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EP0975612A1 - Inhibiteurs de proteases - Google Patents

Inhibiteurs de proteases

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Publication number
EP0975612A1
EP0975612A1 EP98919821A EP98919821A EP0975612A1 EP 0975612 A1 EP0975612 A1 EP 0975612A1 EP 98919821 A EP98919821 A EP 98919821A EP 98919821 A EP98919821 A EP 98919821A EP 0975612 A1 EP0975612 A1 EP 0975612A1
Authority
EP
European Patent Office
Prior art keywords
pyrrolidin
6alkyl
benzyloxycarbonylamino
compound according
het
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98919821A
Other languages
German (de)
English (en)
Other versions
EP0975612A4 (fr
Inventor
Kevin J. Duffy
Scott K. Thompson
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0975612A1 publication Critical patent/EP0975612A1/fr
Publication of EP0975612A4 publication Critical patent/EP0975612A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero 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
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • This invention relates to novel protease inhibitors, particularly 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.
  • Cathepsin K is a member of the family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 1251 1-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
  • Cathepsin K has been variously denoted as cathepsin O, cathepsin X or cathepsin 02 in the literature.
  • the designation cathepsin K is considered to be the more appropriate one (name assigned by Nomenclature Committee of the International Union of Biochemistry and Molecular Biology).
  • Cathepsins of the papain superfamily of cysteine proteases function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue.
  • elevated levels of these enzymes in the body can result in pathological conditions leading to disease.
  • cathepsins have been implicated in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like.
  • 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.
  • 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.
  • cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, 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.
  • 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.
  • protease inhibitors most particularly inhibitors of cathepsin K, and these compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis and periodontal disease.
  • An object of the present invention is to provide 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 a method 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.
  • the present invention provides compounds of formula (I):
  • R 1 is R", R"C(0), R"C(S), R"S0 2 , R"0C(0), or R"0C(0)NR'CH(R 6 )C(0);
  • R2 is H, Cj-galkyl, C2_6al enyl, Ar-C ⁇ -6alkyl, or Het-Co_6alkyl;
  • R3 is H, Ci-galkyl, C2-6 alkenyl, C2-6alkynyl, C ⁇ .gcycloalkyl-Co-g 'kyl, Ar-Co-6 a lkyl, or Het-Co-6 a lkyl
  • R 4 is H, Ci.galkyl, C2_6alkenyl, Ar-C ⁇ -6alkyl, or Het-C 0 -6alkyl;
  • R 5 is C ⁇ galkyl, Ar-C 0 _6alkyl, Het-C 0 -6alkyl, CH(R 6 )NR R 7 , CH(R 6 )Ar, CH(R 6 )OAr, or NR 8 R 9 ; each R independently is H, C ⁇ .galkyl, C2-6alkenyl, C3.gcycloalkyl-C0.6- alkyl, Ar-C ⁇ -6alkyl, Het-Co_6alkyl; R 7 is R", R"C(0), R"C(S), R"S ⁇ 2, R"0C(0), or R"0C(0)NR CH(R 6 )C(0);
  • R 8 is H, Cj.galkyl, C2_6alkenyl, Ar-Co- alkyl, or Het- Co-6 a 'kyl and R 9 is Cj.galkyl, C3_6cycloalkyl-Co_6alkyl, Ar-Co_6 lkyl, or Het-Cg-galkyl; or R° and R" are combined to form a 3-7 membered monocyclic or 7-10-membered bicyclic carbocyclic or heterocyclic ring, optionally substituted with 1-4 of C j .galkyl, Ar- Co-6alkyl, Het-Co_6alkyl, Cj.galkoxy, Ar-Co-6alkoxy, Het-CQ-6alkoxy, OH, (CH2) ⁇ _ 6 NR R", or 0(CH 2 ) ⁇ .6NR R";
  • R 1 ⁇ is H, Cj.galkyl, C2-6 alkenyl, C2-6 a lkynyl, C3_gcycloalkyl-Co_6alkyl, Ar-Co-6 a lkyl, or Het-Co-6 a lkyl; each R independently is H, Ci .galkyl, C2_6 a l enyl, Ar-C ⁇ -6alkyl, or Het-C ⁇ - 6 auc yi; each R independently is Cj.galkyl, Ar-C ⁇ -6 a 'kyl, or Het-Cg- ⁇ alkyl; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • 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.
  • R 2 , R 4 and R 10 are H and R 3 is H, C ⁇ galkyl, C2-6 alkenyl or C3_6cycloalkyl-CH 2 .
  • R 5 is CH(R 6 )NR R 7 , in which R 6 is i-butyl and R' is H. More preferably, R 7 is R" ⁇ C(0) or R"C(0), in which R" is C ⁇ _6alkyl, Ar-C()-6alkyl, or and, most preferably, R is
  • R-> is Ar, in which Ar in said R ⁇ group is
  • R 1 is R" ⁇ C(0) or R"C(0), in which R" in said R 1 group is
  • n is 1 or 2.
  • n is 1.
  • this invention is a compound of formula (II):
  • the formula (II) compound of this invention is a compound of formula
  • novel intermediates useful in the preparation of formula (I) compounds represented by: 2-benzyloxyphenylboronic acid; ethyl 2-(2-benzyloxyphenyl)thiazol-4-carboxylate; 2-(2-benzyloxyphenyl)thiazol-4-carboxylic acid;
  • 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 T )2, C(0)N(R")2, carbamyl or C]-4alkyl, where R' is H or Ci-galkyl.
  • C ⁇ alkyl means that no alkyl group is present in the moiety.
  • Ar-C ⁇ alkyl is equivalent to Ar.
  • C3-6cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C2-6alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C2-6 a lkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • Halogen or “halo” means F, Cl, Br, and I.
  • "Ar” or “aryl” means unsubstituted phenyl or naphthyl; or phenyl or naphthyl substituted by one or more of Ph-Co-6 a lkyl, Het-Co- ⁇ alkyl, Cj.galkoxy, Ph-Co-6 a lkoxy, Het-Co-6alkoxy, OH, (CH2) ⁇ -6NR R ' , 0(CH2) I_6NR'R'; wherein each R independently is H, C j -galkyl, Ar-Co-6 a lkyl, or Het-Co-6 a lkyl; or phenyl or naphthyl substituted by one to three moieties selected from C ⁇ -4alkyl, OR', W) 2 , SR ⁇ CF 3 , NO 2 , CN, CO 2 R', COW), F, Cl, Br and I.
  • Het represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four 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, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • 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 C ⁇ _4alkyl, OR', N(R T )2, SR', CF 3 , N0 2 , CN, C0 2 R', CON(R'), F, Cl, Br and I, where R' is C ⁇ -6alkyl.
  • heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyr
  • HetAr or “heteroaryl” means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, e.g., pyridinyl, quinolinyl, isoquinolinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, furyl, thienyl, benzoxazolyl, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl, 1,6- napthyrid
  • heterocyclic ring described as includes thiazoles, oxazoles, triazoles, thiadiazoles, oxadiazoles, isoxazoles, isothiazols, imidazoles, pyrazines, pyridazines, pyrimidines, triazines and tetrazines which are available by routine chemical synthesis and are stable.
  • the single and double bonds (i.e., — ) in such heterocycles are arranged based upon the heteroatoms present so that the heterocycle is aromatic (e.g., it is a heteroaryl group).
  • heteroatom as applied herein refers to oxygen, nitrogen and sulfur.
  • W is preferably an electron withdrawing group, such as halogen, -CN, -CF3, -NO2, -COR , -C0 2 R ' , -CONHR ' , -S0 2 NHR', -NHS0 2 R ' , -NHCOR ' , -0-COR', -SR ' or NRT* ' , or a similar electron withdrawing substituent as known in the art.
  • an electron withdrawing group such as halogen, -CN, -CF3, -NO2, -COR , -C0 2 R ' , -CONHR ' , -S0 2 NHR', -NHS0 2 R ' , -NHCOR ' , -SR ' or NRT* ' , or a similar electron withdrawing substituent as known in the art.
  • t-Bu refers to the tertiary butyl radical
  • Boc or BOC refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz or CBZ refers to the benzyloxycarbonyl radical.
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP is 2,6-dimethylaminopyridine
  • EDC or EDCI refers to N-ethyl- N'(dimethylaminopropyl)-carbodiimide.
  • HOBT or HOBt refers to 1-hydroxybenzotriazole
  • DMF refers to dimethyl formamide
  • BOP refers to benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
  • DMAP is dimethylaminopyridine
  • Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4- disulfide
  • NMM is N-methylmorpholine
  • TFA refers to trifluoroacetic acid
  • TFAA refers to trifluoroacetic anhydride
  • KHMDS refers to potassium hexamethyldisilazide
  • THF refers to tetrahydrofuran.
  • Jones reagent is a solution of chromium trioxide, water, and sulfuric acid well-known in the art.
  • the 2-aminothiazole 1 -Scheme 1 is readily prepared by the condensation of thiourea with ethyl bromopyruvate in acetone at 45°C. Diazotisation of 1 -Scheme 1 is performed with sodium nitrite in aqueous acidic media, such as hydrobromic acid, and the resulting diazo compound treated with copper bromide affording the bromothiazole 2 ⁇ Scheme 1.
  • Coupling of 2-Scheme 1 with an aryl boronic acid is carried out using catalytic tetrakis(triphenyl- phosphine)palladium and a base, such as sodium hydrogen carbonate, in refluxing toluene/ethanol to afford 3-Scheme 1.
  • a base such as sodium hydrogen carbonate
  • D-Methionine (or L-methionine - not shown) is treated with a chloroformate, such as benzylchloroformate, in the presence of base, such as aqueous sodium hydroxide, to afford 2-Scheme 1.
  • a chloroformate such as benzylchloroformate
  • base such as aqueous sodium hydroxide
  • 2-Scheme 1 Condensation of 2-Scheme 1 with tert-butyl carbazate in the presence of a peptide coupling reagent, such as EDCI.HCl/HOBt, in an aprotic solvent, such as DMF, provides 2-Scheme 2.
  • a peptide coupling reagent such as EDCI.HCl/HOBt
  • an aprotic solvent such as DMF
  • Removal of the tert-butoxycarbonyl protecting group is carried out by treatment with an appropriate acid, such as hydrochloric acid of trifluoroacetic acid, in an aprotic solvent, such as 1,4-dioxane of dichloromethane, and the resulting amine hydrochloride is immediately coupled with an appropriate thiazole carboxylic acid (4- Scheme 1 ) in the presence of a peptide coupling reagent, such as EDCI.HCl/HOBt, and a base, such as N-methylmorpholine, in an aprotic solvent, such as DMF, to provide the hydrazides 5-Scheme 2.
  • an appropriate acid such as hydrochloric acid of trifluoroacetic acid
  • an aprotic solvent such as 1,4-dioxane of dichloromethane
  • R 2 and R 4 are H, R 3 is Cj.galkyl R ⁇ is unsubstituted or substituted aromatic, Z is N, X is CH, Y is S, and n is 1 are prepared by methods analogous to those described in Scheme 3.
  • D-Methionine was converted into the sodium salt 1 -Scheme 3 upon treatment with sodium hydroxide in aqueous ethanol.
  • 1 -Scheme 3 Treatment of 1 -Scheme 3 with trimethyl- acetaldehyde in an appropriate solvent, such as pentane or hexane, at reflux affords the imine 2-Scheme 3 which is further treated with a chloroformate, such as benzyl chloroformate, at low temperature (-15 to 5°C) in an appropriate solvent, such as dichloromethane or chloroform, to give the oxazolidinone 3-Scheme 3.
  • a chloroformate such as benzyl chloroformate
  • Removal of the tert- butoxycarbonyl protecting group from 8-Scheme 3 is carried out by treatment with an appropriate acid, such as hydrochloric acid of trifluoroacetic acid, in an aprotic solvent, such as 1,4-dioxane of dichloromethane, and the resulting amine hydrochloride is immediately coupled with an appropriate thiazole carboxylic acid (4-Scheme 1) in the presence of a peptide coupling reagent, such as EDCI.HCl/HOBt, and a base, such as N- methylmorpholine, in an aprotic solvent, such as DMF, to provide the hydrazides 9-Scheme 3.
  • an appropriate acid such as hydrochloric acid of trifluoroacetic acid
  • an aprotic solvent such as 1,4-dioxane of dichloromethane
  • R 2 , R 3 and R 4 are H, R? is arylcarboxamido or alkoxy- or aryloxycarbonylamino- substituted alkyl, Z is N, X is CH, Yis S, and n is 1 are prepared by methods analogous to those described in Scheme 4.
  • a commercially available urethane protected L-leucine (such as CBZ-leucine or BOC-leucine) was treated with isobutyl chloroformate in the presence of N-methyl morpholine then with methanolic ammonia to give 1 -Scheme 4.
  • Treatment of 1 -Scheme 4. with Lawesson's reagent afforded the thioamide 2-Scheme 4. which was condensed with ethyl bromopyruvate in acetone at 45°C to afford 3-Scheme 4.
  • Hydrolysis to the corresponding carboxylic acid 4-Scheme 4 occurs readily at room temperature on treatment with aqueous base, such as sodium hydroxide of lithium hydroxide.
  • the starting materials used herein are commercially available amino acids or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I- VI (published by Wiley-Interscience).
  • the unnatural amino acids starting materials such as side-chained substituted methionine for formula (I) compounds wherein n is 1 and side-chained substituted ornithine for formula (I) compounds wherein n is 2, are readily prepared using standard amino acid syntheses known in the art, for example glycine alkylation and Strecker synthesis, to prepare formula (I) compounds wherein R*0 is other than H. Coupling methods to form amide bonds herein are generally well known to the art.
  • 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.
  • compositions which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of formula (I) may be used in the manufacture of a medicament.
  • Pharmaceutical 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. Examples of 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.
  • 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 compounds of formula (I) are useful as protease inhibitors, particularly 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 as inhibitors of cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of the present invention.
  • 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 inhibitor of cathepsin K, including a compound of the present invention.
  • This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of formula (I), alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • a compound of formula (I) alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone may be used to prevent bone loss or to increase bone mass.
  • parenteral administration of a compound of formula (I) is preferred.
  • 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.
  • an inventive compound which is therapeutically effective 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, in a manner such that the concentration of drug is sufficient to inhibit bone resorption 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 this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
  • v V m A /[K a (l + I K it app) +A] (1)
  • 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] vcut t + (vo - vss) [1 - exp (-k o bs ] / k 0 bs (2)
  • the cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 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 4 /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.
  • Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.
  • CDCI3 is deuteriochloroform
  • DMSO-d6 is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane.
  • Tetrakis(triphenylphosphine)palladium(0) (0.65 g, 057mmol) was added and heating at 85 °C was continued for 5 h.
  • the mixture was diluted with water (60mL) and extracted with ethyl acetate (2 X 120mL). The combined extracts were washed with saturated aqueous NaHC ⁇ 3 and saturated brine, dried (MgS ⁇ 4), filtered and concentrated. The residue was purified by flash chromatography on 180 g of 230-400 mesh silica gel, eluting with 15% ethyl acetate in hexanes, to provide the title compound as a white solid (3.22 g, 56%).
  • N-benzyloxycarbonyl-L-leucinamide To a stirring solution of N-benzyloxycarbonyl-L-leucine (4.6 g, 17.3mmol) in THF, cooled to -40 °C, was added N-methylmorpholine (3.68 g, 36.4mmol; 4.0mL) and isobutyl chloroformate (2.37 g, 17.3mmol; 2.25mL). After stirring for 15 min, ammonia was bubbled through the solution for 5 min.
  • Example 1(b) The compound of Example 1(b) (2.20 g, 7.83mmol) was dissolved in acetone (35mL), cooled to -10 °C, and ethyl bromopyruvate (1.68 g, 8.62mmol, 1.08mL) was added. After stirring for 1 h, the solution was poured into dichloromethane/water, then into saturated aqueous NaHC ⁇ 3. The aqueous layer was extracted dichloromethane and the combined organic layers were washed with saturated brine, dried (MgSU4), filtered and concentrated.
  • This powder was suspended in dichloromethane (250mL), cooled to 0"C, then treated with benzyloxycarbonyl chloride (17.1mL, 120mmol) and the resulting suspension was stirred at 0"C for 6d then allowed to warm to room temperature for 24h. The mixture was quenched with water (lOOmL) and the layers were separated then the aqueous layer was extracted with more dichloromethane (2X). The combined extracts were was washed with 3N hydrochloric acid, saturated aqueous NaHCO,, water and saturated brine, then were dried (MgS ⁇ 4), filtered and concentrated.

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Abstract

Cette invention se rapporte à des composés représentés par la formule (I) dans laquelle X, Y et Z sont indépendamment N, O, S ou CR', à condition qu'au moins deux des éléments que sont X, Y et Z soient des hétéroatomes et qu'au moins l'un d'entre eux soit N; ou bien l'un des éléments que sont X, Y et Z est C=N, C=C ou N=N et les deux autres sont CR' ou N, à condition que X, Y et Z comportent dans leur ensemble au moins deux N; - - - indique une liaison simple ou double; R1 est R', R'C(O), R'C(S), R'SO¿2?, R'OC(O) ou R'OC(O)NR'CH(R?6¿)C(O); R2 est H, alkyle C¿1-6?, alkényle C2-6, Ar-alkyle C0-6 ou Het-alkyle C0-6; R?3¿ est H, alkyle C¿1-6?, alkényle C2-6, alkynyle C2-6, cycloalkyle C3-6- alkyle C0-6, Ar-alkyle C0-6 ou Het-alkyle C0-6; R?4¿ est H, alkyle C¿1-6?, alkényle C2-6, Ar-alkyle C0-6 ou Het-alkyle C0-6; R?5¿ est alkyle C¿1-6?, Ar-alkyle C0-6, Het-alkyle C0-6, CH(R?6)NR'R7, CH(R6¿)Ar, CH(R6)OAr ou NR8R9; R6, R¿7, R¿8 et R¿9? étant définis dans les spécifications de l'invention; R?10¿ est H, alkyle C¿1-6?, alkényle C2-6, alkynyle C2-6, cycloalkyle C3-6- alkyle C0-6, Ar-alkyle C0-6 ou Het-alkyle C0-6; et n est égal à 1, 2 ou 3. L'invention se rapporte également à des sels pharmaceutiquement acceptables de ces composés, qui sont des inhibiteurs de cystéine protéases, et notamment de la cathepsine K, et s'avèrent utiles au traitement de maladies dans lesquelles l'inhibition de la déperdition osseuse joue un rôle.
EP98919821A 1997-04-15 1998-04-15 Inhibiteurs de proteases Withdrawn EP0975612A4 (fr)

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US4309697P 1997-04-15 1997-04-15
US43096P 1997-04-15
US4453197P 1997-04-23 1997-04-23
US44531P 1997-04-23
PCT/US1998/007969 WO1998046582A1 (fr) 1997-04-15 1998-04-15 Inhibiteurs de proteases

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NZ520588A (en) 2000-03-21 2004-06-25 Smithkline Beecham Corp Protease inhibitors
HN2002000136A (es) 2001-06-11 2003-07-31 Basf Ag Inhibidores de la proteasa del virus hiv, compuestos que contienen a los mismos, sus usos farmaceuticos y los materiales para su sintesis
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
EP2714667B1 (fr) * 2011-05-27 2020-11-25 Laxman S. DESAI Inhibiteurs d'aminooxazole de kinases dépendantes d'une cycline

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US5244867A (en) * 1989-09-26 1993-09-14 Basf Aktiengesellschaft Oxazole- and thiazolecarboxamides
US5618792A (en) * 1994-11-21 1997-04-08 Cortech, Inc. Substituted heterocyclic compounds useful as inhibitors of (serine proteases) human neutrophil elastase

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