WO2000048993A1 - Arylaminoalkylamides - Google Patents
Arylaminoalkylamides Download PDFInfo
- Publication number
- WO2000048993A1 WO2000048993A1 PCT/EP2000/001197 EP0001197W WO0048993A1 WO 2000048993 A1 WO2000048993 A1 WO 2000048993A1 EP 0001197 W EP0001197 W EP 0001197W WO 0048993 A1 WO0048993 A1 WO 0048993A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- aryl
- lower alkyl
- nmr
- mhz
- Prior art date
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- 0 CC(NC1(CCCCC1)C(NCCNc1c(*)c(*)c(*)cc1)=O)=O Chemical compound CC(NC1(CCCCC1)C(NCCNc1c(*)c(*)c(*)cc1)=O)=O 0.000 description 3
- MYROVWFCBNTXHO-UHFFFAOYSA-N CC(C)COc(cc1)ccc1NCCN(C)C(C1(CCCCC1)NC(c1cc2ccccc2[o]1)=O)=O Chemical compound CC(C)COc(cc1)ccc1NCCN(C)C(C1(CCCCC1)NC(c1cc2ccccc2[o]1)=O)=O MYROVWFCBNTXHO-UHFFFAOYSA-N 0.000 description 1
- LQCIHXRYWIAFRV-UHFFFAOYSA-N CC(C)COc(cc1)ccc1NCCNC(C1(CCCCC1)NC(c1ccc(C2CCN(CCOC)CC2)cc1)=O)=O Chemical compound CC(C)COc(cc1)ccc1NCCNC(C1(CCCCC1)NC(c1ccc(C2CCN(CCOC)CC2)cc1)=O)=O LQCIHXRYWIAFRV-UHFFFAOYSA-N 0.000 description 1
- XTUCWVDCROKAQV-QFIPXVFZSA-N CC(C)C[C@@H](C(N(CCNc(cc1)ccc1OC(C)C)I)=O)NC(c1cc(cccc2)c2[o]1)=O Chemical compound CC(C)C[C@@H](C(N(CCNc(cc1)ccc1OC(C)C)I)=O)NC(c1cc(cccc2)c2[o]1)=O XTUCWVDCROKAQV-QFIPXVFZSA-N 0.000 description 1
- QRUPNBYADDKWNU-AWEZNQCLSA-N CC(C)C[C@@H](C(NCCN)=O)NC(OCc1ccccc1)=O Chemical compound CC(C)C[C@@H](C(NCCN)=O)NC(OCc1ccccc1)=O QRUPNBYADDKWNU-AWEZNQCLSA-N 0.000 description 1
- ABPSKKCXEFYKQF-SANMLTNESA-N CC(C)C[C@@H](C(NCCNc(cc1)ccc1OC)=O)NC(CN(CC1)CCN1c(cc1)ccc1OC)=O Chemical compound CC(C)C[C@@H](C(NCCNc(cc1)ccc1OC)=O)NC(CN(CC1)CCN1c(cc1)ccc1OC)=O ABPSKKCXEFYKQF-SANMLTNESA-N 0.000 description 1
- IJTODUASIQRBBU-QHCPKHFHSA-N CC(C)C[C@@H](C(NCCNc(cc1)ccc1OC)=O)NC(c1ccc(C(C)C)cc1)=O Chemical compound CC(C)C[C@@H](C(NCCNc(cc1)ccc1OC)=O)NC(c1ccc(C(C)C)cc1)=O IJTODUASIQRBBU-QHCPKHFHSA-N 0.000 description 1
- PTGYWSWHAPVSMA-NDEPHWFRSA-N CC(C)C[C@@H](C(NCCNc(cc1)ccc1OC)=O)NC(c1ccc(CCCc2cnccc2)cc1)=O Chemical compound CC(C)C[C@@H](C(NCCNc(cc1)ccc1OC)=O)NC(c1ccc(CCCc2cnccc2)cc1)=O PTGYWSWHAPVSMA-NDEPHWFRSA-N 0.000 description 1
- YQPAJRYVYCLIFJ-SFHVURJKSA-N CC(C)C[C@@H](C(NCCNc(cc1)ccc1OC1CCCC1)=O)N Chemical compound CC(C)C[C@@H](C(NCCNc(cc1)ccc1OC1CCCC1)=O)N YQPAJRYVYCLIFJ-SFHVURJKSA-N 0.000 description 1
- QYEHSHNAGORASG-SANMLTNESA-N CC(C)C[C@@H](C(NCCNc(cc1)ccc1OCCN1CCCC1)=O)NC(OCc1ccccc1)=O Chemical compound CC(C)C[C@@H](C(NCCNc(cc1)ccc1OCCN1CCCC1)=O)NC(OCc1ccccc1)=O QYEHSHNAGORASG-SANMLTNESA-N 0.000 description 1
- BPPZMSDSWLONGI-UHFFFAOYSA-N CN(CC1)CCN1c(cc1)ccc1C(NC1(CCCCC1)C(NCCNC(CC1)=CC=C1OCC(CC1)=CC=C1F)=O)=O Chemical compound CN(CC1)CCN1c(cc1)ccc1C(NC1(CCCCC1)C(NCCNC(CC1)=CC=C1OCC(CC1)=CC=C1F)=O)=O BPPZMSDSWLONGI-UHFFFAOYSA-N 0.000 description 1
- DHLUJPLHLZJUBW-UHFFFAOYSA-N Cc(nc1)ccc1O Chemical compound Cc(nc1)ccc1O DHLUJPLHLZJUBW-UHFFFAOYSA-N 0.000 description 1
- XGYKDNMYBHOMMX-UHFFFAOYSA-N Cc(nc1)ccc1Oc(cc1)ccc1C(O)=O Chemical compound Cc(nc1)ccc1Oc(cc1)ccc1C(O)=O XGYKDNMYBHOMMX-UHFFFAOYSA-N 0.000 description 1
- QBNGCACETWQCRD-UHFFFAOYSA-N Cc1cc(Cc(cc2)ccc2C(O)=O)cnc1 Chemical compound Cc1cc(Cc(cc2)ccc2C(O)=O)cnc1 QBNGCACETWQCRD-UHFFFAOYSA-N 0.000 description 1
- KQBQURAHBMPHNK-UHFFFAOYSA-N O=C(C1(CCCCC1)NC(OCc1ccccc1)=O)NCCNc(cc1)ccc1OCC1CC1 Chemical compound O=C(C1(CCCCC1)NC(OCc1ccccc1)=O)NCCNc(cc1)ccc1OCC1CC1 KQBQURAHBMPHNK-UHFFFAOYSA-N 0.000 description 1
- KSMDLHIHBOTGPL-UHFFFAOYSA-N OC(C1(CCCCC1)NC(c1cc(cccc2)c2[nH]1)=O)NCCNC1C=CC(OCC(CC2)CC=C2F)=CC1 Chemical compound OC(C1(CCCCC1)NC(c1cc(cccc2)c2[nH]1)=O)NCCNC1C=CC(OCC(CC2)CC=C2F)=CC1 KSMDLHIHBOTGPL-UHFFFAOYSA-N 0.000 description 1
- BBYDXOIZLAWGSL-UHFFFAOYSA-M [O-]C(c(cc1)ccc1F)=O Chemical compound [O-]C(c(cc1)ccc1F)=O BBYDXOIZLAWGSL-UHFFFAOYSA-M 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- 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
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- 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
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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- C07D211/44—Oxygen atoms attached in position 4
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
- C07D213/62—Oxygen or sulfur atoms
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with 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
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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- C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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- C07D295/088—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D295/14—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C07C2601/14—The ring being saturated
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
Definitions
- This invention relates to inhibitors of cysteine proteinases, in particular to arylaminoalkylamide cathepsin K inhibitors and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsin K is implicated.
- Cathepsin K is a member of the family of lysosomal cysteine cathepsin enzymes, e.g. cathepsins B, K, L and S, which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and immunologically mediated diseases (including transplant rejection).
- cathepsins B, K, L and S lysosomal cysteine cathepsin enzymes, e.g. cathepsins B, K, L and S, which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabil
- arylaminoalkylamides are useful as cathepsin K inhibitors and can be used for the treatment of the above-cited cysteine cathepsin dependent conditions.
- the present invention provides an aminoacid-arylaminoalkylamide in which the C-terminal carboxy group of the amino acid is substituted by an arylaminoalkylamino substituent and in which the amino nitrogen atom of the amino acid forms a peptide or pseudopeptide linkage which optionally additionally comprises a -methylene-hetero atom- linker or an additional hetero atom, through which it is directly substituted by aryl, lower alkyl, lower alkenyl, lower alkynyl or heterocyclyl, or a physiologically-acceptable and -cleavable ester or a salt thereof.
- the invention also provides an aminoacid-arylaminoalkylamide as defined above, for use as a pharmaceutical.
- the invention further provides a pharmaceutical composition comprising an aminoacid- arylaminoalkylamide as defined above as an active ingredient.
- the invention yet further provides a method of treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated, comprising administering an effective amount of an aminoacid-arylaminoalkylamide as defined above to the patient.
- the invention further includes the use of an aminoacid-arylaminoalkylamide as defined above for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated.
- the amino acid residue of the aminoacid-arylaminoalkylamides of the invention may be a ⁇ - amino acid residue and is preferably an ⁇ -amino acid residue, including both natural and unnatural ⁇ -amino acid residues.
- the "natural ⁇ -amino acid residues" denotes the 20 amino acids obtainable by translation of RNA according to the genetic code or the corresponding amides thereof, as appropriate.
- "Unnatural ⁇ -amino acid residues” are ⁇ -amino acids which have ⁇ - substituents other than those found in "natural ⁇ -amino acid residues".
- Preferred ⁇ -amino acid residues are 1-amino-cyclohexanecarboxylic acid, 1 -amino-cycloheptanecarboxylic acid, 2-amino- norbornan-2-carboxylic acid, 2-amino-2-ethyl-butanoic acid, phenylalanine, histidine, tryptophan and leucine and derivatives thereof, e.g. as hereinafter described.
- Preferred ⁇ -amino acid residues are those having side chains corresponding to those of the preferred ⁇ -amino acid residues.
- the aryl, lower alkyl, lower alkenyl, lower alkynyl or heterocyclyl substituent (hereinafter referred to as R) is attached to the the N-terminal nitrogen atom of the dipeptide via a peptide linkage, i.e. as R-C(O)-NH-, or via a pseudopeptide linkage.
- Suitable pseudopeptide linkages include sulphur in place of oxygen and sulphur and phosporous in place of carbon, e.g. as R-C(S)- NH-, R-S(O)-NH-, R-S(O) 2 -NH- or R-P(O) 2 -NH and analogues thereof.
- the peptide or pseudopeptide linkage between the R substituent and the N-terminal nitrogen atom may comprise an additional hetero atom, e.g. as R-Het-C(O)-NH-, or a -methylene-hetero atom- linker, e.g. as R-Het-CH 2 -C(O)-NH- or R-CH 2 -Het-C(O)-NH-, wherein Het is a hetero atom selected from O, N or S, and pseudopeptide containing alternatives thereof, e.g. as defined above.
- the linkage between the aryl substituent and the N-terminal nitrogen atom comprises a - methylene-hetero atom- linker
- the methylene group and the hetero atom may be optionally further substituted, e.g. as hereinafter described.
- the R substituent may be further substituted, e.g. by up to 5 substituents independently selected from halogen, hydroxy, amino, nitro, optionally substituted C ⁇ a-kyl (e.g. alkyl substituted by hydroxy, alkyloxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, aryl or heterocyclyl), C ⁇ . 4 alkoxy, C 2 _6alkenyl, CN, trifluoromethyl, trifluoromethoxy, aryl, (e.g.phenyl or phenyl substituted by CN, CF 3 , halogen, C ⁇ . 6 alkyl), aryloxy, (e.g.
- alkyl moiety of the aminoacid-arylaminoalkylamides of the invention is typically lower alkylene, preferably C 2 to C 6 lower alkylene, especially ethylene (i.e. -CH 2 -CH 2 -).
- the invention provides a compound of formula I, or a physiologically-acceptable and -cleavable ester or a salt thereof
- R is optionally substituted (aryl, lower alkyl, lower alkenyl, lower alkynyl, or heterocyclyl);
- R 2 and R 3 are independently hydrogen, or optionally substitued [lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-lower alkyl]; or R 2 and R 3 together represent lower alkylene, optionally interrupted by O, S or NR ⁇ , so as to form a ring with the carbon atom to which they are attached wherein R is hydrogen, lower alkyl or aryl-lower alkyl; or either R 2 or R 3 are linked by lower alkylene to the adjacent nitrogen to form a ring;
- Ar is optionally substituted aryl;
- X is -C(O)-, -C(S)-, -S(O)-, -S(0) 2 -, -P(O)(OR 6 )- where
- L is optionally substituted -Het-, -Het-CH - or -CH 2 -Het-, wherein Het is a hetero atom selected from O, N or S; n is 0 or 1 ; m is 1, 2, 3, 4 or 5; x is 0 or 1.
- aryl denotes both carbocyclic and heterocyclic aryl.
- R, R 2 , R 3 , Ar and L may be further substituted by one or more, e.g. up to 5, substituents independently selected from lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, heterocyclyl, -CN, -halogen, -OH, -NO 2 , -NR9R10, -lower alkyl-NR 9 R ⁇ 0 , -X 3 -R 7 , -lower alkyl-X 3 -R 8 , halo-substituted lower alkyl-, wherein R 7 is optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), and
- R 8 is H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl),
- X 3 is -O-, -S-, -NRg-, -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -C(O)O-, -C(S)O-, - C(O)NR 8 -, or -CH 2 - wherein R 8 is as defined above, R 9 and R 10 are independently as defined above for R 8 , or -X -R 8 , wherein X 4 is -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -C(O)O-, -C(S)O-, - C(O)NR 6 - wherein R 6 is as defined above, or R 9 and Rj 0 together with N form a heteroaryl group or a saturated or unsaturated heterocycloalkyl group, optionally containing one or more additional heteroatoms selected from O, N or S.
- Ar comprises an aryl or hetero aryl ring comprising from 5 to 8 ring atoms one of which may be may be a hetero atom, e.g. O, N or S, optionally substituted, e.g. by up to 3 substituents, for instance to provide a compound of formula II, or a physiologically-acceptable and -cleavable ester or a salt thereof
- R, R 2 , R 3 , L, Xi, x, n and m are as defined and R t , R 5 , Re and R 7 independently are H, lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy), aryl-lower alkoxy (e.g. -O- benzyl), cycloalkoxy, cycloalkyl-lower alkoxy (e.g. cycloalkylmethoxy), heterocyclyloxy, heterocyclyl-lower alkoxy, halogen, e.g. Cl, Br or F, or trifluoromethyl
- Y is -CH- or a heteroatom selected from O, N or S, and o is 0,1,2 or 3.
- n is 0 and/or m is 1 and/or o is 1, for instance to provide compounds of formulae V and II', or physiologically- acceptable and -cleavable esters or salts thereof
- R comprises aryl
- the aryl is optionally substituted (phenyl, naphthyl, phenanthrenyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzothienyl and benzofuranyl).
- R 2 is hydrogen
- R 3 is optionally substituted (lower alkyl, aryl-lower alkyl or cycloalkyl-lower alkyl), or R 3 and R 2 together with the carbon atom to which they are attached form a C 5 -C 8 , especially a C 6 or C 7 , cycloalkylgroup.
- R 3 is -CH 2 -CH(CH 3 ) 2 , or optionaUy substituted benzyl, cyclohexylmethyl, naphthalenylmethyl, indolylmethyl, benzothienylmethyl or benzofuranylmethyl, or R 3 and R 2 together with the carbon atom to which they are attached form a cyclohexane or cycloheptane ring.
- Ar is optionally substituted (phenyl, naphthyl, phenanthrenyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzothienyl and benzofuranyl). More preferably Ar is optionally substituted (phenyl, naphthyl, quinolinyl or 1,2,3,5-tetrahydroquinolinyl).
- Y is CH.
- R t , R 5 , R O , or R 7 preferably R 4 is lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy, butoxy, benzyloxy, pentafluorophenylmethoxy), or haloJe.g. chloro or fluoro).
- -X,- is -C(O)-.
- x is 0, or when x is 1 L is -CH 2 -O-.
- R 3 and R 2 together with the carbon atom to which they are attached form a C 5 -C 8 , especially a C 6 or C 7 , cycloalkyl group (including internally- bridged cycloalkyl groups, e.g. norborane); for instance to provide compounds of formula III
- R, L, X Ar, n and m are as defined above and p is 1, 2, 3 or 4; or physiologically- acceptable and -cleavable esters or salts thereof (and compounds in which the cycloalkyl group comprises an internal carbon-carbon bond or lower alkylene, e.g. methylene, bridge).
- the invention provides compounds of formulae and IV and IV, or physiologically- acceptable and -cleavable esters or salts thereof
- R' is optionally substituted (aryl or heterocyclyl);
- L' is -CH 2 -O-, -CH 2 -, -OC(R ⁇ R ]5 )- or a direct bond, where R 14 and R ⁇ 5 are independently
- R 2 ' is H and R ' is lower alkyl or cycloalkyl
- R 4 ', R 5 ' and R 7 ' are independently H, halogen, aryl-lower alkoxy, lower alkyl, lower alkoxy, cycloalkyloxy, cycloalkyl-lower alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy or optionally substituted amino-lower alkoxy.
- R 3 ' is isobutyl, propyl or cyclopentyl.
- R' as aryl is preferably phenyl (e.g. optionally substituted, preferably at the 4-position, e.g. by 4-methylpiperazinyl, phenyl, methoxy, isopropoxy, tertiary butoxy, ethyl, isopropyl, imidazolyl, oxazolyl, halogen, methylcarbonyl, diethylamino, pyrazolyl, l-(2-methoxyethyl)piperidin-4-yl, 1- methyl-3-imidazol-l-ylpropyl and 5-chloropyrid-2-yloxy, 6-methyl-pyridin-3-yloxy, 5-methyl- pyridin-3-ylmethyl, 5-chloro-pyridin-3-yloxy, 5-chloro-pyridin-3-yloxy, or 3-pyrid-3-ylpropyl).
- phenyl e.g. optionally substituted, preferably at the 4-position
- R' as heterocyclyl is preferably piperidinyl (e.g. 4-phenylpiperidin-l-yl), piperazinyl (e.g. 4- methoxypiperazinyl), indole, 1 -methylindole or oxindole.
- piperidinyl e.g. 4-phenylpiperidin-l-yl
- piperazinyl e.g. 4- methoxypiperazinyl
- indole e.g. 4- methoxypiperazinyl
- R t ' as halogen is preferably chloro or fluoro.
- R t ' as aryl-lower alkoxy is preferably phenyl-lower alkoxy (e.g. benzyloxy, 4- fluorobenzyloxy, pentafluorobenzyloxy), imidazo-lower alkoxy (e.g. 2-imidazol-l-ylethyoxy) or pyridyl-lower alkoxy (e.g. pyrid-4-ylmethyl).
- phenyl-lower alkoxy e.g. benzyloxy, 4- fluorobenzyloxy, pentafluorobenzyloxy
- imidazo-lower alkoxy e.g. 2-imidazol-l-ylethyoxy
- pyridyl-lower alkoxy e.g. pyrid-4-ylmethyl
- R t ' as lower alkyl is preferably methyl.
- Rt' as lower alkoxy is preferably methoxy, isopropoxy, butoxy or isobutoxy.
- Rt' as cycloalkyloxy is preferably cyclopentyloxy or cyclohexyloxy.
- Rt' as cycloalkyl-lower alkoxy is preferably cyclopentylmethoxy or cyclopropylmethoxy.
- Rt' as heterocyclyloxy is preferably, tetrahydropyranoxy, piperidyloxy (e.g. 1- methylpiperid-4-yloxy) .
- Rt' as heterocyclyl-lower alkoxy is preferably piperidyl-lower alkoxy (e.g. 2-piperid- l- ylethoxy) or morpholino-lower alkoxy (e.g. 2-morpholinoethoxy).
- Rt' as optionally substituted amino-lower alkoxy is preferably dimethylaminoethyl.
- R 5 ' is preferably H, lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy) or halogen.
- R 7 ' is preferably H or halogen.
- the compounds of formulae I, F, II, IF, and IV depending on the nature of substituents, may possess one or more asymmetric carbon atoms.
- the resulting diastereomers and enantiomers are encompassed by the instant invention.
- the compounds of formulae I, F, II, IF and IV are provided in pure or substantially pure epimeric form, e.g. as compositions in which the compounds are present in a form comprising at least 90%, e.g. preferably at least 95% of a single epimer (i.e. comprising less than 10%, e.g. preferably less than 5% of other epimeric forms).
- Preferred compounds of formula I are those wherein the asymmetric carbon atom to which R 2 and/or R 3 are attached corresponds to that of an L-amino acid precursor and is generally assigned the (S)-conf ⁇ guration.
- Preferred compounds of formula I wherein R 2 represents hydrogen can be represented by formulae V, V, V", V" and V ' corresponding to preferred compounds of formulae I, F, II, IF and IV respectively.
- the invention provides a compound of formula V, V, V' or V"
- lower referred to above and hereinafter in connection with organic radicals or compounds respectively defines a compound or radical which may be branched or unbranched with up to and including 7, preferably up to and including 4 and (as unbranched) one or two carbon atoms.
- a lower alkyl group is branched or unbranched and contains 1 to 7 carbon atoms, preferably 1-4 carbon atoms.
- Lower alkyl represents, for example, methyl, ethyl, propyl, butyl, isopropyl or isobutyl.
- Lower alkenyl represents either straight chain or branched alkenyl of 2 to 7 carbon atoms, preferably 2-4 carbon atoms, e.g. as vinyl, propenyl, isopropenyl, butenyl, isobutenyl or butadienyl.
- Lower alkynyl represents either straight chain or branched alkynyl of 2 to 7 carbon atoms, preferably 2-4 carbon atoms, e.g. as acetylenyl, propynyl, isopropynyl, butynyl or isobutynyl.
- Lower alkyl, lower alkenyl and lower alkynyl may be substituted by up to 3 substituents selected from lower alkoxy, aryl, heterocyclyl, hydroxy, halogen, cyano, optionally substituted amino, optionally substituted amino-oxy- or trifluoromethyl.
- Lower alkylene represents either straight chain or branched alkylene of 1 to 7 carbon atoms, i.e. a divalent hydrocarbon radical of 1 to 7 carbon atoms; for instance, straight chain lower alkylene being the bivalent radical of formula -(CH 2 ) consult-, where n is 1, 2, 3, 4, 5, 6 or 7.
- Preferably lower alkylene represents straight chain alkylene of 1 to 4 carbon atoms, e.g.
- a methylene, ethylene, propylene or butylene chain or said methylene, ethylene, propylene or butylene chain mono-substituted by C ⁇ -C 3 -alkyl (advantageously methyl) or disubstituted on the same or different carbon atoms by C ⁇ -C 3 -alkyl (advantageously methyl), the total number of carbon atoms being up to and including 7.
- a lower alkoxy (or alkyloxy) group preferably contains 1 -7 carbon atoms, advantageously 1-6 carbon atoms, and represents for example ethoxy, propoxy, isopropoxy, isobutoxy, preferably methoxy.
- Lower alkoxy includes cycloalkyloxy and cyloalkyl-lower alkyloxy.
- Halogen preferably represents chloro or fluoro but may also be bromo or iodo.
- Aryl represents carbocyclic or heterocyclic aryl.
- Carbocyclic aryl represents monocyclic, bicyclic or tricyclic aryl, for example phenyl or phenyl mono-, di- or tri-substituted by one, two or three radicals selected from lower alkyl. lower alkoxy, aryl, hydroxy, halogen, cyano, amino, amino-lower alkyl, trifluoromethyl, lower alkylenedioxy and oxy-C 2 -C 3 -alkylene; all of which are optionally further substituted, for instance as hereinbefore defined; or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl.
- Lower alkylenedioxy is a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy.
- Oxy-C 2 -C 3 -alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or oxypropylene.
- An example for oxy-C 2 -C 3 -alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.
- carbocyclic aryl is naphthyl, phenyl or phenyl mono- or disubstituted by lower alkoxy, phenyl, halogen, lower alkyl or trifluoromethyl, especially phenyl or phenyl mono- or disubstituted by lower alkoxy, halogen or trifluoromethyl, and in particular phenyl.
- substituted phenyl groups as R are, e.g. 4-chlorophen- 1 -yl, 3,4-dichlorophen- 1-yl, 4-methoxyphen- 1 -yl, 4-methylphen- 1 -yl, 4-aminomethylphen-l-yl, 4- methoxyethylaminomethylphen- 1 -yl, 4-hydroxyethylaminomethylphen- 1 -yl, 4-hydroxyethyl- (methyl)-aminomethylphen-l-yl, 3-aminomethylphen-l-yl, 4-N-acetylaminomethylphen-l-yl, 4- aminophen-1-yl, 3-aminophen-l-yl, 2-aminophen-l-yl, 4-phenyl-phen-l-yl, 4-(imidazol-l-yl)- phen-1-yl, 4-(imidazol-l-ylmethyl)-phen-l-yl, 4-(mo holin-
- Heterocyclic aryl represents monocyclic or bicyclic heteroaryl, for example pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted, especially mono- or di-substituted, by e.g. lower alkyl, nitro or halogen.
- Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3- pyridyl.
- Thienyl represents 2- or 3-thienyl.
- Quinolinyl represents preferably 2-, 3- or 4- quinolinyl.
- Isoquinolinyl represents preferably 1 -, 3- or 4-isoquinolinyl.
- Benzopyranyl, benzothiopyranyl represent preferably 3-benzopyranyl or 3-benzothiopyranyl, respectively.
- Thiazolyl represents preferably 2- or 4-thiazolyl, advantageously 4-thiazolyl.
- Triazolyl is preferably 1-, 2- or 5-(l,2,4-triazolyl).
- Tetrazolyl is preferably 5-tetrazolyl.
- heterocyclic aryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted, especially mono- or di-substituted, by lower alkyl or halogen; and in particular pyridyl.
- Biaryl may be carbocyclic biaryl, preferably e.g. biphenyl, namely 2, 3 or 4-biphenyl, advantageously 4-biphenyl, each optionally substituted by e.g. lower alkyl, lower alkoxy, halogen, trifluoromethyl or cyano, or heterocyclic-carbocyclic biaryl, preferably e.g. thienylphenyl, pyrrolylphenyl and pyrazolylphenyl.
- Cycloalkyl represents a saturated cyclic hydrocarbon optionally substituted by lower alkyl which contains 3 to 10 ring carbons and is advantageously cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl optionally substituted by lower alkyl.
- Bicycloalkyl is for example norbornanyl.
- Amino may be optionally substituted, e.g. by lower alkyl.
- Heterocyclyl represents a saturated cyclic hydrocarbon containing one or more, preferably 1 or 2, hetero atoms selected from O, N or S, and from 3 to 10, preferably 5 to 8, ring atoms; for example, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholino; all of which may be optionally substituted, for instance as hereinbefore defined for carbocyclic aryl.
- Aryl-lower alkyl represents preferably (carbocyclic aryl or heterocylic aryl)-lower alkyl.
- Carbocyclic aryl-lower alkyl preferably represents aryl-straight chain or -branched in which carbocyclic aryl has meaning as defined above, e.g. benzyl or phenyl-(ethyl, propyl or butyl), each unsubstituted or substituted on the phenyl ring as defined for carbocyclic aryl above, advantageously optionally substituted benzyl.
- Heterocyclic aryl-lower alkyl represents preferably straight chain or branched heterocyclic aryl-C ⁇ -4-alkyl in which heterocyclic aryl has meaning as defined above, e.g. 2-, 3- or 4- pyridylmethyl or (2, 3- or 4-pyridyl)-(ethyl, propyl or butyl); or 2- or 3-thienylmethyl or (2- or 3- thienyl)-(ethyl, propyl or butyl); 2-, 3- or 4-quinolinylmethyl or (2-, 3- or 4-quinolinyl)-(ethyl, propyl or butyl); or 2- or 4-thiazolylmethyl or (2- or 4-thiazolyl)-(ethyl, propyl or butyl).
- Cycloalkyl-lower alkyl represents e.g. (cyclopentyl- or cyclohexyl)-(methyl or ethyl).
- Biaryl-lower alkyl represents e.g. 4-biphenylyl-(methyl or ethyl).
- salts of the acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-arnmonium salts.
- bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-arnmonium salts.
- acid addition salts such as of mineral acids, organic carboxylic and organic sulfonic acids e.g. hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.
- the compounds of the invention exhibit valuable pharmacological properties in mammals and are particularly useful as inhibitors of cathepsin K.
- the cathepsin K inhibitory effects of the compound of the invention can be determined in vitro by measuring the inhibition of e.g. recombinant human cathepsin K.
- the in vitro assay is carried out as follows: For cathepsin K:
- the assay is performed in 96 well microtiter plates at ambient temperature using recombinant human cathepsin K. Inhibition of cathepsin K is assayed at a constant enzyme (0.16 nM) and substrate concentration (54 mM Z-Phe-Arg-AMCA - Peptide Institute Inc. Osaka, Japan) in 100 mM sodium phosphate buffer, pH 7.0, containing 2 mM dithiothreitol, 20 mM Tween 80 and 1 mM EDTA. Cathepsin K is preincubated with the inhibitors for 30 min, and the reaction is initiated by the addition of substrate. After 30 min incubation the reaction is stopped by the addition of E-64 (2 mM), and fluorescence intensity is read on a multi-well plate reader at excitation and emission wavelengths of 360 and 460 nm, respectively.
- Compounds of the Invention are particularly useful in mammals as agents for treatment and prophylaxis of diseases and medical conditions involving elevated levels of cathepsin K.
- diseases include diseases involving infection by organisms such as pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, crithidia fusiculata, as well as parasitic diseases such as schistosomiasis and malaria, tumours (tumour invasion and tumour metastasis), and other diseases such as metachromatic leukodystrophy, muscular dystrophy, amytrophy and similar diseases.
- Cathepsin K has been implicated in diseases of excessive bone loss, and thus the Compounds of the Invention may be used for treatment and prophylaxis of such diseases, including osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, e.g. tumour-induced hypercalcemia and metabolic bone disease. Also the Compounds of the Invention may be use for treatment or prophylaxis of diseases of excessive cartilage or matrix degradation, including osteoarthritis and rheumatoid arthritis as well as certain neoplastic diseases involving expression of high levels of proteolytic enzymes and matrix degradation.
- Compounds of the Invention are also indicated for preventing or treating coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases and immunologically mediated diseases (including transplant rejection).
- Compounds of the Invention are particularly indicated for preventing or treating osteoporosis of various genesis (e.g. juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or by cortico-steroid therapy or inactivity).
- various genesis e.g. juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or by cortico-steroid therapy or inactivity.
- the antiarthritic efficacy of the compounds of the invention for the treatment of rheumatoid arthritis can be determined using models such as or similar to the rat model of adjuvant arthritis, as described previously (R.E. Esser, et. al. J. Rheumatology, 1993, 20, 1 176.)
- the efficacy of the compounds of the invention for the treatment of osteoarthritis can be determined using models such as or similar to the rabbit partial lateral meniscectomy model, as described previously (Colombo et al. Arth. Rheum. 1993 26, 875-886).
- the efficacy of the compounds in the model can be quantified using histological scoring methods, as described previously (O'Byrne et al. Inflamm Res 1995, 44, S I 17-S118).
- the efficacy of the compounds of the invention for the treament of osteoporosis can be determined using an animal model such as the ovariectomised rat or other similar species, e.g. rabbit or monkey, in which test compounds are administered to the animal and the presence of markers of bone resorption are measured in urine or serum (e.g. as described in Osteoporos Int (1997) 7:539-543).
- an animal model such as the ovariectomised rat or other similar species, e.g. rabbit or monkey, in which test compounds are administered to the animal and the presence of markers of bone resorption are measured in urine or serum (e.g. as described in Osteoporos Int (1997) 7:539-543).
- the compounds of the invention of formula I are prepared by: a) reacting a compound of formula VI
- R, R 2 , R 3 , L, Xi, x and n are as previously defined and Rio is OH or a leaving group; or b) for preparation of a compound of formula I in which -X is -C(O)- and x is 0, reacting a compound of formula VIII
- R 2 , R 3 , Ar, n and m are as previously defined and Z is H, an amino protecting group or solid phase support, with a compound of formula RCORj 0 , wherein R and Rio are as defined above; and in the above processes, if required, temporarily protecting any interfering reactive groups and then isolating the resulting compound of the invention; and if desired, converting any resulting compound into another compound of the invention; and/or if desired, converting a resulting compound into a salt or ester, or a resulting salt or ester into the free acid or base or into another salt or ester; and if required recovering the resulting product from a solid phase.
- Linking of the amine of formula VI with the amino acid derivative of formula VII, according to process (a), can be carried out according to methods well known in the art for the formation of amide bonds, for instance as hereinafter described in the Examples.
- the amine of formula VI may be used in the form of an acid salt, e.g. the hydrochloride salt.
- the reaction may be carried out in an organic solvent, e.g. DMF, in the presence of a base, such as DIEA (diisopropylethylamine), for instance at room temperature.
- Suitable leaving groups as Rio are activated ester groups, such as hydroxy- succinimide or hydroxybenzotriazole.
- a coupling reagent such as HATU is normally used.
- the amine starting material of formula VI may be prepared by reacting the corresponding aiylamine of formula Ar-NH , preferably in the form of an acid salt, e.g. Ar-NH 2 .HC1, with oxazolidinone in the presence of a suitable solvent, such as 2-(2-methoxyethoxy)ethanol, preferably at elevated temperature, e.g. a temperature of ca. 170°C.
- a suitable solvent such as 2-(2-methoxyethoxy)ethanol
- the arylaminoalkyl aminoacid amide derivative of formula VIII may be reacted with the compound of formula R-CORio to form an amide bond substantially as described above.
- Both solution and solid phase synthesis procedures may be used.
- the derivative of formula VIII, attached to a solid phase, e.g. Rink resin is contacted with the acid R-COOH in solution in an organic solvent, e.g. DMF, in the presence of a coupling reagent such as HATU and a base such DIEA.
- the resulting product may be cleaved from the solid phase; for instance, by acid treatment, e.g. TFA/CH 2 C1 2 .
- R ]0 is a suitable leaving group
- the derivative of formula VIII, and the compound of formula R-CORio can be coupled in the presence of a base e.g. DIEA and in a solvent such as DMF.
- the derivative of formula VIII may be prepared by linking a protected amino acid of formula IX
- R 2 , R3 and Rj 0 are as defined above, and Rn is an amino protecting, e.g. Fmoc,
- the arylaminoalkylamine of formula X may be linked to a solid support, by linking an appropriately protected form of the arylaminoalkylamine of formula Ar-NH-(CH 2 )m-CH2-NH 2 to an appropriate solid phase, e.g. Rink resin, using reagents and procedures analogous to those customarily used in solid phase chemistry; for instance, as hereinafter described in the Examples.
- an appropriate solid phase e.g. Rink resin
- Compounds of the Invention which have acidic groups may be converted into salts with pharmaceutically acceptable bases, e.g. an aqueous alkali metal hydroxide, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. Resulting salts may be converted into the free compounds e.g. by treatment with acids. These or other salts can also be used for purification of the compounds obtained. Ammonium salts are obtained by reaction with the appropriate amine, e.g. diethylamine, and the like. Compounds of the Invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts.
- inorganic acids such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid
- organic carboxylic acids such as (C ⁇ -Gt)alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen
- acetic acid such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid
- organic sulfonic acids such as (C C )-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen).
- the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
- the Compounds of the Invention which comprise free hydroxyl groups may also exist in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such are included within the scope of the invention.
- Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiological conditions to the corresponding Compounds of the Invention which comprise free hydroxyl groups.
- Suitable pharmaceutically acceptable prodrug esters are those derived from a carboxylic acid, a carbonic acid monoester or a carbamic acid, advantageously esters derived from an optionally substituted lower alkanoic acid or an arylcarboxylic acid.
- compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal, topical, and parenteral administration to mammals, including man, to inhibit cathepsin K activity, and for the treatment of cathepsin K dependent disorders, in particular inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis, and comprise an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers.
- compositions comprise an effective cathepsin K inhibiting amount of a Compound of the Invention.
- the pharmacologically active Compounds of the Invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
- tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g.
- diluents e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
- lubricants e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene
- compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
- Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeuticaUy valuable substances.
- Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
- Tablets may be either film coated or enteric coated according to methods known in the art.
- Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier.
- Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
- transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controUed and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
- Matrix transdermal formulations may also be used.
- Suitable formulations for topical application are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
- the pharmaceutical formulations contain an effective cathepsin K inhibiting amount of a Compound of the Invention as defined above, either alone or in combination with another therapeutic agent.
- a Compound of the Invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
- the dosage of active compound administered is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, and on the form of administration.
- a unit dosage for oral administration to a mammal of about 50 to 70 kg may contain between about 5 and 500 mg of the active ingredient.
- the present invention also relates to methods of using Compounds of the Invention and their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in mammals for inhibiting cathepsin K, and for the treatment of cathepsin K dependent conditions, such as the cathepsin K dependent conditions, described herein, e.g. inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.
- cathepsin K dependent conditions such as the cathepsin K dependent conditions, described herein, e.g. inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.
- the present invention relates to a method of selectively inhibiting cathepsin K activity in a mammal which comprises administering to a mammal in need thereof an effective cathepsin K inhibiting amount of a Compound of the Invention.
- Such relates to a method of treating osteoporosis, rheumatoid arthritis, osteoarthritis, and inflammation (and other diseases as identified above) in mammals comprises administering to a mammal in need thereof a correspondingly effective amount of a Compound of the Invention.
- the Compounds of the invention may be synthesised using sohd phase chemistry.
- the reaction scheme for synthesis of typical arylaminoethyl amides is given below together with the experimental procedures used, including procedures for a variety of Ar substituents.
- Rink chloride resin is prepared according to a reported literature procedure. See: Garigipati, R. S. Tetrahedron Lett. 1997, 38, 6807.
- reaction mixture is poured into a mixture of CH 2 C1 and 0.5 N aq citric acid.
- the layers are separated and the organic layer is washed with H 2 O and brine.
- the organic phase is dried (Na 2 SO ), and the solvent is removed in vacuo.
- the resultant residue is purified by flash chromatography (2: 1 toluene:EtOAc) to provide N-2-oxo-ethyl-phthalimide as a white solid.
- the residue is dissolved in AcOEt/sat. aq NH CI.
- the layers are separated and the aqueous phase is . extracted once more with AcOEt.
- the combined organic layers are washed with brine, dried (Na 2 SO ) and the solvent is removed in vacuo.
- the residue is purified by flash chromatography (8:2 hexanes:AcOEt) to provide of 2- ⁇ 2-[4-(tert-butyl- diphenylsilanyloxy)-phenylamino]-ethyl ⁇ -isoindole-l,3-dione as a yellow solid that is recrystallized from ethe ⁇ hexane.
- the resin is treated with a 20% solution of piperidine in DMF (1.5 mL) for 5 min. The supernatant is then removed and the resin is washed with DMF, MeOH, THF and CH 2 C1 2 . The procedure is repeated 8 times.
- a solution of acid (0.086 mmol), HATU (0.086 mmol) and DIEA (0.2 * 13 mmol) in DMF (1.5 mL) is shaken for 10 min prior to addition to the resin (0.043 mmol).
- the resultant suspension is shaken for 1.5 h at r.t.
- the resin is allowed to settle and the supernatant is then removed.
- the resin is washed with DMF, THF, CH 2 C1 2 , MeOH, CH 2 C1 2 and MeOH (3 times each) and dried.
- the resin is then treated with a 1 : 1 :8 Ac 2 O:Pyr:DMA solution (1.5 mL) for 10 min.
- Examples 1 14 to are prepared by solution phase chemistry involving coupling of various 4-substituted benzoic acid derivatives with 1-amino- cyclohexane carboxylic acid [2-(4-methoxy-phenylamino)-ethyl]-amide; as described below for the preparation of 4-isopropyl-N- ⁇ l-[2-(4-methoxy-phenylamino)-ethylcarbamoyl]-cyclohexyl ⁇ - benzamide.
- Example 1 14 4-isopropyl-.N.- ⁇ l-[2-(4-methoxy-phenylamino)-ethylcarbamoyl]-cyclohexyl ⁇ - benzamide.
- HATU O-(7-azabenzotriazol-l-yl)-N, N, N ⁇ N'-tetramethyluronium hexafluorophosphate.
- Red-AI [(CH 3 OCH 2 CH 2 0) 2 AIH 2 ]Na
- (5-Methyl-pyridin-3-yl)-methanol is prepared by reduction of methyl 5-methylnicotinate with sodium bis(2-methoxyethoxy)aluminum hydride at r.t. in a manner similar to that described in the literature (Nishikawa, Y; Shindo, T.; Ishii, K.; Nakamura, H.; Kon, T.; Uno, H. 7. Med. Chem. 1989, 32, 583-593.)
- 4-Allyl-benzoic acid methyl ester is synthesized by a procedure analogous to that used for the preparation of 4-allyl-benzonitrile. See: Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, 1701 and references therein.
- 4-(3-Pyridin-3-yl-propyl)-benzoic acid methyl ester is hydrolyzed by treatment with 1 : 1 cone. HCl:H 2 O (10 mL) at 100 °C for 2 h. The solvents are removed in vacuo to provide 4-(3-pyridin- 3-yl-propyl)-benzoic acid as its HCI salt.
- 4-(3-Iodo-l-methyl-propyl)-benzoic acid tert-butyl ester is prepared from tert-butyl 4- acetylbenzoate according to the literature procedure of Nomura et al. (Kotake, Y; Okauchi, T; Iijima, A.; Yoshimatsu, K.; Nomura, H. Chem. Pharm. Bull. 1995, 43, 829).
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
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AU28046/00A AU2804600A (en) | 1999-02-16 | 2000-02-14 | Arylaminoalkylamides |
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GBGB9903548.7A GB9903548D0 (en) | 1999-02-16 | 1999-02-16 | Organic compounds |
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AU (1) | AU2804600A (fr) |
CO (1) | CO5160245A1 (fr) |
GB (1) | GB9903548D0 (fr) |
PE (1) | PE20001423A1 (fr) |
WO (1) | WO2000048993A1 (fr) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002070517A2 (fr) * | 2001-03-02 | 2002-09-12 | Merck Frosst Canada & Co. | Inhibiteurs de cysteine protease de type cathepsine |
WO2003024923A1 (fr) * | 2001-09-14 | 2003-03-27 | Axys Pharmaceuticals, Inc. | Composes sulfonamide en tant qu'inhibiteurs de protease |
WO2004011457A1 (fr) * | 2002-07-26 | 2004-02-05 | Yuhan Corporation | Derives de la 1-phenylpiperidin-3-one et leurs procedes de preparation |
WO2004084842A2 (fr) * | 2003-03-24 | 2004-10-07 | Irm Llc | Inhibiteurs de cathepsine s |
US6982263B2 (en) | 2001-06-08 | 2006-01-03 | Boehringer Ingelheim Pharmaceuticals, Inc. | Nitriles useful as reversible inhibitors of cysteine proteases |
US7173051B2 (en) | 2003-06-13 | 2007-02-06 | Irm, Llc | Inhibitors of cathepsin S |
US7256207B2 (en) | 2003-08-20 | 2007-08-14 | Irm Llc | Inhibitors of cathepsin S |
US7358373B2 (en) | 2005-07-27 | 2008-04-15 | Roche Palo Alto Llc | Cathepsin K inhibitors |
US7384970B2 (en) | 2003-03-24 | 2008-06-10 | Irm Llc | Inhibitors of cathepsin S |
US8680114B2 (en) | 2003-11-21 | 2014-03-25 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
AU2011265309B2 (en) * | 2003-11-21 | 2014-06-05 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
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WO1994001771A1 (fr) * | 1992-07-14 | 1994-01-20 | Patchornik, Zipora | Reactifs standard universels, procede de preparation et utilisation de ces reactifs |
WO1995009149A1 (fr) * | 1993-09-30 | 1995-04-06 | Napier University Ventures Limited | Derives d'anthracene utilises en tant qu'agent anticancereux ou en tant que teinture |
-
1999
- 1999-02-16 GB GBGB9903548.7A patent/GB9903548D0/en not_active Ceased
-
2000
- 2000-01-27 CO CO00004735A patent/CO5160245A1/es unknown
- 2000-02-14 AU AU28046/00A patent/AU2804600A/en not_active Abandoned
- 2000-02-14 WO PCT/EP2000/001197 patent/WO2000048993A1/fr active Application Filing
- 2000-02-14 PE PE2000000115A patent/PE20001423A1/es not_active Application Discontinuation
Patent Citations (2)
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WO1994001771A1 (fr) * | 1992-07-14 | 1994-01-20 | Patchornik, Zipora | Reactifs standard universels, procede de preparation et utilisation de ces reactifs |
WO1995009149A1 (fr) * | 1993-09-30 | 1995-04-06 | Napier University Ventures Limited | Derives d'anthracene utilises en tant qu'agent anticancereux ou en tant que teinture |
Non-Patent Citations (3)
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FILIPPOVA, IRINA YU. ET AL: "Fluorogenic peptide substrates for assay of aspartyl proteinases", ANAL. BIOCHEM. (1996), 234(2), 113-18, XP000907265 * |
MORIER-TEISSIER, ELISABETH ET AL: "Synthesis and antitumor properties of an anthraquinone bisubstituted by the copper chelating peptide Gly-Gly-L-His", J. MED. CHEM. ( 1993 ), 36(15), 2084-90, XP002138282 * |
NAEGLER, DORIT K. ET AL: "Major Increase in Endopeptidase Activity of Human Cathepsin B upon Removal of Occluding Loop Contacts", BIOCHEMISTRY (1997), 36(41), 12608-12615, XP000907282 * |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002070517A3 (fr) * | 2001-03-02 | 2003-01-16 | Merck Frosst Canada Inc | Inhibiteurs de cysteine protease de type cathepsine |
WO2002070517A2 (fr) * | 2001-03-02 | 2002-09-12 | Merck Frosst Canada & Co. | Inhibiteurs de cysteine protease de type cathepsine |
US6982263B2 (en) | 2001-06-08 | 2006-01-03 | Boehringer Ingelheim Pharmaceuticals, Inc. | Nitriles useful as reversible inhibitors of cysteine proteases |
WO2003024923A1 (fr) * | 2001-09-14 | 2003-03-27 | Axys Pharmaceuticals, Inc. | Composes sulfonamide en tant qu'inhibiteurs de protease |
US6900237B2 (en) | 2001-09-14 | 2005-05-31 | Axys Pharmaceuticals, Inc. | Sulfonamide compounds as protease inhibitors |
WO2004011457A1 (fr) * | 2002-07-26 | 2004-02-05 | Yuhan Corporation | Derives de la 1-phenylpiperidin-3-one et leurs procedes de preparation |
US7342027B2 (en) | 2002-07-26 | 2008-03-11 | Yuhan Corporation | 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof |
US7109243B2 (en) | 2003-03-24 | 2006-09-19 | Irm Llc | Inhibitors of cathepsin S |
WO2004084842A3 (fr) * | 2003-03-24 | 2004-11-25 | Irm Llc | Inhibiteurs de cathepsine s |
WO2004084842A2 (fr) * | 2003-03-24 | 2004-10-07 | Irm Llc | Inhibiteurs de cathepsine s |
US7384970B2 (en) | 2003-03-24 | 2008-06-10 | Irm Llc | Inhibitors of cathepsin S |
US7173051B2 (en) | 2003-06-13 | 2007-02-06 | Irm, Llc | Inhibitors of cathepsin S |
US7256207B2 (en) | 2003-08-20 | 2007-08-14 | Irm Llc | Inhibitors of cathepsin S |
US7507755B2 (en) | 2003-08-20 | 2009-03-24 | Irm Llc | Inhibitors of cathepsin s |
US8680114B2 (en) | 2003-11-21 | 2014-03-25 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
AU2011265309B2 (en) * | 2003-11-21 | 2014-06-05 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
US7358373B2 (en) | 2005-07-27 | 2008-04-15 | Roche Palo Alto Llc | Cathepsin K inhibitors |
Also Published As
Publication number | Publication date |
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PE20001423A1 (es) | 2001-01-02 |
AU2804600A (en) | 2000-09-04 |
GB9903548D0 (en) | 1999-04-07 |
CO5160245A1 (es) | 2002-05-30 |
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