The present invention relates to novel selective cathepsin S inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

This Application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsin S.
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increase expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. An increase in cathepsin S activity contributes to the pathology and/or symptomatology of a number of diseases. Accordingly, molecules that inhibit the activity of cathepsin S protease are useful as therapeutic agents in the treatment of such diseases.
This Application relates to compounds of Formula I:
in which:
X1 and X2 are both methylene or X1 is ethylene and X2 is a bond;
R1 is hydrogen and R2 is cyano, hetero(C5)aryl or (C1-4)alkyl-substituted hetero(C5)aryl or both R1 and R2 are hydrogen, halo, (C1-4)alkyl or xe2x80x94X3OR9, wherein X3 and R9 are as defined below, or R1 and R2 together with the carbon atom to which both R1 and R2 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene;
R3 is xe2x80x94CR5xe2x95x90CHR6 or xe2x80x94CR7xe2x95x90NR8, wherein R5 and R6 together with the atoms to which R5 and R6 are attached form (C2-6)alkenyl, (C5-12)cycloalkenyl, hetero(C5-12)cycloalkenyl, (C6-12)aryl, hetero(C6-12)aryl, (C9-12)bicycloaryl or hetero(C8-12)bicycloaryl and R7 and R8 together with the atoms to which R7 and R8 are attached form hetero(C5-12)cycloalkenyl, hetero(C6-12)aryl or hetero(C8-12)bicycloaryl, wherein R3 optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR9R9, xe2x80x94X3OR9, xe2x80x94X3SR9, xe2x80x94X3C(O)NR9R9, xe2x80x94X3C(O)OR9, xe2x80x94X3S(O)R10, xe2x80x94X3S(O)2R10 and xe2x80x94X3C(O)R10, wherein X3 is a bond or (C1-2)alkylene, R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R10 is (C1-3)alkyl or halo-substituted (C1-3)alkyl; and
R4 is xe2x80x94C(O)X4R11 or xe2x80x94S(O)2X4R11, wherein X4 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR12xe2x80x94, wherein R12 is hydrogen or (C1-6)alkyl, and R11 is (i) (C1-6)alkyl optionally substituted by xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R13, xe2x80x94C(O)R13, xe2x80x94C(O)OR3, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, xe2x80x94NR14C(O)R13, xe2x80x94NR14C(O)OR13, xe2x80x94NR14C(O)NR13R14 or xe2x80x94NR14C(NR14)NR13R14, wherein R13 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl and R14 at each occurrence independently is hydrogen or (C1-6)alkyl, or (ii) (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkly, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl or (iii) (C3-6)cycloalkyl(C0-3)alkyl, hetero(C5-6)cycloalkyl(C0-3)alkyl, phenyl(C0-3)alkyl or hetero(C5-6)aryl(C0-3)alkyl substituted by xe2x80x94X5OR15, xe2x80x94X5SR15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15, xe2x80x94X5C(O)R 15, xe2x80x94X5C(O)OR15, xe2x80x94X5C(O)NR15R16, xe2x80x94X5NR15R16, xe2x80x94X5NR16C(O)R15, xe2x80x94X5NR16C(O)OR15, xe2x80x94X5NR16C(O)NR15R16 or xe2x80x94X5NR16C(NR16)NR15R16, wherein X5 is a bond or methylene, R15 is (C3-6)cycloalkyl(C0-3)alkyl, hetero(C5-6)cycloalkyl(C0-3)alkyl, phenyl(C0-3)alkyl or hetero(C5-6)aryl(C0-3)alkyl and R16 is hydrogen or (C1-6)alkyl; wherein R4 optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, nitro, halo-substituted (C1-3)alkyl, xe2x80x94X5NR17R17, xe2x80x94X5NR17C(O)OR17, xe2x80x94X5NR17C(O)NR17R17, xe2x80x94X5NR17C(NR17)NR17R17, xe2x80x94X5OR17xe2x80x94X5SR17, xe2x80x94X5C(O)OR17, xe2x80x94X5C(O)NR17R17, xe2x80x94X5S(O)2NR17R17, xe2x80x94X5P(O)(OR8)OR17, xe2x80x94X5OP(O)(OR8)OR17, xe2x80x94X5NR17C(O)R18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18 and xe2x80x94X5C(O)R18 and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, xe2x80x94NR17R17, xe2x80x94NR C(O)OR17, xe2x80x94NR17C(O)NR17R17, xe2x80x94NR17C(NR17)NR17R17, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94C(O)OR17, xe2x80x94C(O)NR17R17, xe2x80x94S(O)2NR17R17, xe2x80x94P(O)(OR17)OR17, xe2x80x94OP(O)(OR17) OR17, xe2x80x94NR17C(O)R18, xe2x80x94S(O)R18, xe2x80x94S(O)2R18 and xe2x80x94C(O)R18, wherein X5 is a bond or (C1-6)alkylene, R17 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R18 is (C1-6)alkyl or halo-substituted (C1-3)alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
A second aspect of the invention is a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
A third aspect of the invention is a method for treating a disease in an animal in which inhibition of cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a N-oxide derivative, individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt thereof.
A fourth aspect of the invention is the processes for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts thereof.
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings.
xe2x80x9cAlicyclicxe2x80x9d means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAliphaticxe2x80x9d means a moiety characterized by a straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAlkylxe2x80x9d represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g., (C1-6)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g., as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C6-12)aryl(C0-3)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
xe2x80x9cAlkylenexe2x80x9d, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g., (C1-6)alkylene includes methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), trimethylene (xe2x80x94CH2CH2CH2xe2x80x94), tetramethylene (xe2x80x94CH2CH2CH2CH2xe2x80x94) 2-butenylene (xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94), 2-methyltetramethylene (xe2x80x94CH2CH(CH3)CH2CH2xe2x80x94), pentamethylene (xe2x80x94CH2CH2CH2CH2CH2xe2x80x94) and the like).
xe2x80x9cAlkenylxe2x80x9d means alkyl, as defined in this Application, provided that the radical is comprised of at least one double bond. Hence, optionally substituted (C2-6)alkenyl as used in this Application to define R3 includes 2-bromovinyl (xe2x80x94CHxe2x95x90CHBr), buta-1,3-dienyl (xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CH2), 2-chloro-1-methylpropenyl (xe2x80x94C(CH3)xe2x95x90CClxe2x80x94CH3), 2-chlorovinyl (xe2x80x94CHxe2x95x90CHCl), 4-isopropenyl (xe2x80x94C(CH3)xe2x95x90CH2), 1-methylpropenyl (xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH3), 2-methylpropenyl (xe2x80x94CHxe2x95x90C(CH3)2), 2-nitrovinyl (xe2x80x94CHxe2x95x90CHNO2), propenyl (xe2x80x94CHxe2x95x90CHxe2x80x94CH3), 2-trifluormethylvinyl (xe2x80x94CHxe2x95x90CHxe2x80x94CF3), trifluorovinyl (xe2x80x94CFxe2x95x90CF2), vinyl (xe2x80x94CHxe2x95x90CH2), and the like).
xe2x80x9cAlkylidenexe2x80x9d means a straight or branched saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C1-6)alkylidene includes methylene (xe2x95x90CH2), ethylidene (xe2x95x90CHCH3), isopropylidene (xe2x95x90C(CH3)2), propylidene (xe2x95x90CHCH2CH3), allylidene (xe2x95x90CHCHxe2x95x90CH2), and the like).
xe2x80x9cAminoxe2x80x9d means the radical xe2x80x94NH2. Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
xe2x80x9cAnimalxe2x80x9d includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
xe2x80x9cAromaticxe2x80x9d means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2.
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring is comprised of 6 ring carbon atoms and is aromatic or when fused with a second ring forms an aromatic ring assembly. For example, optionally substituted (C6-12)aryl as used in this Application to define R3 includes biphenyl-2-yl, 2-bromophenyl, 2-bromocarbonylphenyl, 2-bromo-5-fluorophenyl, 4-tert-butylphenyl, 4-carbamoylphenyl, 4-carboxy-2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonylphenyl, 4-chlorocarbonylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl, 6-chloro-2-nitrophenyl, 2,6-dibromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-difluoromethoxyphenyl, 3,5-dimethylphenyl, 2-ethoxycarbonylphenyl, 2-fluoropheny, 2-lodophenyl, 4-isopropylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 5-methyl-2-nitrophenyl, 4-methylsulfonylphenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl, and the like. Optionally substituted (C6-12)aryl as used in this Application to define R4 includes 3-acetylphenyl, 3-tert-butoxycarbonylaminomethylphenyl, biphenyl-4-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, naphth-2-yl, 3-phenoxyphenyl, phenyl, and the like.
xe2x80x9cBicycloarylxe2x80x9d means a bicyclic ring assembly containing the number of ring carbon atoms indicated, wherein the rings are linked by a single bond or fused and one, but not both, of the rings comprising the assembly is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C9-12)bicycloaryl includes cyclohexylphenyl, 1,2-dihydronaphthyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, phenylcyclohexyl, 1,2,3,4-tetrahydronaphthyl, and the like).
xe2x80x9cCarbamoylxe2x80x9d means the radical xe2x80x94C(O)NH2. Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cCarbocyclic ketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(O)xe2x80x94.
xe2x80x9cCarboxyxe2x80x9d means the radical xe2x80x94C(O)OH. Unless indicated otherwise, the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d means cycloalkyl, as defined in this Application, provided that the ring assembly is comprised of at least one double bond. Hence, optionally substituted (C5-12)cycloalkenyl as used in this Application to define R3 includes cyclopent-1-enyl, 2-methylcyclopent-1-enyl, 2-nitrocyclopent-1-enyl, 2-fluorocyclopent-1-enyl, 2-chlorocyclopent-1-enyl, 2-trifluoromethylcyclopent-1-enyl, cyclohex-1-enyl, 2-methylcyclohex-1-enyl, 2-nitrocyclohex-1-enyl, 2-fluorocyclohex-1-enyl, 2-chlorocyclohex-1-enyl, 3-cyclohexa-1,3-dienyl, and the like).
xe2x80x9cCycloalkylxe2x80x9d means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of ring carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C3-12)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like).
xe2x80x9cCycloalkylenexe2x80x9d means a divalent saturated or partially unsaturated, monocyclic ring or bridged polycyclic ring assembly containing the number of ring carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, the instance wherein xe2x80x9cR1 and R2 together with the carbon atom to which both R1 and R2 are attached form (C3-8)cycloalkylenexe2x80x9d includes, but is not limited to, the following:
xe2x80x9cDiseasexe2x80x9d specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the xe2x80x9cside effectsxe2x80x9d of such therapy.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo.
xe2x80x9cHalo-substituted alkylxe2x80x9d, as an isolated group or part of a larger group, means xe2x80x9calkylxe2x80x9d substituted by one or more xe2x80x9chaloxe2x80x9d atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C1-3)alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).
xe2x80x9cHeteroatom moietyxe2x80x9d includes xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group.
xe2x80x9cHeterocycloalkylenexe2x80x9d means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen or (C1-6)alkyl. For example, the instance wherein R1 and R2 together with the carbon atom to which both R1 and R2 are attached form hetero(C3-8)cycloalkylenexe2x80x9d includes, but is not limited to, the following:
in which R is hydrogen, (C1-6)alkyl, or a protecting group.
xe2x80x9cHeteroarylxe2x80x9d means aryl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl, a protecting group or represents the free valence which serves as the point of attachment to a ring nitrogen, and each ring is comprised of 5 or 6 ring atoms. For example, optionally substituted hetero(C5-12)aryl as used in this Application to define R3 includes 4-amino-2-hydroxypyrimidin-5-yl, benzothiazol-2-yl, 1H-benzoimidazol-2-yl, 2-bromopyrid-5-yl, 5-bromopyrid-2-yl, 4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl, 5-carboxy-2,6-dimethylpyrid-3-yl, 3,5-dimethylisoxazol-4-yl, 5-ethoxy-2,6-dimethylpyrid-3-yl, 5-fluoro-6-hydroxypyrimidin-4-yl, fur-2-yl, fur-3-yl, 5-hydroxy-4,6-dimethylpyrid-3-yl, 8-hydroxy-5,7-dimethylquinolin-2-yl, 5-hydroxymethylisoxazol-3-yl, 3-hydroxy-6-methylpyrid-2-yl, 3-hydroxypyrid-2-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-indol-3-yl, isothiazol-4-yl, isoxazol-4-yl, 2-methylfur-3-yl, 5-methylfur-2-yl, 1-methyl-1H-imidazol-2-yl, 5-methyl-3H-imidazol-4-yl, 5-methylisoxazol-3-yl, 5-methyl-2H-pyrazol-3-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 2-methylpyrid-3-yl, 2-methylthiazol-4-yl, 5-nitropyrid-2-yl, 2H-pyrazol-3-yl, 3H-pyrazol-4-yl, pyridazin-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-pyrid-3-yl-2H-[1,2,4]triazol-3-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1H-pyrrol-3-yl, quinolin-2-yl, 1H-tetrazol-5-yl, thiazol-2-yl, thiazol-5-yl, thien-2-yl, thien-3-yl, 2H-[1,2,4]triazol-3-yl, 3H-[1,2,3]triazol-4-yl, 5-trifluoromethylpyrid-2-yl, and the like Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. Optionally substituted hetero(C5-12)aryl as used in this Application to define R4 includes benzofur-2-yl, fur-2-yl, fur-3-yl, pyrid-3-yl, pyrid-4-yl, quinol-2-yl, quinol-3-yl, thien-2-yl, thien-3-yl, and the like.
xe2x80x9cHeterobicycloarylxe2x80x9d means bicycloaryl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl, a protecting group or represents the free valence which serves as the point of attachment to a ring nitrogen, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, optionally substituted hetero(C8-12)bicycloaryl as used in this Application to define R3 includes 2-amino-4-oxo-3,4-dihydropteridin-6-yl, and the like. In general, the term heterobicycloaryl as used in this Application includes, for example, benzo[1,3]dioxol-5-ylcarbonyl, 3,4-dihydro-2H-[1,8]naphthyridinyl, 3,4-dihydro-2H-quinolinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 1,2,3,4,5,6-hexahydro[2,2xe2x80x2]bipyridinylyl, morpholinylpyridyl, 3-oxo-2,3-dihydrobenzo[1,4]oxazinyl, piperidinylphenyl, 5,6,7,8-tetrahydroquinolinyl, and the like. For example, hetero(C5-12)aryl as used in this Application to define R4 includes benzo[1,3]dioxol-5-yl. For example, hetero(C8-12)bicycloaryl(C0-3)alkyl used to describe R11 in this Application, includes 1-oxo-1,3-dihydroisoindol-2-yl, quinolin-3-yl, quinolin-2-yl, 3a,7a-dihydrobenzo[1,3]-dioxol-5-yl, naphthalen-2-yl, 3-chlorobenzo[b]thiophen-2-yl, benzo[b]thiophen-2-yl and 1H-indol-5-yl, and the like.
xe2x80x9cHeterocycloalkenylxe2x80x9d means heterocycloalkyl, as defined in this Application, provided that the ring assembly is comprised of at least one double bond. Hence, optionally substituted hetero(C5-12)cycloalkenyl as used in this Application to define R3 includes 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl, 2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl, 5-hydroxy-4-oxo-4H-pyran-2-yl, 5-methoxy-4-oxo-4H-pyran-2-yl, 6-oxo-1,6-dihydropyrimidin-5-yl, 4-oxo-1,4-dihydropyrid-2-yl, 6-oxo-1,6-dihydropyrid-2-yl, 6-oxo-1,6-dihydropyrid-3-yl, and the like).
xe2x80x9cHeterocycloalkylxe2x80x9d means cycloalkyl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl, a protecting group or represents the free valence which serves as the point of attachment to a ring nitrogen, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term hetero(C5-12)cycloalkyl includes [1,4xe2x80x2]bipiperidinylyl, 1xe2x80x2,2xe2x80x2-dihydro-2H-[1,4xe2x80x2]bipyridinylyl, imidazolidinyl, morpholinyl, 1-morpholin-4-ylpiperidinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like). Thus, for example, optionally substituted hetero(C5-12)cycloalkyl as used in this Application to define R4 includes 4-tert-butoxycarbonylpiperazin-1-yl, 4-ethoxycarbonylpiperazin-1-yl, 4-fur-2-ylcarbonylpiperazin-1-yl, morpholin-4-yl, and the like. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a compound of Formula I wherein R4 is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g., wherein R4 is 4-tert-butoxycarbonylpiperazin-1-ylcarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cHydroxyxe2x80x9d means the radical xe2x80x94OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like.
xe2x80x9ciminoketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(NR)xe2x80x94, wherein R is hydrogen or (C1-6)alkyl.
xe2x80x9cIsomersxe2x80x9d mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and stereoisomers that are nonsuperimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d or sometimes xe2x80x9coptical isomersxe2x80x9d. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomers or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixturexe2x80x9d. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition, March, Jerry, John Wiley and Sons, New York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers. Thus , for example, the name N-[1-cyanomethylcarbamoyl-2-(4-methylbenzylsulfonyl)ethyl]benzamide is meant to include N-[1S-cyanomethylcarbamoyl-2-(4-methylbenzylsulfonyl)ethyl]benzamide and N-[1R-cyanomethylcarbamoyl-2-(4-methylbenzylsulfonyl)ethyl]benzamide and any mixture, racemic or otherwise, thereof.
xe2x80x9cKetone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(O)xe2x80x94.
xe2x80x9cMethylenexe2x80x9d means the divalent radical xe2x80x94CH2xe2x80x94.
xe2x80x9cNitroxe2x80x9d means the radical xe2x80x94NO2.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase xe2x80x9cR3 optionally is substituted by 1 to 5 radicalsxe2x80x9d means that R3 may or may not be substituted in order to fall within the scope of the invention.
xe2x80x9cOrthoxe2x80x9d and xe2x80x9cmetaxe2x80x9d have the meaning typically associated with their usage in organic chemistry. Hence, the phrase xe2x80x9cR22 at the first occurrence is attached at the ring carbon ortho or meta to the 1-position of the phenyl moietyxe2x80x9d, refers to the following illustrative example:
wherein R22 is attached at the 2 or 3-position.
xe2x80x9cN-oxide derivativesxe2x80x9d means derivatives of compounds of Formula I in which nitrogens are in an oxidized state (i.e., Oxe2x80x94N) and which possess the desired pharmacological activity.
xe2x80x9cPathologyxe2x80x9d of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I. For example an ester of a compound of Formula I containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of Formula I containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of Formula I containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of compounds of Formula I containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379. An especially useful class of esters of compounds of Formula I containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
xe2x80x9cProtected derivativesxe2x80x9d means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protecting groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cathepsin S inhibitors. A comprehensive list of suitable protecting groups can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. 1999.
xe2x80x9cTherapeutically effective amountxe2x80x9d means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
xe2x80x9cThioketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(S)xe2x80x94.
xe2x80x9cTreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any administration of a compound of the present invention and includes:
(1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or
(3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc. Alternatively, the compounds are named by AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, a compound of Formula I in which R1 and R2 are each hydrogen, R3 is phenyl, X2 is methylene and R4 is naphthalen-2-yl-methanoyl; that is, a compound having the following structure:
is named N-(2-benzylsulfonyl-1R-cyanomethylcarbamoylethyl)naphthalene-2-carboxamide or naphthalene-2-carboxylic acid [(R)-1-(cyanomethyl-carbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide;
While the broadest definition of the invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. For example, R1 particularly represents hydrogen and R2 represent hydrogen, hetero(C5)aryl or (C1-4)alkyl-substituted hetero(C5)aryl or together with the carbon atom to which both R1 and R2 are attached form (C3-5)cycloalkylene or (C5-6)heterocycloalkylene.
Preferably X1 and X2 are both methylene and R3 represents (C2-6)alkenyl, (C6-12)aryl or hetero(C5-12)aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR9R9, xe2x80x94X3OR9, xe2x80x94X3SR9, xe2x80x94X3C(O)NR9R9, xe2x80x94X3C(O)OR9, xe2x80x94X3S(O)R10, xe2x80x94X3S(O)2R10 and xe2x80x94X3C(O)R10, wherein X3 is a bond or (C1-2)alkylene, R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R10 is (C1-3)alkyl or halo-substituted (C1-3)alkyl. R3 more preferably represents biphenyl, isooxazolyl, naphthyl, phenyl, pyridyl, thienyl or vinyl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR9R9, xe2x80x94X3OR9, xe2x80x94X3SR9, xe2x80x94X3C(O)NR9R9, xe2x80x94X3C(O)OR9, xe2x80x94X3S(O)R10, xe2x80x94X3S(O)2R10 and xe2x80x94X3C(O)R10, wherein X3 is a bond or (C1-2)alkylene, R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R10 is (C1-3)alkyl or halo-substituted (C1-3)alkyl. R3 more preferably represents biphenyl-2-yl, 2,4-bistrifluoromethylphenyl, 2,5-bistrifluoromethylphenyl, 4-tert-butylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorothien-2-yl, 2-chloro-5-trifluoromethyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 1,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,5-dimethylisooxaxol-4-yl, 3,5-dimethylphenyl, 2-fluoro-6-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methyl-2-fluorophenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl, prop-2-en-1-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl, 3-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl or 2,3,6-trifluorophenyl.
In particular, X1, X2 and R3 along with the sulfonyl moiety to which X1 and X2 are attached together represent a group having the following formula:
in which n is 0, 1, 2, 4 or 5 and R22 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR9R9, xe2x80x94X3OR9, xe2x80x94X3SR9, xe2x80x94X3C(O)NR9R9, xe2x80x94X3C(O)OR9, xe2x80x94X3S(O)R10, xe2x80x94X3S(O)2R10 and xe2x80x94X3C(O)R10, wherein X3 is a bond or (C1-2)alkylene, R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R10 is (C1-3)alkyl or halo-substituted (C1-3)alkyl; more particularly in which n is 0, 1 or 2 and R22 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94OR9, xe2x80x94SR9 and xe2x80x94C(O)OR9, wherein R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl; more particularly in which R22 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl; more particularly in which at the first occurrence is attached at the ring carbon ortho or meta to the 1-position of the phenyl moiety.
Preferably n is 1 or 2 and R22 at the first occurrence is selected from a group consisting of difluoromethoxy, trifluoromethoxy, trifluorosulfanyl and nitro and R22 at the second occurrence, if present, is selected from a group consisting of (C1-4)alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl. Preferably R22 at the first occurrence is in the ortho position.
R4 preferably may represent xe2x80x94C(O)X4R11 or xe2x80x94S(O)2X4R11, wherein X4 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR12xe2x80x94, wherein R12 is hydrogen or (C1-6)alkyl, and R11 is (C1-6)alkyl, (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-10)aryl(C0-3)alkyl, hetero(C5-10)aryl(C0-3)alkyl, hetero(C8-12)bicycloaryl(C0-3)alkyl, hetero(C5-6)cycloalkyl(C0-3)alkyl or phenyl(C0-3)alkyl, wherein the hetero(C5-6)cycloalkyl or phenyl is substituted in the ring by xe2x80x94X5OR15 or xe2x80x94X5C(O)R15, wherein X5 is a bond or methylene and R15 is phenyl(C0-3)alkyl or hetero(C5-6)aryl(C0-3)alkyl, wherein any aryl or heteroaryl group comprising R4 optionally is substituted in the ring by 1 to 2 substituents selected from (C1-6)alkyl, halo, halo-substituted (C1-3)alkyl, xe2x80x94X5OR17, xe2x80x94X5NR17C(O)OR17, xe2x80x94X5C(O)OR17 or xe2x80x94X5C(O)R18, wherein X5 is a bond or (C1-6)alkylene, R17 is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R18 is (C1-6)alkyl or halo-substituted (C1-3)alkyl. R4 more preferably may represent 3-acetylbenzoyl, allyloxycarbonyl, 2-aminopyrid-3-ylcarbonyl, 6-aminopyrid-3-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, benzoyl, 4-benzoylbenzoylcarbonyl, benzo[1,3]dioxol-3-ylcarbonyl, benzofur-2-ylcarbonyl, biphenyl-4-ylcarbonyl, 4-bromobenzoyl, 3-bromothien-2-yl, tert-butoxycarbonyl, 3-tert-butoxycarbonylaminomethylbenzoyl, 4-teir-butoxycarbonylpiperazin-1-ylcarbonyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 3-chlorothienylcarbonyl, cyclopentylcarbonyl, 3,4-difluorobenzoyl, 3,4-dimethoxybenzoyl, dimethylcarbamoyl, 4-ethoxycarbonylpiperazin-1-ylcarbonyl, 4-fluorobenzoyl, 3-fluoro-4-methoxybenzoyl, fur-2-ylcarbonyl, fur-3-ylcarbonyl, 4-fur-2-ylcarbonylpiperazin-1-ylcarbonyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, 4-hydroxypyrid-3-yl, 6-hydroxypyrid-3-yl, 1H-indol-4-ylcarbonyl, isopropylcarbamoyl, isobutyloxycarbonyl, isopropyloxycarbonyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 3-methylbenzoyl, 5-methylthienylcarbonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, naphth-2-ylcarbonyl, naphth-2-ylsulfonyl, 3-phenoxybenzoyl, 3-phenylacryloyl, phenylsulfonyl, pyrazin-2-ylcarbonyl, 3-pyrid-3-ylacryl, pyrid-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, quinol-2-ylcarbonyl, quinol-3-ylcarbonyl, thien-2-ylcarbonyl, thien-3-ylcarbonyl, thien-2-ylsulfonyl, 4-trifluoromethoxybenzoyl or 4-trifluoromethylbenzoyl.
R4 more preferably is benzoyl, morpholin-4-ylcarbonyl, thienylcarbonyl, indolylcarbonyl or pyridinylcarbonyl, optionally substituted in the ring by 1 to 2 substituents selected from fluoro and methyl. In particular, R4 represents one of the following formulae:
namely benzoyl, morpholin-4-ylcarbonyl, thien-2-yl, thien-3-yl, indol-4-yl and pyridin-4-yl, respectively, optionally substituted in the ring by 1 to 2 substituents selected from fluoro and methyl.
Preferred are compounds of Formula II:
in which n is 1, 2, 3, 4 or 5 and each R1, R2, R3 and R22 are as defined in the Summary of the Invention and in the preferred embodiments.
Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups.
Particular compounds of the invention are selected from the compounds formed by joining the acyl carbon atom (C*) of one of the fragments (A1 to A36 or A40 to A71) shown in Table 1 to the nitrogen atom (N*) of one of the substituted aminoalkyl fragments (B1 to B75) shown in Table 2, and joining the methine carbon atom (CH*) of one of the substituted aminoalkyl fragments (B1 to B75) shown in Table 2 to the acyl carbon atom (C*) of one of the acyl-aminoalkylnitrile fragments(C1 to C9) depicted in Table 3.
Further particular compounds of the invention are selected from the compounds formed by joining the sulphonyl atom (SO2*) of one of the fragments (A37 to A39) shown in Table 1 to the nitrogen atom (N*) of one of the substituted aminoalkyl fragments (B1 to B75) shown in Table 2, and joining the methine carbon atom (CH*) of one of the substituted aminoalkyl fragments (B1 to B75) shown in Table 2 to the acyl carbon atom (C*) of one of the acyl-aminoalkylnitrile fragments(C1 to C9) depicted in Table 3.
Thus, for example, in the above list the compound denoted as A20-B2-C1 is the product of the combination of group A20 in Table 1 and B2 in Table 2 and C1 in Table 3, namely N-(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-4-hydroxy-benzamide:
Further preferred are compounds of Formula I selected from a group consisting of:
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A24-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A25-B2-C1);
Pytidine-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide (compound denoted as A62-B2-C1);
Pyrazine-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A63-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A65-B2-C1);
2-Amino-N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A67-B 2xe2x80x94C1);
6-Amino-N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A66-B2-C1);
3-Hydroxy-pyridine-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide (compound denoted as A68-B2-C1);
Morpholine-4-carboxylic acid-{(R)-1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-[2-1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide (compound denoted as A2-B2-C4);
Morpholine-4-carboxylic acid-{(R)-1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide (compound denoted as A2-B2-C5);
(R)-N-Cyanomethyl-3-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-2-(3,3-dimethyl-ureido)-propionamide, (compound denoted as A56-B2-C1);
{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-carbamic acid allyl ester, (compound denoted as A53-B2-C1);
{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-carbamic acid isobutyl ester, (compound denoted as A51-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-3,4-difluro-benzamide, (compound denoted as A46-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-3-methyl-benzamide, (compound denoted as A48-B2-C1);
Thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A28-B2-C1);
4-Bromo-N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A43-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A44-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-4-trifluoromethoxy-benzamide, (compound denoted as A45-B2-C1);
Naphthalene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-amide, (compound denoted as A7-B2-C1);
(E)-N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-phenyl-acrylamide, (compound denoted as A59-B2-C1);
5-Methyl-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A31-B2-C1);
Biphenyl-4-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A11-B2-C1);
1H-Indole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A60-B2-C1);
Benzo[1,3]dioxole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-amide, (compound denoted as A8-B2-C1);
Benzo[b]thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-amide, (compound denoted as A35-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A69-B2-C1);
Quinoline-3-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A 13-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A70-B2-C1);
4-Chloro-N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A42-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A41-B2-C1);
3-Bromo-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A33-B2-C1);
3-Chloro-benzo[b]thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A36-B2-C1);
3-Chloro-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A32-B2-C1);
N-{(R)-(Cyanomethyl-carbamoyl)-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A40-B2-C1);
(R)-N-Cyanomethyl-3-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-2-(naphthalene-2-sulfonylamino)-propionamide, (compound denoted as A38-B2-C1);
Cyclopentanecarboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A34-B2-C1);
N-[1R-cyanomethylcarbamoyl-2-(3-trifluromethoxybenzylsulfonyl)ethyl]benzamide, (compound denoted as A1-B2-C1);
N-[1R-cyanomethylcarbamoyl-2-(2-difluoromethoxybenzylsulfonyl)ethyl]benzamide, (compound denoted as A1-B2-C1);
N-[1R-cyanomethylcarbamoyl-2-(2-trifluoromethoxybenzylsulfonyl)ethyl]benzamide, (compound denoted as A1-B42-C1);
N-(1R-cyanomethylcarbamoyl-2-(3-difluoromethoxybenzylsulfonyl)ethyl]benzamide, (compound denoted as A1-B24-C1);
N-[1R-cyanomethylcarbamoyl-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide, (compound denoted as A2-B2-C1);
N-[1R-(i-cyanocyclopropylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]-morpholine-4-carboxamide, (compound denoted as A2-B2-C3); and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
Particularly preferred are compounds of Formula I selected from a group consisting of:
N-[1R-cyanomethylcarbamoyl-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide, (compound denoted as A2-B2-C1);
thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A28-B2-C1);
thiophene-3-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A29-B2-C1);
N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-benzamide, (compound denoted as A49-B2-C1);
morpholine-4-carboxylic acid-{(R)-1-(4-cyano-1-methyl-piperidin-4-ylcabamoyl)-2-[2(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A2-B2-C5);
5-methyl-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A31-B2-C1);
1H-indole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A60-B2-C1);
N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-( 1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-methyl-benzamide, (compound denoted as A2-B2-C1);
N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-( 1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-methyl-benzamide, (compound denoted as A46-B2-C1);
N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-( 1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-isonicotinamide, (compound denoted as A25-B2-C1);
N-[1R-(1-cyanocyclopropyl-carbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)-ethyl]morpholine-4-carboxamide, (compound denoted as A2-B2-C3); and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
The compounds of the invention are selective inhibitors of cathepsin S and, as such, are useful for treating diseases in which cathepsin S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating autoimmune disorders, including, but not limited to, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis, allergic disorders, including, but not limited to, asthma, and allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts.
Cathepsin S also is implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g., emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease such as plaque rupture and atheroma. Cathepsin S is implicated in fibril formation and, therefore, inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.
The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of a peptide based substrate. Details of assays for measuring protease inhibitory activity are set forth in Examples 11,12, 13 and 14, infra.
In general, compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I may range from about 1 micrograms per kilogram body weight (xcexcg/kg) per day to about 1 milligram per kilogram body weight (mg/kg) per day, typically from about 10 xcexcg/kg/day to about 0.1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from about 100 xcexcg/day to about 100 mg/day, typically from about 1 xcexcg/day to about 10 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01%w to 10%w, preferably 0.3%w to 1%w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example 15.
Processes for Making Compounds of Formula I:
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of Formula I can be prepared by proceeding as in the following Reaction Scheme 1:
in which each X1, X2, R1, R2, R3 and R4 are as defined for Formula I in the Summary of the Invention.
Compounds of Formula I can be prepared by condensing an acid of Formula 2 with an aminoalkanonitrile of the formula NH2CR1R2CN and then oxidizing. The condensation reaction can be effected with an appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidinophosphonium hex afluorophosphate (PyBOP(copyright)), 1-(3-dimethylaminopropyl)-3-ehtylcarbodiimide hydrochloride (EDCI), O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or the like and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotrizol-1-yl)-1,1,3,3, tetra-methyluroniumhexafluorophosphate (HATU), or the like) and non-nucleophilic base (e.g., N-methylpyrrolidinone, N-methylmorpholine, and the like, or any suitable combination thereof) at ambient temperature and requires 5 to 10 hours to complete.
The oxidation can be carried out with an oxidizing agent (e.g., Oxone(copyright), or the like) in a suitable solvent (e.g., methanol, water, or the like, or any suitable combination thereof) at ambient temperature and requires 16 to 24 hours to complete. A detailed description for the synthesis of a compound of Formula I by the processes in Reaction Scheme 1 is set forth in the Examples 1, 2, 8 and 10, infra.
Compounds of Formula I can be prepared by proceeding as in the following Reaction Scheme 2:
in which n is 0 or 2, L is a leaving group and each X1, X2, R1, R2, R3 and R4 are as defined for Formula I in the Summary of the Invention.
Compounds of Formula I can be prepared by condensing a compound of Formula 3 with a compound of the formula R4L (e.g., 3-acetylbenzoic acid, nicotinic acid, morpholin-4-ylcarbonyl chloride, or the like) and then oxidizing when n is 0. When L is chloro the condensation can be carried out at ambient temperature in the presence of a suitable non-nucleophilic base (e.g., triethylamine, N-methylmorpholine, or the like) in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, or the like) and requires 16 to 24 hours to complete. When L is hydroxy the condensation typically is effected in the presence of a suitable coupling agent (e.g., (PyBOP(copyright)), EDCI, HBTU, DCC, or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), or the like) in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, or the like, or any suitable combination thereof) at ambient temperature and requires 16 to 24 hours to complete.
The oxidization can be carried out by the process described above for Reaction Scheme 1. Detailed procedures for the syntheses of compounds of Formula I by the processes described in Scheme 2 are set forth in the Examples 3, 4 and 5, infra.
Compounds of Formula I in which R4 is xe2x80x94NR13R14 or xe2x80x94NR20R21 can be prepared by proceeding as in the following Reaction Scheme 3:
in which R19 is xe2x80x94NR13R14 or NR20R21, wherein R20 and R21 together with the nitrogen atom to which R20 and R21 are attached form hetero(C5-12)cycloalkyl and each X1, X2, R1, R2, R3, R13 and R14 are as defined in the Summary of the Invention.
Compounds of Formula I in which R4 is xe2x80x94C(O)NR13R14 or xe2x80x94C(O)NR20R21, wherein R20 and R21 together with the nitrogen atom to which R20 and R21 are attached form hetero(C5-12)cycloalkyl and R13 and R14 are as defined in the Summary of the Invention can be prepared by condensing a compound of Formula 4 with a compound of the formula NHR13R14 or NHR20R21, respectively, and then oxidizing when n is 0. The condensation reaction can be carried out at ambient temperature in a suitable solvent (e.g., dichloromethane, or the like) and requires 16 to 24 hours to complete. The oxidization can be carried out by the process described above for Reaction Scheme 1. A detailed description for the synthesis of a compound of Formula I by the processes in Scheme 3 is set forth in the Example 6, infra.
Compounds of Formula I can be prepared by proceeding as in the following Reaction Scheme 4:
in which L is a leaving group and each X1, X2, R1, R2, R3 and R4 are as defined for Formula I in the Summary of the Invention.
Compounds of Formula I can be prepared by reacting a compound of Formula 5 with a compound of the formula R3X2L and then oxidizing. The reaction is carried out in the presence of base (e.g., potassium hydroxide, or the like) at ambient temperature and requires 2 to 3 hours to complete. The oxidization can be carried out by the process described above for Reaction Scheme 1. A detailed description for the synthesis of a compound of Formula I by the processes in Scheme 4 is set forth in the Examples 7 and 9, infra.
Compounds of Formula 2 can be prepared by reacting a compound of Formula 6:
with a compound of the formula R4L, in which L is a leaving group and X1, X2 and R3 are as defined in the Summary of the Invention. The reaction can be carried out in the presence of base (e.g., 1 N aqueous sodium hydroxide, or the like) at about 0.5xc2x0 C. A detailed description for the synthesis of a compound of Formula 2 by the processes described above is set forth in the References 1 and 7, infra. Compounds of Formula 6 are commercially available or otherwise can be prepared by methods known in the art or analogous to those described elsewhere in this Application.
Compounds of Formula 2 in which X1 is ethylene can be prepared by condensing a diester of Formula 7:
with a compound of the formula R3SCH2CH2L to provide a compound of Formula 8:
in which L is a leaving group and R3 and R4 are as defined in the Summary of the Invention, decarbalkoxylating to provide a corresponding monoester and then converting the monoester to a corresponding carboxylic acid. The condensation reaction can be carried out in the presence of a suitable nonnucleophilic base (e.g., N-methylpyrrolidone) and lithium hydroxide. The decarbalkoxylation can be effected under strongly basic conditions (e.g., in the presence of 1 N aqueous sodium hydroxide) in a suitable solvent (e.g, methanol) and requires 4 to 6 hours to complete. A detailed description for the synthesis of a compound of Formula 2 by the processes described above is set forth in the Reference 2, infra.
Compounds of Formula 3 can be prepared by condensing a compound of Formula 9:
with an aminoalkanonitrile of the formula NH2CR1R2CN, in which PG is a protecting group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention, group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention, with an appropriate condensing agent (e.g., N,N-dicyclohexyldiimide, diisopropylcarbodiimide, carbonyldiimidazole, or the like) and a suitable non-nucleophilic base (e.g., N-methylpyrrolidinone, N-methylmorpholine, or the like, or any suitable combination thereof) in a suitable solvent (e.g., dichloromethane, or the like) at ambient temperature and requires 2 to 3 days to complete. Oxidization can be carried out by the process described above for Reaction Scheme 1. Deprotection can be effected by any means which removes the protective group and gives the desired product in reasonable yield. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T. W. Greene, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. 1999. A convenient method of deprotecting is by treatment with a suitable acid (e.g., p-toluenesulfonic acid, or the like) providing the acid addition salt in the process. A detailed description for the synthesis of a compound of Formula 3 by the processes described above is set forth in the References 3, 4 and 5, infra. Compounds of Formula 4 can be prepared by reacting a compound of Formula 3 with phosgene. The reaction is carried out conveniently in a biphasic solvent (e.g., an equal mixture of dichloromethane and saturated sodium bicarbonate solution at ambient temperature. A detailed description for the synthesis of a compound of Formula 4 by the processes described above is set forth in the Reference 6, infra.
Compounds of Formula 5 can be prepared by sequentially condensing an acid of Formula 10:
with an aminoalkanonitrile of the formula NHR2CR3R4CN and a compound of the formula R4L and then deprotecting. The condensation reaction is carried out in a fashion analogous to the process described above for the preparation of the compounds of Formula 3. The condensation reaction with the compound of the formula R4L is carried out in a fashion analogous to the process described above for the preparation of the compounds of Formula I by Scheme 2. The deprotection can be effected by treatment with a suitable reducing agent (e.g., tris-butyl phosphine, tris-carboxyethyl phosphine, or the like) in the presence of base (e.g., aqueous potassium hydroxide, or the like) in a suitable solvent (e.g., DMIF, or the like) under an inert atmosphere and at ambient temperature and requires 12 to 24 hours. A detailed description for the synthesis of a compound of Formula 5 by the processes decribed above is set forth in the Reference 8, infra.
Additional Processes for Preparing Compounds of Formula I:
A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula I in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0xc2x0 C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80xc2x0 C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like).
Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. 1999.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc. (1981).
In summary, the compounds of Formula I are made by a process which comprises:
(A) reacting a compound of Formula 2:
with a compound of the formula NH2CR1R2CN, in which X1, X2, R1, R2, R3 and R4 are as defined in the Summary of the Invention for Formula I; or
(B) reacting a compound of Formula 3:
with a compound of the formula R4L, in which n is 0 or 2, L is a leaving group and each X1, X2, R1, R2, R3 and R 4 are as defined in the Summary of the Invention for Formula I, and then oxidizing when n is 0; or
(C) reacting a compound of Formula 4:
with a compound of formula NHR13R14 or NHR20R21 to provide a compound of Formula I in which R4 is xe2x80x94C(O)NR13R14 or xe2x80x94C(O)NR2OR21, respectively, wherein n is 0 or 2, R20 and R21 together with the nitrogen atom to which R20 and R21 are attached form hetero(C5-12)cycloalkyl and each X1, X2, R1, R2, R3, R13 and R14 are as defined in the Summary of the Invention for Formula I, and then oxidizing when n is 0; or
(D) reacting a compound of Formula 5:
with a compound of R3X2L in which L is a leaving group and each X1, X2, R1, R2, R3 and R4 are as defined in the Summary of the Invention for Formula I; and
(E) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;
(F) optionally converting a salt form of a compound of Formula I to non-salt form;
(G) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(H) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;
(I) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers;
(J) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(K) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.

Compounds and compositions as cathepsin S inhibitors


Quenching of a coil for a superconducting magnet is detected by placing a temperature sensor proximate the coil of the superconducting magnet and monitoring the temperature sensor for a rise in temperature of the coil of the superconducting magnet. AC and DC field variations of the coil of the superconducting magnet do not substantially adversely affect such temperature monitoring, thus facilitating reliable and accurate detection of such quenching. This accurate and reliable detection of quenching assures that the superconducting magnet can be shut down in a controlled manner, so as to prevent damage thereto when quenching occurs. The method and apparatus of the present invention finds particular use in maglev applications.

Superconducting magnets for generating very powerful magnetic fields are well known. Such superconducting magnets find application in the suspension and propulsion systems of maglev (magnetic levitation) transportation systems, among other things. Such superconducting magnets are utilized in both electrodynamic suspension (EDS) and electromagnetic suspension (EMS) magnetic levitation systems. Superconducting magnets are extremely efficient when utilized in such applications since no energy is lost to resistive or joule heating along the superconducting current path.
However, every superconducting material has an associated critical temperature T.sub.c above which the material ceases to function as a superconductor and becomes a normal conductor within which joule heating occurs. This effect is known in the art as quenching.
As long as the region where such quenching occurs is small enough or receives sufficient cooling, then the heat produced by such normal resistance will dissipate and the material will generally resume a superconducting state.
However, if the region of joule heating is sufficiently large that the system's ability to dissipate heat is overwhelmed, then the area of loss of superconductivity will be maintained and will tend to grow in size. Such propagation of the region of normal conductivity typically results in catastrophic failure of the superconducting magnet, thereby potentially causing damage to the associated apparatus. This effect is particularly undesirable in maglev applications.
For example, if such catastrophic failure of the superconducting magnet were to occur when a maglev vehicle is traveling at a high speed, then undesirable contact of the vehicle with the track may result, potentially resulting in serious damage to the vehicle and/or the track.
When it is known that quenching has occurred, then the superconducting magnet can be shut down in a controlled and safe manner, thereby avoiding such damage. Thus, it is desirable to quickly and accurately identify the loss of superconductivity within the coils of superconducting magnets.
Various attempts at detecting the loss of superconductivity within a superconducting magnet have been tried in the prior art. Although such prior art detection schemes have proven generally suitable for their intended purposes, none address the particular problems of detecting loss of superconductivity within the coils of a superconducting magnet utilized in maglev applications.
The best of such prior art methodologies for detecting quenching of the coils of superconducting magnets measure a resistive voltage signal or phase change within the superconductive coil. Moreover, such methodologies are not feasible in maglev applications due to the extremely wide bandwidth of AC and DC field fluctuations associated therewith. For example, the DC field for providing base excitation in such maglev applications is approximately 1 Hz, which results from compensating for slow changes in the maglev vehicle loading; 10-20 Hz oscillations due to uneven air gap length between the iron poles and the rail; and up to 1.5 kHz oscillations due to air gap permeance variations caused by slots in the iron rail. As those skilled in the art will appreciate, a broad spectrum of field fluctuations makes it difficult to utilize quench detection techniques based upon voltage changes within the coil of the superconducting magnet. It is very difficult to identify those voltage changes which are caused solely by a temperature rise, as opposed to those having a contribution from such field fluctuations.
In view of the foregoing, it is desirable to provide means for reliably and accurately detecting quenching of the coil of a superconducting magnet utilized in maglev applications in a manner which is sufficiently timely to facilitate controlled shut down thereof.

Method and apparatus for detecting quenching of a coil for a superconducting magnet


The intensified visual display relates to visual displays which combine generated images with the view of the environment surrounding a user and transmit such combined visual information to the eye position of the user. A fold mirror (1) frequently utilized in such displays reflects only a fraction of the light striking it and, similarly, transmits only a different fraction of the light reaching it. The fold mirror (1) will reflect a maximum amount of light when such light is S polarized and transmit a maximum amount of light when the light is P polarized. If the image generator produces S polarized light, one quarter-wave plate (3) is used to assure that image light to be reflected by the fold mirror (1) is S polarized while image light to be transmitted through the fold mirror (1) is P polarized. If the image generator produces P polarized light, a first quarter-wave plate (31) and a second quarter-wave plate (32) are employed.

It is often desirable to provide visual information to a living being, usually a person. Frequently one wishes to superimpose such visual information upon the being's view of the real world.
Such a display requires, in a form known as a folded catadioptric display, an image generator; a beam splitter, which receives the image light from the image generator and sends a fraction, designated the reflected fraction, of such image light to a reflective combiner that both allows light from the real world to pass through such combiner and reflects the image light such that both the real-world light and the image light are transmitted to the eye of the user through the beam splitter.
The beam splitter will transmit a fraction, designated the transmitted fraction, of the image light reflected from the collimator-combiner. Of course, only a fraction of the real-world light is also transmitted by the beam splitter; but attention is directed only to the image light since it is image light that tends to be critically low in intensity.
To correct for aberrations and distortions produced by the beam splitter and the combiner, a correction lens is often placed in the optical path between the image generator and the beam splitter.
The light emitted from liquid crystal displays is linearly polarized because liquid crystal displays utilize polarizers to modulate amplitude. The only cathode ray tubes which produce linearly polarized light are those which are colored with an active wave plate, such as the Tektronics Pi cell, all of the light from which is linearly polarized.
When a fold mirror is selected as the beam splitter, it is plastic or glass having, preferably, a dielectric or holographic dichromated gelatin coating. Metal coatings are unacceptable because the fold mirror must first reflect light to the combiner and then transmit light from the combiner to the eye of the user.


An efficient energy accumulation element comprising a compression spring which uses end caps and flexible rope to pre-compress the spring for using in actuators and other devices. The efficient energy accumulation element is independent of external surfaces or end construction of the spring. The accumulation and release of energy happens noiselessly.

Accumulation and release of mechanical energy is a phenomenon deployed in several devices. Springs are one of the commonest elements used for this purpose. Both compression as well as extension springs are made use of.
For using compression springs, pre-compression is the first pre-requisite. Pre-compression is either achieved by surfaces external to the spring or by constraining the spring modularly. The first method viz. pre-compression by external surfaces requires skillful and time consuming assembly.
The second method viz. modular constraining is described, particularly for actuators in German patent DE 9314412, a U.S. Pat. No. 8,181,947 and also in patent Application WO2010/063514. In all these, the minimum length of cartridge is fixed. So even if the spring can be compressed to the solid length, the limitation of cartridge design does not allow. Further, these methods cannot be used efficiently for varying diameter compression springs which can be otherwise compressed up to coil thickness.

Efficient energy accumulation element for actuators and other devices


The present invention relates to a process for preparing haptens for immunoassay of phosphorothioate pesticides, which comprises the steps of reacting O-methyl(ethyl) dichlorothiophosphate with a phenolic compound to obtain O-methyl(ethyl) O-aryl chlorothiophosphate, and reacting the O-(methyl)ethyl O-aryl chlorothiophosphate thus obtained with aminocarboxylic acid to give desired haptens. In accordance with the present invention, haptens having a structure of O-methyl(ethyl) O-aryl N-(carboxyalkyl)phosphoramidothioate or O-methyl(ethyl) O-aryl N-alkyl-N-(carboxyalkyl)phosphoramidothioate can be simply prepared with a high yield by employing two-step processes in a cost-efficient manner.

1. Field of the Invention
The present invention relates to a process for preparing haptens for immunoassay of phosphorothioate pesticides, more specifically, to a process for preparing haptens for immunoassay of organophosphorus phosphorothioate pesticides, by reacting O-methyl(ethyl) dichlorothiophosphate with a phenolic compound to obtain O-methyl(ethyl) O-aryl chlorothiophosphate, and reacting O-methyl(ethyl) O-aryl chlorothiophosphate thus obtained with aminocarboxylic acid.
2. Background of the Invention
Since Schrader's discovery of an organophosphorus compound possessing insecticidal activity in the 1930's, lots of organophosphorus pesticides with high biological activities have been actively developed in the art, in line with the movement of prohibiting the use of organochlorine pesticides. Nowadays, organophosphorus pesticides hold a large majority in current pesticides. Further, it is remarkable that about 100,000 of them have been identified to possess insecticidal activity, and more than 100 of them are commercially available.
Organophosphorus pesticides are classified into phosphate, phosphorothioate, phosphorothiolate, phosphorodithioate, phosphonate, phosphonothioate, phosphonodithioate, phosphorothiolothinate, and phosphoroamidate, depending on their chemical structures around a phosphorus atom (see: Table 1). Among them, phosphorothioate and phosphorodithioate are considered to be the most important pesticides in agriculture and have become the main subject of assaying residual pesticides.
The assay of residual pesticide has been carried out mainly by the aid of GC or HPLC, both of which have innate disadvantages that a time-consuming step of pre-treatment, high-priced machinery and tools, and labors with professional techniques are required and, in the case of GC, it is impossible to assay thermolabile material and in the case of HPLC, it is hard to assay pesticides having no chromophore. To solve these problems, many attempts to employ an immunoassay method for analysing residual pesticides, which was mainly used for assay of bio-components or a clinical diagnosis, began to be made in the 1970's. Immunoassay of residual pesticides is more favorable than the conventional methods in the points that: it is highly sensitive; pre-treatment of samples is not required; and, it costs a less deal since it allows the rapid assay of multiple samples in a simultaneous manner.
Immunoassay is based on the specific binding with a high affinity between antibodies and antigens. Thus, to develop immunoassay, an appropriate antigen should be prepared to generate antibodies against a substance to be assayed. However, low-molecular weight materials, such as pesticides, cannot serve as antigens in themselves and thus, antibodies cannot be generated. Under the circumstances, the need has been raised that haptens having a similar structure to pesticide and a functional groups capable of forming covalent bonds with proteins, should be synthesized for preparing pesticide-specific antigens. Also, synthesis of haptens has been required for preparing an enzyme tracer and a coating antigen, a competitor to be used for a competitive-immunoassay method.
TABLE 1Classification of organophosphorus pesticidesClassStructureExamplePhosphateDichlorvos PhosphorothioateParathion PhosphorothiolateOmethoate PhosphorodithioateMalathion Phosphonatetrichlorfon PhosphonothioateEPN PhosphonodithioateFonfos PhosphorothiolothionateEthoprop PhosphoroamidateDimefox
In general, haptens used for immunoassay of phosphorothioate pesticides have a chemical structure as following:
wherein,                R1 is methyl or ethyl group;        R2 is aryl group;        R3 is hydrogen or alkyl group; and,        R4 is alkylidene group.
Among the above haptens, haptens having the structure in which R3 is hydrogen and R4 is di- or pentamethylene group have been synthesized so far. The haptens having the structure in which R3 is hydrogen and R4 is dimethylene group have been synthesized by a process comprising the steps of: (i) reacting 3-aminopropanoic acid (1) with benzylchloroformate to obtain 3-(benzyloxycarbonylamino)propanoic acid (2); (ii) reacting 3-(benzyloxycarbonylamino)propanoic acid (2) thus obtained with tert-butanol in the presence of dicyclohexalcarbodiimide(DCC) to obtain tert-butyl 3-(benzyloxycarbonylamino)propanoate (3); (iii) eliminating amino protective group from tert-butyl 3-(benzyloxycarbonylamino)propanoate (3) thus obtained by way of hydrogenation using a catalyst to obtain tert-butyl-3-aminopropanoate (4); (iv) reacting tert-butyl 3-aminopropanoate (4) thus obtained with O-methyl dichlorothiophosphate (5) to obtain tert-butyl 3-[chloro(methoxyl)phosphorothioylamino]propanoate (6); (v) reacting tert-butyl 3-[chloro(methoxyl) phosphorothioylamino]propanoate thus obtained with a sodium salt of phenol (7) to obtain tert-butyl 3-[methoxy(aryloxy)phosphorothioylamino]propanoate (8); and, (vi) removing tert-butyl protective group from tert-butyl 3-[methoxy(aryloxy)phosphorothioylamino]propanoate (8) with an aid of trifluoroacetic acid(TFA) to obtain 3-[methoxy(aryloxy)phosphorothioylamino]propanoic acid (9).

It has been known that O-alkyl O-aryl N-(2-carboxyalkyl)phosphoramidothioates synthesized by the above process is can be a haptens highly preferable for generating antibodies for phosphothioate pesticides. However, the said process has revealed shortcomings that it is very complicated, time- and cost-consuming and poorly yielded, since the said method goes through a process comprising total six steps or seven steps provided a step of preparing a sodium salt of phenol is added.
Under the circumstances, there are strong reasons for developing a process for preparing haptens for immunoassay of phosphothioate pesticide in a more efficient manner.

Process for preparing haptens for immunoassay of phosphorothioate pesticides


A TROCAR catheter assembly employs a regulated gas flow between a catheter and the inner wall of a cannula sleeve in which the catheter moves. Annular grooves are formed in the wall of the sleeve and the grooves are connected to a source of gas which produces a pressure differential which causes gas to flow in a manner to control passage of gas to or from a body cavity in which the sleeve is inserted. In one embodiment, one of the annular grooves is connected to a bladder which is inflated to seal the entire opening defined by the inner wall of the sleeve when the catheter is absent.

A trocar catheter is generally employed to penetrate an abdominal wall of a patient and can include a central stylet for the actual penetration and a surrounding tube through which gases and/or fluids may be injected or removed into or exhausted from the abdomen of the patient Frequently, also a protective tube or cannula is used to encompass the entire device to be inserted into the abdomen once penetration has occurred. Additionally various types of catheters and surgical instruments are manipulated through cannulas in endoscopic surgery.
A significant problem with catheters and surgical instruments, which have concentric, axial displaceable components, is to provide a seal between the components yet permit free axial displacement. A common solution to this problem is to provide some form of wiping seal or an inflatable collar which is expanded to fill the gap between such components. U.S. Pat. No. 4,932,959, issued Jun. 12, 1990, discloses an inflatable collar to this end used to release or secure a guide wire within a catheter. Also, U.S. Pat. No. 5,085,636 issued Feb. 4, 1992, discloses a balloon which is operative as an inflation and deflation valve to provide a fluid tight seal around a guide wire. In each instance, air pressure inflates an inflatable member which expands to occupy a space between components of the instrument. Such a mechanism is expensive, occupies considerable space, is not entirely reliable, and more importantly generates mechanical drag restricting free manipulation of the catheter.

Far Hills, Chester Township, Morris County


A service organizer node 30 transmits mediate information indicating contents of a service to be provided to a mediator node 12. A consumer node 20 transmits the data requesting the mediate information of the service organizer node 30 to the mediator node 12. The mediator node 12 transmits the mediate information to the consumer node 20 in response to a request from the consumer node 20. The consumer node 20 transmits the data indicating the service to be provided to the service organizer node 30. The service organizer node 30 transmits the program module etc. for realizing the service to the consumer node 20 to provide the requested service.

1. Field of the Invention
The present invention relates to a multimedia network system and a method of multimedia communication with which provision of information and provision of services can be efficiently and systematically carried out.
2. Description of the Related Art
Multimedia network systems which integrate computer, broadcasting, publishing, and other media are now being researched and developed.
The multimedia network systems which have been proposed up to now have been comprised by a large number of terminals for consumers utilizing so-called multimedia computers etc, and information and service organizers for providing multimedia information such as audio and video data and text data or providing services such as banking or shopping connected via a digital communication network such as an integrated services digital network (ISDN) communication network, cable television (CATV) communication network, and asynchronous transfer mode (ATM) communication network with data being transmitted among these nodes.
In such a multimedia network system, a provider of a service stores content and provides the same to the network, while a consumer connects to the server of the provider to receive the provision of the information. This is the same for both the Internet and other networks such as CATV communication networks. Alternatively, the network provider has the function of providing of a service and realizes a similar service. The contents are expressly stored in the server and then provided to the network.
However, as the configuration of the multimedia network system becomes more complex and sophisticated, the number of the types of the nodes having different functions (network elements) is increased. For example, the present day multimedia network systems do not distinguish between an information provider providing multimedia information and a service organizer providing a service and treat them in the same way. However, in the provision of multimedia information, for example, audio and video information, the characterizing feature is that the amount of data transmitted from the provider side toward the consumer is enormous while the data transmitted from the consumer toward the provider is limited to the data for designating the information etc. so the amount of the data is very small. On the other hand, in the provision of a service, the characterizing feature is that the total amount of the transmitted data is small in comparison with the case of provision of multimedia information, but it is necessary to transmit the data in two directions between the service organizer and the consumer. Is the processing contents of nodes having respective characterizing features and performing different roles in this way are handled without distinguishing between them, the control of the communication among the nodes of the multimedia network system becomes complex and the systematic provision of multimedia information and services becomes difficult.
Further, for example, in the case of a video-on-demand (VOD) system for sending audio and video data (VOD data) in response to a request of a consumer, a VOD data generating apparatus for generating the VOD data and a VOD data transmitting apparatus for transmitting the generated VOD data to the viewers become necessary. In this way, the realization of complex and sophisticated data processing and communication processing sometimes requires that a plurality of nodes which are connected to each other via the multimedia network system be made to operate in a cooperative and coordinated manner (cooperate) to realize a single function. however, the multimedia network systems proposed at present do not function to support cooperative and coordinated operations of a plurality of nodes. For this reason, it is necessary to provide all of the constituent elements required by the data and service organizing systems including a plurality of nodes, and it is difficult for a plurality of data and service organizing systems to share hardware resources.
Further, it is conceivable that there will become required to connect a plurality of multimedia network systems with each other to constitute a further larger scale network system. In such a case, not all of the plurality of multimedia network systems will always be constituted using the same communication networks. For example, it may become necessary to connect a multimedia network system using for example a CATV communication network or ISDN network etc. and a multimedia network system using an ATM communication network with each other.

Multimedia network system and method of communication of same


A zoom lens consists of, in order from the object side, a first lens unit having a positive refractive power, a second lens unit having a negative refractive power, a third lens unit having a positive refractive power, a fourth lens unit having a negative refractive power, and a fifth lens unit having a positive refractive power. The first lens unit and the second lens unit move during zooming from the wide angle end to the telephoto end. The zoom lens satisfies the following conditional expressions (1), (2), and (3):ft/fw>6.0  (1),Fno(T)<3.5  (2),andΣd/ft<0.6  (3).

1. Field of the Invention
The present invention relates to a zoom lens and an image pickup apparatus equipped with the same.
2. Description of the Related Art
In recent times, digital cameras that pick up an image of an object using a solid state image pickup element such as a CCD or CMOS have replaced film cameras and become the mainstream. Furthermore, various categories of digital cameras ranging from popular-priced compact type cameras to function-rich cameras for professionals have been developed.
Users of popular-priced digital cameras wish to enjoy easy shooting in various shooting situations anywhere at any time. For this reason, such users tend to favor small size digital cameras, especially slim digital cameras that can be conveniently carried in a pocket of clothes or a bag. Therefore, a further reduction in the size of the taking lens system is demanded.
On the other hand, there is a trend toward an increase in the number of pixels of image pickup elements, and high optical performance consistent with the increased numbers of pixels of image pick up elements are demanded. Furthermore, while zoom lenses having zoom ratios higher than 10 have been developed to widen the variety of shooting and have become popular, a further increase in the zoom ratio is expected.
Digital cameras capable of performing image processing for extending the sensitivity range or dynamic range to enable shooting in high-contrast situations have also been developed, enabling shooting without limitations in situations.
In shooting in dark places, while contrast can be corrected electronically to some extent, use of a large-diameter lens or a fast lens allows shooting in darker places and will increase the variety of scenes that can be shot.
Since fast, large-diameter lenses enable clear image shooting even with small incident light quantities, they can provide increased choice, such as higher shutter speeds in continuous shooting of a moving object, to photographers. For this reason, large-diameter lenses have been receiving attention in recent times.
As a prior art zoom lens having a relatively high zoom ratio and high speed (or small F-number) throughout the entire focal length range from the wide angle end to the telephoto end, a zoom lens including, in order from the object side, a positive first lens unit, a negative second lens unit, a positive third lens unit, negative fourth lens unit, and a positive fifth lens unit have been known (Japanese Patent Application Laid-Open No. 2008-304706).

Zoom lens and image pickup apparatus equipped with same