Classifications

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  • 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
  • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
  • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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  • 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
  • C07C323/62—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 atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
  • C07D211/60—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
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
• • 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
  • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/096—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • 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
  • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • 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
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

• the present invention relates to compounds that are useful for treating inflammatory and immune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.
• Inflammation results from a cascade of events that includes vasodilation accompanied by increased vascular permeability and exudation of fluid and plasma proteins. This disruption of vascular integrity precedes or coincides with an infiltration of inflammatory cells.
• Inflammatory mediators generated at the site of the initial lesion serve to recruit inflammatory cells to the site of injury. These mediators (chemokines such as IL-8, MCP-1, MIP-1, and RANTES, complement fragments and lipid mediators) have chemotactic activity for leukocytes and attract the inflammatory cells to the inflamed lesion.
• chemotactic mediators which cause circulating leukocytes to localize at the site of inflammation require the cells to cross the vascular endothelium at a precise location. This leukocyte recruitment is accomplished by a process called cell adhesion.
• Cell adhesion occurs through a coordinately regulated series of steps that allow the leukocytes to first adhere to a specific region of the vascular endothelium and then cross the endothelial barrier to migrate to the inflamed tissue (Springer, T.A., 1994, "Traffic Signals for Lymphocyte Recirculation and Leukocyte Emigration: The Multistep Paradigm", Cell. 76: 301 -314; Lawrence, M.B., and Springer, T.
• the first step consists of leukocytes rolling along the vascular endothelial cell lining in the region of inflammation.
• the rolling step is mediated by an interaction between a leukocyte surface oligosaccharide, such as Sialylated Lewis-X antigen (Slex), and a selectin molecule expressed on the surface of the endothelial cell in the region of inflammation.
• a leukocyte surface oligosaccharide such as Sialylated Lewis-X antigen (Slex)
• a selectin molecule expressed on the surface of the endothelial cell in the region of inflammation.
• the selectin molecule is not normally expressed on the surface of endothelial cells but rather is induced by the action of inflammatory mediators such as
• TNF- ⁇ and interleukin-1 Rolling decreases the velocity of the circulating leukocyte
• the firm adhesion is accomplished by the interaction of integrin molecules that are present on the surface of the rolling leukocytes and their counter- receptors (the Ig superfamily molecules) on the surface of the endothelial cell.
• the Ig superfamily molecules or CAMs are either not expressed or are expressed at low levels on normal vascular endothelial cells.
• the CAM's like the selectins, are induced by the action of inflammatory mediators like TNF-alpha and IL-1.
• the final event in the adhesion process is the extravasation of leukocytes through the endothelial cell barrier and their migration along a chemotactic gradient to the site of inflammation. This transmigration is mediated by the conversion of the leukocyte integrin from a low avidity state to a high avidity state.
• the adhesion process relies on the induced expression of selectins and CAM's on the surface of vascular endothelial cells to mediate the rolling and firm adhesion of leukocytes to the vascular endothelium.
• ICAM-1 intercellular adhesion molecule
• the present invention discloses compounds which bind to the interaction- domain (I-domain) of LFA-1, thus interrupting endothelial cell-leukocyte adhesion by blocking the interaction of LFA-1 with ICAM-1, ICAM-3, and other adhesion molecules. These compounds are useful for the treatment or prophylaxis of diseases in which leukocyte trafficking plays a role, notably acute and chronic inflammatory diseases, autoimmune diseases, tumor metastasis, allograft rejection, and reperfusion injury.
• R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, cycloalkyl and carboxaldehyde; with the proviso that at least one of R 1 or R 3 is selected from the group consisting of
• cis- cyclopropanamide "trans- cyclopropanamide", wherein R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, hydroxyalkyl and carboxyalkyl;
• R 8 and R 9 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, alkylaminocarbonylalkyl and dialkylaminocarbonylalkyl; and R 10 and R 11 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino; wherein R 10 andR 11 may be joined to form a three to seven membered heterocyclyl ring, said ring optionally being substituted with one or more substituents R 15 , each substituent R 15 independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, cycloalkyl, aryl, heterocyclyl, heterocyclylcarbonyl, heterocyclylalkylaminocarbonyl, hydroxy, hydroxyalkyl, hydroxyalkoxyalkyl, carboxy,
• Presently preferred compounds of Formula I have R 3 as "cis- cyclopropanamide” or “trans-cyclopropanamide”; R 4 and R 5 each independently as hydrogen or alkyl; and R 1 and R 2 each independently as hydrogen, halogen, haloalkyl or nitro.
• the present invention is also directed to compounds of the structure
• R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, carboxyalkoxy, carboxyalkyl and heterocyclyl; and, R 10 and R 1 ' are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino; wherein R 10 and R 1 ' may be joined to form a three to seven-membered heterocyclyl ring, said ring being optionally substituted with one or more substituents R 15 , wherein R 15 at each occurrence is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, cycloalkyl, aryl, heterocyclyl, heterocyclylcarbonyl, heterocyclylalkylaminocarbonyl, hydroxy,
• the ring may be piperidine, piperazine, morpholine, pyrrolidine or azetidine; p may be one; q may be one or two; R 13 , at each occurrence, may be halogen or haloalkyl; and R 12 may be halogen, alkyl, alkoxy, carboxyalkoxy, carboxyalkyl or heterocyclyl.
• R and R are each independently selected from the group consisting of hydrogen, halogen and haloalkyl
• R 14 and R 15 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and carboxy; and wherein R 1 , R 2 , R 14 and R 15 are unsubstituted or substituted with at least one electron donating or electron withdrawing group.
• circle T may be pyrrolidine, n may be three; and circle Q may be a three to seven membered heterocyclic ring such as piperidine or morpholine.
• the compounds represented by structural Formula I, above may be prepared by synthetic processes or by metabolic processes.
• Processes for the preparation of the compounds of the present invention by metabolic processes include those occurring in the human or animal body (in vivo) or by processes occurring in vitro.
• the present invention is also directed to a method of treatment or prophylaxis in which the inhibition of inflammation or suppression of immune response is desired, comprising administering a therapeutic amount of a compound having Formula I; and pharmaceutical compositions containing compounds of Formula I in pharmaceutically acceptable carriers.
• alkanoyl refers to an alkyl group attached to the parent molecular group through a carbonyl group.
• alkanoylamino refers to an alkanoyl group attached to the parent molecular group though an amino group.
• alkanoylaminoalkyl refers to an alkanoylamino group attached to the parent molecular group through an alkyl group.
• alkanoyloxy refers to an alkanoyl group attached to the parent molecular group through an oxygen radical.
• alkanoyloxyalkyl refers to an alkanoyloxy group attached to the parent molecular group through an alkyl group.
• alkoxy refers to an alkyl group attached to the parent molecular group through an oxygen atom.
• alkoxyalkoxy refers to an alkoxy group attached to the parent molecular group through an alkoxy group.
• alkoxyalkyl refers to an alkoxy group attached to the parent molecular group through an alkyl group.
• alkoxycarbonyl refers to an alkoxy group attached to the parent molecular group through a carbonyl group.
• alkoxycarbonylalkyl refers to an alkoxycarbonyl group attached to the parent molecular group through an alkyl group.
• alkyl refers to a saturated straight or branched chain group of 1-10 carbon atoms derived from an alkane by the removal of one hydrogen atom.
• alkyl(alkoxycarbonylalkyl)amino refers to an amino group substituted with one alkyl group and one alkoxycarbonylalkyl group.
• alkyl(alkoxycarbonylalkyl)aminoalkyl refers to an alkyl(alkoxycarbonylalkyl)amino group attached to the parent molecular group through an alkyl group.
• alkylene refers to a divalent group of 1-10 carbon atoms derived from a straight or branched chain alkane by the removal of two hydrogen atoms.
• alkylsulfonyl refers to an alkyl radical attached to the parent molecular group through an -SO 2 - group.
• alkylsulfonylaminocarbonyl refers to an alkylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
• amino refers to a radical of the form -NR a R 0 , or to a radical of the form -NR a -, where Ra and R b are independently selected from hydrogen, alkyl or cycloalkyl.
• aminoalkanoyl refers to an amino group attached to the parent molecular group through an alkanoyl group.
• aminoalkyl refers to an amino group attached to the parent molecular group through an alkyl group.
• aminocarbonyl refers to an amino group attached to the parent molecular group through a carbonyl group.
• aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings.
• the aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring.
• the aryl groups of this invention can be optionally substituted with alkyl, halogen, hydroxy, or alkoxy substituents.
• arylalkoxy refers to an aryl group attached to the parent molecular group through an alkoxy group.
• arylalkoxycarbonyl refers to an arylalkoxy group attached to the parent molecular group through a carbonyl group.
• arylsulfonyl refers to an aryl radical attached to the parent molecular group through an -SO 2 - group.
• arylsulfonylaminocarbonyl refers to an arylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
• carbboxaldehyde refers to the radical -CHO.
• carboxylate or “carboxamido” as used herein refer to an amino group attached to the parent molecular group through a carbonyl group.
• carboxamidoalkyl refers to a carboxamido group attached to the parent molecular group through an alkyl group.
• Carboxy refers to the radical -COOH.
• Carboxyalkyl refers to a carboxy group attached to the parent molecular group through an alkyl group.
• carboxyalkylamino refers to a carboxyalkyl group attached to the parent molecular group through an amino group.
• carboxyalkoxy refers to a carboxy group attached to the parent molecular group through an alkoxy group.
• carboxycarbonyl refers to a carboxy group attached to the parent molecular group through a carbonyl group.
• carboxycycloalkoxy refers to a carboxy group attached to the parent molecular group through a cycloalkoxy group.
• carboxythioalkoxy refers to a carboxy group attached to the parent molecular group through a thioalkoxy group.
• cyano refers to the radical -CN.
• cycloalkyl refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of 3-12 carbons derived from a cycloalkane by the removal of a single hydrogen atom. Cycloalkyl groups may be optionally substituted with alkyl, alkoxy, halo, or hydroxy substituents.
• cycloalkoxy refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of 3-12 atoms derived from a cycloalkane by the removal of a single hydrogen atom, linked to the parent molecular group through an oxygen atom. Cycloalkoxy groups may be optionally substituted with alkyl, alkoxy, halo or hydroxy substituents.
• haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
• heterocycle or “heterocyclyl” represent a 4-, 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
• the 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds.
• heterocycle or “heterocyclic” as used herein additionally refers to bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring.
• Heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrid
• Heterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as
• Heterocyclics also include compounds of the formula o * where X* and Z* are independently selected from -CH2-, -CH 2 NH-, -CH 2 O-, -NH- and -O-,
• heterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl, 1,3- benzimidazol-2-one and the like.
• the heterocycle groups of this invention can be optionally substituted with alkyl, halogen, carboxy, hydroxy or alkoxy substituents.
• heterocyclylalkyl refers to a heterocyclic group attached to the parent molecular group through an alkyl group.
• heterocyclylalkylamino refers to a heterocyclylalkyl group attached to the parent molecular group through an amino group.
• heterocyclylalkylaminocarbonyl refers to a heterocyclylalkylamino group attached to the parent molecular group through a carbonyl group.
• heterocyclylamino refers to a heterocyclyl group attached to the parent molecular group through an amino group.
• heterocyclylcarbonyl refers to a heterocyclyl group attached to the parent molecular group through a carbonyl group.
• heterocyclylsulfonyl refers to a heterocyclyl radical attached to the parent molecular group through an -SO 2 - group.
• heterocyclylsulfonylaminocarbonyl refers to a heterocyclylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
• hydroxyalkanoyl refers to a hydroxy radical attached to the parent molecular group through an alkanoyl group.
• hydroxyalkoxy refers to a hydroxy radical attached to the parent molecular group through an alkoxy group.
• hydroxyalkoxyalkyl refers to a hydroxyalkoxy group attached to the parent molecular group through an alkyl group.
• hydroxyalkyl refers to a hydroxy radical attached to the parent molecular group through an alkyl group.
• hydroxyalkylaminocarbonyl refers to a hydroxyalkyl group attached to the parent molecular group through an aminocarbonyl group.
• perfluoroalkyl refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
• phenyl refers to a monocyclic carbocyclic ring system having one aromatic ring.
• the phenyl group can also be fused to a cyclohexane or cyclopentane ring.
• the phenyl groups of this invention can be optionally substituted with alkyl, halogen, hydroxy or alkoxy substituents.
• prodrugs as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
• prodrug represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
• sulfonate refers to the radical -SO 3 H
• tetrazole or “tetrazolyl” as used herein refers to the heterocyclic radical -CN 4 H.
• thioalkoxy refers to an alkyl group attached to the parent molecular group through a sulfur atom.
• trans-cinnamyl refers to an acrylamido group
• aminocarbonylethenyl attached to the parent molecular group through C-3 of the acrylamido group, such that the aminocarbonyl and the parent molecular group exist in a trans relationship about the ethenyl group.
• lower refers to a C ⁇ -C 6 unit for a particular functionality.
• lower alkyl means C ⁇ -C 6 alkyl.
• substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogen, trifluoromethoxy, trifluoromethyl, aralkyl, alkenyl, alkynyl, aryl, carboxyalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers.
• groups such as alcohols, ethers, esters, amides, sulfones, s
• the linkers are typically short chains of 1 -3 atoms containing any combination of -C-, -C(O)-, -NH-, -S-, -S(O)-, -O-, -C(O)O- or -S(O)-. Rings may be substituted multiple times.
• electrostatically-withdrawing or “electron-donating” refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied the same position in the molecule. These terms are well-understood by one skilled in the art and are discussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18, inco ⁇ orated herein by reference.
• Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium and trifluoromethyl among others.
• Electron donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto and disulfide among others.
• substituents may have electron donating or electron withdrawing properties under different chemical conditions.
• the present invention contemplates any combination of substituents selected from the above-identified groups.
• the most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl. carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkylamino), amine lower mercapto, mercaptoalkyl, alkylthio and alkyldithio.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
• Stereoisomers include enantiomers and diastereomers, and mixtures of
• enantiomers or diastereomers are designated ( - ).
• Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
• Geometric isomers can also exist in the compounds of the present invention.
• the present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
• Substituents around a carbon-carbon double bond are designated as being in the Z or E configuration wherein the term "Z” represents substituents on the same side of the carbon-carbon double bond and the term “E” represents substituents on opposite sides of the carbon- carbon double bond.
• the arrangement of substituents around a carbocyclic ring are designated as cis or trans wherein the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
• Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated cis/trans.
• the compounds of this invention are diaryl sulfides, which are substituted with a cyclopropanoyl or cyclopropanamido moiety.
• the cyclopropanoyl or cyclopropanamido functionality may be placed either ortho- or para- to the linking sulfur atom, although para-substitution is preferable.
• amide or carboxyl moiety is readily modified; a variety of secondary and tertiary amides are active, and alternatively a heterocyclic ring may be attached at this position. Modifications of the amide or carboxyl functionality are particularly useful in modulating physicochemical and pharmacokinetic properties.
• the compounds of Formula I are useful in a variety of forms, i.e., with various substitutions as identified. Examples of particularly desirable compounds are quite diverse, and many are mentioned herein. Included are compounds in which R 1 is a "cis- cyclopropane” or a "trans- cyclopropane", and R 3 is hydrogen; or where R 3 is a "cis- cyclopropane” or a "trans- cyclopropane", and R 1 is hydrogen, or R 1 , R 2 , and R 4 are each independently hydrogen or alkyl, and R 5 is halogen, haloalkyl or nitro.
• R 10 and R 11 are each independently hydrogen, alkyl, cycloalkyl, alkoxycarbonylaalkyl, hydroxyalkyl, or heterocyclylalkyl, or where NR 1 ⁇ 11 is heterocyclyl or substituted heterocyclyl, and where A is aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl.
• the ring When R 10 and R n are joined to form a ring, the ring will be heterocyclyl, due to the presence of the nitrogen from which R 10 and R 11 are appended. Depending upon which R 10 and R 11 substituents are chosen, the ring formed may contain at least one additional heteroatom, such as oxygen, nitrogen or sulfur.
• circle Q represents a heterocyclyl, nitrogen containing ring. This ring may contain at least one additional heteroatom, such as oxygen, nitrogen or sulfur; and may be substituted or unsubstituted.
• circle T represents a heterocyclyl, amide containing ring. This ring may contain at least one additional heteroatom such as oxygen, nitrogen or sulfur, and may be substituted or unsubstituted.
• Compounds of the present invention include, but are not limited to: ( ⁇ )-(2- bromophenyl)[2-trifluoromethyl-4-(tr ⁇ /w-(2-((3-( 1 -pyrrolidin-2-onyl)-prop- 1 - ylamino)carbonyl)cycloprop- 1 -yl)phenyl]sulfide, ( ⁇ )-(2-isopropylphenyl)[2,3- dichloro-4-(trans-(carboxymethylamino)carbonyl) cycloprop- 1 -yl)phenyl]sulfide, ( ⁇ )- (2-isopropylphenyl)[2,3-dichloro-4-(tra «5-(2-(3-carboxypiperidine))carbonyl) cycloprop- 1 -yl)phenyl] sulfide, ( ⁇ )-(2-(2-carboxyethyl)phenyl) [2-trifluoromethyl
• compositions and Methods of Treatment also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more pharmaceutically-acceptable carriers.
• the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
• compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
• parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
• compositions of this invention for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
• suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged abso ⁇ tion of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay abso ⁇ tion such as aluminum monostearate and gelatin.
• adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
• Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and
• the abso ⁇ tion of the drug in order to prolong the effect of the drug, it is desirable to slow the abso ⁇ tion of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amo ⁇ hous material with poor water solubility. The rate of abso ⁇ tion of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed abso ⁇ tion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically-acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) abso ⁇ tion accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and
• compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
• the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically- acceptable emulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• the oral compositions can also include adjuvants such as wetting agents, emuls
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• Compounds of the present invention can also be administered in the form of liposomes.
• liposomes are generally derived from phosphohpids or other lipid substances. Liposomes are formed by mono- or multi- lamellar hydrated liquid crystals that are dispersed in an aqueous medium.
• any non- toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used.
• the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
• the preferred lipids are the phosphohpids and the phosphatidyl cholines (lecithins), both natural and synthetic.
• compositions of the present invention may be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids.
• pharmaceutically-acceptable salt is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically-acceptable salts are well-known in the art. For example, S. M. Berge, et al.
• the salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
• Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecano
• the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
• long chain halides such as decyl
• Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
• a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
• Pharmaceutically-acceptable basic addition salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimefhylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
• Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
• Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
• the active compound is mixed under sterile conditions with a pharmaceutically-acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
• Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
• Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention maybe varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
• the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
• dosage levels of about 0.1 to about 50 mg, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally or intravenously to a mammalian patient.
• the effective daily dose may be divided into multiple doses for pu ⁇ oses of administration, e.g. two to four separate doses per day.
• Scheme 1 describes the synthesis of a typical cyclopropane-substituted diaryl sulfide 5 through an aldehyde intermediate 2.
• Aldehyde 2 is prepared by reaction of a thiophenol (for example 2,4-dichlorothiophenol, 2-bromothiophenol, or the like) with halo-substituted benzaldehyde derivative 1 (e.g. 2-chlorobenzaldehyde, 3-chloro,4- fluorobenzaldehyde, or the like) in the presence of base (e.g. sodium carbonate, triethylamine, or the like) and a polar solvent (e.g. dimethylformamide, dimethylsulfoxide, or the like) .
• base e.g. sodium carbonate, triethylamine, or the like
• a polar solvent e.g. dimethylformamide, dimethylsulfoxide, or the like
• the aldehyde group is homologated to the corresponding cinnamic ester 3, using an acetate equivalent (for example, malonic acid, triethoxyphosphonoacetate, or the like) in the presence of an appropriate base and solvent.
• the cyclopropane acid 4 is prepared by treatment with trimethylsulfoxonium iodide in the presence of base (for example, NaH) followed by hydrolysis of the intermediate ester (for example using sodium hydroxide in alcohol).
• the acid group is activated (for example using thionyl chloride, or dicyclohexylcarbodiimide and N-hydroxysuccinimide, or the like) and reacted with a primary or secondary amine (for example, 6-aminohexanol, pyrrolidone-3- propylamine, or the like) to provide the desired analog 5.
• a primary or secondary amine for example, 6-aminohexanol, pyrrolidone-3- propylamine, or the like
• a halo- acetophenone can replace benzaldehyde 2; the resultant cyclopropanes 5 are substituted with a methyl group.
• a substituted halocyclopropane acid 6 (e.g. 3-chloro-2-nitrocyclopropane acid or the like) may be coupled with a primary or secondary amine (e.g. N-acetylpiperazine or the like) as described above to give the corresponding amide 7.
• the halo-group can then be displaced with a substituted thiophenol in the presence of base to provide the product 8.
• a number of the compounds described herein may be prepared from intermediate halides or triflates like 9 (Scheme 3) Heck reaction (for example, using palladium acetate and tri-o-tolylphosphine) with alkenes (like methyl acrylate) followed by olefin functionalization (e.g. hydrogenation utilizing palladium on carbon) provides analogs with structures related to 10.
• the halides or triflates may be coupled with amines (primary and secondary) and alcohols under transition metal catalysis (for example tris(dibenzylideneacetone)dipalladium(0) and
• Cyclopropanes like 14 may be prepared from halo(or triflo)-substituted derivatives 12 by palladium-mediated coupling [e.g. using tetrakis(triphenylphosphine) palladium (0), Pd 2 (dba) , or the like] with alkene derivatives 13 (Scheme 4). Cyclopropanation (e.g. ethyl diazoacetate and rhodium catalyst) then yields cyclopropanes 14. Direct coupling with cyclopropane derivatives also yields diarylsulfide cyclopropanes 14. Scheme 5
• a mixture of isomers is referred to as a compound number, such as compound 1, and the individual isomers are given an A designation (indicating the first isomer, i.e. 1 A) or a B designation (indicating the second isomer, i.e. IB).
• a designation indicating the first isomer, i.e. 1 A
• B designation indicating the second isomer, i.e. IB.
• Trifluoromethanesulfonic anhydride (5.74 mL, 34.1 mmoles) was added to a suspension of 2,3-dichloro-4-hydroxy-benzaldehyde (synthesized according to the procedure of Bicking et al., J. Med. Chem., 1976, 19, 534, 5.92 g, 31.0 mmoles) in pyridine (31 mL) at 0 °C. The reaction was warmed to room temperature and stirred for one hour. The crude products were poured onto ice and extracted with Et 2 O (2x). The combined organics were washed with IN HC1 (2x) and brine before being dried over Na 2 SO 4 . Concentration provided 10 g of the corresponding crude triflate.
• 25 25 was prepared from the compound 24 by the procedures described in
• N,N-Diisopropylethylamine (0.11 mL, 0.63 mmoles) was added to a solution of the compound 25 (0.1000 g, 2622 mmoles), l-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.0704 g, 0.367 mmoles), 1 -hydroxybenzotriazole hydrate (0.0602 g, 0.4457 mmoles), and glycine methyl ester hydrochloride (0.0658 g, 0.52 mmoles) in DMF (0.66 mL). The reaction was stined at room temperature overnight.
• Triethylamine (0.074 L, 0.53 mmoles) and methyl acrylate (0.048 mL, 0.53 mmoles) were added to a solution of the compound 19 (0.1200 g, 0.2216 mmoles), palladium acetate (0.0025 g, 0.011 mmoles), and tri(o-tolyl)phosphine (0.0202 g, 0.0604 mmoles) in NMP (1.0 mL).
• the reaction was heated to 85 °C for ten hours.
• the reaction was diluted with Et 2 O and washed with sat. NH 4 C1, H 2 O (2x), and brine.
• the organic layer was dried over Na 2 SO and concentrated in ' vacuo.
• Example 8 ( ⁇ )-(2-M ⁇ holin- 1 -ylphenyl) [2-chloro-4-(trans-(2-((3-( 1 -pyrrolidin-2-onyl)- prop-l-ylamino)carbonyl)cycloprop-l-yl)phenyl] sulfide, 29, was synthesized according to the following procedure.
• Example 12 ( ⁇ )-(2-Mo ⁇ holin-l -ylphenyl) [2,3-dichloro-4-(/ra «5-(2-carboxycycloprop-l - yl)phenyl]sulfide, 33, was synthesized according to the following procedure.
• the title compound 33 was prepared first by the procedure described in Example 2, substituting 2-bromobenzenethiol for 2-isopropylbenzenethiol. The resultant aldehyde was converted to the conesponding cyclopropanecarboxylic acid according to Example 1, steps IB and IC. The title compound was then prepared
• Example 14 ( ⁇ )-(2-Bromophenyl) [2,3-dichloro-4-(tra «5-(2-((3-(l -pyrrolidin-2-onyl)-prop- l-ylamino)carbonyl)cycloprop-l-yl)phenyl] sulfide, 35, was synthesized according to the following procedure.
• the title compound 35 was prepared by the procedure described in Example 2, substituting 2-bromobenzenethiol for 2-isopropylbenzenethiol.
• the resultant aldehyde was then converted to the title compound by following the procedures of
• the title compound 36 was prepared by the procedure described in Example 2, substituting 2-bromobenzenethiol for 2-isopropylbenzenethiol.
• the resultant aldehyde was then converted to the title compound by following the procedure of
• Example 16 ( ⁇ )-(2-Isopropylphenyl) [2,3-dichloro-4-(/r ⁇ «s-(2-(2-carboxyethylamino) carbonyl)cycloprop-l-yl)phenyl]sulfide, 37, was synthesized according to the following procedure.
• the title compound 41 was prepared by the procedure described in Example 3, substituting mo ⁇ holine for ethyl nipectotate and omitting the final hydrolysis
• the title compound 42 was prepared by the procedure described in Example 3, substituting N-acetylpiperazine for ethyl nipectotate and omitting the final hydrolysis
• Example 22 ( ⁇ )-(2-Isopropylphenyl) [2,3-dichloro-4-(tr ⁇ «s-(2-((3-(l -pyrrolidin-2-onyl)- prop-l-ylamino)carbonyl)cycloprop-l-yl)phenyl] sulfide, 43, was synthesized according to the following procedure.
• the title compound 44 was prepared by the procedure described in Example 3, substituting pyrrolidine for ethyl nipectotate and omitting the final hydrolysis
• the title compound 46 was prepared by the procedure described in Example 3 substituting azetidine for ethyl nipectotate and omitting the final hydrolysis protocol.
• the title compound 47 was prepared by the procedure described in Example 3 substituting 4-(2-aminoethyl)mo ⁇ holine for ethyl nipectotate and omitting the final
• Example 31 (2-(3-Carboxypiperidin-l-yl)phenyl) [2,3-dichloro-4-(tra «5-(2-((3-(l- pyrrolidin-2-onyl)-prop-l-ylamino)carbonyl)cycloprop-l-yl)phenyl] sulfide; Isomer #2, 49B, was synthesized according to the following procedure.
• Example 32 (2-(3-Carboxypiperidin-l-yl)phenyl) [2,3-dichloro-4-(tra «5-(2-((3-(l- pyrrolidin-2-onyl)-prop- 1 -ylamino)carbonyl)cycloprop- 1 -yl)phenyl] sulfide; Isomer #1 , 49A, was synthesized according to the following procedure. 32A. Isomer #1, 35A, was also isolated from the procedure described in Example 31, step A.
• Compound 51 was prepared according to the procedures of Example 2A and 2B, substituting 2-methoxythiophenol for 2-isopropylthiophenol and eliminating the final hydrolysis procedure.
• Example 33 substituting ⁇ -alanine ethyl ester for glycine methyl ester hydrochloride.
• Example 35 (2-Methoxyphenyl)[2,3-dichloro-4-(tr ⁇ «s-2-(3-carboxypropylamino)carbonyl) cycloprop- l-yl)phenyl] sulfide, Isomer #1, 53 A, was synthesized according to the following procedure.
• Example 38 (2-Methoxyphenyl)[2,3-dichloro-4-(tr ⁇ rt5-2-(2-carboxypiperidin- 1 - yl)carbonyl)cycloprop-l-yl)phenyl]sulfide, Isomer #1, 56A, was synthesized according to the following procedure.
• Example 41 (2-Methoxyphenyl)[2,3-dichloro-4-(/ratt5-2-(3-carboxypropylamino)carbonyl) cycloprop- l-yl)phenyl]sulfide, Isomer #2, 53B, was synthesized according to the following procedure.
• the title compound 53B was prepared by the procedures described in Example 39, substituting ethyl 4-aminobutyrate for glycine methyl ester
• a primary biochemical assay described below as assay 46A, was utilized to measure the ability of the present compounds to block the interaction between the integrin LFA-1 and its adhesion partner ICAM-1. 46 A.
• ICAM-1 / LFA-1 Biochemical Interaction Assay 100 mL of anti-LFA-1 antibody (ICOS Co ⁇ oration) at a concentration of 5 mg/ml in Dulbecco's phosphate-buffered saline (D-PBS) is used to coat wells of a 96-well microtiter plate overnight at 4°C.
• D-PBS Dulbecco's phosphate-buffered saline
• wash buffer D-PBS w/o Ca** or Mg**, 0.05% Tween 20
• Recombinant LFA-1 100 mL of 0.7 mg/ml, ICOS Co ⁇ oration
• Incubation continues for 1 hour at room temperature and the wells are washed twice with wash buffer.
• Serial dilutions of compounds being assayed as ICAM-1 /LFA-1 antagonists prepared as 10 mM stock solutions in dimethyl sulfoxide (DMSO), are diluted in D-PBS, 2mM MgCl 2 , 1% fish skin gelatin and 50 mL of each dilution added to duplicate wells. This is followed by addition of 50 mL of 0.8 mg/ml biotinylated recombinant ICAM-1/Ig (ICOS Co ⁇ oration) to the wells and the plates are incubated at room temperature for 1 hour.
• DMSO dimethyl sulfoxide
• the wells are then washed twice with wash buffer and 100 mL of Europium-labeled Streptavidin (Wallac Oy) diluted 1 : 100 in Delfia assay buffer (Wallac Oy) are added to the wells. Incubation proceeds for 1 hour at room temperature. The wells are washed eight
• background refers to wells that are not coated with anti-LFA-1 antibody.
• Compounds of the present invention exhibit inhibitory activity in the above assay as illustrated in Table 1.
• Fluorescent tagged JY-8 cells (a human EBV-transformed B cell line expressing
• Dilutions of compounds to be assayed for ICAM-1 /LFA-1 antagonistic activity are prepared in RPMI- 1640/ 1% fetal bovine serum from lOmM stock solutions in
• DMSO and 50 ⁇ L are added to duplicate wells. Microtiter plates are incubated for
• the ability of the compounds of this invention to treat arthritis can be demonstrated in a murine collagen-induced arthritis model according to the method of Kakimoto, et al., Cell Immunol 142: 326-337, 1992, in a rat collagen-induced arthritis model according to the method of Knoerzer, et al., Toxicol Pathol 25:13-19, 1997, in a rat adjuvant arthritis model according to the method of Halloran, et al., Arthitis Rheum 39: 810-819, 1996, in a rat streptococcal cell wall-induced arthritis model according to the method of Schimmer, et al., J Immunol 160: 1466-1477, 1998, or in a SCID-mouse human rheumatoid arthritis model according to the method of Oppenheimer-Marks et al., 7 Clin Invest 101: 1261-1272, 1998
• the ability of the compounds of this invention to treat Lyme arthritis can be demonstrated according to the method of Gross et al.,
• the ability of compounds of this invention to treat inflammatory bowel disease can be demonstrated in a rabbit chemical-induced colitis model according to the method of Bennet et al., J Pharmacol Exp Ther 280:988-1000, 1997.
• the ability of compounds of this invention to treat autoimmune diabetes can be demonstrated in an NOD mouse model according to the method of Hasagawa et al., Int Immunol 6:831-838, 1994, or in a murine streptozotocin-induced diabetes model according to the method of Herrold et al., Cell Immunol 157:489-500. 1994.
• the ability of compounds of this invention to treat inflammatory liver injury can be demonstrated in a murine liver injury model according to the method of Tanaka et al., J Immunol 151:5088-5095, 1993.
• graft- vs.-host disease can be demonstrated in a murine lethal GVHD model according to the method of Haming et al., Transplantation 52:842-845, 1991.
• the ability of compounds of this invention to treat cancers can be demonstrated in a human lymphoma metastasis model (in mice) according to the method of Aoudjit et al., J Immunol 161:2333-2338, 1998.

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  • 2001-06-22 JP JP2002507779A patent/JP2004502672A/ja active Pending
  • 2001-06-22 AU AU2001268724A patent/AU2001268724B2/en not_active Ceased

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