmaceutical compositions comprising as an active ingredient, at least one compound compound, preferably in a pharmacologically effective amount, more preferably in a therapeutically effective amount, according to the present in- vention together with one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of a compound according to the present invention.
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the present invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublin- gual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules.
  • Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non- aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot in- jectable formulations are also contemplated as being within the scope of the present invention.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • the formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. Examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid.
  • pharmaceutically acceptable salts refers to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base.
  • a compound according to the present invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid.
  • a compound according to the present invention contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • a suitable cation such as sodium or ammonium ion.
  • Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of the present invention and these form a further aspect of the present invention.
  • solutions of a compound according to the present invention in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be em- ployed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospho- lipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or dilu- ent may include any sustained release material known in the art, such as glyceryl mono- stearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the novel compounds of the present invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • compositions intended for oral use may be prepared according to any known method, 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 may 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 corn 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 absorption 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. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, incorpo- rated herein by reference, to form osmotic therapeutic tablets for controlled release.
  • Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as 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, heptadecaethyl- eneoxycetanol, 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 polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents,
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alchol. 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 anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents may also be present.
  • the pharmaceutical compositions of the present invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and conden- sation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propyl- ene glycol, sorbitol or sucrose.
  • compositions may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectible aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above.
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conveniently employed as solvent or suspending medium.
  • compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter and polyethylene glycols, for example.
  • creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the present invention are contemplated.
  • topical applications shall include mouth washes and gargles.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multi- lamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as choles- terol, stearylamine, or phosphatidylcholines.
  • a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug therof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain:
  • composition of the present invention may comprise a compound according to the present invention in combination with further active substances such as those described in the foregoing.
  • the HPLC pump is connected to two eluent reservoirs containing: A: 0.01% TFA in water
  • HPLC conditions, detector settings and mass spectrometer settings used are giving in the following table.
  • a mixture of a compound of the general formula (1) and a compound of the general formula (2) in toluene is heated at reflux for 6 hours. After cooling the crystals are filtered and washed with toluene, diethylether and dried. The isolated compound of the general formula (3) is used without further purification in step B.
  • the compound of the general formula (9) is either stirred in 5 ml ether, filtered off and then washed with H 2 0, or purified by Prep-HPLC (eluent H 2 O:CH 3 CN as gradient from 95/5 - > 0/100).
  • Step A Reductive amination of Barany-type linker
  • Step B Acylation of resin bound amine
  • a solution of the acid chloride (0.64 mmole, 0.8 ml of a 0.6 mol/l solution in NMP) is added, followed by the addition of DIPEA (0.136 ml.
  • the resulting mixture is shaken at room temperature for 15 hours, the washed with ( 5 x 1.0 ml ) NMP
  • Step C Methylester cleavage.
  • Step D To the resin bound carboxylic acid the amine ( 0.8 ml, 0.6 mol/l in NMP) was added, followed by DIPEA (0.136 ml) and PyBroP ( 0.4 ml, 1.0 mol/l in NMP). The mixture was shaken at room temperature for 16 hours then washed with NMP (5 x 1ml) and DCM (5 x
  • Step E Cleavage in 50 % TFA in DCM, 2- 5 hours
  • the title compound was prepared from methyl 3-hydroxy-2-naphthoate and 4- dipropylsulfamoyl-benzoyl chloride in 70 % yield.
  • Example 2 (General procedure (A)) - 3-(4-Dipropylsulfamoyl-benzoyloxy)-naphthalene-2-carboxylic acid 3-carboxy-naphthalen-2-yl ester.
  • the title compound was prepared from 3-hydroxy-2-naphthoic acid and 4-dipropylsulfamoyl- benzoyl chloride in 5% yield.
  • the title compound was purified by column chromatography.
  • the title compound was prepared from 3-hydroxy-2-naphthoic acid and 4-dipropylsulfamoyl- benzoyl chloride in 2 % yield.
  • the title compound was purified by column chromatography.
  • the title compound was prepared from 3-amino-2-naphthoic acid and 4-dipropylsulfamoyl- benzoyl chloride in 31 % yield.
  • the title compound was prepared from 2-aminobenzoic acid and 4-dipropylsulfamoyl-benzoyl chloride in 55 % yield.
  • the title compound was prepared from 2-methylaminobenzoic acid and 4-dipropylsulfamoyl- benzoyl chloride in 47 % yield.
  • Step A The intermediate 3-(4-dipropylsulfamoyl-benzoylamino)-naphthalene-2-carboxylic acid methyl ester was prepared from methyl 3-amino-2-naphthoate and 4-dipropylsulfamoyl- benzoyl chloride in 96 % yield.
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 2-aminothiazol in 51 % yield
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 2,4,6-trimethoxybenzylamine hydrochloride in 30 % yield
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 4-methylsulphonylbenzylamine hydrochloride in 9 % yield
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 2-phenylbenzylamine in 17 % yield
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 3-phenylbenzylamine in 41 % yield
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 4-phenylbenzylamine in 87 % yield
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and benzylamine in 78 % yield.
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 1-naphthalenemethylamine in 41 % yield
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 1-(4-chlorobenzhydryl)-piperidine in 37 % yield
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 3-amino-1 ,2,3,4-tetrahydro-naphthalene in 39 % yield.
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 1-(4-methoxyphenyl)ethylamine in 39 % yield.
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and methyl 4-(aminomethyl)benzoate in 45 % yield.
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 1-(1-phenylethyl)-piperazine in 47 % yield.
  • Step B The title compound was prepared from 3-(4-dipropylsulfamoyl-benzoylamino)- naphthalene-2-carboxylic acid methyl ester and 2-phenylglycinol in 56 % yield.
  • Tris Tris(hydroxymethyl)aminomethane
  • ATP Adenosinetriphosphate
  • LPS Lipopolysaccharide
  • a pure enzyme assay is based on MAPKAP-K2 phosphorylation of a substrate peptide.
  • Purified recombinant human MAPKAP-K2, 0.4-2 unit/ml is reacted with 30 ⁇ M peptide substrate (KKLNRTLSVA) in the reaction buffer (50 mM Tris/HCL pH 7.5, 0.1 % Bovine serum albumin, 5 M GSH, 0.5 mM EDTA, 100 ⁇ M ATP,1 ⁇ Ci 33P-g-ATP) for 15 min at 30 degrees and stopped by adding 13 ⁇ l 2 % H 3 P0 4 . Samples are spotted on to P30 paper, washed extensively in 0.5 % H 3 P0 4 and counted by liquid scintillation.
  • a whole blood assay has been established to measure the effect of a MAPKAP-K2 inhibitor on LPS induced cytokine production.
  • Rat blood is collected in heparinised vacutainers.
  • Whole blood is diluted 1:1 in RPM1 1640 media and the assay is performed by preincubation for 30 min with compound before addition of 100 ng/mL of LPS for 5 hours.
  • the assay is stopped by centrifugation at 2000 g for 10 min at 4 degrees and the supernatant is collected.
  • the supernatant is assayed for TNF ⁇ content by ELISA using a commercial kit from BD Bio- sciences.

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Abstract

L'invention concerne des composés de formule générale (I) dans laquelle les variables sont telles que définies dans les revendications, ces composés étant utilisés comme inhibiteurs de la MAPKAP kinase 2.
PCT/DK2004/000301 2003-05-07 2004-05-04 Composes utilises comme inhibiteurs de kinase Ceased WO2004099127A1 (fr)

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WO2005085234A3 (fr) * 2004-03-03 2006-01-26 Syngenta Participations Ag Nouveaux insecticides
US7385059B2 (en) 2003-07-22 2008-06-10 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
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
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US7622583B2 (en) 2005-01-14 2009-11-24 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2
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US7884110B2 (en) 2007-07-12 2011-02-08 Chemocentryx, Inc. Fused heteroaryl pyridyl and phenyl benzenesuflonamides as CCR2 modulators for the treatment of inflammation
US7999109B2 (en) 2002-05-24 2011-08-16 Millennium Pharmaceuticals, Inc. CCR9 inhibitors and methods of use thereof
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US10973809B2 (en) 2016-11-23 2021-04-13 Chemocentryx, Inc. Method of treating focal segmental glomerulosclerosis
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US7812170B2 (en) 2004-03-03 2010-10-12 Syngenta Crop Protection, Inc. Insecticides
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US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
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US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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US11324736B2 (en) 2016-11-23 2022-05-10 Chemocentryx, Inc. Method of Treating Focal Segmental Glomerulosclerosis
US10973809B2 (en) 2016-11-23 2021-04-13 Chemocentryx, Inc. Method of treating focal segmental glomerulosclerosis
US11382915B2 (en) 2017-10-11 2022-07-12 Chemocentryx, Inc. Treatment of focal segmental glomerulosclerosis with CCR2 antagonists
US10758540B2 (en) 2017-10-11 2020-09-01 Chemocentryx, Inc. Treatment of focal segmental glomerulosclerosis with CCR2 antagonists
US12138254B2 (en) 2018-09-04 2024-11-12 Eli Lilly And Company Chronic nightly dosing of lasmiditan for migraine prevention
US11827618B2 (en) 2019-07-09 2023-11-28 Eli Lilly And Company Processes and intermediate for the large-scale preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, and preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate
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