WO2003076416A1 - Composes oxo azabicycliques - Google Patents

Composes oxo azabicycliques Download PDF

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Publication number
WO2003076416A1
WO2003076416A1 PCT/EP2002/003240 EP0203240W WO03076416A1 WO 2003076416 A1 WO2003076416 A1 WO 2003076416A1 EP 0203240 W EP0203240 W EP 0203240W WO 03076416 A1 WO03076416 A1 WO 03076416A1
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Prior art keywords
compound
formula
alkyl
group
oxo
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PCT/EP2002/003240
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English (en)
Inventor
Bernard Gaudilliere
Henry Jacobelli
Catherine Kostlan
Jack Li
Wen-Song Yue
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Warner-Lambert Company Llc
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Priority to AU2002249275A priority Critical patent/AU2002249275A1/en
Priority to PCT/EP2002/003240 priority patent/WO2003076416A1/fr
Priority to SV2003001495A priority patent/SV2003001495A/es
Priority to OA1200400234A priority patent/OA12782A/en
Priority to CNA038048752A priority patent/CN1738806A/zh
Priority to IL16381803A priority patent/IL163818A0/xx
Priority to EP03708181A priority patent/EP1492775A2/fr
Priority to APAP/P/2004/003125A priority patent/AP2004003125A0/en
Priority to CA002478706A priority patent/CA2478706A1/fr
Priority to EA200401053A priority patent/EA200401053A1/ru
Priority to MXPA04008681A priority patent/MXPA04008681A/es
Priority to ARP030100749A priority patent/AR039562A1/es
Priority to BR0308280-6A priority patent/BR0308280A/pt
Priority to PL03372622A priority patent/PL372622A1/xx
Priority to PCT/EP2003/002277 priority patent/WO2003076417A2/fr
Priority to KR10-2004-7013994A priority patent/KR20040095270A/ko
Priority to PA20038568501A priority patent/PA8568501A1/es
Priority to JP2003574636A priority patent/JP2005526070A/ja
Priority to UY27700A priority patent/UY27700A1/es
Priority to AU2003212307A priority patent/AU2003212307A1/en
Priority to PE2003000218A priority patent/PE20031018A1/es
Priority to US10/384,115 priority patent/US6894057B2/en
Priority to US10/417,073 priority patent/US6747147B2/en
Publication of WO2003076416A1 publication Critical patent/WO2003076416A1/fr
Priority to IS7414A priority patent/IS7414A/is
Priority to CO04082792A priority patent/CO5601020A2/es
Priority to MA27842A priority patent/MA27183A1/fr
Priority to TNP2004000169A priority patent/TNSN04169A1/fr
Priority to EC2004005278A priority patent/ECSP045278A/es
Priority to NO20044041A priority patent/NO20044041L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel oxo azabicyclic compounds which are useful for preparing medicinal products for treating complaints involving a therapy with a matrix metalloprotease-13 (MMP-13) inhibitor.
  • MMP-13 matrix metalloprotease-13
  • These medicinal products are useful in particular for treating certain mflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancers.
  • MMPs Matrix metalloproteases
  • TMPs tissue inhibitors of metalloprotease
  • MMP-13 matrix metalloprotease-13 is a collagenase-type MMP which constitutes the predominant collagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
  • MMP inhibitors in order to prevent and/or correct the imbalance in the renewal of extracellular matrix tissue, such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPD), age-related macular degeneration (ARMD) and cancer.
  • MMP-inhibitor compounds are known. Most of these MMP-inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or by Clark et al. (2000).
  • the compounds of the present application are novel and represent powerful inhibitors of MMP-13. They are consequently of use in the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPDs), age-related degeneration (ARMD) and cancer.
  • the applicant has identified novel oxo azabicyclic compounds that are matrix metalloprotease inhibitors, and more specifically compounds that are selective MMP-13 inhibitors.
  • Xi, X 2 , and X 3 independently of each other, represent a nitrogen atom or a group -CR 3 in which R 3 represents a group selected from hydrogen, (C ⁇ -C 6 )alkyl, amino, rnono ⁇ - C 6 )all-ylamino, d ⁇ -C ⁇ alkylamino, hydroxy, ( -C ⁇ alkoxy, and halogen, with the proviso that not more than two of the groups Xi, X 2 and X 3 simultaneously represent a nitrogen atom,
  • G ⁇ represents a group selected from those of formulae (i/a) and (i/b):
  • R 5 identical or different, independently of each other, represent a group selected from hydrogen, (d-C ⁇ alkyl, aryl, aryl(C ⁇ -C 6 )alkyl, cycloalkyl, cycloalkyl(C 1 -C 6 )alkyl, heteroaryl, heteroary ⁇ CrC ⁇ alkyl, heterocycloalkyl, and heterocycloalky ⁇ -C ⁇ alkyl,
  • - Re represents a group selected from :
  • ⁇ S hydrogen, trifluoromethyl, OR 7 , NR 7 Rs, in which R 7 and Rs, identical or different independently of each other, represent hydrogen or (C ⁇ -C 6 )alkyl, ⁇ (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, aryl(C ⁇ -C 6 )alkyl, cycloalkyl(C ⁇ -C 6 )alkyl, heteroaryl, heteroaryl(C ⁇ -C 6 )alkyl, heterocycloalkyl, and heterocycloalkyl(C ⁇ -C 6 )alkyl, these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from halogen, amino, mono(C ⁇ -C 6 )alkylamino, d ⁇ -C ⁇ alkylamino, each alkyl moiety being identical or different independently of each other, cyano,
  • Yi represents a group selected from oxygen, sulphur, -NH and -N(C ⁇ -C6)alkyl
  • Y 2 represents a group selected from oxygen, sulphur, -NH and -N(C 1 -Ce)alkyl
  • n represents an integer from 0 to 6 inclusive
  • hydrocarbon chain Z ⁇ optionally contains one to two isolated or conjugated multiple bonds
  • one of said -CR9R10 may optionally be replaced with a group selected from oxygen, S(O) nl in which nl is as defined hereinbefore, -NH and -N(C C 6 )alkyl,
  • A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
  • Ri represents a group selected from :
  • hydrocarbon chain Z 2 optionally contains one or two isolated or conjugated multiple bonds
  • one of said -CR ⁇ R 12 may optionally be replaced with a group selected from oxygen, S(O) n ⁇ in which nl is as defined hereinbefore, -NH, -N(C ⁇ -C 6 )alkyl, and carbonyl,
  • V B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
  • V q is an integer from 0 to 7 inclusive
  • - X 4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (C ⁇ -C 6 )alkyl group,
  • - k is an integer from 0 to 3 inclusive
  • - kl is an integer from 0 to 2 inclusive
  • - k2 is an integer from 1 to 4 inclusive
  • R 13 , R 1 and R ⁇ 5 which may be identical or different independently of each other, are selected from hydrogen and (d-C6)alkyl,
  • Ri 6 represents a group selected from (d-C 6 )alkyl, -R 19 -NR 13 R 14 , in which R 19 represents a linear or branched (d-C 6 )alkylene group, and R ⁇ , R ⁇ 4 and R 15 are as defined hereinbefore,
  • R 17 represents a (C 3 -C 6 )cycloalkyl group
  • - X 5 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-C 6 )alkyl group,
  • - X 7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (C 1 -C 6 )alkyl,
  • - k is an integer from 0 to 3 inclusive
  • R 7 and Rs which may be identical or different independently of each other, are selected from hydrogen and (d-C 6 )alkyl,
  • - X 8 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-C 6 )alkyl group,
  • R 2 o represents 5- or 6-menbered monocycle aryl, heteroaryl, cycloalkyl, or heterocycloalkyl which is optionally substituted by one or more groups, which may be identical or different, selected from (C ⁇ -C 6 )alkyl, halogen, hydroxy and amino, and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur,
  • the invention relates to compounds of formula (I) wherein :
  • the invention relates to compounds of formula (I) wherein :
  • n represents an integer from 1 to 6 inclusive
  • the invention relates to compounds of formula (I) wherein :
  • A represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
  • the invention relates to compounds of formula (I) wherein :
  • Ri represents a hydrogen atom or a group of formula (i/d) :
  • - X 4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (d-C 6 )alkyl group,
  • - k is an integer from 0 to 3 inclusive
  • - kl is an integer from 1 to 2 inclusive
  • - k2 is an integer from 1 to 4 inclusive
  • R13, R 14 and R 15 which may be identical or different independently of each other, are selected from hydrogen and (C ⁇ -C 6 )alkyl
  • - R 16 represents a group selected from (d-C 6 )alkyl, -R ⁇ 9 -NR 13 R 14 , in which R 19 represents a linear or branched (d-C 6 )alkylene group, and R 13 , R ⁇ 4 and R 15 are as defined hereinbefore
  • - R 17 represents a (C -C 6 )cycloalkyl group
  • - X 5 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C ⁇ -C 6 )alkyl group,
  • R ⁇ 8 represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or
  • substituent Rt that is preferred according to the invention is the group of formula (i/d):
  • Z 2 represents a group -CR ⁇ R 12 in which Rn and R ⁇ 2 represents each a hydrogen atom.
  • p, B, G 3 and q are as defined in the compound of formula (I).
  • substituent Ri that is preferred according to the invention is the group of formula (i/d):
  • substituent Ri that is preferred according to the invention is the group of formula (i/d) :
  • B represents a phenyl group
  • q is equal to 0 or 1
  • the invention relates also to the compounds of formula (I) wherein Gi represents a group of formula (i/a) in which 1- represents a hydrogen atom or a methyl group, or a group of formula (i/b) in which and R , identical, represent each a hydrogen atom or a methyl group, and Re represents a hydrogen atom or a methyl group, and X ls X 2 , X 3 , G 2 , Z 1 ⁇ n, m and R 2 are as defined in formula (I).
  • Preferred compounds of the invention are compounds of formula (I) wherein Xi represents a group -CR 3 in which R 3 represents a hydrogen atom, X 2 represents a nitrogen atom or a group -CR 3 in which R 3 represents a hydrogen atom, and X 3 represents a group -CR 3 in which R 3 represents a hydrogen atom.
  • Other preferred compounds of the invention are compounds wherein G 2 represents a carbon-carbon triple bond or a group of formula (i/c) in which Y ⁇ represents an oxygen atom, and Y 2 represents a group -NH.
  • Still more preferred compounds of the invention are those compounds of formula (I) wherein Zi represents -CR9R 1 0 in which R 9 and Rio represent each a hydrogen atom, and n is one.
  • Especially preferred compounds of the invention are compounds wherein A represents a group selected from phenyl and pyridyl, m is zero or one, and R 2 represents a (C ⁇ -C 6 )alkoxy group or a hydrogen atom.
  • the invention relates to the following compounds of formula (I) :
  • optical isomers, the N-oxides, as well as the addition salts with a pharmaceutically- acceptable acid or base, of the preferred compounds form an integral part of the invention.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient an effective amount of a compound of formula (I) together with one or more pharmaceutically-acceptable excipients or carriers.
  • Another embodiment of the invention concerns the use of the compound of formula (I) for the preparation of a medicinal product intended for treating a disease involving therapy by inhibition of matrix metalloprotease, and more particularly of type- 13 matrix metalloprotease.
  • the invention also relates to a method for treating a living body afflicted with a disease involving a therapy by inhibition of matrix metalloprotease, and more particularly of type- 13 matrix metalloprotease, the said method comprising the administration of an effective amount of a compound of formula (I) to a patient in need thereof.
  • a preferred method of treatment according to this invention is treatment of a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
  • a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
  • a preferred method of treatment according to this invention is treatment of disease selected from arthritis, osteoarthritis and rheumatoid arthritis.
  • a (d-C6)alkyl group denotes a linear or branched group containing from 1 to 6 carbon atoms ; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl,
  • - a (C 2 -C 6 )alkenyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more double bonds ; examples of such groups without implying any limitation are vinyl, allyl, 3-buten-l-yl, 2-methyl-buten-l-yl, hexenyl, - a (C 2 -C )alkynyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more triple bonds ; examples of such groups without implying any limitation are ethynyl, propynyl, 3-butyn-l-yl, 2-methyl-butyn-l-yl, hexynyl,
  • - a (d-C6)alkoxy group means the alkyl group as mentioned above bound through an oxygen atom ; examples of such compounds without implying any limitation are methoxy, ethoxy, n-propyloxy, tert-butyloxy,
  • - a mono(C ⁇ -C 6 )alkylamino denotes a amino group substituted by one (C ⁇ -C 6 )alkyl group as defined hereinbefore ;
  • example of such groups, without implying any limitation are methyl amino, isobutyl amino, ethylamino, - a di(C ⁇ -C 6 )alkylamino denotes a amino group substituted by two (d-C ⁇ alkyl groups as defined hereinbefore, each alkyl group being identical or different ; example of such groups, without implying any limitation are dimethylamino, diethylamino,
  • an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated ; examples of such groups without implying any limitation are, phenyl, naphthyl, indenyl, benzocyclobutenyl,
  • a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen ; examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl,
  • a cycloalkyl group denotes a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character ; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl,
  • heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen,
  • a bicycle denotes two fused-monocycle and, - a trihalogeno(C 1 -C6)alkyl group denotes an alkyl group as defined above which contains a trihalogeno group ; examples of such groups without implying any limitation are trifluoromethyl, 2,2,2-trifluoroethyl,
  • - a (C ⁇ -C 7 )acyl group denotes an alkyl group or a aryl group as defined above bound through a carbonyl group ; examples of such groups without implying any limitation are acetyl, ethylcarbonyl, benzoyl,
  • a multiple bond denotes double bond or triple bond
  • a halogen atom means fluoro, chloro, bromo or iodo
  • the invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I).
  • a review of the pharmaceutically acceptable salts will be found in J. Pharm. Sci., 1977, 66, 1-19.
  • Pharmaceutically acceptable acids mean non-toxic salts derived from mineral or organic acids. Among those there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc...
  • Pharmaceutically acceptable bases mean non-toxic salts derived from mineral or organic bases.
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (H):
  • compounds of formulae (I/a), (I/b), (I/c) and (I/d) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into ⁇ -oxide thereof.
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (X):
  • compounds of formula (I e) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
  • An alternative way to obtain the compound of formula (XD-I/a) from compound of formula (XI) is described in the following scheme 1:
  • compound of formula (XI) is treated with an aqueous solution of ammonium hydroxide to yield compound of formula (XVa) which is reacted with triethyl orthoformate in the presence of a catalytic amount of acid like r ⁇ -toluene sulfonic acid (PTSA).
  • PTSA r ⁇ -toluene sulfonic acid
  • the 3H-quinazolin-4-one (Xl/b) obtained is condensed in basic medium to a compound of formula Ri- ⁇ al, in which Ri is as defined in the compound of formula (I) and Hal represents a halogen, to yield the compound of formula (XHI/a),
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (Xi ⁇ /e) :
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XHI/e) :
  • compounds of formula (I/f) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XLX) : in which Hal represents a halogen atom,
  • compounds of formula (I/g) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
  • the compounds of the invention that are present in the form of a mixture of diastereoisomers are isolated in a pure form by using conventional separation techniques such as chromatography.
  • compounds of formula (I) of the present invention are matrix metalloprotease inhibitors, and more particularly inhibitors of the enzyme MMP- 13.
  • the use of the compounds of the present invention may be recommended for the treatment of any pathology in which destruction of extracellular matrix tissue occurs, and most particularly pathologies such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration and cancers.
  • pathologies such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration and cancers.
  • the present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an isomer thereof, aN-oxide thereof, or an addition salt thereof with a pharmaceutically-acceptable acid or base, alone or in combination with one or more pharmaceutically-acceptable, inert, non-toxic excipients or carriers.
  • compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
  • compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspension and emulsions, and also sterile powders for reconstituting injectable solutions or dispersions.
  • compositions according to the invention for oral administration in solid form especially include tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, for oral, nasal, buccal or ocular administration in liquid form, especially include emulsions, solutions, suspensions, drop, syrups and aerosols.
  • compositions for rectal or vaginal administration are preferably suppositories, and those for per- or trans-cutaneous administration especially include powders, aerosols, creams, ointment, gels and patches.
  • compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
  • inert, non-toxic excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colourants, aromatizing agents etc...
  • the useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments.
  • the dosage ranges from 2 mg to 1 g per day in one or more administrations.
  • the compositions are prepared by methods that are common to those skilled in the art and generally comprise 0.5% to 60% by weight of active principle (compound of formula (I)) and 40% to 99.5% by weight of pharmaceutically acceptable excipients or carriers.
  • the starting materials used are products that are known or that are prepared according to known operating procedures.
  • the various preparations yield synthetic intermediates that are useful in preparation of the compounds of the invention. Some of these intermediates are new compounds.
  • TOTU O-(ethoxycarbonyl)cyanomethylamino]-N-N-N'-N'-tetramethyl uronium fluoroborate
  • DIPEA dusopropylethylamine
  • Step 1 4-Amino-isophthalic acid
  • Step 2 4-Amino-3-[(4-methoxy)-benzylcarbamoyl]-phenyl-l-carboxylic acid 4-methoxy- benzylamide
  • Step 2 6-Amino-N-(4-methoxy-benzyl)-isophthalamic acid
  • Step 3 Methyl 4- ⁇ [2-Amino-5-(4-methoxy-benzylcarbamoyl)-benzoylamino]-methyl ⁇ - benzoate
  • the desired compound is obtained according to the procedure described in the Step 1 of Preparation 2 using as starting material the compound obtained in the preceding step 2 and as reactant the methyl 4-(aminomethyl)benzoate hydrochloride. It is purified by chromatography over silica gel using a mixture of dichloromethane/ether as eluant.
  • Step 1 6-iodo-lH-henzo[a][l,3]oxazine ⁇ 2,4-dione
  • Step 3 3-(4-fluorobenzyl)-6-iodo-3H-quinazotin-4-one
  • Step 2 Methyl 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoate
  • Step 1 6-Iodo-lH-pyrido[3,4-d][l,3]oxazine-2,4-dione
  • 2-amino-5-iodo-isonicotinic acid (18.0 mmol) in H2O (20 ml) and concentrated HC1 (5 ml) is added dioxane (50 ml) until a clear solution is obtained.
  • Neat diphosgene (5.95 g, 30.0 mmol) is added dropwise (with cooling at times so that the solution does not boil) until a precipitate formed.
  • H2O 100 ml
  • the filter cake is dried in vacuo to give the desired compound.
  • Step 3 3-(4-Fluoro-benzyl)-6-iodo-3H-pyrido[3,4-d]pyrimidin-4-one
  • Step 2 To a solution of the compound obtained in Step 2 (7.27 mmol) in triethyl orthoformate is added a catalytic amount of ⁇ r -toluenesulfonic acid. The solution is refluxed for 5 hours, and cooled to room temperature. After removal of all volatiles in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
  • Step 1 Methyl 4- ⁇ [(5-Amino-2-iodo-pyridine-4-carbonyl)-amino]-methyl ⁇ -benzoate
  • Step 2 Methyl 4-(6-Iodo-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl)-benzoate
  • Step 2 To a solution of the compound obtained in Step 1 (4.84 mmol) in triethyl orthoformate is added a catalytic amount of TsOH. The solution is refluxed for 5 hours, and cooled to room temperature. After removal of all volatile solvents in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
  • the compound is obtained according to the procedure described in Preparation 7 but using in step 1 the compound obtained in Preparation 3 in which 4-(pyrrolidine-l-sulfonyl)- benzylamine is used in place of 4-fluorobenzylamine in the Step 2.
  • the compound is obtained according to the procedure described in the second step of Example 3 using as substrate the compound obtained in the Example 5.
  • Step 1 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoic acid
  • Step 2 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
  • Example 13 4-[6-(3-phenyI-prop-l-ynyI)-4-oxo-4H-pyrido[3 5 4-dlpyrimidin- 3-ylmethyl]-benzoic acid
  • Step 1 4-(6-Iodo-4-oxo-4H-pyrido[3,4--t pyrimidin-3-ylmethyl)-benzoic acid
  • Example 1 4-Oxo-3-[4-(pyrrolidine-l-sulfonyl)-benzyll-3,4-dihydro-quinazoline- 6-carboxylic acid 4-methoxy-benzylamide
  • the compound is obtained according to the procedure described in Example 14 using as substrate the compound obtained in Preparation 9 and 4-methoxybenzylamine.
  • Example 17 4-[6-(3-Methoxy-benzylcarbamoyl)-4-oxo-4H-quinazoiin-3-ylmethylI- benzoic acid.
  • the desired product is obtained by following the procedure of Example 14, except 4- flurobenzylamine in step 2 of the preparation 3 is replaced by tert-butyl 3-aminomethyl- benzoate, and at the end stirring the collected residue in an excess amount of trifluoroacetic acid for 30 minutes at room temperature. After removing the volatiles in vacuum, the residue is filtered to furnish the desired product as an off white solid.
  • Example 18 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyll- benzoic acid
  • Step 1 tert-Butyl 4-[4-oxo-6-(3 -phenyl-prop- 1 -ynyl)-4H-quinazoline-3 -ylmethyl] - benzoate
  • Step 2 4-[4-oxo-6-(3 -phenyl-prop- 1 -ynyl)-4H-quinazoline-3 -ylmethyl] -benzoic acid
  • the product is obtained by following the procedure of Example 18, the only difference is that 3 -phenyl- 1-propyne used in Step 1 is replaced by l-methoxy-4-prop-2-ynyl-benzene.
  • the product is obtained as a white solid.
  • Example 18 0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop of DMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room temperature for an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuum and the residue is washed with 1:1 water:methanol to yield 70 mg of an off-white powder as the desired product.
  • Step 2 Methyl 3-(3-fluorobenzyl)-4-oxo-3,4-dihydro-pyrido[3,4- ]pyrimidine-6- carboxylate
  • Step 1 The compound obtained in the preceding Step 1 (3.0 g, 1.07 mmol), is dissolved in 50 ml of methanol, with an excess amount of triethylamine, and a catalytic amount of Pd(dppf)Cl 2 .
  • the reaction solution is poured into an autoclave and heated at 100°C for 4 hours under the carbon monoxide atmosphere.
  • the reaction is cooled to room temperature and filtered.
  • the filtrate is concentrated in vacuum and the residue is purified on a silica gel column using 1 : 1 Hex:EtOAc to yield the desired product as a white solid (100%).
  • Step 3 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide
  • Example 25 4-[4-Oxo-6-(3-phenyl-propa-l,2-dienyl)-4H-quinazolin-3-ylmethyll- benzoic acid
  • the inhibitory activity of the compounds of formula (I) according to the invention with respect to matrix metalloprotease-13 is evaluated by testing the ability of the compounds of the invention to inhibit the proteolysis of a peptide substrate with MMP- 13.
  • the peptide substrate used in the test is the following peptide: Ac-Pro-Leu-Gly-thioester-
  • the inhibitory activity of a compound of formula (I) according to the invention is expressed as the IC 50 value, which is the concentration of inhibitor for which an inhibition of 50% of the activity of the matrix metalloprotease under consideration is observed.
  • reaction medium of 100 ⁇ l volume is prepared, containing: 50 mM of HEPES buffer, 10 mM of CaCl 2 and 1 mM of 5,5'-dithiobis-(2-nitrobenzoic acid)
  • the concentrations of inhibitors present in the test samples range from 100 ⁇ M to 0.5 nM.
  • the measurement of the proteolysis of the substrate peptide is monitored by measuring the absorbence at 405 nm using a spectrophotometer for reading microplates, at the laboratory temperature, the measurements being carried out continuously for 10 to 15 minutes.
  • the IC 5 0 values are calculated from a curve in which the percentage of the catalytic activity relative to the control is represented on the X-axis and the concentration of inhibitor is represented on the Y-axis.
  • the IC 5 0 values on MMP-13 of the compounds of Examples 1 to 10 are all below 1 ⁇ M.
  • the test described above for the inhibition of MMP-13 was also adapted and used to determine the ability of the compounds of formula (I) to inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-14.
  • the results obtained show that the compounds according to the invention generally have IC50 values for MMP-13 which are about 100 times lower than the IC 5 o values for the same compounds with respect to the other matrix metalloproteases tested.

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Abstract

L'invention concerne un composé sélectionné dans la formule (I) dans laquelle: X1, X2, et X3, représentent N ou CR3, R3 ayant la signification indiquée dans la description; G1 représente un groupe sélectionné parmi ceux des formules (i/a) et (i/b) dans lesquelles R4, R5, et R6 ont la signification indiquée dans la description; G2 représente un groupe sélectionné parmi une triple liaison carbone-carbone, -CH=C=CH-, C=O, C=S, S(O)n1 dans laquelle n1 représente un nombre entier compris entre 1 et 2 inclus, ou un groupe de formule (i/c) dans laquelle Y1 représente O, S, -NH ou Nalkyle, et Y2 représente O, S, -NH ou Nalkyle; n est un nombre entier compris entre 1 et 6 inclus, et m est un nombre entier compris entre 1 et 7 inclus; Z1 représente -CR9R10, R9 et R10 ayant la signification indiquée dans la description; A représente un système cyclique; R1 représente un groupe sélectionné parmi H, alkyle, alcényle, alkynyle, éventuellement substitué et le groupe de formule (i/d) dans laquelle p, Z2, B, q et G3 ont la signification indiquée dans la description, et éventuellement ses isomères optiques, N-oxyde, et sels d'addition présentant un acide ou une base pharmaceutiquement acceptable. L'invention concerne également des produits médicinaux contenant ledit composés, utilisés en tant qu'inhibiteurs spécifiques de la matrice de métalloprotéase de type 13.
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AU2002249275A AU2002249275A1 (en) 2002-03-08 2002-03-08 Oxo azabicyclic compounds
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SV2003001495A SV2003001495A (es) 2002-03-08 2003-03-04 Compuestos oxo-azabiciclicos
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PA20038568501A PA8568501A1 (es) 2002-03-08 2003-03-06 Compuestos oxo-azabiciclicos
IL16381803A IL163818A0 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
EP03708181A EP1492775A2 (fr) 2002-03-08 2003-03-06 Composes oxo-azabicycliques
APAP/P/2004/003125A AP2004003125A0 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
CA002478706A CA2478706A1 (fr) 2002-03-08 2003-03-06 Composes oxo-azabicycliques
EA200401053A EA200401053A1 (ru) 2002-03-08 2003-03-06 Оксо-азабициклические соединения
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ARP030100749A AR039562A1 (es) 2002-03-08 2003-03-06 Compuestos oxo-azabiciclicos
BR0308280-6A BR0308280A (pt) 2002-03-08 2003-03-06 Compostos oxo-azabicìclicos
OA1200400234A OA12782A (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds.
PCT/EP2003/002277 WO2003076417A2 (fr) 2002-03-08 2003-03-06 Composes oxo-azabicycliques
KR10-2004-7013994A KR20040095270A (ko) 2002-03-08 2003-03-06 옥소-아자비시클릭 화합물
CNA038048752A CN1738806A (zh) 2002-03-08 2003-03-06 氧代－氮杂双环化合物
JP2003574636A JP2005526070A (ja) 2002-03-08 2003-03-06 オキソ−アザ二環系化合物
UY27700A UY27700A1 (es) 2002-03-08 2003-03-06 Compuestos oxo - azabiclícos.
AU2003212307A AU2003212307A1 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
PE2003000218A PE20031018A1 (es) 2002-03-08 2003-03-06 Compuestos oxo-azabiciclicos
US10/384,115 US6894057B2 (en) 2002-03-08 2003-03-07 Oxo-azabicyclic compounds
US10/417,073 US6747147B2 (en) 2002-03-08 2003-04-16 Oxo-azabicyclic compounds
IS7414A IS7414A (is) 2002-03-08 2004-08-19 Oxó-azabísýklísk efnasambönd
CO04082792A CO5601020A2 (es) 2002-03-08 2004-08-25 Compuestos ox-azabiciclicos
MA27842A MA27183A1 (fr) 2002-03-08 2004-08-31 Composes oxo-azabicycliques
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WO2012052451A1 (fr) 2010-10-18 2012-04-26 Merz Pharma Gmbh & Co. Kgaa Modulateurs des récepteurs métabotropes au glutamate
WO2015144803A1 (fr) 2014-03-26 2015-10-01 Astex Therapeutics Ltd Dérivés de quinoxaline utiles en tant que modulateurs de la kinase fgfr
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WO2004014923A1 (fr) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Inhibiteurs de metalloprotease bicycliques condenses avec la pyrimidinone
AU2003250466A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc 3-isoquinolinone derivatives as matrix metalloproteinase inhiitors
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WO2004014384A2 (fr) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Composes cycliques contenant des groupes liant le zinc en tant qu'inhibiteurs de metalloprotease de matrice
WO2004014384A3 (fr) * 2002-08-13 2004-07-22 Warner Lambert Co Composes cycliques contenant des groupes liant le zinc en tant qu'inhibiteurs de metalloprotease de matrice
WO2005016926A1 (fr) * 2003-08-19 2005-02-24 Warner-Lambert Company Llc Derives de pyrido[3,4-d]pyrimidine utiles comme inhibiteurs de la metalloproteinase-13 de matrice
JP4848286B2 (ja) * 2004-04-30 2011-12-28 武田薬品工業株式会社 複素環アミド化合物及びｍｍｐ−１３阻害剤としてのその用途
WO2005123696A1 (fr) * 2004-06-15 2005-12-29 Astrazeneca Ab Quinazolones substitues en tant qu'agents anticancereux
WO2012052451A1 (fr) 2010-10-18 2012-04-26 Merz Pharma Gmbh & Co. Kgaa Modulateurs des récepteurs métabotropes au glutamate
WO2015144803A1 (fr) 2014-03-26 2015-10-01 Astex Therapeutics Ltd Dérivés de quinoxaline utiles en tant que modulateurs de la kinase fgfr
WO2017050864A1 (fr) 2015-09-23 2017-03-30 Janssen Pharmaceutica Nv Nouveaux composés
US11155555B2 (en) 2015-09-23 2021-10-26 Janssen Pharmaceutica Nv Compounds
US11542247B2 (en) 2015-09-23 2023-01-03 Janssen Pharmaceutica Nv Bi-heteroaryl substitute 1,4-benzodiazepines and uses thereof for the treatment of cancer

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CA2478706A1 (fr) 2003-09-18
AP2004003125A0 (en) 2004-09-30
CO5601020A2 (es) 2006-01-31
NO20044041L (no) 2004-10-07
WO2003076417A3 (fr) 2003-11-13
KR20040095270A (ko) 2004-11-12
SV2003001495A (es) 2003-11-04
ECSP045278A (es) 2004-10-26
EA200401053A1 (ru) 2005-04-28
BR0308280A (pt) 2004-12-28
PA8568501A1 (es) 2003-12-19
MXPA04008681A (es) 2004-12-06
JP2005526070A (ja) 2005-09-02
WO2003076417A2 (fr) 2003-09-18
UY27700A1 (es) 2003-10-31
EP1492775A2 (fr) 2005-01-05
IS7414A (is) 2004-08-19
IL163818A0 (en) 2005-12-18
AU2002249275A1 (en) 2003-09-22
AR039562A1 (es) 2005-02-23
PL372622A1 (en) 2005-07-25
AU2003212307A1 (en) 2003-09-22
OA12782A (en) 2006-07-10
CN1738806A (zh) 2006-02-22
MA27183A1 (fr) 2005-01-03
TNSN04169A1 (fr) 2007-03-12
PE20031018A1 (es) 2004-01-09

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