WO1999011637A1 - Protease inhibitors - Google Patents
Protease inhibitors Download PDFInfo
- Publication number
- WO1999011637A1 WO1999011637A1 PCT/US1998/018289 US9818289W WO9911637A1 WO 1999011637 A1 WO1999011637 A1 WO 1999011637A1 US 9818289 W US9818289 W US 9818289W WO 9911637 A1 WO9911637 A1 WO 9911637A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- guanidine
- benzyl
- 6alkyl
- thiazol
- phenyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates in general to thiazoleguanidine protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K.
- Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
- Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated.
- Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
- Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
- Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
- the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
- the low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed.
- osteoblasts lay down a new protein matrix that is subsequently mineralized.
- disease states such as osteoporosis and Paget's disease
- the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle.
- this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
- inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone reso ⁇ tion. For example, Delaisse, et al., Biochem.
- cy statin an endogenous cysteine protease inhibitor
- PTH stimulated bone reso ⁇ tion in mouse calvariae Other studies, such as by Delaisse, et al., Bone, 1987, 8, 305, Hill, et al., J. Cell. Biochem., 1994, 56, 118, and Everts, et al., J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone reso ⁇ tion. Tezuka, et al., J. Biol. Chem., 1994, 269, 1 106, Inaoka, et al, Biochem.
- cathepsin K which has also been called cathepsin O
- a cysteine protease is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.
- cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
- Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
- selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis.
- Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix.
- selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.
- N-phenyl-N'-(2-phenyloxazol-4-ylcarbonyl)hydrazide as well as its N-(2,4-dinitrophenyl) derivative, have been described in Afridi, A., et al., J. Chem. Soc, Perkin Trans. 1, 1976, 3, 315-20.
- Benko, A.,et al., Justus Liebigs Ann. Chem., 1968, 717, 148-53 describes the preparation of N-(4-ethoxycarbonylthiazol-2-yl)-N'-[2-(4- pyridinyl)thiazol-4-ylcarbonyl]hydrazide.
- cysteine protease inhibitors have been identified.
- these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapid plasma clearance.
- An object of the present invention is to provide thiazoleguanidine protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases.
- this invention provides a compound according to Formula I.
- this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
- this invention provides methods of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
- proteases particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
- the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
- X, X], X2, and X3 are independently selected from -H, -C ⁇ _6alkyl, -Ci-6alkyl substituted by 1-3 fluorines, -C3_7cycloalkyl, -CN, -C(0)R ⁇ , -C(0)OR ⁇ , -
- NR1R2 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; R2 -S H, -C ⁇ _6alkyl, -CF3 or -CH 2 CF 3 ;
- R3 is -Ci-6alkyl, -CF or -CH 2 CF 3 ;
- X is -H, -C ⁇ _6alkyl , -C3-7cycloalkyl, -COAr, -COOC j ⁇ alkyl, or COOAr.
- Preferred embodiments of the present invention include compounds of Formula I wherein: X, X j , X ,and X3 are independently H or halogen;
- Still more preferred embodiments of the present invention include compounds of Formula I wherein: X, X ⁇ , X2,and X3 are independently H or Cl;
- the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
- Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
- Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
- amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
- Ci-6alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
- Any Ci-6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R 2 > C(0)N(R')2 ' carbamyl or C ⁇ _4alkyl, where R' is Ci-6alkyl.
- C ⁇ alkyl means that no alkyl group is present in the moiety.
- Ar-CQalkyl is equivalent to Ar.
- C3-7cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. When substituted, substituents are defined as for “C ⁇ _6alkyl", above.
- Halogen means F, Cl, Br, and I.
- Ar or “aryl” means phenyl or naphthyl, optionally independently substituted by one or more of Ph-Co_6 a lkyl, Het-C ⁇ _6alkyl, C ⁇ alkyl, Cj.galkoxy, Ph-Co_6 a -koxy, Het- C 0 _6alkoxy, OH, (CH 2 ) ⁇ _6NR4R5, 0(CH2) ⁇ _6NR R 5 , C0 2 R ⁇ or halogen.
- R 4 and R 5 are independently H, C ⁇ alkyl, C2_6alkenyl, Ar-C Q _6al yl, or Het-Co_6alkyl.
- Two Chalky 1 groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring.
- Ph may be optionally substituted with one or more of C j .galkyl, C j .galkoxy, OH, (CH 2 ) ⁇ _6N R4R5, 0(CH 2 ) 1 _ 6 N R4R5, C0 2 R', or halogen.
- Het or "heterocyclic"
- NR ⁇ R2 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S", represent a stable 5- to 7-membered heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
- the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from the group consisting of Ph-Co_6 a lkyl, Het-Co-6 alkyl, C ⁇ _6 a ---y ⁇ . C galkoxy, Ph-C ⁇ - ⁇ alkoxy, Het-C 0 .6alkoxy, OH, (CH ) ⁇ _6NR4R5, 0(CH 2 ) ⁇ _6 R4R5, CO2R '. Two Cj.galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Het ring.
- Ph may be optionally substituted with one or more of C ⁇ alkyl, C ⁇ alkoxy, OH, (CH2) ⁇ _6NR4R5, 0(CH 2 ) ⁇ _6NR4R5, CO2R', or halogen.
- heterocycles include the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, mo ⁇ holinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, ind
- t-Bu refers to the tertiary butyl radical
- Boc refers to the t-butyloxycarbonyl radical
- Fmoc refers to the fluorenylmethoxycarbonyl radical
- Ph refers to the phenyl radical
- Cbz refers to the benzyloxycarbonyl radical.
- DMAP dimethylaminopyridine
- DMF dimethyl formamide
- TFA trifluoroacetic acid
- THF tetrahydrofuran
- Methods of Preparation Hydroxyacetophenones 1 -Scheme 1 may be alkylated by treatment with an a,w- dihaloalkane, such as l-bromo-3-chloropropane and a suitable base, such as potassium hydroxide, in an appropriate solvent, such as refluxing methanol.
- an a,w- dihaloalkane such as l-bromo-3-chloropropane
- a suitable base such as potassium hydroxide
- an appropriate solvent such as refluxing methanol.
- methoxyalkoxy-acetophenone 2-Scheme 1 may also be isolated as a by-product.
- 3-(4-Methoxybutoxy)acetophenone 1 -Scheme 2 may be transformed to the thiazoleguanidine 2-Scheme 2 by treatment first with an appropriate brominating agent, such as bromine, in a halogenated solvent, such as dichloromethane, followed by reaction with 2-imino-4-thiobiuret in a refluxing alcoholic solvent, such as ethanol.
- an appropriate brominating agent such as bromine
- a halogenated solvent such as dichloromethane
- 2-imino-4-thiobiuret in a refluxing alcoholic solvent, such as ethanol.
- the guanidine group is activated towards alkylation by preparing a suitable derivative, for example the t- butoxycarbonylguanidine, which can be formed by treating the compound 2-Scheme 2 with the appropriate carbamylating reagent, such as di-t-butyldicarbonate, under appropriate conditions, such as dichloromethane solvent with dimethylaminopyridine coreagent.
- Alkylation of the activated guanidine can then proceed by deprotonation with a suitable base, especially sodium hydride, in a suitable solvent, such as dimethylformamide, followed by addition of the desired alkylating agent, in this example, benzyl bromide, provides compound 3-Scheme-2.
- a suitable base especially sodium hydride
- a suitable solvent such as dimethylformamide
- 3-(4-chlorobutoxy)acetophenone 1 -Scheme 3 may be used to alkylate an aniline, in this example N-methylaniline, in a suitable solvent, such as dimethylformamide or nitromethane at high heat.
- a suitable solvent such as dimethylformamide or nitromethane at high heat.
- the resulting acetophenone 2-Scheme 3 may be transformed to the thiazoleguanidine 3-Scheme 3 by treatment first with an appropriate brominating agent, such as bromine in a halogenated solvent, such as dichloromethane, followed by reaction with 2-imino-4-thiobiuret in a refluxing alcoholic solvent, such as ethanol.
- the bromination conditions lead to /. ⁇ r ⁇ -bromination of the aniline ring as well as formation of the ⁇ -bromoketone intermediate.
- the guanidine group is then activated towards alkylation by forming a suitable derivative, for example the t- butoxycarbonylguanidine, which can be formed by treating the compound 3-Scheme 3 with the appropriate carbamylating reagent, such as di-t-butyldicarbonate, under appropriate conditions, such as dichloromethane solvent with dimethylaminopyridine coreagent.
- Alkylation of the activated guanidine can then proceed by deprotonation with a suitable base, especially sodium hydride in a suitable solvent, such as dimethylformamide, followed by addition of the desired alkylating agent, in this example, benzyl bromide.
- a suitable base especially sodium hydride in a suitable solvent, such as dimethylformamide
- the desired alkylating agent in this example, benzyl bromide.
- Deprotection of the guanidine with, for example, trifluoroacetic acid in dichloromethane, provides the final product 4-Scheme 3.
- the monosubstituted guanidine 1 -Scheme 5 is activated towards alkylation by formation of a suitable derivative, such as a carbamate, especially the t- butyoxycarbonylguanidine 2-Scheme 5. which is formed by reaction with a suitable carbamylating reagent , such as di-r-butyldicarbonate, under appropriate reaction conditions, such as using dimethylaminopyridine as a coreagent and dichloromethane- methanol as the solvent.
- a suitable carbamylating reagent such as di-r-butyldicarbonate
- the .-butoxycarbonylguanidine 2-Scheme 5 may be deprotonated with a suitable base, such as sodium hydride, in an appropriate solvent, such as dimethylformamide, followed by treatment with an alkylating reagent, for example with methyl iodide or with benzyl bromide and added sodium iodide, to provide the desired t- butoxycarbonyl-protected disubstituted guanidine 3-Scheme 5.
- a suitable base such as sodium hydride
- an appropriate solvent such as dimethylformamide
- the chloroalkoxyaromatic 1 -Scheme 6 may be used to alkylate an aniline, for example N-methylaniline in a suitable solvent, especially dimethylformamide, acetonitrile or nitromethane, at high heat, with or without the addition of sodium iodide. These reaction conditions also cause the removal of the r-butoxycarbonyl group to provide the final products 2-Scheme 6.
- an aniline for example N-methylaniline in a suitable solvent, especially dimethylformamide, acetonitrile or nitromethane
- halogen exchange reactions such treatment with sodium iodide in refluxing acetone, may precede the anilination reaction.
- the iodobutoxyaromatic 1 -Scheme 7 may be reacted with a secondary amine, in these examples with mo ⁇ holine or N-r-butoxycarbonylpiperazine, in a suitable solvent, such as dimethylformamide at high heat to provide the aminated compounds 2-Scheme 7.
- a suitable solvent such as dimethylformamide
- Aminothiazole 1 -Scheme 8 may be treated with an isocyanate, such as benzyl isocyanate in an appropriate solvent, such as refluxing toluene, to provide the substituted thiazole urea 2-Scheme 8.
- an isocyanate such as benzyl isocyanate
- an appropriate solvent such as refluxing toluene
- the iodopropoxyaromatic 1 -Scheme 9 may be treated with the anion of a carbamate, especially the benzyl or r-butyl carbamates, of 3,4-dichloroaniline to prepare the anilinated intermediate.
- the anion may be formed by treatment of the protected aniline with a suitable base, for example a butyllithium or a metal hydride, especially sodium hydride, in a suitable solvent, such as tetrahydrofuran or dimethyformamide, especially dimethylformamide.
- Removal of the r-butoxycarbonyl group(s) may be achieved by treatment of the intermediate with suitable reagents, such as trifluoroacetic acid in the appropriate solvent, such as dichloromethane to provide the disubstituted aniline 2-Scheme 9 and the benzylcarbamate substituted analog 3-Scheme 9.
- suitable reagents such as trifluoroacetic acid in the appropriate solvent, such as dichloromethane
- Coupling methods to form amide bonds herein are generally well known to the art.
- the methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEP ⁇ DES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are inco ⁇ orated herein by reference.
- amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
- Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
- Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
- Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH4 + are specific examples of cations present in pharmaceutically acceptable salts.
- Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
- This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament.
- compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration.
- Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
- the liquid formulation may be a buffered, isotonic, aqueous solution.
- suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
- Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
- these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
- Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
- Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
- Liquid carriers include syrup, peanut oil, olive oil, saline and water.
- the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
- the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
- a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
- Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
- the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
- the thiazoleguanidines of this invention are uncompetitive inhibitors that are comparatively poor inhibitors at low substrate concentrations. More specifically, we have discovered that these compounds display a dual mode of inhibition: 1) Induced substrate inhibition in the presence of substrate (that is, the protein which the enzyme degrades or otherwise operates on) wherein at higher K m levels of substrate, the present compounds induce the substrate to become an inhibitor of the enzyme.
- substrate that is, the protein which the enzyme degrades or otherwise operates on
- the present compounds induce the substrate to become an inhibitor of the enzyme.
- the present thiazoleguanidines appear to bind exclusively to an enzyme form that has already bound substrate; and 2) Double inhibition studies with the present thiazoleguanidines and exemplary protease inhibitors that are active-site directed, mechanism-based inhibitors (most particularly of cathepsin K, as disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997) show that the present compounds and the mechanism-based inhibitors can both bind at
- the compounds of Formula I are useful as protease inhibitors.
- the compounds of Formula I are particularly useful as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K.
- the present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
- the present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease.
- Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
- the present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family.
- These methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof an effective amount of a compound or combination of compounds of the present invention, optionally together with an effective amount of an active-site directed, mechanism-based inhibito, the enzyme inhibition properties of which are capable of being augmented by the presence of the inventive compounds.
- Exemplary such inhibitors are disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997.
- the present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof an effective amount of a compound or combination of compounds of the present invention, optionally together with an effective amount of an active-site directed, mechanism-based inhibitor (for instance, as disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997), the enzyme inhibition properties of which are capable of being augmented by the presence of the inventive compounds.
- an active-site directed, mechanism-based inhibitor for instance, as disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997), the enzyme inhibition properties of which are capable of being augmented by the presence of the inventive compounds.
- an active-site directed, mechanism-based inhibitor for instance, as disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997), the enzyme inhibition properties of which are capable of being augmented by the presence of the
- the present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
- diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata;
- This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to an animal, particularly a mammal, most particularly a human in need thereof an effective amount of a compound or combination of compounds of Formula I, optionally together with an effective amount of an inhibitor of cathepsin K capable of being augmented by the presence of the inventive co- inhibitors (for instance, as disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997), optionally in combination with other inhibitors of bone reso ⁇ tion, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
- bisphosphonates i.e., allendronate
- hormone replacement therapy i.e., anti-estrogens, or calcitonin.
- treatment with a compound of this invention optionally together with an effective amount of an inhibitor of cathepsin K capable of being augmented by the presence of the inventive compounds(for instance, as disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997), and an anabolic agent, such as bone mo ⁇ hogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.
- an anabolic agent such as bone mo ⁇ hogenic protein, iproflavone
- parenteral administration of a compound of Formula I optionally simultaneously or sequentially with an effective amount of a protease inhibitor capable of being augmented by the presence of the inventive compounds (for instance, as disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997) is preferred.
- an intravenous infusion of the inventive compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients is most effective, although an intramuscular bolus injection is also useful.
- the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K.
- the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
- the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
- the compounds of this invention may also be administered orally to the patient, optionally simultaneously or sequentially with an effective amount of a protease inhibitor capable of being augmented by the presence of the inventive compounds (for instance, as disclosed in International Publication No. WO 97/16433, having an International Publication Date of May 9, 1997), in a manner such that the concentration of drug is sufficient to inhibit bone reso ⁇ tion or to achieve any other therapeutic indication as disclosed herein.
- a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
- the oral dose would be about 0.5 to about 20 mg/kg.
- the compounds of the present invention may be tested in one of several biological assays to determine the concentration of compound which is required to provide a given pharmacological effect.
- v is the velocity of the reaction with maximal velocity V m
- A is the concentration of substrate with Michaelis constant of K a
- / is the concentration of inhibitor
- [AMC] v ss t + (vo - v ss ) [1 - exp (-k 0 b S t)l / k 0 b s (2)
- the cells were washed x2 with cold RPMI-1640 by centrifugation (1000 ⁇ m, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber. Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.
- the beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded. The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample.
- the cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xl0 ⁇ /mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL).
- the tubes were incubate at 37°C for 30 min. 0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL / well in a 6- well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C.
- the slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
- the TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.
- Example 1 a N-benzyl-N-.-butoxycarbony 1-N - ⁇ 4- [3-(4-methoxybutoxy)pheny l]thiazol-2- yl ⁇ guanidine was prepared following the procedures described in Example 1, m.p. 70- 71°C.
- N-r-Butoxycarbonyl-N'- ⁇ 4-[3-(4-N-(4-bromophenvD-N- methylaminobutoxy)phenyllthiazol-2-yl ) guanidine A mixture of N- ⁇ 4-[3-(4-N-(4-bromophenyl)-N- methylaminobutoxy)phenyl]thiazol-2-yl ⁇ guanidine (0.44 g, 0.92 mmol), di-t- butyldicarbonate (0.25 g, 1.15 mmol) and several crystals of 4-(N,N- dimethylamino)pyridine in dichloromethane (5 mL) was stirred at room temperature under argon for 20h.
- N-Benzyl- N-r-butoxycarbonyl-N'-f4-r3-(4-iodobutoxy)phenyl]thiazol-2-yl ) guanidine A mixture of N-benzyl-N-/-butoxycarbonyl-N'- ⁇ 4-[3-(4- chlorobutoxy)phenyl]thiazol-2-yl ⁇ guanidine (0.26 g, 0.51 mmol) and sodium iodide (0.23 g, 1.53 mmol) in acetone (10 mL) was refluxed for 48 h.
- N-Benzyl-N - ⁇ 4- [3-(4-N-mo ⁇ holinobutox v)phenyl1thiazol-2-yl ) guanidine A solution of N-benzyl-N-t-butoxycarbonyl-N'- ⁇ 4-[3-(4-N- mo ⁇ holinobutoxy)phenyl]thiazol-2-yl ⁇ guanidine (0.14 g, 0.25 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 5 h.
- N-f- Butoxycarbonyl-N'-(4-f3-(4-iodobutoxy)phenyllthiazol-2-vU guanidine A mixture of N-t-butoxycarbonyl-N '- ⁇ 4-[3-(4-chlorobutoxy)phenyl]thiazol-2- yljguanidine (3.52 g, 8.27 mmol) and sodium iodide (3.70 g, 24.8 mmol) in acetone (75 mL) was refluxed for 24 h.
- N-Benzyl-N-r-butoxycarbonyl-N'- 4-[3-(4-(N-t- butoxycarbonylpiperazinobutoxy)phenvnthiazol-2-yl 1 guanidine
- N-benzyl-N-_-butoxycarbonyl-N'- ⁇ 4-[3-(4- bromobutoxy)phenyl]thiazol-2-yl ⁇ guanidine (0.24 g, 0.42 mmol)
- N-t- butoxycarbonylpiperazine (0.39 g, 2.1 mmol) in dimethylformamide (5 mL) was heated at 135-140°C for 3 h.
- N-Benzyl-N'-f4-r3-( ' 4-N-piperazinobutoxy phenv ⁇ thiazol-2-y ⁇ guanidine A solution of N-benzyl-N-f-butoxycarbonyl-N'- ⁇ 4-[3-(4-N-t- butoxycarbonylpiperazinobutoxy)phenyl]thiazol-2-yl ⁇ guanidine (0.29 g, 0.42 mmol) and trifluoroacetic acid (1.5 mL) in dichloromethane (1.5 mL) was stirred at room temperature for 5 h.
- the reaction was diluted with water, was neutralized (sodium bicarbonate), was three times extracted with 5/95 methanol/dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.2:2:8 ammonium hydroxide:methanol:dichloromethane, provided the title compound (0.11 g, 58%) as a waxy, pale pink solid, m.p. 130-134°C.
- N-benzyl-N'- ⁇ 4- ⁇ 4-[3- iodopropoxy]phenyl ⁇ thiazol-2-yl Jurea (0.17 g, 0.35 mmol) and N-(3,4-dichlorophenyl)-N- methylamine (0.13g, 0.7 mmol) in dimethylformamide (3 mL) was heated at 135-140°C for 8 h, then at room temperature for 18 h. The reaction was diluted with water and was extracted twice with ethyl acetate. The combined organic phase was washed three times with water, once with brine, was dried (magnesium sulfate) and was evaporated.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002302361A CA2302361A1 (en) | 1997-09-04 | 1998-09-03 | Protease inhibitors |
JP2000508676A JP2001514257A (en) | 1997-09-04 | 1998-09-03 | Protease inhibitor |
EP98945850A EP1015438A4 (en) | 1997-09-04 | 1998-09-03 | Protease inhibitors |
AU93002/98A AU9300298A (en) | 1997-09-04 | 1998-09-03 | Protease inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5752797P | 1997-09-04 | 1997-09-04 | |
US60/057,527 | 1997-09-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999011637A1 true WO1999011637A1 (en) | 1999-03-11 |
Family
ID=22011125
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/018289 WO1999011637A1 (en) | 1997-09-04 | 1998-09-03 | Protease inhibitors |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1015438A4 (en) |
JP (1) | JP2001514257A (en) |
AU (1) | AU9300298A (en) |
CA (1) | CA2302361A1 (en) |
CO (1) | CO4970736A1 (en) |
MA (1) | MA26540A1 (en) |
PE (1) | PE115699A1 (en) |
SA (1) | SA98190653A (en) |
WO (1) | WO1999011637A1 (en) |
ZA (1) | ZA988064B (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6534498B1 (en) | 1999-11-10 | 2003-03-18 | Smithkline Beecham Corporation | Protease inhibitors |
US6583137B1 (en) | 1999-11-10 | 2003-06-24 | Smithkline Beecham Corporation | Protease inhibitors |
US6596715B1 (en) | 1999-11-10 | 2003-07-22 | Smithkline Beecham Corporation | Protease inhibitors |
US6699866B2 (en) | 2001-04-17 | 2004-03-02 | Sepracor Inc. | Thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonin receptors and transporters, and methods of use thereof |
US7071184B2 (en) | 2000-03-21 | 2006-07-04 | Smithkline Beecham Corporation | Protease inhibitors |
US7282512B2 (en) | 2002-01-17 | 2007-10-16 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors |
US7342027B2 (en) | 2002-07-26 | 2008-03-11 | Yuhan Corporation | 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof |
US7405209B2 (en) | 1998-12-23 | 2008-07-29 | Smithkline Beecham Corporation | Protease inhibitors |
EP2366697A1 (en) | 2004-02-19 | 2011-09-21 | Abbott GmbH & Co. KG | Guanidine compounds and use of same as binding partners for 5-HT5 receptors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59225172A (en) * | 1983-06-03 | 1984-12-18 | Yamanouchi Pharmaceut Co Ltd | Novel guanidinothiazole derivative and its preparation |
-
1998
- 1998-09-01 MA MA25238A patent/MA26540A1/en unknown
- 1998-09-03 JP JP2000508676A patent/JP2001514257A/en not_active Withdrawn
- 1998-09-03 CO CO98050517A patent/CO4970736A1/en unknown
- 1998-09-03 ZA ZA988064A patent/ZA988064B/en unknown
- 1998-09-03 WO PCT/US1998/018289 patent/WO1999011637A1/en not_active Application Discontinuation
- 1998-09-03 EP EP98945850A patent/EP1015438A4/en not_active Withdrawn
- 1998-09-03 CA CA002302361A patent/CA2302361A1/en not_active Abandoned
- 1998-09-03 AU AU93002/98A patent/AU9300298A/en not_active Abandoned
- 1998-09-04 PE PE1998000830A patent/PE115699A1/en not_active Application Discontinuation
- 1998-10-17 SA SA98190653A patent/SA98190653A/en unknown
Non-Patent Citations (2)
Title |
---|
DATABASE STN WPIDS 1 January 1900 (1900-01-01), "NEW QUANIDINO THIAZOLE DERIVS. - USEFUL AS HISTAMINE H1 AND H2 RECEPTOR ANTAGONISTS AND FOR PROTECTING GASTRIC MUCOSA", XP002915165 * |
See also references of EP1015438A4 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7405209B2 (en) | 1998-12-23 | 2008-07-29 | Smithkline Beecham Corporation | Protease inhibitors |
US6534498B1 (en) | 1999-11-10 | 2003-03-18 | Smithkline Beecham Corporation | Protease inhibitors |
US6583137B1 (en) | 1999-11-10 | 2003-06-24 | Smithkline Beecham Corporation | Protease inhibitors |
US6596715B1 (en) | 1999-11-10 | 2003-07-22 | Smithkline Beecham Corporation | Protease inhibitors |
US7071184B2 (en) | 2000-03-21 | 2006-07-04 | Smithkline Beecham Corporation | Protease inhibitors |
US7563784B2 (en) | 2000-03-21 | 2009-07-21 | Smithkline Beecham Corporation | Protease inhibitors |
US6699866B2 (en) | 2001-04-17 | 2004-03-02 | Sepracor Inc. | Thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonin receptors and transporters, and methods of use thereof |
US7087623B2 (en) | 2001-04-17 | 2006-08-08 | Sepracor Inc. | Thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonin receptors and transporters, and methods of use thereof |
US7282512B2 (en) | 2002-01-17 | 2007-10-16 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors |
US7342027B2 (en) | 2002-07-26 | 2008-03-11 | Yuhan Corporation | 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof |
EP2366697A1 (en) | 2004-02-19 | 2011-09-21 | Abbott GmbH & Co. KG | Guanidine compounds and use of same as binding partners for 5-HT5 receptors |
EP2366392A1 (en) | 2004-02-19 | 2011-09-21 | Abbott GmbH & Co. KG | Guanidine compounds and use of same as binding partners for 5-HT5 receptors |
Also Published As
Publication number | Publication date |
---|---|
SA98190653A (en) | 2005-12-03 |
CO4970736A1 (en) | 2000-11-07 |
EP1015438A1 (en) | 2000-07-05 |
PE115699A1 (en) | 2000-01-13 |
JP2001514257A (en) | 2001-09-11 |
ZA988064B (en) | 1999-05-28 |
CA2302361A1 (en) | 1999-03-11 |
AU9300298A (en) | 1999-03-22 |
MA26540A1 (en) | 2004-12-20 |
EP1015438A4 (en) | 2000-11-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6642252B2 (en) | Acid derivatives useful as serine protease inhibitors | |
ES2298288T3 (en) | DERIVATIVES OF 4,6-DIFENYL PIRIDINE AS ANTI-INFLAMMATORY AGENTS. | |
CA2287567A1 (en) | Protease inhibitors | |
WO1998048799A1 (en) | Protease inhibitors | |
WO2013106761A2 (en) | Antimicrobial agents | |
WO1998008802A1 (en) | Inhibitors of cysteine protease | |
US6518267B1 (en) | Protease inhibitors | |
JP2004517060A (en) | Acid derivatives useful as serine protease inhibitors | |
WO1999011637A1 (en) | Protease inhibitors | |
US20060173057A1 (en) | Methods of treating factor VIIa-associated conditions with compounds having an amine nucleus | |
CN115304603B (en) | Preparation and application of quinazoline inhibitor | |
US20020049316A1 (en) | Protease inhibitors | |
WO1999059570A1 (en) | Protease inhibitors | |
US5576334A (en) | Acylurea derivatives | |
JP4313678B2 (en) | Hydroxamic acid derivative and MMP inhibitor containing the same | |
US7807720B2 (en) | Hydroxamic acid derivatives of 3-phenyl propionic acids useful as therapeutic agents for treating anthrax poisoning | |
US6846838B2 (en) | Ureido-substituted aniline compounds useful as serine protease inhibitors | |
MX2008000751A (en) | 2-cyano-pyrimidines and -triazines as cysteine protease inhibitors. | |
CZ380999A3 (en) | Inhibitors of proteases | |
KR20050096063A (en) | Novel acryl derivative having strong inhibiting activity against sortase enzyme and the pharmaceutical composition comprising the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AU BA BB BG BR CA CN CZ EE GE HU ID IL IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1998945850 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2302361 Country of ref document: CA Ref country code: CA Ref document number: 2302361 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09486995 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: KR |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2000 508676 Kind code of ref document: A Format of ref document f/p: F |
|
WWP | Wipo information: published in national office |
Ref document number: 1998945850 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1998945850 Country of ref document: EP |