EP1399146A1 - Composes et compositions d'inhibiteurs de cathepsine - Google Patents

Composes et compositions d'inhibiteurs de cathepsine

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Publication number
EP1399146A1
EP1399146A1 EP02739721A EP02739721A EP1399146A1 EP 1399146 A1 EP1399146 A1 EP 1399146A1 EP 02739721 A EP02739721 A EP 02739721A EP 02739721 A EP02739721 A EP 02739721A EP 1399146 A1 EP1399146 A1 EP 1399146A1
Authority
EP
European Patent Office
Prior art keywords
phenylmethanesulfonylmethyl
cyclohexylmethyl
alkyl
cyanomethyl
malonamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02739721A
Other languages
German (de)
English (en)
Other versions
EP1399146A4 (fr
Inventor
John W. Patterson
Sheila Zipfel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Axys Pharmaceuticals Inc
Original Assignee
Axys Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Axys Pharmaceuticals Inc filed Critical Axys Pharmaceuticals Inc
Publication of EP1399146A1 publication Critical patent/EP1399146A1/fr
Publication of EP1399146A4 publication Critical patent/EP1399146A4/fr
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/25—Aminoacetonitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • X 1 is -NHCCR ⁇ CR ⁇ X 2 or -NHX 3 ;
  • R 6 is hydrogen or (C 1 . 6 )alkyl
  • R 7 is hydrogen or (C I )alkyl and R 8 is hydroxy or R 7 and R 8 together form oxo
  • R 9 is hydrogen, halo, (C M )alkyl, (C 5 . 10 )aryl(C 0.6 )alkyl or (C 5.10 )heteroaryl(C 0.6 )alkyl;
  • X 3 comprises a heteromonocyclic ring containing 4 to 6 ring member atoms or a fused heterobicyclic ring system containing 8 to 14 ring member atoms and any carbocyclic ketone, iminoketone or thioketone derivative thereof; wherein within R 5 , X 2 or X 3 any alicyclic or aromatic ring system may be substituted further by 1 to 5 radicals independently selected from (C ⁇ alkyl, (C 1 . 6 )alkylidene, cyano, halo, halo-substituted(C 1 .
  • R 12 at each occurrence independently is hydrogen, (Cj alkyl or halo-substitated(C 1 . 6 )alkyl;
  • R 13 is (C ⁇ . 6 )alkyl or halo-substituted(C ] . 6 )alkyl;
  • R 14 is (C 3.10 )cycloalkyl(C 0-6 )alkyl, hetero(C 3 . 10 )cycloalkyl(C 0 . 3 )alkyl, (C 6 . 10 )aryl(C 0 . 6 )alkyl, hetero(C 5 . 10 )aryl(C 0 . 6 )alkyl, (C 9 . 10 )bicycloaryl(C 0 . 6 )alkyl or hetero(C 8 . 10 )bicycloaryl(C 0 . 6 )alkyl;
  • R 1 is hydrogen, halo or (C 1-6 )alkyl and R 2 is selected from a group consisting of hydrogen, cyano, halo, -X 4 NR 12 R 12 , -X 4 NR ,2 C(O)R 12 , -X NR 12 C(O)OR 12 , -X 4 NR 12 C(O)NR 12 R 12 , -X 4 NR 12 C(NR 12 )NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C(O)OR 12 , -X C(O)R !2 , -X OC(O)R 12 , -X C(O)NR 12 R 12 , -X 4 S(O) 2 NR ,2 R 12 , -X 4 NR ,2 S(O) 2 R 12 , -X P(O)(OR 12 )OR 12 , -X 4 OP(O)(OR 12 )OR 12
  • any heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (Ci. 6 )alkyl, (C 1 .
  • R 3 is -C(R 6 )(R 6 )X 5 , wherein R 6 is as defined above and X 5 is selected from -X NR 12 R 12 , -X 4 NR I2 C(O)R 12 , -X 4 NR I2 C(O)OR 12 , -X 4 NR I2 C(O)NR ,2 R 12 ,
  • 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.
  • Alicyclic 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.
  • Aliphatic 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.
  • Alkyl represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g., (C ⁇ 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 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., (C 6 . 10 )aryl(C 0 . 3 )alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
  • Alkylene unless indicated otherwise, means a sfraight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g., (C 1 . 6 )alkylene includes methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), trimethylene
  • amino means the radical -NH 2 .
  • 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.
  • Animal 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).
  • non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like
  • non-mammals e.g., birds, and the like.
  • Aromatic means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp 2 hybridized and the total number of pi electrons is equal to 4n+2.
  • Aryl means a monocyclic or fused bicyclic ring assembly 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.
  • Bicycloaryl 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 at least one of the rings comprising the assembly is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C 9 .
  • bicycloaryl includes cyclohexylphenyl, 1,2-dihydronaphthyl, 2,4-dioxo-l,2,3,4-tefrahydronaphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, and the like).
  • Carbamoyl means the radical -C(O)NH 2 . Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbony ⁇ , benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
  • Carbocyclic ketone derivative means a derivative containing the moiety -C(O)-.
  • Carboxy means the radical -C(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.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycychc ring assembly containing the number of ring carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C 3 0 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, and the like). .
  • Cycloalkylene means a divalent saturated or partially unsaturated, monocyclic ring or bridged polycychc ring assembly containing the number of ring carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof.
  • R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form (C 3.s )cycloalkylene includes, but is not limited to, the following:
  • Disease 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 "side effects" of such therapy.
  • Halo means fluoro, chloro, bromo or iodo.
  • Halo-substituted alkyl as an isolated group or part of a larger group, means
  • alkyl substituted by one or more "halo” atoms, as such terms are defined in this Application.
  • Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C ] . 3 )alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like).
  • R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form hetero(C 3 . 8 )cycloalkyl includes, but is not limited to, the following:
  • R is hydrogen, (C ] . 6 )alkyl, or a protecting group.
  • aryl as used in this Application includes, but is not limited to, 4-ammo-2-hydroxypyrinfrdin-5-yl, benzothiazol-2-yl, lH-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-
  • Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
  • Optionally substituted hetero(C 5 . 10 )aryl as used in this Application to define R 4 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.
  • optionally substituted hetero(C 8 . 10 )bicycloaryl as used in this Application includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, and the like.
  • heterobicycloaryl as used in this Application includes, for example, benzo[l,3]dioxol-5-yl, 3,4-dihydro-2H-[l ,8]naphthyridinyl, 3,4-dihydro-2H-quinolinyl, 2,4-dioxo-3,4-dihydro- 2H-quinazolinyl, l,2,3,4,5,6-hexahydro[2,2']bipyridinylyl, 3-oxo- 2,3-dihydrobenzo[l,4]oxazinyl, 5,6,7,8-tetrahydroquinolinyl, and the like.
  • cycloalkyl includes imidazolidinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like).
  • Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nifrobenzyl, and the like. Both the unprotected and protected derivatives fall within the scope of the invention.
  • “Hydroxy” means the radical -OH. 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.
  • Iminoketone derivative means a derivative containing the moiety -C(NR)-, wherein R is hydrogen or (C ⁇ ancyl.
  • Isomers 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 “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers". A carbon atom bonded to four nonidentical substituents is termed a "chiral center”.
  • a compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture".
  • a compound that has more than one chiral center has 2" " ' 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 "diastereomeric mixture”.
  • 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, fr gold 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 “Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & 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.
  • N-[l-(l-Benzylcarbamoyl- methanoyl)-propyl]-4-mo ⁇ holm-4-yl-4-oxo-2-phenylmethanesulfonylmeth.yl-butyramide is meant to include N-[(S)-l-(l-Benzylcarbamoyl-memanoyl)-propyl]-4-mo ⁇ holin-4-yl-4- oxo-2-phenylmethanesulfonylmethyl-butyramide and N-[(R)- 1 -( 1 -B enzylcarbamoyl- me anoyl)-propyl]-4-mo ⁇ holm-4-yl-4-oxo-2-phenylmemanesulfonylmemyl-butyramide and any mixture, racemic or otherwise, thereof.
  • Ketone derivative means a derivative containing the moiety -C(O)-.
  • X 3 can be 2-acetoxy-azetidin-3-yl.
  • the "carbocyclic ketone derivative” of this example of X 3 would be 2-acetoxy-4-oxo-azetidin-3-yl (see Table 3, C32).
  • ⁇ itro means the radical - ⁇ O 2 .
  • “Optional” or “optionally” 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.
  • the phrase "wherein within R 3 and R 4 any alicyclic or aromatic ring system may be substituted further by 1-5 radicals" means that R 3 and R 4 may or may not be substituted in order to fall within the scope of the invention.
  • Oxoalkyl means alkyl, as defined above, wherein one of the number of carbon atoms indicated is replaced by an oxygen group (-O-), e.g., oxo(C 2 . 6 )alkyl includes methoxymethyl, etc.
  • N-oxide derivatives means derivatives of compounds of Formula I in which nitrogens are in an oxidized state (i.e., O- ⁇ ) and which possess the desired pharmacological activity.
  • Pathology 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.
  • “Pharmaceutically acceptable” 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.
  • “Pharmaceutically acceptable salts” 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, benzenesul
  • 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.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I.
  • a compound of Formula I containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • 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-j9-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • esters of compounds of Formula I containing a carboxy group are for example those described by FJ.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 (mo ⁇ holino-methyl)benzoates, e.g. 3- or 4-(mo ⁇ holinomethyI)- benzoates, and (4-alkylpiperazm-l-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-l-yI)- benzoates.
  • Protected derivatives 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 & Sons, Inc. 1999.
  • “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • Thioketone derivative means a derivative containing the moiety -C(S)-.
  • Treatment or “treating” means any administration of a compound of the present invention and includes:
  • X 1 is - ⁇ HC(R')(R 2 )X 2 or -NHX 3 ;
  • X 3 comprises a heteromonocyclic ring containing 4 to 6 ring member atoms or a fused heterobicyclic
  • R 1 is hydrogen or (C 1.6 )alkyl and R 2 is hydrogen, -X 4 OR 12 , (C 5 . 10 )heteroaryl(C 0 . 6 )alkyl, (C 5.10 )aryl(C 0 .g)alkyl, (C 5-10 )cycloalkyl(C 0 .g)alkyl, (C 5 .
  • R 3 is -CH 2 X 5 , wherein X 5 at each occurrence independently is selected from -X 4 SR 12 , -X 4 C(O)NR 12 R 12 , -X 4 S(O) 2 R 13 , -X 4 C(O)R 13 , -X 4 SR 14 , -X 4 R 12 , -R 14 , -X 4 S(O) 2 R 14 , -X 4 C(O)R 14 , -X 4 C(O)NR 14 R 12 , wherein X 4 , R 12 , R 13 and R 14 are as defined above; R 4 is - NR 6 R 6 , -NR 6 R 14 , -NR 6 R 15 or -NR 6 X 5 C(O)R 14 wherein R 6 , X 5 and R 14 are as described above and R 15 is hydrogen, -(C,.
  • X 1 is -NHC(R')(R 2 )X 2 or -NHX 3 ;
  • X 2 is cyano, -C(O)X 3 , -CF 3 , -CF 2 CF 3 , (E)-2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro-acetyl, 1-benzylcarbamoyl-methanoyl, l-benzyloxy(oxalyl), 2-benzyloxy-acetyl, 2-benzenesulfonylamino-ethanoyl or 2-oxo-2-phenyl-ethanoyl;
  • X 3 is lH-benzoimidazol-2-yl, pyrimidin-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, pyridazin-3-yl, 3-phenyl-[l,2,4
  • R 1 is hydrogen or methyl and R 2 is hydrogen, methoxymethyl, (C 1 . 6 )alkyl, phenethyl, thiophen-2-yl or 5-methyl-furan-2-yl, or (ii) R 1 and R 2 taken together with the carbon atom to which both R 1 and R 2 are attached form cyclopropylene, tetrahydro-pyran-4-ylene or methyl-piperidin-4-ylene.
  • R 3 more preferably is thiophene-2-sulfonylmethyl
  • R 4 more preferably is phenylamino, benzylamino, 4-phenoxy-phenylamino, phenemylamino, 3-phenyl-propylamino, mo ⁇ holin-4-yl, cyclohexylamino, naphthalen-1- ylmethyl-amino, pyridin-3-ylamino, 6-methoxy-pyridin-3-ylamino, diisobutylamino, 4- nitro-benzylamino, 2-thiophen-2-yl-ethylamino, 3-phenoxy-phenylamino, cyanomethyl- amino, (pyridm-3-ylmemyl)-amino, 5,6,7,8-tefrahydro-naphthalen-l-ylamino, 2-pyridin-2- yl-ethylamino, 2,3-dihydro-indol-l-yl, 3,4-dihydro-lH-iso
  • Particular compounds of the invention are selected from the compounds formed by joining the acyl carbon atom (C*) of one of the fragments (Al to A37) shown in
  • Table 1 to the methine carbon atom (*CH*) of one of the fragments (Bl to B88) shown in Table 2, and joining the methine carbon atom (*CH*) of one of the fragments (Bl to B88) shown in Table 2 to the acyl carbon atom (C*) of one of the fragments (Cl to C36) depicted in Table 3.
  • the following tables are intended to provide guidance to better carry out the present invention. However, they do not limit the scope of the invention. People of ordinary skill may selectively make particular compounds by joining of one of the fragments shown in Table 1 to any one of the fragments shown in Table 2, and then joining the fragments shown in Table 2 to the any of one of the fragments Table 3. TABLE 1
  • the compound denoted as A2-B45-C35 is the product of the combination of group A2 in Table 1 and B45 in Table 2 and C35 in Table 3, namely N-[l-(l-benzooxazol-2-yl-methanoyl -3-phenyl-propyl]-N-benzyl-2- cvclohexylmethyl-malonamide:
  • 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.
  • 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 6-9, infra.
  • 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 one or more therapeutic agents.
  • 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.
  • therapeutically effective amounts of a compound of Formula I may range from about 1 micrograms per kilogram body weight ( ⁇ g/kg) per day to about 1 milligram per kilogram body weight (mg/kg) per day, typically from about 10 ⁇ g/kg/day to about 0.1 mg/kg/day.
  • a therapeutically effective amoxmt for a 80 kg human patient may range from about 100 ⁇ g/day to about 100 mg/day, typically from about 1 ⁇ g/day to about 10 mg/day.
  • compositions can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., fransdermal, infranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous).
  • routes e.g., oral, systemic (e.g., fransdermal, infranasal 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.
  • 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.
  • 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 l%w, of active ingredient with the remainder being the excipient or excipients.
  • 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 10.
  • Compounds of Formula I can be prepared by condensing an acid of Formula 2 with a compound of formula
  • the condensation reaction can be effected with an appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlori.de (EDCI), 0-benzotriazol-l-yl-N,NN , ,N-tetramethyluronium hexafluorophosphate (HBTU), 1,3-dicyclohexyl-carbodiimide (DCC), or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), l-hydroxy-7- azabenzotriazole (HOBt), l-hydroxy-7- azabenzotriazole (HOBt), l-hydroxy-7-
  • - Compounds of Formula I can be prepared by condensing an acid of Formula 2 with a compound of formula NH 2 X 3 .
  • the condensation reaction can be effected with an appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDO), O-benzotriazol-l-yl-N,N,N,N-teframe ylmo um hexafluorophosphate (HBTU), 1,3-dicyclohexyl-carbodiimide (DCC), or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), l-hydroxy-7- azabenzotriazole (HOBt), l-hydroxy-7- azabenzotriazole (HOB
  • 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.
  • 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.
  • 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.
  • a compound of Fonnula 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 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).
  • N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art.
  • 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 0°C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • 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 80°C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, or the like
  • 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 ⁇ /.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate,/r ⁇ r ⁇ -mtrophenyl carbonate, or the like).
  • a suitable carbamylating agent e.g., l,l-acyloxyalkylcarbonochloridate,/r ⁇ r ⁇ -mtrophenyl 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.
  • Compoxmds 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 compoxmds 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 & Sons, Inc. (1981).
  • the compounds of Formula I are made by a process which comprises: (A) reacting a compound of Formula 2:
  • ethyl 2-cyclohexylmalonate (8.52 g, 37 mmol) in ethylacetate (80 ml) was cooled to 0° C and treated with dimethylformade (50 ⁇ L) and then oxalylchloride (3.93 ml, 45 mmol). The reaction temperature was raised to room temperature and after 2 hours the solvents were removed under reduced pressure to give ethyl 2-cyclohexylmalonyl chloride.
  • the malonylchloride above was diluted to 28 ml volume with ethylacetate and 2 ml of that solution was added to a solution of phenethylamine (0.376 ml, 3 mmol) and N- methylmo ⁇ holine (0.40 g, 4 mmol) in ethylacetate (4 ml) at -20°c. After 15 minutes the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with ethylacetate (5 ml) and ice water (5 ml). The organic layer was separated and washed with cold 0.05 ⁇ HCl, then aqueous ⁇ aHCO 3 , then brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by radial chromatography to give ethyl 2-cyclohexylmethyl-N-phenethyl malonamate (0.366 g, 1.10 mmol, 42% yield).
  • Ethyl 2-cyclohexylmethylmalonyl chloride prepared as in Reference 3 (0.307 g, 1.25 mmol), was condensed with 4-aminomethyl pyridine using the method of Reference 3 to give ethyl 2-cyclohexylmethyl-4-pyrin-4-ylmethylmalonamate (0.237 g, 0.74 mmol, 58% yield).
  • a solution comprised of 2-Cyclohexylmethyl-N-phenyl-malonamic acid (350 mg,
  • Cathepsin S Assay Solutions of test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM). Human cathepsin S (0.158 pMoles in 25 ⁇ L of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient temperature.
  • DMSO dimethyl sulfoxide
  • test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: N,N- bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM).
  • BES N,N- bis(2-hydroxyethyl)-2-aminoethanesulfonic acid
  • PES polyoxyethylenesorbitan monolaurate
  • DTT dithiothreitol
  • test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).
  • assay buffer 40 ⁇ L, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).
  • Human cathepsin K (0.0906 pMoles in 25 ⁇ L of assay buffer) was added to the dilutions.
  • the assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient temperature.
  • Z-Phe-Arg-AMC (4 nMoles in 25 ⁇ L of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at ( ⁇ 460 nm) for 5 minutes. Apparent inhibition constants (Kj) were calculated from the enzyme progress curves using standard mathematical models.
  • test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).
  • assay buffer 40 ⁇ L, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).
  • Human cathepsin L (0.05 pMoles in 25 ⁇ L of assay buffer) was added to the dilutions.
  • the assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient temperature.

Abstract

L'invention concerne des inhibiteurs sélectifs de cathepsine S, des sels et des N-oxydes de ces inhibiteurs, acceptables sur le plan pharmaceutique, leurs utilisations en tant qu'agents thérapeutiques et des procédés de leur fabrication.
EP02739721A 2001-06-04 2002-06-04 Composes et compositions d'inhibiteurs de cathepsine Withdrawn EP1399146A4 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse
WO2001019796A1 (fr) * 1999-09-16 2001-03-22 Axys Pharmaceuticals, Inc. Composes et compositions pharmaceutiques utilises comme inhibiteurs de la cathepsine s

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WO1997048688A1 (fr) * 1996-06-21 1997-12-24 Pharmacia & Upjohn Company Inhibiteurs thiadiazole amide de la metalloprotease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse
WO2001019796A1 (fr) * 1999-09-16 2001-03-22 Axys Pharmaceuticals, Inc. Composes et compositions pharmaceutiques utilises comme inhibiteurs de la cathepsine s

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Title
See also references of WO02098406A1 *

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CA2449021A1 (fr) 2002-12-12
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EP1399146A4 (fr) 2006-01-18
SG143979A1 (en) 2008-07-29
PL368825A1 (en) 2005-04-04
MXPA03011207A (es) 2004-02-26
CO5540292A2 (es) 2005-07-29
ZA200309371B (en) 2005-05-27
JP2005500275A (ja) 2005-01-06
KR20040028769A (ko) 2004-04-03
EA007334B1 (ru) 2006-08-25
NZ529903A (en) 2005-09-30
WO2002098406A1 (fr) 2002-12-12

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