EP0817778A1 - Reversible protease inhibitoren - Google Patents

Reversible protease inhibitoren

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Publication number
EP0817778A1
EP0817778A1 EP96910499A EP96910499A EP0817778A1 EP 0817778 A1 EP0817778 A1 EP 0817778A1 EP 96910499 A EP96910499 A EP 96910499A EP 96910499 A EP96910499 A EP 96910499A EP 0817778 A1 EP0817778 A1 EP 0817778A1
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EP
European Patent Office
Prior art keywords
optionally substituted
alkyl
hydroxy
hydrogen
group
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.)
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Application number
EP96910499A
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English (en)
French (fr)
Inventor
James T. Palmer
David Rasnick
Jeffrey L. Klaus
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
Arris Pharmaceutical Corp
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Publication date
Application filed by Arris Pharmaceutical Corp filed Critical Arris Pharmaceutical Corp
Publication of EP0817778A1 publication Critical patent/EP0817778A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • 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
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/6533—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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

  • the invention relates to novel reversible protease inhibitors
  • the inhibitors are selective for cysteine proteases
  • cysteine proteases contain a cysteine residue at the active site responsible for proteolysis Since cysteine proteases have been implicated in a number of diseases, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomeruloneph ⁇ tis, malaria, and other parasite-borne infections, methods for selectively and irreversibly inactivating them provide opportunities for new drug candidates See, for example, Esser, R E et al , Arthritis & Rheumatism (1994) 37, 236, Meyers, M H M et al , Agents Actions (1993), 39 (Special Conference Issue), C219, Machleidt, W et al, Fibnnolysis (1992), 6 Suppl 4, 125, Sloane, B F et al , Biomed Biochim Acta (1991), 50, 549, Duffy, M J , Clin Exp Metastasis (1992), 10, 145, Rosenthal, P J , Wollish, W S , Palmer, J T
  • Aldehydes have been transformed into ⁇ , ⁇ -unsaturated esters and sulfones by means of the Wadsworth-Emmons-Horner modification of the Wittig reaction, shown below (Wadsworth, W S and Emmons, W D (J Am Chem Soc (1961), 83, 1733)
  • R alkyl, aryl, etc
  • EWG COOEt, SO j Me. etc
  • cysteine protease inhibitors include epoxysuccinyl peptides, including E-64 and its analogs (Hanada, K e a/., Agr ⁇ c Biol Chem (1978), 42, 523, Sumiya, S ef a/., Chem Pharm.
  • An aspect of this invention is a protease inhibitor comprising a targeting group linked through a two carbon atom chain to an electron withdrawing group, wherein the dissociation constant for inhibition of the protease with said inhibitor (K,) is no greater than about 100 ⁇ M
  • An additional aspect of this invention is a protease inhibitor comprising a targeting group linked either directly or through a linker selected from the group consisting of an intermediate carbon atom or a two carbon atom chain to a sulfone group group, wherein the dissociation constant for inhibition of the protease with said inhibitor (K,) is no greater than about 100 ⁇ M
  • a further aspect of this invention is a compound, preferably a protease inhibitor, of Formula I
  • n 0 to 13
  • A-B represents a linkage selected from -C(0)NR 3 -, -CH 2 NR 3 -, -C(0)CH 2 - and -NR 3 C(0)-, wherein R J is hydrogen or as defined below,
  • X represents a bond, methylene or the linkage -CH 2 CH(R 4 )-, wherein R 4 is hydrogen, alkyl or arylalkyl
  • Y is -CH(R 5 )- or -NR 5 -, wherein R 5 is hydrogen or as defined below,
  • Z is -(CH 2 ) 2 -, -C(R 6 )(R 7 )- or -N(R 7 )-, wherein R 6 is hydrogen or methyl and R 7 is as defined below,
  • Z 1 is -(CH 2 ) 2 -, -C(R 6 )(R 8 )- or -N(R 8 )-, wherein R 6 is hydrogen or methyl and R 8 is as defined below,
  • R 1 is hydrogen, alkyloxycarbonylalkanoyl, alkyloxycarbonyl, alkanoyl (optionally substituted with a radical selected from carboxy, alkyloxycarbonyl and heterocycloalkylalkanoylamino), cycloalkylcarbonyl, heterocycloalkylcarbonyl (optionally substituted with a radical selected from hydroxy, alkyl, alkanoyl, alkyloxycarbonyl, arylalkyloxycarbonyl and heterocycloalkylcarbonyl), arylalkyloxycarbonyl, carbamoyi, aikylcarbamoyl, dialkylcarbamoyi, arylcarbamoyi, arylaikylcarbamoyl, arylalkanoyl, aroyl, alkylsulfonyl, dialkylaminosulfonyl, arylsulfonyl or heteroarylsulfony
  • R 7 and R ⁇ are independently hydrogen, alkyl (optionally substituted with a radical selected from hydroxy, ammo, alkylamino, dialkylamino, u ⁇ edo, mercapto, alkylthio, carboxy, carbamoyi, aikylcarbamoyl, dialkylcarbamoyi, alkylsulfonyl and guanidino, or a protected derivative thereof), cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, a group selected from aryl and arylalkyl (which group is optionally substituted at its aryl ring with one to three radicals selected from hydroxy, ammo, guanidino, halo, optionally halo-substituted alkyl, alkyloxy and aryl, or a protected derivative thereof) or together with an adjacent R 3 or R 5 forms a divalent radical selected from (C 3 ⁇ )m
  • R 2 is hydrogen, alkyl (optionally substituted with one or more radicals selected from ammo, guanidino, halo, hydroxy, alkyloxy, nitro, alkylsulfonyl and arylsulfonyl, or a protected derivative thereof), cycloalkyl, cycloalkylalkyl or a group selected from aryl and arylalkyl (which group is optionally substituted at its aryl ring with one to two radicals selected from ammo, halo, hydroxy, optionally halo-substituted alkyl, alkyloxy, nitro, alkylsulfonyl and arylsulfonyl, or a protected derivative thereof), and the pharmaceutically acceptable salts, individual isomers and mixtures of isomers thereof, preferably wherein the dissociation constant for inhibition of the protease with said inhibitor (K,) is no greater than about 100 ⁇ M
  • An additional aspect of this invention is a compound, preferably a protease inhibitor, of Formula II
  • R 9 is cyano, -C(0)OR 1 °, -P(O)(OR 10 ) 2 , -S(O)(NR 10 )R 10 , C(0)R 11 , -S(0)R 11 , -C(0)NR 12 R 13 , -S(0) 2 NR 12 R 13 , -C(0)NHR 14 or -S(0) 2 NHR 14 , wherein each R 10 is independently hydrogen, alkyl (optionally substituted with one or more radicals selected from ammo, halo, hydroxy, alkyloxy, nitro, alkylsulfonyl and arylsulfonyl, or a protected derivative thereof), cycloalkyl, cycloalkylalkyl or a group selected from aryl and arylalkyl (which group is optionally substituted at its aryl ring with one to two radicals selected from ammo, halo, hydroxy, optionally halo-substituted alkyl, alkyl
  • n, A, B, Y, Z, R 1 and R 10 are as defined above, and the pharmaceutically acceptable salts; individual isomers and mixtures of isomers thereof, preferably wherein the dissociation constant for inhibition of the protease with said inhibitor (K,) is no greater than about 100 ⁇ M.
  • a further aspect of this invention is a compound, preferably a protease inhibitor, of Formula III:
  • R 5 is hydrogen, methyl, fluoro or a group selected from Formulae (a) and (b) as defined above, and R 16 is a group selected from phenyl or (C 5 ⁇ )heteroaryl (which group is optionally substituted with at least one radical selected from aikylcarbamoyl, dialkylcarbamoyi, alkyloxycarbonyl, alkylsulfmamoyl, dialkylsulfinamoyl, alkylsulfonyl, carboxy, nitro, sulfinamoyl, sulfo, carbamoyi, phosphono, alkyloxyphosphinyl, dialkyloxyphosphinyl, alkanoyl, cyano, alkylsulfinyl, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkyloxysulfonyl, aryl, hetero
  • An additional aspect of this invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a cysteine protease inhibitor of the invention, or of an individual isomer, a mixture of isomers, or the pharmaceutically acceptable salt or salts thereof, in combination with one or more pharmaceutically acceptable excipients.
  • a further aspect of this invention is a method for treating a condition capable of amelioration by inhibition of a cysteine protease in an animal in need thereof, which method comprises administering to such animal a therapeutically effective amount of a cysteine protease inhibitor of the invention, or of an individual isomer, mixture of isomer, or the pharmaceutically acceptable salt or salts thereof.
  • Another aspect of this invention is a method for detecting a cysteine protease in a sample, which method comprises
  • An aspect of this invention are the processes for preparing the cysteine protease inhibitors of this invention
  • Figure 1 depicts Scheme I, the synthesis of Formula I compounds when X is a bond
  • the synthetic steps are as follows a) HC0 2 H, H 2 0, b) HBr/acetic acid, c) 4-methylmorphol ⁇ ne, isobutyl chloroformate, Mu-ROH, and d) chromatographic purification
  • the groups are as defined herein
  • Figure 2 depicts Scheme 2, the synthesis of Formula I compounds when X is a methylene group
  • the synthetic steps are as follows a) 4-methylmorphol ⁇ ne, isobutyl chloroformate, followed by NaBH 4 reduction in water/THF, b) CH 3 S0 2 CI, t ⁇ ethylamine, CH 2 CI 2 , c) R,SH, NaH, CH 3 OH, THF, heat, d) 4-chloroperbenzo ⁇ c acid, CH 2 CI 2 , e) HCI/dioxane or p-CH 3 C 6 H 4 S0 3 H/ether, and f) Mu-ROH, 4- met ylmorpholine, isobutyl chloroformate
  • Figure 3 depicts Scheme 3, the synthesis of Formula I compounds when X is a methylene group
  • the synthetic steps are as follows a) (CH 3 ) 3 CH 2 CH 2 SH, NaH, MeOH, THF, heat, b) 4-chloroperbenzo ⁇ c acid, c) (n-C 4 H 9 ) 4 N , THF, followed by BrCH 2 CI, heat, d) HCI/dioxane or 4-CH 3 C 6 H 4 S0 3 H/ether, and, e) 4-methylmorphol ⁇ ne, isobutyl chloroformate, Mu-PheOH
  • Figure 4 depicts Scheme 4, the synthesis of Formula II compounds
  • the synthetic steps are as follows a) Cl H 2 N * (CH 3 )OCH 3 , dicyclohexylcarboiimide, Et 3 N/CH 2 CI 2 , b) LiAIH ⁇ F, c) NaH/THF, d) Hcl/d ⁇ oxane/CH 2 CI 2 , e) 4-methylmorphol ⁇ ne, isobutyl chloroformate/THF, and f) H 2 , 5% Pd/C
  • Figure 5 depicts Scheme 5, the synthesis of Formula I compounds when X is an ethylene
  • Figure 6 depicts the synthesis of compounds of Formula II in which R 9 is -COOH
  • Figure 7 depicts the synthesis of compounds of Formula II in which R 9 is -P(O)(R 10 ) 2 .
  • the synthetic scheme is as follows: a) NaH THF; b) anhydrous p-CH 3 C 6 H 4 S0 3 H/ether; c) 4-methylmorpholine, isobutyl chloroformate/THF, and; d) H 2 , Pd/C.
  • Figure 8 depicts the synthesis of compounds of Formula II in which R 9 is -C(0)NHR 14 .
  • the synthetic scheme is as follows: a) NaOH/EtOH, followed by Hcl/H 2 0; b) benzylamine, dicyclohexylcarbodiimide, CH 2 CI 2 ; c) NaH/THF, diethyl benzylamidomethylenephosphonate; d) HCI/dioxane; e) 4-methylmorpholine, isobutyl chloroformate, THF; f) H 2 , Pd/C, and as an alternative preparation from carboxylates as synthesized via Scheme 6, above; and g) aniline, dicyclohexylcarbodiimide, CH 2 CI 2 .
  • Figure 9 depicts the general synthesis of compounds of Formula II.
  • Figure 10 depicts the synthesis of compounds of Formula III.
  • the synthetic steps are as follows: a) CH 3 CN or other suitable solvent, reflux; b) H 2 0, NaOH, followed by extraction into organic medium; c) phosphorane, THF (Wittig reaction); d) p-CH 3 C 6 H 4 S0 3 H, ether; e) Mu-PheOH, 4-methylmorpholine, isobutyl chloroformate, THF; and f) H 2 , Pd/C.
  • Alkyl as in alkyl, alkyloxy, alkylthio, alkylsulfonyl, aikylcarbamoyl, dialkylcarbamoyi, heteroarylalkyl, arylalkyl, and the like, means a straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 10 carbon atoms or the number of carbon atoms indicated (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, ferf-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, etc.).
  • Alkyloxyphosphinyl and “dialkyloxyphosphinyl” mean the radicals -P(0)(OH)OR and -P(0)(OR) 2 , respectively, wherein R is alkyl as defined above.
  • Alkanoyl as in alkanoyl, alkanoyloxy, heterocycloalkylalkanoylamino, and the like, means the radical -C(0)R, wherein R is alkyl as defined above, having overall from 1 to 11 carbon atoms or the number of carbon atoms indicated (e.g., (C, ⁇ )alkanoyl includes the radicals formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.).
  • Aryl means an aromatic monocyclic or polycyclic hydrocarbon radical containing 6 to 14 carbon O 96/30353 US96/03844
  • aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, 1 ,2,3,4-tetrahydro-5-naphthyl, 1 -oxo-1 , 2-d ⁇ hydro-5-naphthyl, 1-th ⁇ oxo-1 ,2-d ⁇ hydro-5-naphthyl, etc )
  • Aroyl means the radical -C(0)Ar, wherein Ar is aryl as defined above, having overall from 7 to 15 carbon atoms or the number of carbon atoms indicated (e g , (C 7 n)aroyl includes benzoyi, naphthoyi, etc )
  • Cycloalkyl as in cycloalkyl and cycloalkylalkyl, means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon radical containing 3 to 20 carbon atoms or the number of carbon atoms indicated, wherein the carbon atom with the free valence is a member of a non-aromatic ring and any carbocyclic ketone and thioketone derivative thereof (e g , the term cycloalkyl is meant to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, b ⁇ cyclo[2 2 2]octyl, 1 ,2,3,4-tetrahydro- 1 -naphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 9-fluorenyl, etc )
  • Halo means fluoro, chloro, bromo or lodo
  • Heterocycloalkyl as in heterocycloalkyl, heterocycloalkylalkanoylamino, heterocycloalkylcarbonyl, heterocycloalkylcarbonyl, and the like, means cycloalkyl as defined above wherein 1 to 5 of the indicated carbon atoms is replaced by a heteroatom chosen from N, O, S, P or As, wherein the atom with the free valence is a member of a non-aromatic ring, and any heterocychc ketone, thioketone, sulfone or sulfoxide derivative thereof, (e g , the term heterocycloalkyl is meant to include pipe ⁇ dyl, pyrrolidinyl, pyrrolinyl, imidazo dinyl, indolmyl, quinuclidinyl, morpholinyl, piperazinyl, ⁇ /-methylp ⁇ peraz ⁇ nyl, piperadinyl, 4,4-d ⁇ oxo
  • Heteroaryl means an aromatic monocyclic or polycyclic hydrocarbon radical containing overall from 5 to 14 atoms or the number of atoms indicated, wherein 1 to 5 of the indicated carbon atoms are replaced by a heteroatom chosen from N, O, S, P or As, wherein the atom with the free valence is a member of an aromatic ring, and any heterocychc ketone and thioketone derivative thereof (e g , the term heteroaryl is meant to include thienyl, furyl, pyrrolyl, py ⁇ midmyl, isoxazolyl, oxaxolyl, dolyl, benzo[b]th ⁇ enyl, isobenzofuranyl, punnyl, isoqumolyl, pterdinyl, py ⁇ midinyl, imidazolyl, py ⁇ dyl, pyrazolyl, pyrazinyl, 4-oxo-1 ,2-d ⁇ hydro-1 -
  • R ⁇ -Z-A- in which Y is -N(R 5 ), Z is -CH(R 7 )-, A is carbonyl and R 7 together with R 5 forms 1 ,2-diphenylenedimethylene means a group of following formula:
  • Substituted derivatives of the 1 ,2-phenylenedimethylene divalent radical may contain a hydroxy group on any carbon within the ring system or an oxo group on either of the unsaturated ring carbon atoms.
  • Phosphono means the radical -P(0)(OH) 2 .
  • Methylene as in “(C 3J) )methylene”and “(C 3 . 7 )methylene” mean a straight, saturated divalent radical having the number of carbon atoms indicated; "(C 3 ⁇ )methylene” includes trimethylene (-(CH 2 ) 3 -) and tetramethylene (-(CH 2 ) 4 -)
  • a preferred embodiment herein utilizes a proline residue as an A-B-Z group, wherein A-B represents CH 2 -NR 3 and R 3 together with either R 7 or R ⁇ form a C3 methylene.
  • the group R 1 -Y-Z-A- in which Y is -(NR 5 )-, Z is -CH(R 7 )-, A is carbonyl and R 7 together with R 5 forms trimethylene means a group of following formula:
  • Substituted derivatives of the trimethylene and tetramethylene divalent radicals may contain a hydroxy group, or a protected derivative thereof, or an oxo group on any of the ring carbon atoms. Suitable hydroxy protective groups are defined below.
  • Oxa(C 3 . 7 )methylene and "aza(C 3 . 7 )methylene” mean methylene as defined above wherein one of the indicated carbon atoms is replaced by an oxygen or nitrogen atom, respectively.
  • oxa(C 5 )methylene includes 3-oxapentamethylene (-CH 2 CH 2 OCH 2 CH 2 -) and 2-oxapentamethylene (-CH 2 OCH 2 CH 2 CH 2 -).
  • -CfOJNR ⁇ R 22 means the radical 4-morpholinylcarbonyl when R 21 and R 22 together form 3-oxapentamethylene and the radical 1-piperazinylcarbanoyl when R 21 and R 22 together form 3-azapentamethylene.
  • Adjacent as use in the phrase “R 7 together with an adjacent R 3 ", means that the atoms to which the R 7 and R 3 groups are respectively attached are in turn attached to one another
  • Animal includes humans, non-human mammals (e g , dogs, cats rabbits, cattle, horses, sheep, goats, swine, deer, etc ) and non-mammals (e g , birds, etc )
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i e , the "side effects" of such therapy
  • EWG Electrode withdrawing group
  • Preferred electron withdrawing groups are those which would similarly stabli ze ylides of the general formula (RO) 2 P(0)C(R)EWG Suitable electron withdrawing
  • Leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i e , an atom or group displaceable under alkylatmg conditions, and includes halo and alkane- or arenesulfonyloxy, sucha mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy, and alkaesulfonylamino, alkanecarbonylamino, aminosulfonylamino, aminocarbonylamino and the like.
  • Isomerism is the phenomenon wherein compounds have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of theri atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “steroisomers”. 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 ⁇ 1 enantiomeric pairs, where n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as ether an individual diasteromer or as a mixture of diastereomers, termed a "diastereomeric mixture”.
  • Compounds of Formulae I, II and III can exist as individual steroisomers or mixtures of stereoisomers.
  • compounds of Formulae I, II and III contain a chiral center at the carbon to which the substituent R ⁇ is attached.
  • compounds of Formulae I, II and III in which Z is -C(R 6 )(R 7 ) contain a chiral center at the carbon to which the R 7 substituent is attached.
  • compounds of Formulae I, II and III in which n is 0 and Z is -C(R 6 )(R 7 ) will have two chiral centers and can exist as four individual stereoisomers or any mixture thereof.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog and then the absolute descriptor R is assigned if the three highest ranked substituents are arranged in space (with the fourth lowest ranked substituent directed away from the observer) from high to low priority in a clockwise sequence and the absolute descriptor S is assigned for a counterclockwise arrangement.
  • the absolute descriptor R or S is cited in parenthesis followed by a hyphen and the chemical name of the compound.
  • the absolute descriptor R or S is cited immediately after the appropriate locant.
  • Acyl radicals derived from naturally occurring amino acids are referred to as their amino acid radicals preceded by the descriptor L (e.g., L-phenylalanine).
  • the nonnatural enantiomers of amino acid acyl radicals are preceded by the descriptor D.
  • the amino acid side chains are the (S) or L-form, due to the stereospecificity of enzymes, although the D-forms may be used in some cases.
  • R 1 is 4-morphol ⁇ nylcarbonyl
  • R 8 is 2-phenylethyl and lies on the same side of the reference plane as the R 7 substituent
  • R 7 is benzyl
  • R 19 is phenylsulfonyl
  • R 8 is 2-phenylethyl and lies on the same side of the reference plane as the R 7 substituent, R 7 is benzyl and R 19 is ethoxycarbonyl
  • compositions of the invention are pure diasteromers
  • compositions contain mixtures of diasteromers
  • Preferred embodiments have greater than about 70% of a single disasteromer, with at least about 90% being particularly preferred
  • Protective group has the meaning conventially associated with it in synthetic organic chemistry, i e , a group which blocks a reactive site in a compound See for example Greene et al , Protective Groups in Organic Synthesis, 2nd Ed , John Wiley & Sons, 1991 , hereby incorporated by reference
  • hydroxy protective groups include heterocycloalkyl-carbonyl such as 4-morphol ⁇ nylcarbonyl and the like, aroyl such as benzoyi and arylalkyl such as benzyl and the like
  • am o protective groups include aryloxycarbonyl such as benzyloxycarbonyl and the like, aroyl such as benzoyi and the like and oxycarbonyl such as ethoxycarbonyl and 9-fluorenylmethoxycarbonyl and the like
  • guanidino protective groups include sulfonyl such as 2,3,5-t ⁇ methyl-4-methoxyphenyl-sulfon
  • cysteine protease-associated disorders pathological conditions associated with cysteine proteases
  • the condition is associated wtih increased levels of cysteine proteases, for example, arthritis, muscular distrophy, inflammation, tumor invasion, and glomerulonephritis are all associated with increased levels of cysteine proteases
  • the condition is associated with the appearance of an extracellular cysteine protease activity that is not present in normal tissue
  • a cysteine protease is associated with the ability of a pathogen, such as a virus, to infect or replicate in the host organism
  • cysteine protease associated disorders include, but are not limited to, arthritis, muscular distrophy, inflammation, tumor invasion, glomeruloneph ⁇ tits, malaria, Alzheimer's disease, cancer metastasis, trauma, inflammation, gingivitis, leishmaniasis, fila ⁇ asis, and other bacterial and parasite-borne infections
  • disorders associated with interleukin 1 ⁇ converting enzyme (ICE) are included
  • “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 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, sulfunc 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, succtnic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzo ⁇ c acid, cmnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethaned ⁇ sulfon ⁇ c acid, 2-hydroxyethanesulfon ⁇ c acid, benzene
  • 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
  • Acceptabale inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydoxide
  • Acceptable organic bases include ethanolamine, diethanolamine, t ⁇ ethanolamine, tromethamine, ⁇ /-methylglucam ⁇ ne and the like
  • “Therapeutically effective amount” means that amount which when administered to an animal for treating a disease includes
  • the present invention relates to novel cysteine protease inhibitors Without being bound by theory, it is believed that the inhibitors bind to cysteine proteases based on the following scheme
  • the enzyme is thus reversibly inhibited by means of interactions between the R, Y and Z moieties of the inhibitor and the surface of the binding sites of the enzyme, and by means of hydrogen bonding interactions between the sulfone and active site ammo acid side chains
  • the inhibitors of the present invention inhibit cysteine proteases and do not inhibit serine, aspartyl, and zinc proteases
  • the protease inhibitors of the present invention may have activity against other types of proteases, such as serine, aspartyl or other metalloproteases, but to a lesser extent
  • the electron withdrawing properties of the sulfone group of Formula I polarize the electrons between the sulfone group and the carbon to which it is attached, thus permitting hydrogen bonding between itself and active site residues of a cysteine protease, to allow tight binding between the inhibitor and the cysteine protease, as is generally described below It is to be understood that there is presumably additional electron withdrawing or electron polarization occurring between the sulfur atom and the oxygen atoms, which allows the oxygen atoms to participate in hydrogen bonding with active site residues of the protease and thus contributing even further to the inhibition of the enzyme
  • cysteine protease inhibitor an inhibitor which inhibits cysteine proteases
  • cysteine protease inhibitors are specific to cysteine proteases, that is, they do not inhibit other types of protease such as serine, aspartyl, or other metalloproteases
  • cysteine protease inhibitors of the invention may inhibit other types of proteases as well
  • reversible herein is meant that the inhibitor binds non-covalently to the enzyme, and is to be distinguished from irreversible inhibition See Walsh, Enzymatic Reaction Mechanisms, Freeman & Co , N Y , 1979 "Reversible” in this context is a term understood by those skilled in the art
  • the reversible cysteine protease inhibitors are competitive inhibitors, that is, they compete with substrate in binding reversibly to the enzyme, with the binding of inhibitor and substrate being mutually exclusive
  • the stoichiometry of inhibition is 1 1 , that is, a single inhibitor molecule is sufficient to inhibit a single enzyme molecule
  • cysteine protease inhibitors herein are designed to bind reversibly to cysteine proteases This binding is accomplished by using peptide-based or peptidomimetic structures as targeting groups that mimic naturally occurring substrates and/or inhibitors "Peptidomimetic", for the purposes of this invention, means ammo acid or peptide-hke in structure but wherein one or more of the peptide linkages (i e , -C(O)NR-) is substituted by an isoste ⁇ c form, i e -CH 2 NR-, -C(0)CH 2 - or -NRC(O)- and/or wherein non-naturally occurring ammo acid substituents are present
  • Targeting group for the purposes of this application, means a peptide or peptidomimetic residue of the cysteine protease inhibitor that allows the binding of the inhibitor to a cysteine protease
  • the targeting group of a cysteine protease inhibitor comprises at least two ammo acid side chains or side chain analogs, linked via a peptide bond or isostere
  • the targeting group may comprise up to about 15 am o acids or analogs, although inhibitors are generally from about 1 to 7 ammo acids or analogs, since smaller inhibitors are usually desired in therapeutic applications
  • n is preferably from 0 to 13, with from 0 to 5 being preferred and from 0 to 3 being particularly preferred
  • the targeting group can be represented by a naturally or non-naturally occurring peptide residue of the following formula
  • R 8 and R 7 components represent naturally or non-naturally occurring am o acid analogs or substituents as is more fully described below
  • the targeting group of the inhibitor may also contain additional functional groups, as depicted by R 1 and described herein
  • ammo acid substituents of the targeting group interact with the surface binding sites of the protease to promote binding It is also believed that the ammo acid substituent proximal to the electron withdrawing group (e g , R 8 of the above formula) will occupy the S, position of the substrate binding site and therefore is designated the P, residue of the inhibitor Similarly, the next adjacent ammo acid substituent (e g , R 7 of the above formula) will occupy the S 2 position of the substrate binding site and is designated the P 2 residue of the inhibitor If present, additional am o acid substituents will occupy the S 3 , S 4 , etc positions of the substrate binding site and be designated as the P 3 , P 4 , etc residues of the inhibitor An additional targeting group may be attached to the electron withdrawing group and, if present, its ammo acid substituents will occupy the S,', S 2 ', etc positions of the substrate binding sites and are designated the P 3 ', P 4 ',
  • targeting groups for specific enzymes are determined by rules governing substrate specificity in cysteine proteases (e g , see “Protemase Inhibitors", in Research Monographs in Cell and tissue Physiology (1986), ed Barret ef a/ , Vol 12, Chapter 4 Inhibitors of Cysteine Proteinases, Daniel Rich, Elsevier, New York, and Thornberry ef al , supra , hereby expressly incorporated by reference)
  • ICE ⁇ nterleuk ⁇ n-1 converting enzyme accepts an aspartic acid substituent (i e , 2-carboxyethyl) at the P, position and an alanme (methyl), val e (isopropyl) or histidme (4- ⁇ m ⁇ dazolylmethyl) substituent at the P 2 position
  • Papain accepts a argmine, lysine, N- benzyloxycarbonyllysine (i e 4-benzyloxycarbonylam ⁇ nobuty
  • R 7 and R 8 are independently hydrogen, alkyl (optionally substituted with a radical selected from hydroxy, ammo, alkylamino, dialkylamino, u ⁇ edo, mercapto, alkylthio, carboxy, carbamoyi, aikylcarbamoyl, dialkylcarbamoyi, alkylsulfonyl and guanidino, or a protected derivative thereof), cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, a group selected from aryl and arylalkyl (which group is optionally substituted at its aryl ring with one to three radicals selected from hydroxy, am o, guanidino, halo, optionally halo-substituted alkyl, alkyloxy and aryl, or a protected derivative thereof) or together with an adjacent R 3 or R s forms a divalent radical selected from (C 3 ⁇ )
  • preferred R 7 and R 8 groups are the naturally occunng ammo acid side chains and homologous derivatives These include, but are not limited to, alanme (methyl), argmine (3- guanidmopropyl), asparagme (carbamoylmethyl), citurlline (3-ure ⁇ dopropyl), aspartic acid (carboxymethyl), cysteine (mercaptomethyl), glutamic acid (2-carboxyethyl), glutamine (2- carbamoylethyl), glycine (hydrogen), histidme (4- ⁇ m ⁇ dazolylmethyl), homophenylalanine (2- phenylethyl), homose ⁇ ne (2-hydroxylethyl), isoleucine ((1-methylpropyl), leucme (isobutyl), lysme (4- aminobutyl), methionine (2-methylth ⁇ oethyl), ⁇ -(1-naphthyl)alan ⁇ n
  • n 0 to 5
  • A-B represents a linkage selected from -C(0)NR 3 -, wherein R 3 is hydrogen or as defined below, Y is -N(R 5 )-, wherein R 5 is hydrogen or as defined below, Z is -(CH 2 ) 2 - or -C(R 6 )(R 7 )-, Z 1 is -CH(R 8 )-, R is hydrogen, alkyloxycarbonylalkanoyl of overall 3 to 10 carbon atoms, (C, 9 )alkoxycarbonyl, (C 2 10 )alkanoyl (optionally substituted with a radical selected from carboxy, (C, 9 )alkyloxycarbonyl and hetero(C 4 ⁇ )cycloalkyl(C 2 10 )alkanoylam ⁇ no),
  • alkyl (optionally substituted with a radical selected from hydroxy, ammo, alkylam o, dialkylammo, unedo, mercapto, alkylthio, carboxy, carbamoyi, aikylcarbamoyl, dialkylcarbamoyi, alkylsulfonyl and guanidino or a protected derivative thereof) (C 3 7 )cycloalkyl, (C 3 7 )cycloalkyl(C 1 5 )alkyl, py ⁇ dyl.
  • a radical selected from hydroxy, ammo, alkylam o, dialkylammo, unedo, mercapto, alkylthio, carboxy, carbamoyi, aikylcarbamoyl, dialkylcarbamoyi, alkylsulfonyl and guanidino or a protected derivative thereof
  • More preferred compounds of Formulae I, II and III are those in which n is 0 to 2, A-B represents a linkage selected from -C(0)NR 3 -, wherein R 3 is hydrogen or as defined below, Y is -N(R 5 )-, wherein R 5 is hydrogen or as defined below, Z is -(CH 2 ) 2 - or -C(R 6 )(R 7 )- (with the proviso that when n is 0, Z is not -(CH 2 ) 2 -), Z 1 is -CH(R 8 )-, R 1 is hydrogen, (C 4 ⁇ )alkoxycarbonyl, (C 2 ⁇ )alkanoyl (optionally substituted with a radical selected from carboxy, (C, 5 )alkyloxycarbonyl and hetero(C 4 ⁇ )cycloalkyl(C 4 ⁇ ) alkanoylam o), -C(0)NR 21 R 22 wherein R 21 and R 22 together form aza(C 2 - 6 )
  • R 8 and R 7 are independently (C 5 ⁇ )cycloalkyl, (C 5-6 )cycloalkylmethyl, 3-py ⁇ dyl, 2-th ⁇ enyl, 2-furyl, 4- ⁇ m ⁇ dazolyl, 3- ⁇ ndolyl, 3-pyr ⁇ dylmethyl, 2-th ⁇ enylmethyl, 2-furylmethyl,4- ⁇ m ⁇ dazolylmethyl, 3- ⁇ ndolylmethyl, (C*.
  • alkyl (optionally substituted with a radical selected from mercapto, carboxy, ammo, methylthio, methylsulfonyl, carbamoyi, dimethylcarbamoyl, guanidino and hydroxy, or a protected derivative thereof), a group selected from phenyl, 1-naphthyl, 2-naphthyl, benzyl, 1-naphthylmethyl, 2-naphthylmethyl and 2-phenylethyl (which group is optionally substituted at its aryl ring with one radical selected from hydroxy, ammo, chloro, bromo and fluoro, or a protected form thereof) or together with an adjacent R 3 or R 5 forms a divalent radical selected from (C 3Jl )methylene and 1,2-phenylened ⁇ methylene (which radical is optionally substituted with hydroxy, or a protected derivative thereof, or oxo)
  • Particularly preferred compounds of Formulae I, II and III are those in which n is 0 to 1, A-B represents a linkage selected from -C(0)NR 3 -, Y is -N(R 5 )-, wherein R 5 is hydrogen or as defined below, Z is -C(R ⁇ )(R 7 )-, is -CH(R 8 )-, R 1 is hydrogen, fert-butoxycarbonyl, benzyloxycarbonyl, acetyl, 3-carboxyprop ⁇ onyl, 3-methoxycarbonylprop ⁇ onyl, biotinylaminohexanoyl, phenylacetyl, benzoyi, dimethylammosulfonyl, benzylsulfonyl, 1-p ⁇ peraz ⁇ nylcarbonyl, 4-methylp ⁇ peraz ⁇ n- 1-ylcarbonyl or 4-morphol ⁇ nylcarbonyl, R 7 is 3-pyr ⁇ dylmethyl, 2-th ⁇ enyl
  • More particularly preferred compounds of Formulae I, II and III are those in which n is 0, A-B represents a linkage selected from -C(0)NH-, Y is -NH-, Z is -CH(R 7 )-, T is -CH(R 8 )-, R 1 is hydrogen, fer -butxoycarbonyl, benzyloxycarbonyl, biotinylaminohexanoyl, benzoyi, p ⁇ per ⁇ z ⁇ n-1-ylcarbonyl, 4-methylp ⁇ peraz ⁇ n-1-ylcarbonyl or 4-morphol ⁇ nylcarbonyl, R 7 is (C, 5 )alkyl, optionally substituted benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-pyr ⁇ d ⁇ nylmethyl or 2-methylsulfonylethyl, and R 8 is butyl, 2-phenylethyl or 2-methylsulfonylethyl
  • A-B represents a linkage selected from -C(0)NH-, Y is -NH-, Z is -CH(R 7 )-, Z 1 is -CH(R 8 )-, R 1 is 1-p ⁇ per ⁇ z ⁇ nylcarbonyl, 4-methyl- 1-p ⁇ peraz ⁇ nylcarbonyl or 4-morphol ⁇ nylcarbonyl; R 7 is optionally substituted benzyl, 1-naphthylmethyl or 2-naphthylmethyl, and R 8 is 2-phenylethyl
  • R 2 is independently (C,. 5 )alkyl (optionally substituted with one or two radicals selected from ammo, chloro, bromo, fluoro, hydroxy and methoxy, or a protected derivative thereof).
  • R 4 is hydrogen, (C, 5 )alkyl or (C 6 , 0 )aryl(C, 5 )alkyl
  • R 2 is (C, 5 )alkyl (optionally substituted with one or two radicals selected from ammo, chloro, bromo, fluoro and hydroxy, or a protected de ⁇ vative thereof), perfluoro(C, 5 )alkyl, (C 5 ⁇
  • R 9 is -C(0)OR 10 , -P(O)(OR 10 ) 2 , -S(O)(NR 10 )R 10 , -C(0)NHC(0)R 10 or -S(0) 2 NHC(0)R 10 are those in which each R 10 is independently (C, 5 )alkyl (optionally substituted with one or two radicals selected from ammo, chloro, bromo, fluoro, hydroxy and methoxy or a protected derivative thereof), (C 37 )cycloalkyl, (C 3 7 )cycloalkyl(C, 5 )alkyl, or a group selected from phenyl or phenyl(C 1-6 )alkyl (which group is optionally substituted at its phenyl ring with one to two radicals selected from ammo, chloro, bromo, fluoro, hydroxy, methoxy and optionally halo-substituted methyl, or a protected derivative thereof) More preferred compounds of
  • R 9 is C(0)R 11 or -S(0)R 11 are those in which R 11 is (C, 5 )alkyl, (C 3 7 )cycloalkyl, (C 3 7 )cycloalkyl(C 1 5 )alkyl or a group selected from phenyl and phenyl(C, ⁇ )alkyl (which group is optionally substituted at its aryl ring with one to two radicals selected from ammo, chloro, bromo, fluoro, hydroxy, methyl, t ⁇ fluoromethyl and methoxy) More preferred compounds of Formula II in which R" is C(0)R" or -S(0)R 11 are those in which in which R 11 is ethyl, cyclo(C 5 ⁇ )alkyl, cyclo(C 5 ⁇ )alkylmethyl or a group selected from phenyl and benzyl (which group is optionally substituted at its phenyl ring with one radical selected from ammo hydroxy
  • R 9 is -C(0)NR 12 R 13 or -S(0) 2 NR 1 R 13 are those in which R 12 and R 13 are independently (Chalky!, (C 3 . 7 )cycloalkyl, (C 37 )cycloalkyl (C, 5 )alkyl or a group selected from phenyl and pheny ⁇ C ⁇ alkyl (which group is optionally substituted at its phenyl ring with one to two radicals selected from ammo, chloro, bromo, fluoro, hydroxy, methoxy and optionally halo-substituted methyl) More preferred compounds of Formula II in which R 9 is -C(0)NR 12 R 13 or O 96/30353
  • -S(0) 2 NR 12 R 13 are those in which R 12 and R 13 are independently ethyl, (C 5 ⁇ )cycloalkyl, (C- ⁇ cycloalkylmethyl or a group selected from phenyl and benzyl (which group is optionally substituted at its phenyl ring with one radical selected from amino hydroxy, chloro, bromo or fluoro, or a protected derivative thereof).
  • Preferred compounds of Formula II in which R 9 is -C(0)NHR 14 or -S(0) 2 NHR 14 wherein R 14 is a group selected from Formulae (a) and (b) are those in which each n, A, B, Y, Z, R 1 and R 10 are as defined above with respect to preferred compounds of Formulae I, II and III.
  • R 15 is a group selected from 2-furyl, 2-thienyl, 2-pyrrolyl, 2-phospholyl, 2-arsoyl, 3-pyridyl or 3-phosphorinyl (which group is optionally substituted with at least one radical selected from (C L ⁇ alkylcarbamoyl, di(C 1 . 5 )alkylcarbamoyl, (C 1 . 5 )alkyloxycarbonyl, (C,. 5 )alkylsulfinamoyl, di(C,.
  • R 16 is a group selected from 2-furyl, 2-thienyl, 2-pyrrolyl, 2-phosholyl, 2-arsolyl, 3-pyridyl or 3-phosphorinyl (which group is optionally substituted with at least one radical selected from methylcarbamoyl, dimethylcarbamoyl, methyloxycarbonyl, methylsulfinamoyl, dimethylsulfinamoyl, methylsulfonyl, carboxy, nitro, sulfmamoyl, sulfo, carbamoyi, phosphono, methyloxyphosphinyl, dimethyloxyphosphinyl, formyl, cyano, methylsulfinyl, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, methoxysulfonyl, methylsulfonimidoyl, phenyl
  • R 16 is a group selected from Formulae (a) and (b) are those in which each n, A, B, Y, Z, R 1 and R 10 are as defined above with respect to preferred compounds of Formulae I, II and III.
  • preferred cysteine protease inhibitors of the invention are those in which the absolute configuration of each chiral center present is the (S)-conf ⁇ guration.
  • preferred compounds of Formula I in which n is 0 are those in which the absolute configuration of chiral center to which the R 7 substituent is attached is in the (/ ⁇ -configuration.
  • preferred compounds of Formula I include: /V 2 -(4-mo ⁇ holinylcarbonyl)- ⁇ / 1 -(3-phenyl-1R-phenylsulfonylpropyl)-L-phenylalaninamide (compound 1 ), ⁇ / 2 -(4-morpholinylcarbonyl)- ⁇ / 1 -(3-phenyl-1 S-phenylsulfonylpropyl)-L-phenyalaninamide (compound 2), ⁇ / 2 -(4-morphol ⁇ nylcarbonyl)- ⁇ / 1 -(3-phenyl-1-phenylsulfonylpropyl)-L-phenylalan ⁇ nam ⁇ de (compound 3), ⁇ / 2 -(4-morphol ⁇ nylcarbonyl)-/V 1 -(3-phenyl-1-benzylsulfonylpropyl)-L-leuc ⁇ nam ⁇ de (compound 1
  • Formula I includes structures represented by preferred Species IV as depicted below.
  • M is zero, one or two carbon atoms, A-B are as defined above, R ⁇ R 2 , R 7 and R 8 are as defined above, and Q is NH or CH 2 .
  • Preferred embodiments utilize A-B linkages which contain nitrogen at the B position.
  • the number of carbon atoms between the carbon to which the R 8 group is attached and the sulfur atom of the sulfone group determines whether the compound is an ⁇ -am ⁇ nosulfone, a ⁇ -aminosulfone, or a ⁇ -aminosulfone.
  • compounds may be named as aminosulfones using the names of the amino acids or using the chemical names.
  • Species V is an ⁇ -aminosulfone:
  • Species VI is a ⁇ -aminosulfone:
  • Species VII is a ⁇ -aminosulfon
  • Formula II includes structures of Species VIII, referred to as ⁇ -amino groups, particularly when R 9 is an electron withdrawing group:
  • the dissociation constant for inhibition of a protease with an inhibitor of the invention is at most 100 ⁇ M.
  • binding constant or "dissociation constant” or grammatical equivalents herein is meant the equilibrium dissociation constant for the reversible association of inhibitor with enzyme.
  • the dissociation constants are defined and determined as below.
  • E-l enzyme-inhibitor complex
  • k is the second order rate constant for the formation of the E-l reversible complex
  • k 2 is the first order rate constant for the disassociation of the reversible E-l complex
  • K, k 2 /k
  • K, values may be estimated using the Dixon plot as described by Irwin Segel in Enzyme Kinetics 1 Behavior and analysis of rapid equilibrium and steady-state enzyme systems, 1975, Wiley-lnterscience Publication, John Wiley & Sons, New York, or for competitive binding inhibitors from the following calculation
  • v 0 is the rate of substrate hydrolysis in the absence of inhibitor, and v, is the rate in the presence of competitive inhibitor.
  • dissociation constants are a particularly useful way of quantifying the efficiency of an enzyme with a particular substrate or inhibitor, and are frequently used in the art as such If an inhibitor exhibits a very low K*. it is an efficient inhibitor Accordingly, the cysteine protease inhibitors of the present invention have dissociation constants, K,, of at most about 100 ⁇ M Preferred embodiments have inhibitors that exhibit dissociation constants of at most about 10 ⁇ M, with the most preferred embodiments having dissociation constants of at most about 1 ⁇ M
  • a) is a) CI-H 2 N+(Me)OMe, dicyclohexylcarbodiimide, t ⁇ ethylamine, and b) lithium aluminum hydride
  • N-tert-butoxycarbonyl ammo acid or peptidomimetic derivative thereof is converted to the corresponding ammomethyl aldehyde (e g , see method of Fehrentz, J-A and Castro, B (Synthesis, (1983), 676, Equation 5)
  • the aldehyde is converted to the corresponding vmylogous compound via aWittig reaction or a Wadsworth-Emmons-Horner modification of the Wittig reaction (e g , see Wadsworth et al , J Amer Chem Soc 83 1733 (1991), Equation 6)
  • the vmylogous compound is reduced by catalytic hydrogenation (e g , see Equation 7) and then deprotection and coupling with a suitable N-protected ammo acid or peptide or a peptidomimetic derivative thereof gives the corresponding compound of Formula I or II
  • the vmylogous compound is deprotected and coupled with the N
  • the conversion of N-tert-butoxycarbonyl ammo acid or peptidomimetic derivative thereof to the corresponding ammomethyl aldehyde is carried out with N,0-d ⁇ methylhydroxylam ⁇ ne hydrochlo ⁇ de in the presence of t ⁇ ethylamine and dicyclohexylcarbodiimide in dicloromethane
  • the conversion is carried out by treating the ammo acid or peptidomimetic derivative with t ⁇ ethylamine and the coupling agent benzot ⁇ azol-1-yloxyt ⁇ s(d ⁇ methylam ⁇ no)phosphon ⁇ um hexafluorophosphate (BOP) and then reducing with lithium aluminum hydride to give the corresponding aldehyde (e g , see methos of Fehrentz, J-A and Castro, B , Synthesis, (1983), 676-678)
  • the conversion of the aldehyde to the corresponding vmylogous ester can be carried out with the
  • a suitable N-tert-butoxycarbonyl- ⁇ -ammoaldehyde prepared as described in Equation 5, with the sodium anion of an appropriate sulfonylmethanephosphonate (SMP) (e g, diethyl phenylsulfonylmethanephosphonate, diethyl 2-naphthylsulfonylmethane-phosphonate, diethyl methylsulfonylmethanephosphonate, etc ) gives the corresponding vmylogous sulfone
  • SMP sulfonylmethanephosphonate
  • sulfonylmethanephosphonate e g, diethyl phenylsulfonylmethanephosphonate, diethyl 2-naphthylsulfonylmethane-phosphonate, diethyl methylsulfonylmethanephosphonate, etc
  • SMP s
  • Suitable amidomethylenephosphonates can be prepared by reacting the saponification product of tnethyl phosphonoacetate with an appropriate amme
  • compounds of Formula II in which R 9 is -C(0)NHR 14 can be prepared by reacting a compound of Formula I in which R 9 is -COOH with an appropriate amme
  • the reaction can be carried out in the presence of dicyclohexylcarbodiimide in dichloromethane or by any other peptide coupling reaction sequences known to those of skill in the art.
  • ketones is synthesized by means of the Wadsworth-Emmons reaction between Boc- ⁇ - ammo aldehydes and the appropriate phosphonate, followed by catalytic reduction with hydrogen in the presence of palladium.
  • the aldehyde portion is synthesized as outlined above.
  • the phosphonate if not commercially available, is synthesized by treatment of the enolate anion of methyl or substituted methyl ketones, such as acetone or acetophenone, with diethyl chlorophosphonate.
  • the enolate anion is generated, for example, by treatment of a tetrahydrofuran solution of diisopropylamine with butyllithium, followed by addition of the ketone to the lithium diisopropylamide (LDA) solution (H.O. House, Modern Synthetic Reactions, 2nd Ed. (W. Benjamin, Inc., Menlo Park, CA, Chapter 9). Following formation of the enolate, diethyl chlorophosphonate is added. The Wadsworth-Emmons reagent forms as a consequence of coupling of the enolate with diethyl chlorophosphate.
  • LDA lithium diisopropylamide
  • Synthesis of sulfoxides is performed by means of the Wadsworth-Emmons reaction between Boc- ⁇ - ammo aldehydes and the appropriate phosphonate, followed by hydrogenation in the presence of a suitable catalyst
  • the aldehyde portion is synthesized as outlined above
  • the phosphonate is synthesized by treatment of the anion of methyl sulfoxides with diethyl chlorophosphate The anion is generated by addition of BuLi to diisopropylam e, followed by addition of the methyl sulfoxide
  • Synthesis of sulfonamides is performed by means of the Wadsworth-Emmons reaction between Boc- ⁇ -ammo aldehydes and the appropriate phosphonate, followed by hydrogenation in the presence of a suitable catalyst
  • the aldehyde portion is synthesized as outlined above
  • the phosphonate is synthesized, for instances, by a method such as the following a) diethylphosphoryl methanesulfonates, as prepared by the method of Carretero and Ghosez (Tetrahedron Lett , 28 1104- 1108 (1987)), are converted to sulfonyl chlorides by treatment with phosphorus pentachlo ⁇ de (M Quaedvlieg, in "Methoden der Organische Chemic (Houben-Weyl)", ed.
  • Synthesis of sulfoximines is performed by means of the Wadsworth-Emmons reaction between Boc- ⁇ - ammo aldehydes and the appropriate phosphonate, followed by hydrogenation in the presence of a suitable catalyst.
  • the aldehyde portion is synthesized as outlined above
  • the phosphonate may be synthesized in several ways. For example, N-alkyl or N-aryl phenyl methyl sulfoximines are made by the methods described by Johnson, in "Comprehensive Organic Chemistry (Pergamon Press), supra, Chapter 11.11.
  • the lithium anion of compounds such as N-alkyl phenyl methyl sulfoximine is prepared by the treatment of the neutral compound with buthyl lithium in THF (Cram ef al., J. Amer. Chem. Soc. 92:7369 (1970)). Reaction of this lithium anion with dialkyl chlorophosphates such as the commercially available diethyl chlorophosphate (Aldrich) results in the Wadsworth-Emmons reagent necessary for synthesis of the sulfoximme compounds
  • sulfonates is performed by means of the Wadsworth-Emmons reaction between Boc- ⁇ - ammo aldehydes and the appropriate phosphonate, for instance diethylphosphoryl methanesulfonate, followed by hydrogenation in the presence of a suitable catalyst, such as Raney nickel
  • the phosphonate may be synthesized as follows The anion of methyl dialkyl phosphonates such as the commercially available methyl diethyl phosphonate (Aldrich) is generated by treatment of said phosphonate with a strong base such as LDA The resulting anion is sulfonated with sulfur t ⁇ oxide/trimethylamine complex (Carreto ef al , Tetrahedron Lett , 28 1104-1108 (1987)) to form diethylphosphoryl methanesulfonate, which is capable of reacting in the Wadsworth-Emmons procedure with aldehydes to form ⁇ , ⁇ -unsaturated sulfon
  • the chloride compounds containing R 8 and R 9 groups are generally made using commercially available reagents and products using techniques well known in the art
  • the reaction generally produces a mixture of cis and trans configurations, favoring the trans isomer
  • the cysteine protease inhibitors of this embodiment Upon reduction to the cysteine protease inhibitors of this embodiment, the cis-trans isome ⁇ sm disappears by definition as a single compound is formed
  • cysteine protease inhibitors of the invention are further purified if necessary after synthesis, for example to remove unreacted materials
  • the cysteine protease inhibitors of the present invention may be crystallized, or passed through silica chromatography columns using solvent mixtures to elute the pure inhibitors
  • R 20 is cyano, -S(0) 2 R 2 , -CH 2 S(0) 2 R 2 , -CH 2 CH(R 4 )S(0) 2 R 2 , -(CH 2 ) 2 C(0)OR 10 , -(CH 2 ) 2 P(O)(OR 10 ) 2 , -(CH 2 ) 2 S(O)(NR 10 )R 10 , -CH 2 ) 2 C(0)R 11 , -(CH 2 ) 2 S(0)R 11 , -(CH 2 ) 2 C(0)NR 12 R 13 , -(CH 2 ) 2 S(0) 2 NR 12 R 13 , -(CH 2 ) 2 C(0)NHR 14 , -(CH 2 ) 2 S(0) 2 NHR 14 or -CH 2 CHR 15 R 16 and each A, B, X, Y, Z, R 1 , R 8 R 1 , R 8 , R 2 , R 10 , R 11 , R 12 , R 13
  • cysteine protease inhibitors of the present invention are labelled.
  • a labelled cysteine protease inhibitor herein is meant a cysteine protease inhibitor that has at least one element, isotope or chemical compound attached to enable the detection of the cysteine protease inhibitor or the cysteine protease inhibitor bound to a cysteine protease.
  • labels fall into three classes: a) isotopic labels, which may be radioactive or heavy isotopes; b) immune labels, which may be antibodies or antigens, and c) colored or fluorescent dyes
  • the labels may be incorporated into the cysteine protease inhibitor at any position
  • a label may be attached as the "R 1 " group in Formula 1 , or a radioisotope incorporated into any position
  • useful labels include 14 C, 3 H, biotm, and fluorescent labels as are well known in the art
  • cysteine protease inhibitors of the present invention may be easily screened for their inhibitory effect
  • the inhibitor is first tested against the cysteine protease for which the targeting group of the inhibitor was chosen, as outlined above
  • many cysteine proteases and their corresponding chromogenic substrates are commercially available
  • cysteine proteases are routinely assayed with synthetic chromogenic substrates in the presence and absence of the cysteine protease inhibitor, to confirm the inhibitory action of the compound, using techniques well known in the art
  • the effective inhibitors are then subjected to kinetic analysis to calculate the K, values and the dissociation constants determined
  • a compound inhibits at least one cysteine protease, it is a cysteine protease inhibitor for the purposes of the invention
  • Preferred embodiments have inhibitors that exhibit the correct kinetic parameters against at least the targeted cysteine protease
  • cysteine protease is not commercially available in a purified form
  • the cysteine protease inhibitors of the present invention may also be assayed for efficacy using biological assays
  • the inhibitors may be added to cells or tissues that contain cysteine proteases, and the biological effects measured
  • the cysteine protease inhibitors of the present invention are synthesized or modified such that the in vivo and in vitro proteolytic degradation of the inhibitors is reduced or prevented Generally, this is done through the incorporation of synthetic ammo acids, derivatives, or substituents into the cysteine protease inhibitor Preferably, only one non-naturally occurring am o acid or am o acid side chain is incorporated into the cysteine protease inhibitor, such that the targeting of the inhibitor to the enzyme is not significantly affected
  • some embodiments that use longer cysteine protease inhibitors containing a number of targeting residues may tolerate more than one synthetic derivative
  • non-naturally occurring ammo acid substituents may be designed to mimic the binding of the naturally occurring side chain to the enzyme, such that more than one synthetic substituent is tolerated
  • peptide isosteres are used to reduce or prevent inhibitor degradation
  • the resistance of the modified cysteine protease inhibitors may be tested against a variety of known commercially
  • cysteine proteases that may be inhibited by the inhibitors of the present invention are those of the family of cysteine proteases that bear a thiol group at the active site These proteases are found in bacteria, viruses, eukaryotic microorganisms, plants, and animals Cysteine proteases may be generally classified as belonging to one of four or more distinct superfamilies
  • cysteine proteases that may be inhibited by the novel cysteine protease inhibitors of the present invention include, but are not limited to, the plant cysteine proteases such as papain, ficin, aleuram, oryzam and actmidam, mammalian cysteine proteases such as cathepsms B, H, J, L, N, S, T, O, and C, (cathepsin C is also known as dipeptidyl peptidase I), interleukm converting enzyme (ICE), calcium-activated neutral proteases, calpam I and II, bleomy ⁇ n hydro
  • inhibitors of cysteine proteases are useful in a wide variety of applications
  • the inhibitors of the present invention are used to quantify the amount of cysteine protease present in a sample, and thus are used in assays and diagnostic kits for the quantification of cysteine proteases in blood, lymph, saliva, or other tissue samples, in addition to bacterial, fungal, plant, yeast, viral or mammalian cell cultures
  • the sample is assayed using a standard protease substrate
  • a known concentration of cysteine protease inhibitor is added, and allowed to bind to a particular cysteine protease present
  • the protease assay is then rerun, and the loss of activity is correlated to cysteine protease activity using techniques well known to those skilled in the art
  • the cysteine protease inhibitors are also useful to remove or inhibit contaminating cysteine proteases in a sample
  • the cysteine protease inhibitors of the present invention are added to samples where proteolytic degradation by contaminating cysteine proteases is undesirable
  • the cysteine protease inhibitors of the present invention may be bound to a chromatographic support, using techniques well known in the art, to form an affinity chromatography column A sample containing an undesirable cysteine protease is run through the column to remove the protease
  • the cysteine protease inhibitors are useful for inhibiting cysteine proteases implicated in a number of diseases
  • cathepsms B, L, and S, cruzain, calpains I and II, and mterleukin 1 ⁇ converting enzyme are inhibited
  • These enzymes are examples of lysosomal cysteine proteases implicated in a wide spectrum of diseases characterized by tissue degradation
  • diseases include, but are not limited to, arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, parasite-borne infections, Alzheimer's disease, pe ⁇ odontal disease, and cancer metastasis
  • mammalian lysosomal thiol proteases play an important role in intracellular degradation of proteins and in the processing of some peptide hormones
  • Enzymes similar to cathepsms B and L are released from tumors and may be involved in tumor metastasis
  • Cathepsin L is present in diseased human synovial fluid and transformed tissues
  • the cysteine protease inhibitors also find application in a multitude of other diseases, including, but not limited to, gingivitis, malaria, leishmaniasis, fila ⁇ asis, and other bacterial and parasite-borne infections
  • the compounds also offer application in viral diseases, based on the approach of inhibiting proteases necessary for viral replication
  • many picornoviruses including poliovirus, foot and mouth disease virus, and rh ovirus encode for cysteine proteases that are essential for cleavage of viral polyprotems
  • ICE ⁇ nterleuk ⁇ n-1 ⁇ converting enzyme
  • ICE cysteine protease responsible for processing mterleukin 1 ⁇
  • cardiovascular system including the pericardium, gastrointestinal and urogenital systems, the skin and the mucosal membranes
  • infectious diseases where active infection exists at any body site, such as meningitis and salpmgitis, complications of infections including septic shock, disseminated mtravascular coagulation, and/or adult respiratory distress syndrome, acute or chronic inflammation due to antigen, antibody and/or complement deposition, inflammatory conditions including arthritis, chalangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vascu
  • infectious diseases where active infection exists at any body site, such as meningitis and salpmgitis, complications of infections including septic shock, disseminated mtravascular coagulation, and
  • cysteine protease inhibitors of the present invention find use in drug potentiation applications
  • therapeutic agents such as antibiotics or antitumor drugs can be inactivated through proteolysis by endogeneous cysteine proteases thus rendering the administered drug less effective or inactive
  • cysteine protease inhibitors of the invention may be administered to a patient in conjunction with a therapeutic agent in order to potentiate or increase the activity of the drug This co-administration may be by simultaneous administration, such as a mixture of the cysteine protease inhibitor and the drug, or by separate simultaneous or sequential administration
  • cysteine protease inhibitors have been shown to inhibit the growth of bacteria, particularly human pathogenic bacteria (see Bjorck et al , Nature 337 385 (1989)) Accordingly, the cysteine protease inhibitors of the present invention may be used as antibacterial agents to retard or inhibit the growth of certain bacteria
  • the cysteine protease inhibitors of the invention also find use as agents to reduce the damage of bacterial cysteine proteases to host organisms
  • staphylococcus produces a very active extracellular cysteine protease which degrades insoluble elastin, possibly contributing to the connective tissue destruction seen in bacterial infections such as septicemia, septic arthritis and otitis
  • the cysteine protease inhibitors of the invention may be used to treat bacterial infections to prevent tissue damage
  • cysteine protease inhibitors of this invention 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 cysteine protease inhibitor of the invention or 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.
  • Therapeutically effective amounts of the cysteine protease inhibitors of this invention may range from 10 micrograms per kilogram body weight ( ⁇ g/kg) per day to 10 milligram per kilogram body weight (mg/kg), typically 100 ⁇ g/kg/day to 1 mg/kg/day.
  • a therapeutically effective amount for a 80 kg human may range from 1 mg/day to 1000 mg/day, typically 10 mg/day to 100 mg/day.
  • cysteine protease inhibitors of this invention will be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal, intrapulmonary, or by suppositiory) or parenteral (e.g., intramuscular, intravenous, intrapulmonary or subcutaneous).
  • routes e.g., oral, systemic (e.g., transdermal, intranasal, intrapulmonary, or by suppositiory) or parenteral (e.g., intramuscular, intravenous, intrapulmonary or subcutaneous).
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixiers, aerosols or any other appropriate composiiton and are comprised of, in general, a cysteine protease inhibitor of the invention in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and don not adversely affect the therapeutic benefit of the cysteine protease inhibitor of this invention.
  • 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, glucolse, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium sterate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liguid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, includingthose of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.).
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols.
  • Compressed gases may be used to disperse the cysteine protease inhibitor of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrous oxide, etc.
  • Other suitable pharmaceutical carriers and their formulations are described in A.R. Alfonso Reminton's Pharmaceutical Sciences 1985, 17th ed. Easton, Pa.: Mack Publishing Company, hereby expressly incorporated by reference.
  • the amount of a cysteine protease inhibitor of this invention 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, the final composition will comprise from 0 1%w to 10%w of the cysteine protease inhibitor, preferably 1%w to 10%w, with the remainder being the excipient or excipients
  • the pharmaceutical composition is administered in a single unit dosage form for continuous teatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required
  • Representative pharmaceutical formulations containing a cysteine protease inhibitor of the invention are described in Example 20, infra
  • Xaa 2 ammo acid at P2 position relative to active site of the enzyme
  • ⁇ -C0 2 Et ⁇ -am ⁇ no ethyl ester
  • ⁇ -S0 2 Ph ⁇ -am ⁇ nosulfone with phenyl terminus
  • ⁇ -C0 2 H ⁇ -am ⁇ nocarboxylate
  • ⁇ -PEt ⁇ -am ⁇ nophosphonate
  • ⁇ -AM ⁇ -am ⁇ noam ⁇ de
  • ⁇ -Ar(sub) ⁇ -am ⁇ noaromat ⁇ c compound (substituted as appropriate)
  • ⁇ -S0 2 Ph ⁇ -aminosulfone with phenyl substituent
  • ⁇ -S0 2 Ph ⁇ -aminosulfone with phenyl substituent
  • Hph homophenylalanine
  • PSMP diethyl phenylsulfonylmethylenephosphonate
  • Np2 2-naphthylalan ⁇ ne
  • MeOSuc methoxysuccinyl
  • Xaa 2 Phe (phenylalanine)
  • Xaa, Hph (homophenylalanine,)
  • the diastereomers were separated by flash chromatography on 230-400 mesh silica gel (20- 50% ethyl acetate/CH 2 CI 2 , gradient elution)
  • a representative solution for oral administration contains
  • Cysteine protease inhibitor 100 to 1000 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q s to 100 mL
  • a representative solution for intravenous admmstration contains
  • Cysteine protease inhibitor 10 to 100 mg Dextrose Monohydrate q s to make isotonic Citric Acid Monohydrate 1 05 mg Sodium Hydroxide 0 18 mg Saline for Injection q s to 1 0 mL
  • a representative tablet form may contain:

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DE19817461A1 (de) 1998-04-20 1999-10-21 Basf Ag Neue substituierte Benzamide, deren Herstellung und Anwendung
US6395897B1 (en) 1999-03-02 2002-05-28 Boehringer Ingelheim Pharmaceuticals, Inc. Nitrile compounds useful as reversible inhibitors of #9 cathepsin 5
US6420364B1 (en) 1999-09-13 2002-07-16 Boehringer Ingelheim Pharmaceuticals, Inc. Compound useful as reversible inhibitors of cysteine proteases
EP1218372B1 (de) * 1999-09-13 2003-07-02 Boehringer Ingelheim Pharmaceuticals, Inc. Heterocyclische verbindungen als reversible inhibitoren von cysteinproteasen
AU784746B2 (en) 1999-11-18 2006-06-08 Dendreon Corporation Nucleic acids encoding endotheliases, endotheliases and uses thereof
US7700341B2 (en) 2000-02-03 2010-04-20 Dendreon Corporation Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon
ATE324372T1 (de) 2000-08-14 2006-05-15 Ortho Mcneil Pharm Inc Substituierte pyrazole
US7332494B2 (en) 2000-08-14 2008-02-19 Janssen Pharmaceutica, N.V. Method for treating allergies using substituted pyrazoles
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KR101385855B1 (ko) * 2012-10-16 2014-04-22 이동익 카뎁신 검출용 다이아로마틱 아미노산 기질
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KR19980703261A (ko) 1998-10-15
CZ298197A3 (cs) 1998-03-18
JPH11503417A (ja) 1999-03-26
CN1071751C (zh) 2001-09-26
NO974403L (no) 1997-11-17
MY113489A (en) 2002-03-30
TW470750B (en) 2002-01-01
NZ305626A (en) 2000-01-28
IL117638A0 (en) 1996-07-23
CA2216151A1 (en) 1996-10-03
PL322409A1 (en) 1998-01-19
CN1184472A (zh) 1998-06-10
NO311573B1 (no) 2001-12-10

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