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WO2004007469A1 - Nouveaux composes de quinazoline alcynyles utilises comme inhibiteurs de la mmp-13 - Google Patents

Nouveaux composes de quinazoline alcynyles utilises comme inhibiteurs de la mmp-13 Download PDF

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Publication number
WO2004007469A1
WO2004007469A1 PCT/EP2002/008475 EP0208475W WO2004007469A1 WO 2004007469 A1 WO2004007469 A1 WO 2004007469A1 EP 0208475 W EP0208475 W EP 0208475W WO 2004007469 A1 WO2004007469 A1 WO 2004007469A1
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Prior art keywords
group
alkyl
formula
compound
methyl
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PCT/EP2002/008475
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English (en)
Inventor
Bernard Gaudilliere
Henry Jacobelli
Michael William Wilson
Joseph Armand Picard
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Priority to AU2002331362A priority Critical patent/AU2002331362A1/en
Priority to PCT/EP2002/008475 priority patent/WO2004007469A1/fr
Priority to SV2002001289A priority patent/SV2003001289A/es
Priority to ARP020103820A priority patent/AR037100A1/es
Priority to BR0213239-7A priority patent/BR0213239A/pt
Priority to EP02801341A priority patent/EP1465878A1/fr
Priority to US10/269,197 priority patent/US6962922B2/en
Priority to PE2002001007A priority patent/PE20030541A1/es
Priority to CA002463159A priority patent/CA2463159A1/fr
Priority to JP2003536218A priority patent/JP2005509626A/ja
Priority to UY27485A priority patent/UY27485A1/es
Priority to MXPA04003008A priority patent/MXPA04003008A/es
Priority to PCT/EP2002/012194 priority patent/WO2003033478A1/fr
Priority to PA20028556301A priority patent/PA8556301A1/es
Publication of WO2004007469A1 publication Critical patent/WO2004007469A1/fr
Anticipated expiration legal-status Critical
Priority to US11/148,880 priority patent/US20050245548A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—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
    • 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
    • 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
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • New alkynylated quinazolin compounds as MMP-13 inhibitors as MMP-13 inhibitors.
  • the present invention relates to novel alkynylated quinazolin 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 inflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancers.
  • MMPs Matrix metalloproteases
  • TLMPs tissue inhibitors of metalloprotease
  • rheumatic diseases such as rheumatoid arthritis or osteoarthritis.
  • the cartilage degradation process predominates, leading to a destruction of the tissue and resulting in a loss of function.
  • matrix metalloproteases have been identified to date and are subdivided into four groups, the collagenases, the gelatinases, the stromelysins and the membrane-type MMPs (MT-MMPs), respectively.
  • Matrix metalloprotease-13 is a collagenase-type MMP which constitutes the predominant coliagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
  • MMP inhibitors 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 patent application WO9826664 describes quinazolinone compounds which are used as new antifungic compounds.
  • the US patent 5,389,631 describes new dioxoquinazoline and dioxobenzodiazepine amino acid derivatives which are analogs as fibrinogen receptor antagonists and can be used in the treatment of pathologies wherein inhibition of the fibrinogen of blood and inhibition of the aggregation of blood platelets are involved.
  • 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 alkynylated quinazolin compounds that are matrix metalloprotease inhibitors, and more specifically compounds that are selective MMP-13 inhibitors.
  • Wi represents an oxygen atom, a sulfur atom, or a -NR 3 group in which R 3 represents hydrogen atom, (C 1 -C 6 )alkyl, hydroxyl or cyano,
  • W 2 represents a group selected from :
  • W 3 represents a nitrogen atom or a group -CR 5 in which R 5 is selected from :
  • X 4 represents a nitrogen atom or a group -CR in which R 7 is selected from hydrogen, -NR 8 R 9 , -OR 8 , -SR 8 , (d-C 6 )alkyl, cycloalkyl, aryl, aryl(C 1 -C 1 o)alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH 2 ) p -OH and -(CH 2 ) P -NH2, wherein p is as defined hereinbefore, and in which R 8 and R , identical or different independently of each other, are selected from hydrogen, ( -C ⁇ alkyl and aryl(C 1 -C 6 )alkyl,
  • Xi, X 2 and X 3 identical or different independently of each other, represent a nitrogen atom or a carbon atom, the said carbon atom being optionally substituted by one group selected from :
  • ni represents an integer from 0 to 2 inclusive and R ⁇ , represents an hydrogen atom or a (Ci-Csalkyl group,
  • R 10 and R lls which may be identical or different independently of each other, represent a group selected from hydrogen, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, and aryl(C 1 -C 6 )alkyl, or R 10 and R ⁇ form together with the nitrogen atom to which there are bound, a 5- or 6-ring members which can optionally contain a second hetero atom selected from nitrogen and oxygen, and which can be optionally substituted by a (C 1 -C 6 )alkyl group, with the proviso that not more than two of the groups X ls X 2 and X 3 simultaneously represent a nitrogen atom, a is an integer from 0 to 8 inclusive,
  • hydrocarbon chain Z optionally contains one or two isolated or conjugated multiple bonds
  • one of said -CR 12 R 13 may be replaced with a group selected from oxygen, S(O) n2 in which n2 represents an integer from 0 to 2 inclusive, -NH and -N(C 1 -C 6 )alkyl,
  • A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being a 5- or 6-membered monocycle, or bicycle itself composed of two 5- or 6- membered monocycles,
  • the groups R 2 which may be identical or different independently of each other, are selected from hydrogen, (C ⁇ -Cg)alkyl, halogen, cyano, nitro, trihalogeno(C ⁇ -C 6 )alkyl,
  • R 14 and R 15 identical or different independently of each other, represent hydrogen or (C ⁇ -C 6 )alkyl
  • X 6 represents a single bond, -CH 2 -, an oxygen atom or a sulfur atom which is optionally substituted with one or two oxygen atoms,
  • Rj 6 represents a group selected from aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, each of these groups being optionally substituted by one to four groups, which may be identical or different independently of each other, selected from (C 1 -C 6 )alkyl, halogen, mercapto, (C 1 -C 6 )alkylthio, amino, mono(C ⁇ -C 6 )alkylamino, and di(C 1 -C 6 )alkylamino,
  • q is an integer from 0 to 7 inclusive
  • Ri represents a group selected from:
  • one of said -CR 18 R 19 may be replaced with a group selected from oxygen, -S(O) n3 wherein n3 is an integer from
  • B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being a 5- or 6-membered monocycle, or bicycle itself composed of two 5- or 6-membered monocycles,
  • ⁇ S and R 2 o represents a group selected from -T-OR 14 , -T-NR 10 R ⁇ , -T-C(O)OR 1 , -T-C(O)NR 10 R ⁇ in which T represents a linear or branched (Ci-C 6 )alkylene chain and R 14 , R 10 , and R ⁇ are as defined hereinbefore,
  • optical isomers and optionally, their optical isomers , N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
  • the invention relates to compounds of formula (I) wherein :
  • ⁇ represents an oxygen atom, a sulfur atom, or a -NR 3 group in which R 3 represents hydrogen atom, (C 1 -C 6 )alkyl, hydroxyl or cyano,
  • W 2 represents a group selected from : • hydrogen atom, trifluoromethyl, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, • (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, aryl(C 1 -C 6 )alkyl, cycloalkyl(C 1 -C 6 )alkyl, 5- or 6-membered monocycle heteroaryl, and 5- or 6- membered monocycle heterocycloalkyl, each of these groups being optionally substituted by one to four groups, which may be identical or different independently of each other, selected from halogen, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, cyano, trihalogeno(C 1 -C6)alkyl, (C ⁇ -
  • W 3 represents a nitrogen atom or a group -CR 5 in which R 5 is selected from :
  • R 6 is selected from hydrogen, ( -C ⁇ ⁇ lkyl and aryl(C 1 -C 6 )alkyl;
  • X 4 represents a nitrogen atom or a group -CR in which R 7 is selected from hydrogen, - NR 8 R 9 , -OR 8 , -SR 8 , (C 1 -C 6 )alkyl, cycloalkyl, aryl, aryl(C 1 -C 10 )alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH 2 ) p -OH and -(CH 2 ) -NH 2 , wherein p is as defined hereinbefore, and in which R 8 and R 9 , identical or different independently of each other, are selected from hydrogen, (C 1 -C 6 )alkyl and aryl(d-C 6 )alkyl, and Xi, X 2 , X 3 , R ls R 2 , A, Z, n and q are as defined in formula (I).
  • the invention relates particularly to the compounds of formula (I) in which: W 2 represents a group (CrC6)alkyl, Wi represents an oxygen atom, represents a -CH- group, X 2 represents a -CH- group, X 3 represents a -CH- group, and Ri, R , A, Z, n and q are as defined in formula (I).
  • the invention also relates to the compounds of formula (I) in which: A represents a group selected from phenyl, imidazolyl, lH-[l,2,3]triazolyl, and lH-[l,2,4]triazolyl,
  • q is an integer from 0 to 2 inclusive
  • R 2 which may be identical or different, are selected from hydrogen, -OR 1 , -X 6 -R 16 , and tr ⁇ CrCSalkyl-Si-O- in which each alkyl is identical or different independently of each other, in which :
  • R 14 represents hydrogen or (Ci-Csalkyl
  • R 16 represents a phenyl group and Wi, W 2 , Xi, X 2 , X 3 , Ri, Z and n are as defined in formula (I).
  • Preferred compounds of the invention are those compounds of formula (I) wherein n is equal to one.
  • preferred compounds of the invention are those compounds of formula (I) wherein Z represents a group -CR 12 R 13 in which R 12 and R 13 represent each a hydrogen atom.
  • the substituent A that is preferred according to the invention is the phenyl group or the 1- imidazolyl group optionally substituted by one group R 2 as defined in the compound of the formula (I).
  • Especially preferred compounds of the invention are compounds of formula (I) wherein A, R 2 and q, took together, represent a ⁇ ra-methoxyphenyl group.
  • the substituent Ri that is preferred according to the invention is the group of formula :
  • R 20 represents a group -T-NRioRn, in which T represents a linear or branched (C 2 -C 4 )alkylene chain and R 10 , and R ⁇ are as defined in the compound 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 (C 1 -C 6 )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,
  • (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 6 )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 (C!-C 6 )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, «-propyloxy, tert-butyloxy,
  • a mono ⁇ -CSalkylamino denotes a amino group substituted by one (Q-CSalkyl group as defined hereinbefore ; example of such groups, without implying any limitation are methyl amino, isobutyl amino, ethylamino,
  • - a di(C 1 -C 6 )alkylamino denotes a amino group substituted by two (C 1 -C 6 )alkyl groups as defined hereinbefore, each alkyl group being identical or different independently of each other ;
  • 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
  • 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 or two bridged-monocycle
  • a trihalogeno(Ci-C 6 )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,
  • (d-C ⁇ acyl group denotes an alkyl group or a phenyl 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).
  • Pharmaceutically acceptable acids mean non-toxic 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, pyravic 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 mineral or organic bases. Among those, there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine, dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, quaternary ammonium hydroxides etc...
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (IT):
  • T ⁇ represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester,
  • T ⁇ represents an halogen atom, a mesylate group, or a triflate group, in the presence of a base under conditions of palladium-catalyzed alkynylation with a compound of formula (III):
  • the compounds of formula (I) are purified, where appropriate, according to a conventional purification technique, and separated, where appropriate, into their different isomers according to a conventional separation technique, and converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base.
  • Wi, W 2 , Xi, X 2 , X3 and Ri are as defined in compounds of formula (I) are novel useful intermediates for the preparation of compounds of formula (I).
  • W ls W 2 , Xi, X 2 , X 3 and Ri are as defined in compounds of formula (I) are also novel useful intermediates for the preparation of compounds of formula (I).
  • the compounds of formula (II) used as starting material may be distinguished into two groups which are respectively represented : by the compounds of the formula (IIA) :
  • Wi represents an oxygen atom, a sulfur atom, or a -NR 3 group in which R 3 represents hydrogen atom, (C ⁇ -C6)alkyl, hydroxyl or cyano,
  • W 2 represents a group selected from :
  • T ⁇ represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester, and R ls X l5 X 2 , and X 3 are as defined in the compounds of formula (I),
  • W 3 represents a nitrogen atom or a group -CR 5 in which R 5 is selected from :
  • R 5 is selected from hydrogen, (C ⁇ -C 6 )alkyl and aryl(Ci-C 6 )alkyl;
  • X 4 represents a nitrogen atom or a group -CR 7 in which R 7 is selected from hydrogen, -NR 8 R 9 , -OR 8 , -SR 8 , (Ci-C 6 )alkyl, cycloalkyl, aryl, aryl(C ⁇ -C 10 )alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH 2 ) p -OH and -(CH 2 ) P -NH 2 , wherein p is as defined hereinbefore, S and in which R 8 and R 9 , identical or different independently of each other, are selected from hydrogen, (C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl,
  • ⁇ ⁇ represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester, and R l5 X l5 X 2 , and X 3 are as defined in the compound of formula (I).
  • the process for the preparation of compounds of formula (I) comprises the following step : o reacting as starting material, a compound of formula (H/A) :
  • Wi represents an oxygen atom
  • W 2 represents a (C 1 -C 6 )alkyl group
  • X represents a -CH group
  • X 2 represents a nitrogen atom or a -CH group
  • X represents a - CH group
  • Ti represent a iodine atom or a triflate group
  • R ⁇ represents a group of formula :
  • Y represents a methylene group, m is equal to one, B represents a phenyl group, R 17 is as defined in the compound of formula (I) and r is equal to one,
  • Wi represents an oxygen atom, a sulfur atom, or a -NR 3 group in which R 3 represents hydrogen atom, (d-C 6 )alkyl, hydroxyl or cyano,
  • W 2 represents a group selected from :
  • R 4 represents a hydrogen atom or a (C ⁇ -C 6 )alkyl group
  • Ti represents a halogen atom
  • Ri, X l5 X 2 , and X 3 are as defined in the compounds of formula (I), are also novel useful intermediates for the preparation of compounds of formula (I).
  • the compounds of formula (II/A) may be obtained tlirough the synthetic way described in scheme 1.
  • the starting material (II/A1) is either a commercial product or is obtained according to conventional methods of organic synthesis well known to the person skilled in the art.
  • compounds of formula (II/A), where W ⁇ represents an oxygen atom or a sulfur atom may be obtained through the synthetic way described in scheme 2.
  • the acid function of compound (11/ A3) is transformed into an amide group by reaction with a primary amine in usual conditions of organic chemistry to yield the compound (II/A4).
  • This intermediate is then treated with l,l'-carbonyldiimidazole or 1,1'- thiocarbonyldiimidazole, depending whether Wi is an oxygen atom or a sulfur atom, in ⁇ anhydrous tetrahydrofuran, to yield a compound of formula (11/ A5), which is treated in the same conditions as those described in scheme 1 to obtain the compound of formula (H/A).
  • the compound (II/B5) is obtained from substrate (II/B2) which is commercially available or obtained through usual methods of organic synthesis.
  • the compound (II/B2) is treated with an alkyl N-cyanoimidate to give a compound of formula (II/B4).
  • the substitution of ⁇ H in position 4 with a halide in the presence of a base like cesium carbonate in an aprotic solvent leads to the formation of a compound of formula (II/B5) which represents a particular subgroup of compounds of formula (II) used as starting material in the general process for manufacturing compounds of formula (I).
  • This compound (H/B3) is then treated in an alcoholic solvent such as methanol or ethanol, in the presence of a peroxide for initiating the oxidation of the starting thiol.
  • the amino ketone (LI/B6) obtained thereby is readily cyclized in the presence of acid, in an alcoholic solvent such as zsopropanol to yield a compound of formula (II/B9) which is debenzylated and subsequently substituted on the N4 as described hereinbefore in order to obtain the product of formula (II/Bll).
  • the compound of formula (II/Bll) is a particular subgroup of the compounds of formula (IT) used as starting material in the general process for manufacturing compounds of formula (I).
  • isomers of the compounds of the invention are understood to be optical isomers such as enantiomers and diastereoisomers. More especially, pure enantiomeric forms of the compounds of the invention may be separated by starting from mixtures of enantiomers which are reacted with a racemate-separating agent that can be released, the said agent being itself in the form of a pure enantiomer, which allows the corresponding diastereoisomers to be obtained. The diastereoisomers are then separated according to the separation techniques well known to the person skilled in the art, such as crystallization or chromatography, and the separating agent is then removed using conventional techniques of organic synthesis, resulting in a pure enantiomer.
  • 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, a N-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.
  • Pharmaceutical 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, colorants, 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.
  • the structures of the compounds described in the Examples and Preparations were determined according to the usual specfrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, ...) In the Preparations and Examples, it is understood that : - DMF means Dimethylformamide,
  • TOTU O-(ethoxycarbonyl)cyanomethylamino]-N-N-N -N'-tetramethyl uronium fluoroborate
  • ED AC means 1 -(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Example 1 3-(3,4-Difluoro-benzyl)-l-methyl-6-(3-phenyl-prop»l-ynyl)-ljff- quinazoline-2,4-dione
  • Step 1 6-Iodo-l-methyl-lH-quinazoline-2,4-dione
  • Step 3 3-(3,4-Difluoro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline- 2,4-dione
  • 0.45 g 1.1 mmol
  • 3-(3,4-Difluoro-benzyl)-6-iodo-l-methyl-lH-quinazoline-2,4-dione and 0.56 g (4.4 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis- triphenylphosphine palladium di-chloride (catalytic) followed by Cul (catalytic).
  • Step 1 l-(4-Fluoro-phenyl)-prop-2-yn-l-ol
  • a -78°C solution of 4-fluorobenzaldehyde 5.0 g (40.3 mmol) in 20 ml THF is treated dropwise with a solution of alkynyl magnesium chloride (48.1 mmol, 96.3 ml of a 0.5 M solution in THF). After the addition is complete the mixture is allowed to warm to room temperature and stirred overnight. Saturated aqueous NH C1 is added and the product extracted with 1:1 EtOAc/ Et 2 O (2x). The organic extracts were combined and washed with saturated aqueous NaCI solution, then dried (MgSO 4 ). Purified by flash chromatography with 5% EtOAc/ hexane eluent to obtain a yellow oil. Weight: 4.8 g Yield: 80%
  • Step 2 l-Fluoro-4-prop-2-ynyl-benzene
  • Step 3 3-(3,4-Difluoro-benzyl)-6-[3-(4-fluoro ⁇ phenyl)-prop ⁇ l-ynyl]-l-methyl-lH- quinazoline-2,4-dione
  • Step 2 3-(4-Bromo-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione
  • 0.50 g (1.06 mmol) 3-(4-Bromo-benzyl)-6-iodo-l-methyl-lH-quinazoline-2,4-dione and 0.54 g (4.2 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis- triphenylphosphine palladium di-chloride (catalytic) followed by Cul (catalytic).
  • Example 4 ter « t -ButyI 4-[6-(3-biphenyl-4-yl-prop-l-ynyl)-l-methyl-2,4-dioxo-l,4- dihydro-2 J BT-quinazolin-3-ylmethyl]-benzoate
  • Step 1 iei'i-butyl 4-(6-iod ⁇ -l- ethyl-2,4-dwx ⁇ -l,4-dihyds ' , o-2M-qumaz ⁇ lin-3 -ylmethyl)-benzoate
  • Step 2 l-Biphenyl-4-yl-prop-2-yn-l-ol
  • Step 3 4-Prop-2-ynyl-biphenyl To a solution of 3.0 g (14.4 mmol) l-bi ⁇ henyl-4-yl-prop-2-yn-l-ol in CH 2 C1 2 (20 ml) cooled to -78 °C is added 2.2 g (18.7 mmol) Et 3 SiH in one portion followed by 2.7 g (18.7 mmol) BF 3 Et 2 O dropwise over 2 minutes. The solution was warmed briefly to -20 °C and then re-cooled to -78 C and stirred 1 hour. The mixture is then allowed to warm to room temperature and stir 1 hour. Saturated aqueous NH 4 C1 is added and the solution extracted with EtOAc (2x). The organic extracts are combined and washed with saturated aqueous NaCI solution and dried (MgSO 4 ). Purify by flash chromatography (EtOAc/ hexane eluent). Obtain low melting solid.
  • Step 4 tert-butyl 4-[6-(3-biphenyl-4-yl-prop-l-ynyl)-l-methyl-2,4-di ⁇ xo-l,4-dihydro-
  • Step 1 4 ⁇ (teti-Butyl-dimethyl-sUanyloxy)-bemzaldehyde
  • Step 2 l-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-prop-2-yn-l-ol
  • a -78 °C solution of 4-(tert-Butyl-dimethyl-silanyloxy)-benzaldehyde 3.3 g (13.9 mmol) in 20 ml THF is treated dropwise with a solution of alkynyl magnesium chloride (18.2 mmol, 36.4 ml of a 0.5 M solution in THF). After the addition is complete the mixture is allowed to warm to room temperature and stir overnight. Saturated aqueous NH 4 C1 is added and the product extracted with 1:1 EtOAc/ Et 2 O (2x).
  • Step 3 tert-Butyl-dimethyl-(4-prop-2-ynyl-phenoxy)-silane
  • Step 4 4-(6- ⁇ 3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-prop-l-ynyl ⁇ -l-methyl-2,4- dioxo-l,4-dihydro-2H-quinazolin-3-ylmethyl)-benz ic acid
  • Step 2 Methyl 4-(6 odo-l-methyl-2,4-dioxo-l,4-dihydro-2H-quinaz lin-3-ylmethyl)- benzoate
  • 2.4 g 8.0 mmol triphosgene portionwise.
  • the mixture is heated to reflux for 1.5 hours. Cool and pour onto ice.
  • the solution is made basic with the addition of saturated aqueous NaHCO 3 .
  • the resulting solid is filtered and triturated in hot EtOAc.
  • Step 3 Methyl 4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4-dihydro-2H- quinazolin-3-ylmethyl]-benzoate
  • Step 1 4-[l ⁇ Methyl ⁇ 2,4-dioxo-6-(3 ⁇ phenyl-prop-l-ynyl)-l,4-dihydro-2H-quinazolin-3- ylmethylj-benzoyl chloride
  • Step 2 N,N- imethyl-4-[l--methyl-2,4-diox ⁇ -6-(3-phenyl-pr ⁇ p-l-ynyl)-l,4'dihydr ⁇ - 2H-quin z ⁇ lin-3-ylmethyl]-benzamide
  • the compound is obtained, as a white solid, according to the procedure of Example 9, Step 2, but using piperidine.
  • Example 12 1 -Methyl-3- [4-(4-methyl-piperazine-l -carbonyl)-benzyl] -6-(3-pfaenyl- prop-l-yuyl)-lJEf-quinazoline-2,4-dione
  • Example 13 iV,iV-Bis-(2-hydroxy-ethyl)-4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l- ynyl)-l,4-dihydro-2jfiT-quinazoli ⁇ -3-ylmethyl]-benzamide
  • Step 1 3-(3-Chloro-benzyl)-6-iodo-l-methyl-lH-quinazoline ⁇ 2,4-dione
  • a suspension of 6-iodo-l -methyl- lH-quinazoline-2,4-dione (0.300 g, 0.993 mmol) in 8 ml of DMF was added cesium carbonate (0.971 g, 2.98 mmol).
  • cesium carbonate 0.971 g, 2.98 mmol
  • Step 2 3'(3-Chloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione
  • 3-(3-chloro-benzyl)-6-iodo-l-methyl-lH-quinazoline-2,4-dione (0.224g, 0.525 mmol)
  • Cul 0.010 g, 0.053 mmol
  • Pd(PPh 3 ) 4 0.030 g, 0.026 mmol
  • Step 1 3-(3-Fluoro-benzyl)-6-iodo-l-methyl-lH-quinazoline-2,4-dione
  • Step 2 3-(3-CM ⁇ r ⁇ -benzyl)-l-n ⁇ eihyl-6-(3 hemyl mp-l-ynyl)-lH-qminaz ⁇ lin -2,4- dione
  • Step 1 3-(4-Chloro-benzyl)-6-iodo-l-methyl-lH-quinazoline-2,4-dione
  • the compound is obtained according to the procedure of Example 15, Step 1, but using 4- chlorobenzyl bromide.
  • Step 2 3-(4-Chloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione
  • Example 19_ 3-(3,4-Difluoro-benzyl)-6-(3-imidazol-l-yl-prop-l-ynyl)-l-methyI-ljff- quinazoline-2,4-dione
  • Step 1 3-(3,4-Difluoro-benzyl)-6-iodo-l-methyl-lH-quinazoline-2,4-dione
  • Step 2 3-(3,4-Difluoro-benzyl)-6-(3-imidazol-l-yl-prop-l-ynyl)-l-methyl-lH- quinazoline-2,4-dione
  • Example 20 6-[3-(4-Chloro-phenyl)-prop-l-ynyl]-3-(3,4-difluoro-benzyl)-l-methyl- lif-quinazoline-2,4-dione
  • the compound is obtained according to the procedure of Example 15, Step 2, but using 1- chloro-4-prop-2-ynyl-benzene.
  • the compound is obtained according to the procedure of Example 15, Step 2, but using 1- pro ⁇ -2-ynyl-l ⁇ -[l,2,4]triazole.
  • the compound is obtained according to the procedure of Example 15, Step 2, but using 3- phenyl- 1 -propyne.
  • Step 1 2-amino-N-(4-fluorobenzyl)-5-iodo-benzamide
  • Step 2 3-(4-fluoro-benzyl)-6-iodo-lH-quin zolin-2,4-dione
  • a solution of 13.2 g (35.6 mmol) of the compound obtained in Step 1 in 300 ml dry tefrahydrofurane are added 6.36 g (39.2 mmol) of 1, l'-carbonyldiimidazole.
  • the mixture obtained is heated at 60°C under stirring for 24 hours ; 6.36 g of 1, 1 '-carbonyldiimidazole are added and the solution stirred and heated for further 24 hours.
  • the solvent is evaporated under reduced pressure, the residue triturated in 500 ml water. Filter and dry to give a white solid.
  • Step 3 3-(4-fluoro-benzyl) ⁇ 6-iodo-l-methyl-lH-quinazolit ⁇ -2,4-dione
  • Step 4 3-(4-Fluorobenzyl)-6-[3-phenyl-prop-l-ynyl]-l-methyl-lH-quinazolin- 2,4-dione
  • N.M.R CDC1 3 1H ⁇ (ppm) ; 3.57 (s, 3H); 3.84 (s, 2H); 5.22 (s, 2H); 6.92-7.02 (m, 2H); 7.11 (d, IH) ; 7.27 (d, IH) ; 7.31-7.44 ( , 4H) ; 7.47-7.56 (m, 2H) ; 7.69 (d, IH) ; 8.30 (s, IH).
  • MP 160°C
  • N.M.R CDC1 3 1H ⁇ (ppm) ; 3.58 (s, 3H) ; 3.77 (s, 2H) ; 3.81 (s, 2H) ; 5.22 (s, 2H) ; 6.89 (d, 2H) ; 6.94-7.01 (m, 2H) ; 7.11 (d, IH) ; 7.31 (d, 2H) ; 7.49-7.54 (m, 2H) ; 7.68 (d, IH) ;
  • Example 28 3-(4-Fluorobenzyl)-6-[3-(4-methoxyphenyl)-3-oxo— prop-l-ynyl)-l- methyHH r -qumazolin-2,4-dione
  • Step 1 3-(4-Fluorobenzyl)-6-[2-trimethylsilyl-ethyn-l-yl]-l-methyl-lH-quinazolin- 2,4-dione
  • Step 2 3-(4-Flu ⁇ robenzyl)-6-(ethyn-l-yl)-l-methyl-l -qum z ⁇ lin-2,4-di ⁇ ne
  • a stirred solution of 0.5 g (1.31 mmol) of the compound obtained in Step 1 in 200 ml methanol is added 1.44 ml 1M NaOH solution.
  • the mixture is stirred at room temperature for 2 hours, the insoluble solid filtered off and the filtrate concentrated under vacuum; the residue is partitioned between water and dichloromethane, the organic phase is separated, washed with water, dried over sodium sulfate and concentrated to give the desired product as a white solid.
  • Step 3 3-(4-Fluorobenzyl)-6-[3-(4-methoxyphenyl)-3-oxo-propyn-l-yl]-l-methyl-lH- quinazolin-2,4-dione
  • N.M.R CDC1 3 1H ⁇ (ppm) ; 3.61 (s, 3H) ; 3.91 (s, 3H) ; 5.24 (s, 2H) ; 6.93-7.03 (m, 3H) ; 7.21-7.28 (m, 2H) ; (d, IH) ; 7.49-7.57 (m, 2H) ; 7.92 (d, IH) ; 8.18 (d, 2H) ; 8.54 (s, IH).
  • Example 29 Evaluation of the in vitro activity of the MMP-13 inhibitor compounds according to the invention.
  • 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- Leu-Leu-Gly-OEt.
  • the inhibitory activity of a compound of formula (I) according to the invention is expressed as the IC50 value, which is the concentration of inhibitor for which an inhibition of 50% of the activity of the matrix metalloprotease under consideration is observed.
  • IC50 value is the concentration of inhibitor for which an inhibition of 50% of the activity of the matrix metalloprotease under consideration is observed.
  • a 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) (DTNB), and 100 ⁇ M of substrate, the pH being adjusted to 7.0.
  • concentrations of the inhibitory compound present in a 2.0% DMSO solution and 2.5 nM of the catalytic domain of human MMP-13 are added to the test samples.
  • 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 50 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 50 values on MMP-13 of the compounds of Examples 1 to 28 are all below 10 ⁇ 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 IC 50 values for MMP-13 which are about 100 times lower than the IC 5 Q values for the same compounds with respect to the other matrix metalloproteases tested.

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Abstract

L'invention concerne un composé choisi parmi ceux de la formule (1), dans laquelle W1 représente O, S ou NR3, où R3 représente hydrogène, alkyle, OH ou CN, W2 représente un groupe choisi parmi hydrogène, CF3, NH2, monoalkylamino, dialkylamino, alkyle, alcényle, alcynyle, aryle arylalkyle, cycloalkylalkyle et hétérocycle, ces groupes étant éventuellement substitués, ou W1 et W2 forment ensemble un groupe de formule N=X4-W3- tel que défini dans la description, X1, X2 et X3 représentent N ou C éventuellement substitué, n est compris entre 0 et 8, Z représente CR12R13, R12 et R13 étant tels que définis dans la description, A représente un système à noyau, les groupes R2 représentent hydrogène ou divers groupes chimiques tels que définis dans la description, q vaut entre 0 et 7, et R1 représente hydrogène, alkyle, alcényle, alcynyle ou un système à noyau. L'invention concerne éventuellement des isomères optiques, un N-oxyde et des sels d'additions desdits composés, en combinaison avec un acide ou une base pharmaceutiquement acceptable. Les produits médicaux contenant ces composés sont utiles comme inhibiteurs spécifiques de la métalloprotéase matricielle de type 13.
PCT/EP2002/008475 2001-10-12 2002-07-12 Nouveaux composes de quinazoline alcynyles utilises comme inhibiteurs de la mmp-13 Ceased WO2004007469A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
AU2002331362A AU2002331362A1 (en) 2002-07-12 2002-07-12 New alkynylated quinazolin compounds as mmp-13 inhibitors
PCT/EP2002/008475 WO2004007469A1 (fr) 2002-07-12 2002-07-12 Nouveaux composes de quinazoline alcynyles utilises comme inhibiteurs de la mmp-13
PE2002001007A PE20030541A1 (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado como inhibidores de metaloproteasa de matriz tipo 13
JP2003536218A JP2005509626A (ja) 2001-10-12 2002-10-11 マトリックスメタロプロテアーゼ−１３阻害剤としてのアルキニル化縮合環ピリミジン化合物
BR0213239-7A BR0213239A (pt) 2001-10-12 2002-10-11 Compostos de pirimidina com anel condensado alcinilado como inibidores da metalo-proteinase da matriz de tipo 13
EP02801341A EP1465878A1 (fr) 2001-10-12 2002-10-11 Composes pyrimidiques a anneaux fusionnes alcynyles servant d'inhibiteurs de la metalloprotease matricielle de type 13
US10/269,197 US6962922B2 (en) 2001-10-12 2002-10-11 Alkynylated quinazoline compounds
SV2002001289A SV2003001289A (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado
CA002463159A CA2463159A1 (fr) 2001-10-12 2002-10-11 Composes pyrimidiques a anneaux fusionnes alcynyles servant d'inhibiteurs de la metalloprotease matricielle de type 13
ARP020103820A AR037100A1 (es) 2001-10-12 2002-10-11 Compuesto de pirimidina de anillo fusionado alquinilado, proceso de preparacion, compuestos intermedios, composicion farmaceutica y usi para preparacion de un producto medicinal
UY27485A UY27485A1 (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado
MXPA04003008A MXPA04003008A (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado como inhibidores de metaloproteasa 13 de la matriz.
PCT/EP2002/012194 WO2003033478A1 (fr) 2001-10-12 2002-10-11 Composes pyrimidiques a anneaux fusionnes alcynyles servant d'inhibiteurs de la metalloprotease matricielle de type 13
PA20028556301A PA8556301A1 (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado
US11/148,880 US20050245548A1 (en) 2001-10-12 2005-06-09 Alkynylated fused ring pyrimidine compounds

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WO2008107436A1 (fr) * 2007-03-06 2008-09-12 Novartis Ag Composés organiques bicycliques adaptés au traitement des états inflammatoires ou allergiques
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WO2016159746A1 (fr) * 2015-03-27 2016-10-06 Latvian Institute Of Organic Synthesis Nouvelles éthynylxanthines, leur préparation et leur utilisation en tant qu'inhibiteurs de métalloprotéinases matricielles et d'angiogenèse
GB2553685A (en) * 2015-03-27 2018-03-14 Latvian Inst Organic Synthesis Novel éthynylxanthines, their preparation and use as inhibitors of matrix metalloproteinases and angiogenesis
GB2553685B (en) * 2015-03-27 2020-06-10 Latvian Inst Organic Synthesis Novel ethynylxanthines for use as inhibitors of matrix metalloproteinases and angiogenesis
CN105085495A (zh) * 2015-09-16 2015-11-25 湖南大学 N－炔基苯并咪唑衍生物的制备方法
CN105085495B (zh) * 2015-09-16 2019-01-04 湖南大学 N－炔基苯并咪唑衍生物的制备方法

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