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WO2003033477A1 - Composes alkynylates de pyrimidine a noyau condense sous forme d'inhibiteur de matrice de metalloprotease-13 - Google Patents

Composes alkynylates de pyrimidine a noyau condense sous forme d'inhibiteur de matrice de metalloprotease-13 Download PDF

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Publication number
WO2003033477A1
WO2003033477A1 PCT/EP2001/011824 EP0111824W WO03033477A1 WO 2003033477 A1 WO2003033477 A1 WO 2003033477A1 EP 0111824 W EP0111824 W EP 0111824W WO 03033477 A1 WO03033477 A1 WO 03033477A1
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alkyl
group
formula
compound
atom
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PCT/EP2001/011824
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English (en)
Inventor
Bernard Gaudilliere
Henry Jacobelli
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Warner-Lambert Company Llc
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Application filed by Warner-Lambert Company Llc filed Critical Warner-Lambert Company Llc
Priority to PCT/EP2001/011824 priority Critical patent/WO2003033477A1/fr
Priority to JP2003536218A priority patent/JP2005509626A/ja
Priority to UY27485A priority patent/UY27485A1/es
Priority to EP02801341A priority patent/EP1465878A1/fr
Priority to BR0213239-7A priority patent/BR0213239A/pt
Priority to MXPA04003008A priority patent/MXPA04003008A/es
Priority to SV2002001289A priority patent/SV2003001289A/es
Priority to PA20028556301A priority patent/PA8556301A1/es
Priority to ARP020103820A priority patent/AR037100A1/es
Priority to PE2002001007A priority patent/PE20030541A1/es
Priority to US10/269,197 priority patent/US6962922B2/en
Priority to CA002463159A priority patent/CA2463159A1/fr
Priority to PCT/EP2002/012194 priority patent/WO2003033478A1/fr
Publication of WO2003033477A1 publication Critical patent/WO2003033477A1/fr
Priority to US11/148,880 priority patent/US20050245548A1/en

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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

  • the present invention relates to novel alkynylated fused ring pyrimidine 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
  • TVIPs 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 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.
  • COPDs chronic obstructive pulmonary diseases
  • ARMD age-related degeneration
  • the applicant has identified novel alkynylated fused ring pyrimidine 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 ⁇ -C 6 )alkyl, hydroxyl or cyano,
  • W 2 represents a group selected from :
  • N-X 4 W (in which the nitrogen atom is bonded on the place of the group Wi and the group W 3 is bonded on the place of the group W 2 ) wherein: • W 3 represents a nitrogen atom or a group -CR 5 in which R 5 is selected from :
  • R is selected from hydrogen, (C ⁇ -C 6 )alkyl and (C 5 -C 1 o)aryl(C 1 -C 10 )alkyl; - (C ⁇ -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, the residue of a saturated heterocycle comprising from 3 to 8 ring members including one hetero atom selected from oxygen, sulfur and nitrogen, (C 5 -C ⁇ o)aryl, (C 5 -C ⁇ o)heteroaryl comprising from 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, and (C 5 -C ⁇ o)aryl(C ⁇ -C ⁇ o)alkyl, these groups being optionally substituted by -(CH 2 ) p -OH or -(CH 2 ) P -NH 2 , wherein p is an integer from 0 to 4 inclusive,
  • 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 ⁇ -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, the residue of a saturated heterocycle comprising from 3 to 8 ring members including one hetero atom selected from oxygen, sulfur and nitrogen, (C 5 -C ⁇ o)aryl, (C 5 -C ⁇ o)heteroaryl comprising from 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, and
  • Xi, X 2 and X 3 represent, independently of each other, a nitrogen atom or a carbon atom, the said carbon atom being unsubstituted or substituted with a group selected from :
  • ni represents an integer from 0 to 2 inclusive and P represents an hydrogen atom or a (C ⁇ -C 6 )alkyl group, • and -NRioRi ⁇ wherein Rin and R 11; which may be identical or different, represent a group selected from hydrogen atom, (C ⁇ -C 6 )alkyl, and (C 5 -C]o)aryl(C ⁇ -C ⁇ o)alkyl, or Rio and R u form together with the nitrogen atom to which there are bonded, a 5- or 6-ring members which can optionally contain a second hetero atom selected from nitrogen and oxygen, with the proviso that not more than two of the groups Xi, X 2 and X 3 simultaneously represent a nitrogen atom, n is an integer from 0 to 8 inclusive,
  • the hydrocarbon chain Z optionally contains one or more multiple bonds
  • one of the carbon atoms in the hydrocarbon chain Z may be replaced with an oxygen atom, a sulfur atom which is unsubstituted or substituted with one or two oxygen, or a nitrogen atom which is unsubstituted or substituted with a (C ⁇ -C 6 )alkyl,
  • A represents the residue of an aromatic or non-aromatic 5- or 6-membered monocycle comprising from 0 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, or a bicycle composed of two aromatic or non-aromatic 5- or 6-membered rings, which may be identical or different, comprising from 0 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,
  • the groups R 2 which may be identical or different, are selected from hydrogen, (Ci- C 6 )alkyl, halogen, cyano, nitro, trihalogeno(C ⁇ -C 6 )alkyl, -NRinRu, -OR 14 , -SR ⁇ 4 , -
  • X 5 represents an oxygen atom, a sulfur atom, a -NH group, or a -N(C ⁇ -C 6 )alkyl group
  • R 14 and R ⁇ 5 identical or different, represent hydrogen or (Cj-C 6 )alkyl
  • X 6 represents a single bond, -CH 2 -, an oxygen atom or a sulfur atom which is unsubstituted or substituted with one or two oxygen atoms
  • R ⁇ 6 represents the residue of an aromatic or non-aromatic, heterocyclic or non- heterocyclic, 5- or 6-membered ring which is unsubstituted or substituted with one or more groups, which may be identical or different, selected from (C ⁇ -C 6 )alkyl, halogen, trihalogeno(C ⁇ -C 6 )alkyl, hydroxyl, (C ⁇ -C 6 )alkoxy, mercapto, (C ⁇ -C 6 )alkylthio, amino, mono(C ⁇ -C 6 )alkylamino, di(C ⁇ -C 6 )alkylamino each alkyl moiety being identical or different, and when the ring is heterocyclic, it comprises from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,
  • q is an integer from 0 to 7 inclusive
  • m is an integer from 0 to 8 inclusive
  • the hydrocarbon chain Y optionally contains one or more multiple bonds
  • one of the carbon atoms in the hydrocarbon chain Y may be replaced with an oxygen atom, a sulfur atom which is unsubstituted or substituted with one or two oxygen, or a nitrogen atom which is unsubstituted or substituted with ( -C ⁇ alkyl,
  • B represents a group selected from the residue of an aromatic or non-aromatic, 5- or 6-membered monocycle comprising from 0 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and a bicycle, composed of two aromatic or non-aromatic, 5- or 6- membered rings, which may be identical or different, comprising from 0 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,
  • r is an integer from 0 to 7 inclusive, • the group(s) R ⁇ which may be identical or different are selected from hydrogen,
  • optical isomers 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 : Wi represents an oxygen atom, a sulfur atom, or a -NR 3 group in which R 3 represents hydrogen atom, (C ⁇ -C 6 )alkyl, hydroxyl or cyano, ⁇ represents a group selected from :
  • W 3 represents a nitrogen atom or a group -CR 5 in which R is selected from :
  • Re is selected from hydrogen, (C ⁇ -C 6 )alkyl and (C 5 -C,o)aryl(C,-C ⁇ o)alkyl;
  • X 4 represents a nitrogen atom or a group -CR 7 in which R 7 is selected from hydrogen, -
  • the invention relates particularly to the compounds of formula (I) in which: W 2 represents a group selected from hydrogen atom, (C ⁇ -C 6 )alkyl, (C 5 -C 8 )aryl(C ⁇ -C 6 )alkyl and (C 3 -C 6 )cycloalkyl(C ⁇ -C 6 )alkyl, Wi represents an oxygen atom or a sulfur atom, Xi represents a -CH group, X 2 represents a -CH group or a nitrogen atom,
  • X 3 represents a -CH group
  • Ri, R 2 , A, Z, n and q are as defined in formula (I).
  • the invention also relates to the compounds of general formula (I) in which:
  • W 2 represents a group selected from hydrogen atom, amino, mono(C ! -C ⁇ o)alkylamino, di(C ⁇ -C ⁇ o)alkylamino each alkyl moiety being identical or different, (C ⁇ -C 6 )alkyl, (C -
  • Wi represents an oxygen atom or a sulfur atom
  • Xi represents a nitrogen atom or a -CH group
  • X 2 represents a -CH group
  • X 3 represents a -CH group
  • Ri , R 2 , A, Z, n and q are as defined in formula (I).
  • the invention relates particularly to the compounds of formula (IA) :
  • W 3 represents -CR 5 wherein R 5 represents a hydrogen atom or a methyl group
  • X 4 represents a nitrogen atom or -CR 7 wherein R 7 represents a hydrogen atom or a methyl group, n is an integer from 1 to 4 inclusive, and X l5 X 2 , X 3 , Ri, R 2 , A, Z and q are as defined in the formula (I).
  • the invention also relates to the compounds of formula (I) in which: A represents a group selected from phenyl, pyridyl, thienyl, imidazolyl, furyl, benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, benzo-l,2,5-thiadiazolyl, benzo- 1,2,5-oxadiazolyl and indolyl,
  • q is an integer from 0 to 4 inclusive
  • R 2 which may be identical or different, are selected from hydrogen, (Ci- C 6 )alkyl, halogen, cyano, nitro, -NR ⁇ 4 R 15 , -OR ⁇ 4 , -SO 2 R ⁇ 4 , -
  • R ⁇ 4 and Ri 5 identical or different represent hydrogen or (Ci -C 6 )alkyl
  • R 16 represents a phenyl group which is unsubstituted or substituted with one or more groups, which may be identical or different, selected from (C ⁇ -C 6 )alkyl, halogen, and hydroxyl, and Wi, W 2 , Xi, X 2 , X 3 , Ri, Z and n 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, pyridinyl, thienyl, imidazolyl, furyl, and benzodioxolyl,
  • q is an integer from 0 to 4 inclusive
  • X 5 represents an oxygen atom, a sulfur atom, or a -NH group
  • • k is an integer from 0 and 3 inclusive, • Ri 4 and Ri 5 identical or different represent hydrogen or (C ⁇ -C 6 )alkyl, and Wi, W 2 , Xi, X 2 , X 3 , Ri, Z and n are as defined in formula (I).
  • the invention also relates to the compounds of formula (I) in which Ri represents hydrogen, (C ⁇ -C 6 )alkyl or the group of formula :
  • m is an integer from 0 to 3 inclusive
  • Y represents -CR 18 R ⁇ 9> wherein R ⁇ 8 and R ⁇ 9 independently of each other, represent a group selected from hydrogen, (C ⁇ -C 6 )alkyl, and phenyl, - and when m is greater than or equal to 2, the hydrocarbon chain Y optionally contains one multiple bonds,
  • B represents a group selected from phenyl, pyridinyl, thienyl, imidazolyl, furyl, benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, benzo-l,2,5-thiadiazolyl, benzo-l,2,5-oxadiazolyl, naphtyl and indolyl,
  • R 17 which may be identical or different are selected from hydrogen, (C ⁇ -C 6 )alkyl, halogen, cyano, nitro, trihalogeno(C]-C 6 )alkyl, -NR ⁇ 4 R 15 , -OR] 4 , -SO 2 R ⁇ 4 ,
  • - k is an integer from 0 to 3 inclusive
  • - X 5 represents an oxygen atom, a sulfur atom, or a group -NH
  • - R 14 and R 15 identical or different, represent a hydrogen atom or a (d-C 6 )alkyl group
  • Wi, W 2 , Xi, X 2 , X 3 , R 2 , Z, n and q are as defined in formula (I).
  • the invention relates also to the compound of formula (I) in which Ri represents a group of formula :
  • Y represents -CR ⁇ 8 R ⁇ 9j wherein R 18 and R ⁇ 9 independently of each other, represent a group selected from hydrogen and methyl,
  • the hydrocarbon chain Y optionally contains one double bonds, - and/or one of the carbon atoms in the hydrocarbon chain Y may be replaced with an oxygen atom, a sulfur atom which is unsubstituted or substituted with one or two oxygen, or a nitrogen atom which is unsubstituted,
  • B represents a group selected from phenyl, pyridinyl, thienyl, imidazolyl, furyl, and benzodioxolyl
  • • r is an integer from 0 to 3 inclusive
  • - X 5 represents an oxygen atom, a sulfur atom, or a group -NH
  • R ⁇ 4 and R 15 identical or different, represent a hydrogen atom or a (C ⁇ -C 6 )alkyl group, and Wi, W 2 , Xi, X 2 , X 3 , R2, Z, n and q 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 ⁇ 3 in which R ⁇ 2 and R ⁇ 3 represent each a hydrogen atom.
  • Another preferred compounds of the invention are compounds of formula (I) wherein A represents a 5- to 6- membered aromatic monocycle optionally substituted by one or more groups R 2 as defined in the compound of formula (I).
  • the substituent A that is preferred according to the invention is the phenyl 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 represents a phenyl group and R 2 represents a methoxy group.
  • Still other preferred compounds of the invention are compounds of formula (I) wherein W 2 represents an oxygen atom, Wi represents a linear or branched (C ⁇ -C 6 )alkyl group and Ri represents a group of formula :
  • Y represents a methylene group
  • Still other preferred compounds of the invention are compounds of formula (IA) wherein
  • Ri represents a group of formula :
  • Y represents a methylene group
  • 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 ⁇ -C 6 )alkyl group and a (C ⁇ -C ⁇ o)alkyl group denote a linear or branched group containing respectively from 1 to 6 or from 1 to 10 carbon atoms ; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl, heptyl, 3 -methyl -hexyl, ...
  • a (C 3 -C 6 )alkenyl group denotes a linear or branched group containing from 3 to 6 carbon atoms, and one or more double bonds ; examples of such groups without implying any limitation are allyl, 3-buten-l-yl, 2-methyl-buten-l-yl, hexenyl, ... a (C 3 -C 6 )alkynyl group denotes a linear or branched group containing from 3 to 6 carbon atoms, and one or more triple bonds ; examples of such groups without implying any limitation are 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 metoxy, ethoxy, w-propyloxy, tert-butyloxy, .... a (C ⁇ -C 6 )alkylamino or (C ⁇ -C ⁇ o)alkylamino means the alkyl groups as defined above bound through a nitrogen atom ; example of such groups, without implying any limitation are methyl amino, isobutyl amino, dimethylamino, ethylamino, diethylamino, ...
  • a (C -C ⁇ o)aryl group denotes an aromatic system containing from 5 to 8 carbon atoms ; examples of such groups without implying any limitation are cyclopentadienyl, phenyl, naphthyl, indenyl,...
  • a (C 5 -C 1 o)heteroaryl group denotes an aromatic system 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 (C 3 -C ⁇ o)cycloalkyl group denotes a cyclic system containing from 3 to 10 carbon atoms ; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl, ...
  • a trihalogeno(C ⁇ -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, ...
  • a (C ⁇ -C 6 )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, - optical isomers refer to racemates, enantiomers and diastereoisomers.
  • 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, 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 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 (II):
  • R l5 Wj, W 2 , Xi, X 2 and X 3 have the same defimtions as the compounds of formula (I), and Ti represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester,
  • the compound 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.
  • W l5 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 (11/ A) :
  • Wi represents an oxygen atom, a sulfur atom, or a - ⁇ R 3 group in which R represents hydrogen atom, (C ⁇ -C 6 )alkyl, hydroxyl or cyano,
  • W 2 represents a group selected from :
  • Ti represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester
  • Ri, Xi, 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 :
  • Ti represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester, and Ri, Xi, X 2 , and X are as defined in the compound of formula (I).
  • the process for the preparation of compounds of formula (I) comprises the following step :
  • Wj represents an oxygen atom
  • W 2 represents a (C ⁇ -C 6 )alkyl group
  • X represents a -CH group
  • X 2 represents a nitrogen atom or a -CH group
  • X 3 represents a - CH group
  • T] represent a iodine atom or a triflate group
  • Ri represents a group of formula
  • Y represents a methylene group, m is equal to one, B represents a phenyl group, R ⁇ 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, (C ⁇ -C 6 )alkyl, hydroxyl or cyano,
  • W 2 represents a group selected from :
  • Ti represents a halogen atom
  • Ri, X , 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 substituents Xi, X 2 , X 3 , Wj, W 2 , Ri and Ti are as defined in the compounds of formula (II A).
  • W 2 is as defined hereinbefore and X represents a leaving group.
  • 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.
  • 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 (11/ A4).
  • This intermediate is then treated with lJ '-carbonyldiimidazole or 1,1'- thiocarbonyldiimidazole, depending whether of 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 (II/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 is then debenzylated by usual treatment and the N4-debenzylated atom is substituted by a halide in a basic medium, for example by addition of cesium carbonate in dimethylformamide to yield the product of formula (II/B10).
  • the compound of formula (II/B10) is a particular subgroup of the compounds of formula (II) used as starting material in the general process for manufacturing compounds of formula (I).
  • the compound (II/Bl 1) is obtained starting from compound (II/Bl) which is transformed in a first step into a compound of formula (II/B3) as described hereinbefore.
  • This compound (II/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 (II/B6) obtained thereby is readily cyclized in the presence of acid, in an alcoholic solvent such as tsopropanol 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/Bl 1).
  • the compound of formula (II/Bl 1) is a particular subgroup of the compounds of formula (II) 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-separafing 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, 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.
  • the structures of the compounds described in the Examples and Preparations were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, ...) In the Preparations and Examples, it is understood that : - DMF means Dimethylformamide,
  • THF Tetrahydrofurane
  • TOTU O-(ethoxycarbonyl)cyanomethylamino]-N-N-N'-N'-tetramethyl uronium fluoroborate
  • Step 1 Methyl 4-[(2-amino-5-iodo-benzoylamino)-methyl]-benzoate
  • Step 2 Methyl 4-(6-iodo-2,4-dioxo-l,4-dihydro-2H-quinazolin-3-ylmethyl)- benzoate
  • a solution of 21.35 g (52 mmol) of the compound obtained in Step 1 in 400 ml of dry tetrahydrofurane were added 9.3 g (57.2 mmol) of l, -carbonyldiimidazole. The solution was heated overnight to 60°C. After cooling the precipitate was filtered and dried to afford 19.6 g of the desired product (yield : 68.3%).
  • Step 3 Methyl 4-(6-iodo-l-methyl-2,4-dioxo-l,4-dihydro-2H- quinazolin-3-ylmethyl) -benzoate
  • 11 g (25.2 mmol) of the compound obtained in Step 2 and 110 ml of dry DMF were added 5.22 g (37.8 mmol) of K- 2 CO 3 , at room temperature.
  • 7.85 ml (17.9 g, 126 mmol) of iodomethane were added.
  • the reaction mixture was stirred for 2 hours and the precipitate filtered off and dissolved in a mixture of dichloromethane/methanol.
  • the organic phase was washed with H 2 O, dried over Na 2 SO 4 and concentrated to afford a precipitate corresponding to the desired product (10.1 g ; yield
  • Step 4 4-(6-Iodo-l-methyl-2,4-dioxo-l,4-dihydro-2H-quinazolin-3-yImethyl)- benzoic acid
  • a mixture of 3.0 g (6.66 mmol) of the compound obtained in Step 3, 30 ml of dioxane, 120 ml H 2 O, and 0.56 g (13.3 mmol) of LiOH,H 2 O was heated to reflux over 1 hour. After cooling and acidification with concentrated hydrochloric acid, the precipitate obtained was filtered off and recrystallized in dioxane/ether to afford 1.85 g of the desired product (yield : 64.2%).
  • Step 1 5-(ter- , -Butoxycarbonylamino)-2-methoxypyridine-4-carboxylic acid
  • Step 2 Methyl 4- ⁇ [(5-tert-butoxycarbonylamino-2-methoxy-pyridine-4-carbonyl)- amino]-methyl ⁇ -benzoate
  • the mixture was sti ⁇ ed for 15 minutes at 0°C and then overnight at room temperature.
  • the reaction mixture was washed successively with 200 ml NH 4 OH, 200 ml H 2 O, 200 ml HCl
  • N.M.R CDCI 3 ⁇ ⁇ (ppm) : 1.50 (s,9H) ; 3.90 (2s,6H) ; 4.60 (d,2H) ; 6J0 (sJH) ; 7.0
  • Step 3 Methyl 4- ⁇ [(5-amino-2-methoxy-pyridine-4-carbonyl)-aminomethyl ⁇ - benzoate
  • Step 4 Methyl 4-(6-methoxy-2,4-dioxo-l,4-dihydro-2H-pyrido[3,4- ⁇ -pyrimidin-3- ylmethyl)-benzoate To a solution of 2.5 g (7.9 mmol) of the compound obtained in Step 3 in 110 ml of dry
  • Step 5 Methyl 4-(6-methoxy-l-methyl-2,4-dioxo-l,4-dihydro-2H- pyrido[3,4- ⁇ /Jpyrimidin-3-ylmethyl)-benzoate 2.38 g (7 mmol) of the compound obtained in Step 4 and 52 ml of dry DMF were stirred and heated until dissolution. After cooling to 25°C, 1.45 g (10 mmol) of K 2 CO 3 and 2.2 ml (5.7 g, 35 mmol) of iodomethane were added. The mixture was stirred for 30 minutes at room temperature, then concentrated under vacuum. The residue was treated with H 2 O and the precipitate filtered off, washed with methanol, then dissolved in dichloromethane. The organic phase was washed with H 2 O, dried over Na 2 SO 4 and concentrated under vacuum.
  • Step 7 4-(l-Methyl-2,4-dioxo-6-trifluoromethanesulfonyloxy-l,4-dihydro-2H- pyrido [3,4- ⁇ /] pyrimidin-3-yImethyl)-benzoic acid
  • a solution of 1.2 g of compound obtained in Step 6 in 14 ml of dry pyridin was stirred and cooled to 0°C, and then 1.5 ml (2.52 g, 9 mmol) of trifluoromethanesulfonic anhydride were added.
  • the reaction was allowed to stir at 0°C for 30 minutes then quenched with 30 ml of H 2 O and dichloromethane.
  • the organic phase was washed with H 2 O, HCl 10%, and H 2 O. After concentration the residue was crystallised in a mixture dichloromethane/ether to afford 0.5 g of the desired product (yield : 30%).
  • Step 1 4-Benzyl-7-(trifluoromethylsulfonyloxy)-4/ -[l ,2,4] triazolo [4,3 ] quinazolin -5-one
  • Step 2 7-(Trifluoromethylsulfonyloxy)-4H-[l,2,4]triazolo[4,3- ]quinazolin-5-one
  • a suspension of 10.0 g (23.5 mmol) of the compound obtained in Step 1 and 18.8 g (141 mmol) of aluminium chloride in 200 ml anhydrous benzene was heated at 50°C, under stirring, for lh30. After cooling, the mixture obtained was poured on water/ice. After stirring and homogenization, the insoluble solid was isolated by filtration, washed with several portions of water until neutral pH and dried, then finally washed with a portion of CH 2 C1 2; leaving 7.95 g (99%) of the desired compound.
  • Step 3 Methyl 4-(5-oxo-7-(Trifluoromethylsulfonyloxy)-5H-[l,2,4]triazolo[4,3- ] quinazolin-4-ylmethyl)-benzoate To a stirred solution of 7.9 g (24.3 mmol) of the compound obtained in Step 2 in 100 ml of
  • Step 2 4-(5-oxo-7-(Trifluoromethylsulfonyloxy)-5 ⁇ -[l,2,4]triazolo[4,3- ] quinazolin-4-ylmethyl)-benzoic acid
  • Example 3 4- ⁇ 6-I3-(4-Methoxy-phenyl)-prop-l-ynyl]-l-methyl-2,4-diox -l,4- dihydro-2/?-quinazolin-3-ylmethyl ⁇ -benzoic acid
  • N.M.R DMSO 1H ⁇ (ppm) ; 3.55 (s,3H); 3.75 (s,3H); 3.8 (s,2H); 5J5 (s,2H); 6.9 (d,2H);
  • Example 5 4- ⁇ 6-[3-(4-Methoxy-phenyl)-prop-l-ynyl]-l-methyl-2,4-dioxo-l,4- dihydro-2//-pyrido[3,4-rflpyrimidin-3-ylmethyl ⁇ -benzoic acid
  • N.M.R DMSO 1H ⁇ (ppm); 3.60 (s,3H); 3.75 (s,3H); 3.85 (s,2H); 5.20 (s,2H); 6.9-7.0 (m,2H); 7.30-7.40 (m,2H); 7.45-7.50 (m,2H); 7.80-7.90 (m,3H); 8.90 (sJH); 12.9 (bsJH)
  • N.M.R CDC1 3 1H ⁇ (ppm): 3.8 (s, 2H); 3.8 (s, 3H); 5.5 (s, 2H); 6.9 (d, 2H); 7.2-7.35 (m, 5H); 7.6 (d, 1H); 7.68 (d, 2H); 7.8 (d, 1H); 8.4 (s, 1H); 8.7 (s, 1H).
  • Example 8 Methyl 4- ⁇ 7-[3-(4-methoxy-phenyl)-prop-l-ynyl]-5-oxo-5 ⁇ r- [l,2,4]triazo!o[4,3- ]quinazolin-4-ylmethyl ⁇ -benzoate
  • the compound was obtained according to the procedure described in Example 6 using the compound of the Preparation C Step 3, 1.1 g of 3-(4-methoxyphenyl)prop-l-yne, and 2.72 g of N-ethyl-N,N-diisopropylamine.
  • the crude product was purified by chromatography on a silica column (CH 2 O 2 /CH 3 OH 98/2 v/v). A treatment of the resultant solid with boiling AcOEt gave 1.5 g (yield : 59%) of an off-white solid pure in TLC.
  • N.M.R CDC1 3 ⁇ ⁇ (ppm): 3.79 (s, 2H); 3.81 (s, 3H) ; 3.88(s, 3H) ; 5.56 (s, 2H) ; 6.89 (d, 2H) ; 7.30 (d, 2H) ; 7.60 (d, 1H) ; 7.70 (d, 2H) ; 7.82 (d, 1H) ; 7.97 (d, 2H) ; 8.44 (s, 1H) ; 8.7 (s, 1H).
  • the compound was obtained according to the procedure described in Example 6 using the compound of the Preparation D (0J95 g), 0.067 g of 3-phenylprop-l-yne, and 0.215 g of N-ethyl-N,N-diisopropylamine.
  • the crude product was purified by chromatography on a silica column (CH 2 Cl 2 /CH 3 OH 90/10 then 85/15 v/v) to afford 0.14 g (yield : 77%) of an off-white solid pure in TLC corresponding to the desired product.
  • Mp 262°C
  • N.M.R DMSO 1H ⁇ (ppm): 3.96 (s, 2H); 5.42 (s, 2H); 7.27 (t, 1H); 7.37 (t, 2H); 7.44 (d, 2H); 7.52 (d, 2H); 7.87 (d, 2H); 8.02 (d, 1H); 8.18-8.22 (m, 2H); 9.53 (s, 1H); 12.5-13.2 (m, 1H).
  • the compound was obtained according to the procedure described in Example 5 using the compound of the Preparation A Step 4 (0.59 g, 1.35 mmol), 0J93 g (1.89 mmol) of 1-phenyleth-l-yne, 0.050 g of dichlorobis(triphenylphosphine)palladium, a catalytic amount of Cul and 0.700 g (5.4 mmol) of N-ethyl-N,N-diisopropylamine.
  • N.M.R DMSO 1H ⁇ (ppm): 3.55 (s, 3H) ; 5.21 (s, 2H) ; 7.36-7.50 (m, 5H) ; 7.50-7.65 (m, 3H) ; 7.82-7.99 (m, 3H) ; 8.16 (s, 1H) ; 12.7-13.1 (m, 1H).
  • Example 11 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-
  • the inhibitory activity of a compound of formula (I) according to the invention is expressed as the IC 5 o 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 CaC-2 and 1 mM of 5,5'-dithiobis-(2-nitrobenzoic acid)
  • DTNB DTNB
  • 100 ⁇ M of substrate the pH being adjusted to 7.0.
  • Increasing 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.
  • 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 o 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 o 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 IC 50 values for MMP-13 which are about 100 times lower than the IC 50 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 des composés ayant la formule (I), dans laquelle W1 représente O, S, ou -NR3 Où R3 désigne hydrogène, alkyle, OH ou CN; W2 désigne un groupe sélectionné à partir d'hydrogène, CF3, NH2, monoalkylamino, dialkylamino, alkyle, alcényle, alkynyle, aryle, arylalkyle, cycloalkylalkyle, hétérocycle, les groupes précités étant éventuellement substitués, ou W1 et W2 forment conjointement un groupe de formule -N=X4-W3- tel que défini dans la description, X1, X2 et X3 Désignent N ou C éventuellement substitué, n est compris entre 0 et 8, Z désigne -CR12R13, où R12 et R13 Sont tels que définis dans la description, A désigne un système cyclique, les groupes R2 désignent hydrogène, alkyle, halogène, cyano, nitro, trihalogénoalkyle, -NR10R11, -OR14, -SR14, -SOR14, -SO2R14, acyle, -(CH2)kNR10R11, -X5(CH2)kNR10R11, -(CH2)kSO2NR14R15, -X5(CH2)kC(=O)OR14, -(CH2)kC(=O)OR14, -X5(CH2)kC(=O)NR14R15, -(CH2)kC(=O)NR14R15 et -X6-R16 où X5, k; R10, R11, R14, R15, X6, et R16 sont tels que définis dans la description, q est compris entre 0 et 7; R1 désigne hydrogène, alkyle, alcényle, alkynyle, ou un système cyclique, et éventuellement ses isomères optiques, N-oxyde, et ses sels d'addition avec un acide ou une base pharmaceutiquement acceptable, ainsi que des produits médicinaux contenant les éléments précités utiles comme inhibiteurs spécifiques de la matrice de mettaloprotease de type 13.
PCT/EP2001/011824 2001-10-12 2001-10-12 Composes alkynylates de pyrimidine a noyau condense sous forme d'inhibiteur de matrice de metalloprotease-13 WO2003033477A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
PCT/EP2001/011824 WO2003033477A1 (fr) 2001-10-12 2001-10-12 Composes alkynylates de pyrimidine a noyau condense sous forme d'inhibiteur de matrice de metalloprotease-13
PA20028556301A PA8556301A1 (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado
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
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
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
MXPA04003008A MXPA04003008A (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado como inhibidores de metaloproteasa 13 de la matriz.
SV2002001289A SV2003001289A (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado
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
UY27485A UY27485A1 (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado
PE2002001007A PE20030541A1 (es) 2001-10-12 2002-10-11 Compuestos pirimidina de anillo fusionado alquinilado como inhibidores de metaloproteasa de matriz tipo 13
US10/269,197 US6962922B2 (en) 2001-10-12 2002-10-11 Alkynylated quinazoline compounds
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
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
US11/148,880 US20050245548A1 (en) 2001-10-12 2005-06-09 Alkynylated fused ring pyrimidine compounds

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006913A1 (fr) * 2002-07-17 2004-01-22 Warner-Lambert Company Llc Combinaison d'un inhibiteur allosterique de la metalloproteinase matricielle 13 avec un celecoxib ou valdecoxib
WO2004007024A1 (fr) * 2002-07-17 2004-01-22 Warner-Lambert Company Llc Combinaison d'un inhibiteur allosterique de metalloproteinase matricielle 13 avec un inhibiteur selectif de cyclooxygenase-2, a l'exception du celecoxib ou du valdecoxib
WO2004014880A1 (fr) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives de chromone inhibiteurs de metalloproteinase de matrice
WO2004014909A1 (fr) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives fusionnes de la tetrahydropyridine inhibiteurs de la metalloprotease matricielle
WO2004014921A1 (fr) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives d'uracile fusionnes en 5,6 utilises comme inhibiteurs de metalloproteases matricielles

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4818819A (en) * 1986-10-20 1989-04-04 The Trustees Of Princeton University Process for the preparation of fused pyridine compounds
US4902796A (en) * 1986-10-20 1990-02-20 The Trustees Of Princeton University 6-alkenyl and ethynyl derivatives of 2-amino-4-hydroxypyrido[2,3-d]pyrimidines
US5646141A (en) * 1994-07-28 1997-07-08 Agouron Pharmaceuticals, Inc. Compounds useful as antiproliferative agents and GARFT inhibitors
JPH10195063A (ja) * 1996-10-21 1998-07-28 Dai Ichi Seiyaku Co Ltd エチニルチアゾール誘導体
WO2000044716A1 (fr) * 1999-01-27 2000-08-03 American Cyanamid Company THIOLS ACETYLENIQUES DE SULFONAMIDE UTILISES EN TANT QU'INHIBITEURS DE L'ENZYME DE CONVERSION DU TNF-α OU 'TACE'

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4818819A (en) * 1986-10-20 1989-04-04 The Trustees Of Princeton University Process for the preparation of fused pyridine compounds
US4902796A (en) * 1986-10-20 1990-02-20 The Trustees Of Princeton University 6-alkenyl and ethynyl derivatives of 2-amino-4-hydroxypyrido[2,3-d]pyrimidines
US5646141A (en) * 1994-07-28 1997-07-08 Agouron Pharmaceuticals, Inc. Compounds useful as antiproliferative agents and GARFT inhibitors
JPH10195063A (ja) * 1996-10-21 1998-07-28 Dai Ichi Seiyaku Co Ltd エチニルチアゾール誘導体
WO2000044716A1 (fr) * 1999-01-27 2000-08-03 American Cyanamid Company THIOLS ACETYLENIQUES DE SULFONAMIDE UTILISES EN TANT QU'INHIBITEURS DE L'ENZYME DE CONVERSION DU TNF-α OU 'TACE'

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
E. C. TAYLOR, G. S. K. WONG: "Convergent and Efficient Palladium-Effected Synthesis of 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid (DDATHF)", J. ORG. CHEM., vol. 54, no. 16, 21 July 1989 (1989-07-21), pages 3618 - 3624, XP001062654 *
E. C. TAYLOR, P. S. RAY: "Pteridines. 51. A New and Unequivocal Route to C-6 Carbon-Substituted Pterins and Pteridines", J. ORG. CHEM., vol. 52, no. 18, 4 September 1987 (1987-09-04), pages 3997 - 4000, XP001062678 *
PATENT ABSTRACTS OF JAPAN vol. 12, no. 1998 31 October 1998 (1998-10-31) *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006913A1 (fr) * 2002-07-17 2004-01-22 Warner-Lambert Company Llc Combinaison d'un inhibiteur allosterique de la metalloproteinase matricielle 13 avec un celecoxib ou valdecoxib
WO2004007024A1 (fr) * 2002-07-17 2004-01-22 Warner-Lambert Company Llc Combinaison d'un inhibiteur allosterique de metalloproteinase matricielle 13 avec un inhibiteur selectif de cyclooxygenase-2, a l'exception du celecoxib ou du valdecoxib
WO2004014880A1 (fr) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives de chromone inhibiteurs de metalloproteinase de matrice
WO2004014909A1 (fr) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives fusionnes de la tetrahydropyridine inhibiteurs de la metalloprotease matricielle
WO2004014921A1 (fr) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives d'uracile fusionnes en 5,6 utilises comme inhibiteurs de metalloproteases matricielles
US6869958B2 (en) 2002-08-13 2005-03-22 Warner-Lambert Company Fused tetrahydropyridine derivatives as matrix metalloproteinase inhibitors

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