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WO2004007469A1 - New alkynylated quinazolin compounds as mmp-13 inhibitors - Google Patents

New alkynylated quinazolin compounds as mmp-13 inhibitors 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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French (fr)
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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Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Priority to AU2002331362A priority Critical patent/AU2002331362A1/en
Priority to PCT/EP2002/008475 priority patent/WO2004007469A1/en
Priority to JP2003536218A priority patent/JP2005509626A/en
Priority to PA20028556301A priority patent/PA8556301A1/en
Priority to MXPA04003008A priority patent/MXPA04003008A/en
Priority to ARP020103820A priority patent/AR037100A1/en
Priority to EP02801341A priority patent/EP1465878A1/en
Priority to SV2002001289A priority patent/SV2003001289A/en
Priority to US10/269,197 priority patent/US6962922B2/en
Priority to PCT/EP2002/012194 priority patent/WO2003033478A1/en
Priority to PE2002001007A priority patent/PE20030541A1/en
Priority to BR0213239-7A priority patent/BR0213239A/en
Priority to CA002463159A priority patent/CA2463159A1/en
Priority to UY27485A priority patent/UY27485A1/en
Publication of WO2004007469A1 publication Critical patent/WO2004007469A1/en
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

A compound selected from those of formula (I) wherein W1 represents O, S, or -NR3 in which R3 represents hydrogen, alkyl, OH or CN; W2 represents a group selected from hydrogen, CF3, NH2, monoalkylamino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkylalkyl, heterocycle, these groups being optionally substituted, or W1 and W2 form together a group of formula -N=X4-W3- as defined in the description, X1, X2 and X3 represent N or C optionally substituted, n is 0 to 8, Z represents -CR12R13, wherein R12 and R13 are as defined in the description, A represents a ring system, the groups R2 represent hydrogen or various chemical groups as defined in the description, q is 0 to 7; R1 represents hydrogen, alkyl, alkenyl, alkynyl, or a ring system, and optionally, its optical isomers, N-oxide, and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix metalloprotease.

Description

TITLE OF THE INVENTION
New alkynylated quinazolin compounds as MMP-13 inhibitors.
FIELD OF THE INVENTION
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. 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.
TECHNOLOGICAL BACKGROUND OF THE INVENTION
Matrix metalloproteases (MMPs) are enzymes which are involved in the renewal of extracellular matrix tissue, such as cartilage, tendons and joints. MMPs bring about the destruction of the extracellular matrix tissue, which is compensated for, in a non- pathological physiological state, by its simultaneous regeneration.
Under normal physiological conditions, the activity of these extremely aggressive peptidases is controlled by specialized proteins, which inhibit MMPs, such as the tissue inhibitors of metalloprotease (TLMPs).
Local equilibrium of the activities of MMPs and of TIMPs is critical for the renewal of the extracellular matrix. Modifications of this equilibrium, which result in an excess of active MMPs, relative to their inhibitor, induce a pathological destruction of cartilage, which is observed in particular in rheumatoid arthritis and in osteoarthritis.
In pathological situations, an irreversible degradation of articular cartilage takes place, as is the case in rheumatic diseases such as rheumatoid arthritis or osteoarthritis. In these pathologies, the cartilage degradation process predominates, leading to a destruction of the tissue and resulting in a loss of function. At least twenty different 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 (MMP-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.
There is a need in the prior art for novel MMP inhibitors, more particularly for MMP-13 inhibitors, in order to prevent and/or correct the imbalance in the renewal of extracellular matrix tissue, such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPD), age-related macular degeneration (ARMD) and cancer. MMP-inhibitor compounds are known. Most of these MMP-inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or by Clark et al. (2000).
There is also a need in the prior art for novel inhibitors that are active on matrix metalloprotease-13, in order to enrich the therapeutic arsenal that can be used for treating pathologies associated with the destruction of the extracellular matrix and with cancer.
PRIOR ART DESCRIPTION
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. gUMMAHY OF THE ΪI ENTIOM
The applicant has identified novel alkynylated quinazolin compounds that are matrix metalloprotease inhibitors, and more specifically compounds that are selective MMP-13 inhibitors.
More specifically, the present invention relates to compounds of formula (I) :
Figure imgf000005_0001
wherein
Wi represents an oxygen atom, a sulfur atom, or a -NR3 group in which R3 represents hydrogen atom, (C1-C6)alkyl, hydroxyl or cyano,
W2 represents a group selected from :
• hydrogen atom, trifluoromethyl, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino,
• (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(CrC6)alkyl, cycloalkyl(C1-C6)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(C1-C6)alkylamino, di(C1-C6)alkylamino, cyano, trihalogeno(C1-C6)alkyl, (C1-C )acyl, -C(=O)OR4, -OR4 and -SP , wherein P represents a hydrogen atom or a (C1-C6)alkyl group,
or Wi and 2 form together a group of formula N-X^W:} (in which the nitrogen atom is bound in place of the group W\ and the group W3 is bound in place of the group W2) wherein:
• W3 represents a nitrogen atom or a group -CR5 in which R5 is selected from :
- a hydrogen atom, - -ORfo -SR6 in which R6 Js ^selected from hydrogen, ( -C^alkyl and aryl(Cι-C6)alkyl;
- (Cι-C6)alkyl, cycloalkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)P-NH2, wherein p is an integer from 0 to 4 inclusive,
• X4 represents a nitrogen atom or a group -CR in which R7 is selected from hydrogen, -NR8R9, -OR8, -SR8, (d-C6)alkyl, cycloalkyl, aryl, aryl(C1-C1o)alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)P-NH2, wherein p is as defined hereinbefore, and in which R8 and R , identical or different independently of each other, are selected from hydrogen, ( -C^alkyl and aryl(C1-C6)alkyl,
Xi, X2 and X3, 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 :
• (CrC6)alkyl, hydroxyl, (C1-C6)alkoxy, halogen, trifluoromethyl, cyano, nitro,
• -8(0),,^ wherein ni represents an integer from 0 to 2 inclusive and RΔ, represents an hydrogen atom or a (Ci-Csalkyl group,
• and -NR10R11 wherein: R10 and Rlls which may be identical or different independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, and aryl(C1-C6)alkyl, or R10 and Rπ 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 (C1-C6)alkyl group, with the proviso that not more than two of the groups Xls X2 and X3 simultaneously represent a nitrogen atom, a is an integer from 0 to 8 inclusive,
% represents -CR12R1 , wherein R12 and R1 , identical or different independently of each other, represent a group selected from hydrogen, (Cι-C6)alkyl, trihalogeno(CrC6)alkyl, halogen, amino, mono(Cι-C6)alkylamino, di(C1-C6)alkylamino, -OR4, -SR-., -C(=O)OR4, 4 being as defined hereinbefore, or -CRj Rι3 form together a carbonyl group, and
- wherein when n is greater than or equal to 2, the hydrocarbon chain Z optionally contains one or two isolated or conjugated multiple bonds,
- and/or wherein when n is greater than or equal to 2 one of said -CR12R13 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(C1-C6)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 R2,, which may be identical or different independently of each other, are selected from hydrogen, (Cι-Cg)alkyl, halogen, cyano, nitro, trihalogeno(Cι-C6)alkyl,
-NR10R11, -OR14, -SRM, -SORM, -SO2R14, (d-C^acyl, -(CH2)kNRιoRιι,
-X5(CH2)kNR1oRii> -(CH2)kSO2NR14Ri5, -X5(CH2)kC(=O)ORι4, -(CH2)kC(=O)OR14,
-X5(CH2)kC(=O)NR14R15, -(CH2)kC(=O)NR14R15, -X6-R16 and tri(C1-C6)alkyl-Si-O- in which each alkyl is identical or different independently of each other, and in which : • X5 represents an oxygen atom, a sulfur atom, a -NH group, or a -N(C1-C6)alkyl group,
• k is an integer from 0 to 3 inclusive,
• R10 and Rπ are as defined hereinbefore,
• R14 and R15, identical or different independently of each other, represent hydrogen or (Cι-C6)alkyl,
• X6 represents a single bond, -CH2-, an oxygen atom or a sulfur atom which is optionally substituted with one or two oxygen atoms,
• Rj6 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 (C1-C6)alkyl, halogen,
Figure imgf000008_0001
mercapto, (C1-C6)alkylthio, amino, mono(Cι-C6)alkylamino, and di(C1-C6)alkylamino,
q is an integer from 0 to 7 inclusive,
Ri represents a group selected from:
- hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl, the groups alkyl, alkenyl and alkynyl being optionally substituted by one to three groups, which may be identical or different independently of each other, selected from amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, cyano, trihalogeno(C1-C6)alkyl, -C(=O)OR4, -OR4, -SR4, in which * is as defined hereinbefore,
- and the group of formula :
Figure imgf000008_0002
in which:
• m is an integer from 0 to 8 inclusive, • Y represents -CR18R19) wherein R18 and R19, identical or different independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, phenyl, trihalogeno(C1-C6)alkyl, halogen, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, -OR*, -SR4 and -C(=O)OR4 wherein j is as defined hereinbefore, and - wherein when m is greater than or equal to 2, the hydrocarbon chain Y optionally contains one or two isolated or conjugated multiple bonds,
- and/or wherein when m is greater than or equal to 2, one of said -CR18R19 may be replaced with a group selected from oxygen, -S(O)n3 wherein n3 is an integer from
0 to 2 inclusive, -NH- and -N(Cι-C6)alkyl, • 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,
• r is an integer from 0 to 7 inclusive, o the group(s) R17} which may be identical or different independently of each other, are selected from hydrogen, (C1-C6)alkyl, halogen, cyano, nitro, trihalogeno(C1-C6)alkyl, -NR10Rπ, -OR14, -SR14, -SOR14, -SO2R14, (C C7)acyl, -(CH2)kNRio n, -(CH2)k-OR14, -(CH2)k-SR14, -(CH2)k-SOR14, -(CH2)k-SO2R14, -X5(CH2)kNR10Rπ, -(CH2)kSO2NR14R155 -X5(CH2)kC(=O)OR14, -(CH2)kC(=O)OR14,
-X5(CH2)kC(=O)NR10Rπ, -(CH2)kC(=O)NRιoRιι, -Xβ-Riβ, and -(CH2)k-C(O)-OR20, in which:
■S X5, k, R10, Rπ, R14, R15, X6 and R16 are as defined hereinbefore, ■S and R2o represents a group selected from -T-OR14, -T-NR10Rπ, -T-C(O)OR1 , -T-C(O)NR10Rπ in which T represents a linear or branched (Ci-C6)alkylene chain and R14, R10, and Rπ are as defined hereinbefore,
and optionally, their optical isomers , N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
According to a first embodiment, the invention relates to compounds of formula (I) wherein :
Ψι represents an oxygen atom, a sulfur atom, or a -NR3 group in which R3 represents hydrogen atom, (C1-C6)alkyl, hydroxyl or cyano,
W2 represents a group selected from : • hydrogen atom, trifluoromethyl, amino, mono(C1-C6)alkylamino, di(C 1 -C6)alkylamino, • (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, cycloalkyl(C1-C6)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(C1-C6)alkylamino, di(C1-C6)alkylamino, cyano, trihalogeno(C1-C6)alkyl, (Cι-C7)acyl, -C(=O)OR4, -ORt and -SR^ wherein R4 represents a hydrogen atom or a (Ci-Csalkyl group, and Xi, X2, X3, Ri, R2, A, Z, n and q are as defined hereinbefore. According to a second embodiment, the invention relates to compounds of formula (I) corresponding to formula (IA) :
Figure imgf000010_0001
wherein : W3 represents a nitrogen atom or a group -CR5 in which R5 is selected from :
- a hydrogen atom,
- -OR6, -SRβ in which R6 is selected from hydrogen, ( -Cδ^lkyl and aryl(C1-C6)alkyl;
- (Ci-Csalkyl, cycloalkyl, aryl, ary^ -CSalkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)p-NH2, wherein p is an integer from 0 to 4 inclusive,
X4 represents a nitrogen atom or a group -CR in which R7 is selected from hydrogen, - NR8R9, -OR8, -SR8, (C1-C6)alkyl, cycloalkyl, aryl, aryl(C1-C10)alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2) -NH2, wherein p is as defined hereinbefore, and in which R8 and R9, identical or different independently of each other, are selected from hydrogen, (C1-C6)alkyl and aryl(d-C6)alkyl, and Xi, X2, X3, Rls R2, A, Z, n and q are as defined in formula (I).
The invention relates particularly to the compounds of formula (I) in which: W2 represents a group (CrC6)alkyl, Wi represents an oxygen atom, represents a -CH- group, X2 represents a -CH- group, X3 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,
the group(s) R2, which may be identical or different, are selected from hydrogen, -OR1 , -X6-R16, and tr^CrCSalkyl-Si-O- in which each alkyl is identical or different independently of each other, in which :
• R14 represents hydrogen or (Ci-Csalkyl,
• X6 represents a single bond,
• R16 represents a phenyl group and Wi, W2, Xi, X2, X3, 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.
Advantageously, preferred compounds of the invention are those compounds of formula (I) wherein Z represents a group -CR12R13 in which R12 and R13 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 R2 as defined in the compound of the formula (I).
Especially preferred compounds of the invention are compounds of formula (I) wherein A, R2 and q, took together, represent a^αra-methoxyphenyl group. The substituent Ri that is preferred according to the invention is the group of formula :
Figure imgf000012_0001
in which m is equal to one, Y represents a methylene group, B represents a phenyl group, r is equal to one, and R1 represents a group selected from -(CH2)k-C(=O)OR1 , -(CH2)k-OR14, -(CH2)kC(=O)NR10Rπ, -(CH2)k-C(O)-OR20, in which:
•S k, Rio, Rπ, and R1 are as defined in the compound of formula (I), and R20 represents a group -T-NRioRn, in which T represents a linear or branched (C2-C4)alkylene chain and R10, and Rπ are as defined in the compound of formula (I).
More particularly, the invention related to the following compounds of formula (I) :
• 3-(4-fluorobenzyl)-6-(3-phenyl-prop- 1 -ynyl)- 1 -methyl- lH-quinazolin-2,4-dione,
• 3-(4-fluorobenzyl)-6-[3-(4-methoxyphenyl)-3-oxo~prop-l-ynyl)-l-methyl-lH- quinazolin-2,4-dione,
• methyl 4-[l -methyl-2,4-dioxo-6-(3-phenyl-prop- 1 -ynyl)- 1 ,4-dihydro-2H- quinazolin-3-ylmethyl]-benzoate,
• 3-(4-fluorobenzyl)-6-[3-(4-methoxyphenyl)-prop-l-ynyl]-l-methyl-lH- quinazolin-2,4-dione,
• 3-(3-chloro-benzyl)-l-methyl-6-(3-phenyl-prop-ynyl)-lH-quinazoline-2,4-dione,
• 3-(3-fluoro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione,
• 3-(4-Chloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione,
• 3-(4-bromo-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione, • 3-(3,4-difluoro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione,
• tert-butyl 4-[6-(3-biphenyl-4-yl-prop- 1 -ynyl)- 1 -methyl-2,4-dioxo- 1 ,4-dihydro- 2H-quinazolin-3-ylmethyl]-benzoate, o tert-butyl 4- {6- [3 -(4-fluoro-phenyl)-prop- 1 -ynyl] - 1 -methyl-2,4-dioxo- 1 ,4- dihydro-2H-quinazolin-3-ylmethyl}-benzoate, o 4-[6-(3-imidazol- 1-yl-prop- 1 -ynyl)- 1 -methyl-2,4-dioxo- 1 ,4-dihydro-2H- quinazolin-3-ylmethyl]-benzoic acid - trifluoro-acetic acid, © 3-(3 ,4-difluoro-benzyl)-6-(3-imidazol- 1 -yl-prop-1 -ynyl)- 1 -methyl- 1H- quinazoline-2,4-dione,
• 2-dimethylamino-ethyl 4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4- dihydro-2H-quinazolin-3-ylmethyl]-benzoate,
• 4-(6-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-prop-l-ynyl}-l-methyl-2,4- dioxo-l,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid,
• N,N-dimethyl-4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4-dihydro-2H- quinazolin-3 -ylmethyl] -benzamide,
• l-methyl-6-(3-phenyl-prop-l-ynyl)-3-[4-(piperidine-l-carbonyl)-benzyl]-lH- quinazoline-2,4-dione, • N-ethyl-4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4-dihydro-2H- quinazolin-3-ylmethyl] -benzamide,
• 6-[3-(4-chloro-phenyl)-prop-l-ynyl]-3-(3,4-difluoro-benzyl)-l-methyl-lH- quinazoline-2,4-dione,
• 3-(3-chloro-benzyl)-6-[3-(4-chloro-phenyl)-prop-l-ynyl]-l-methyl-lH- quinazoline-2,4-dione,
• 3-(4-hydroxymethyl-benzyl)- 1 -methyl-6-(3-phenyl-proρ- 1 -ynyl)- 1H- quinazoline-2,4-dione,
• l-methyl-3-[4-(4-methyl-piperazine-l-carbonyl)-benzyl]-6-(3-phenyl-prop-l- ynyl)- 1 H-quinazoline-2,4-dione, • NN-bis-(2-hydroxy-ethyl)-4-[ 1 -methyl-2,4-dioxo-6-(3-phenyl-prop- 1 -ynyl)- 1 ,4- dihydro-2H-quinazolin-3 -ylmethyl] -benzamide,
• 3-(3,4-difluoro-benzyl)-6-[3-(4-fluoro-phenyl)-prop-l-ynyl]-l-methyl-lH- quinazoline-2,4-dione,
• 3-(3,4-difluoro-benzyl)- 1 -methyl-6-(3-[ 1 ,2,3]triazol- 1 -yl-prop- 1 -ynyl)- 1H- quinazoline-2,4-dione,
• 3-(3 ,4-difluoro-benzyl)- 1 -methyl-6-(3-[ 1 ,2,4]triazol- 1 -yl-prop- 1 -ynyl)- 1H- quinazoline-2,4-dione, o 3-(3 ,4-dichloro-benzyl)- 1 -methyl-6-(3-[ 1 ,2,4]triazol- 1 -yl-prop- 1 -ynyl)- 1H- quinazoline-2,4-dione, o and 3 -(3 ,4-dichloro-benzyl)- 1 -methyl-6-(3 -phenyl-prop- 1 -ynyl)- lH-quinazoline- 2,4-dione.
The 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 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.
DETAILED DESCRIPTION OF THE INVENTION
The compounds provided by this invention are those defined in formula (I). In formula (I), it is understood that : - a (C1-C6)alkyl group denotes a linear or branched group containing from 1 to 6 carbon atoms ; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl,
- a (C2-C6)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 (C2-C6)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!-C6)alkoxy group means the alkyl group as mentioned above bound through an oxygen atom ; examples of such compounds without implying any limitation are methoxy, ethoxy, «-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(C1-C6)alkylamino denotes a amino group substituted by two (C1-C6)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 implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, imidazolyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl,
- 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,
- a 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-C6)alkyl group denotes an alkyl group as defined above which contains a trihalogeno group ; examples of such groups without implying any limitation are trifluoromethyl, 2,2,2-trifluoroethyl,
- a (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,
- optical isomers refer to racemates, enantiomers and diastereoisomers.
The invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I). A review of the pharmaceutically acceptable salts will be found in J. Pharm. Set, 1977, 66, 1-19. 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):
Figure imgf000017_0001
in which Ri, Wls W2, Xi, X2 and X3 have the same definitions as the compounds of formula (I), and T\ represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester,
compound of formula (II) which is treated :
❖ either when 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):
Figure imgf000017_0002
in which A, Z, R2, q and n are as defined for the compounds of formula (I), to yield the compounds of formula (I),
Figure imgf000017_0003
❖ or when T\ represents an hydrogen atom, with iodine to yield in situ the corresponding iodide intermediate, which is treated directly without isolation or purification, with a compound of formula (III) as described hereinbefore, under conditions of palladium-catalyzed alkynylation in the presence of abase, to yield the compounds of formula (I), or when T\ represents an iodine atom, with 2-trimethylsilylacetylene under conditions of palladium-catalyzed alkynylation in the presence of a base, to yield the compounds of formula (INa):
Figure imgf000018_0001
in which Ri, Wl5 W2, X1? X2 and X3 are as defined hereinbefore, and subsequently treated the compound of formula (IVa) with a strong base in polar solvant, to yield the free alcyne compound of formula (IN):
Figure imgf000018_0002
in which R1? Wls W2, Xi, X2 and X3 are as defined hereinbefore,
❖ or when Ti represents an acetyl group, first with lithium diisopropylamine at -78°C in an inert solvent to provide an enolate, second with diethyl chlorophosphate and subsequently with lithium diisopropylamine, to yield a compound of formula (IN):
Figure imgf000018_0003
in which Rl5 Wi, W2, Xi, X2 and X3 are as defined hereinbefore, and condensing the compound of formula (IN), in the presence of triphenylphosphin and
PdCl2(PPh3)2, under basic conditions to a compound of formula (V):
Figure imgf000018_0004
in which A, Z, R2, q and n are as defined hereinbefore and G represents a leaving group, to yield the compound of formula (I),
Figure imgf000019_0001
♦♦* or when T\ represents an ester group, with a reductive agent, to yield the corresponding aldehyde compound of formula (VI):
Figure imgf000019_0002
in which Ri, Wi, W2, Xi, X2 and X3 are as defined hereinbefore,
and subsequently :
• either condensing said compound of formula (VI), in basic conditions, with diazomethyl trimethyl silane or with diazomethyl diethoxy phosphonate, to yield, after basic treatment, a compound of formula (IN) as defined hereinbefore :
Figure imgf000019_0003
and adding said compound of formula (IV) to a compound of formula (V) as described hereinbefore :
Figure imgf000019_0004
in which R2, A, Z, q, n and G are as defined hereinbefore, to yield the compound of formula (I), o or reacting, said compound of formula (VI), with tetrabromomethane in the presence of triphenylphosphine in an aprotic solvent to yield a compound of formula (VII) :
Figure imgf000020_0001
in which R\, Wi, W2, Xi, X2 and X3 are as defined hereinbefore, and dehalogenating said compound of formula (VII) through treatment with a strong base in an inert solvent, or with butyllithium in presence of triphenylphosphine and zinc, to yield the compound of formula (IV) as defined hereinbefore, and reacting said compound of formula (IV) with a compound of formula (V) as defined in the previous step to yield a compound of a general formula (I):
Figure imgf000020_0002
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.
The compounds of formula (IV) :
Figure imgf000020_0003
wherein Wi, W2, Xi, X2, X3 and Ri are as defined in compounds of formula (I) are novel useful intermediates for the preparation of compounds of formula (I).
The compounds of formula (VI)
Figure imgf000021_0001
wherein Wls W2, Xi, X2, X3 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) :
Figure imgf000021_0002
wherein :
Wi represents an oxygen atom, a sulfur atom, or a -NR3 group in which R3 represents hydrogen atom, (Cι-C6)alkyl, hydroxyl or cyano,
W2 represents a group selected from :
• hydrogen atom, trifluoromethyl, amino, mono(Ci-C6)alkylamino, di(C1-C6)alkylamino,
• (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Ci-C6)alkyl, cycloalkyl(Cι-C6)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(Ci-C6)alkylamino, di(Ci-C6)aUcylarnino, cyano, trihalogeno(C1-C6)alkyl, (Cι-C )acyl, -C(=O)OK4, -OR4 and -SR4, wherein R4 represents a hydrogen atom or a (Q-CSalkyl group,
T\ represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester, and Rls Xl5 X2, and X3 are as defined in the compounds of formula (I),
> and by the compounds of formula (II/B) :
Figure imgf000022_0001
wherein :
W3 represents a nitrogen atom or a group -CR5 in which R5 is selected from :
- a hydrogen atom, - -OR6, -SR6 in which R5 is selected from hydrogen, (Cι-C6)alkyl and aryl(Ci-C6)alkyl;
- (Cι-C6)alkyl, cycloalkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)P-NH2, wherein p is an integer from 0 to 4 inclusive,
X4 represents a nitrogen atom or a group -CR7 in which R7 is selected from hydrogen, -NR8R9, -OR8, -SR8, (Ci-C6)alkyl, cycloalkyl, aryl, aryl(Cι-C10)alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)P-NH2, wherein p is as defined hereinbefore, S and in which R8 and R9, identical or different independently of each other, are selected from hydrogen, (C1-C6)alkyl and aryl(C1-C6)alkyl,
Υ\ represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester, and Rl5 Xl5 X2, and X3 are as defined in the compound of formula (I). In an advantageous embodiment of the invention, 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) :
Figure imgf000023_0001
in which Wi represents an oxygen atom, W2 represents a (C1-C6)alkyl group, X represents a -CH group, X2 represents a nitrogen atom or a -CH group, X represents a - CH group, and Ti represent a iodine atom or a triflate group, and R} represents a group of formula :
Figure imgf000023_0002
in which Y represents a methylene group, m is equal to one, B represents a phenyl group, R17 is as defined in the compound of formula (I) and r is equal to one,
with, as reagent, a compound of formula (III)
Figure imgf000023_0003
in which Z represents a methylene group, n is equal to one, A is a phenyl group, q is equal to zero or one, and R2 is as defined in the compound of formula (I),
to yield a compound of formula (I/a), which constitutes a particular subgroup of the compounds of formula (I):
W,
Figure imgf000023_0004
in which W2, X2, R2, q and Rι are as defined hereinbefore.
The compounds of formula (H/A)
Figure imgf000024_0001
wherein : Wi represents an oxygen atom, a sulfur atom, or a -NR3 group in which R3 represents hydrogen atom, (d-C6)alkyl, hydroxyl or cyano,
W2 represents a group selected from :
• hydrogen atom, trifluoromethyl, amino, mono(C1-C6)alkylamino, di(d -C6)alkylamino, • (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Cι-C6)alkyl, cycloalkyl(Ci-C6)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(Cι-C6)alkylamino, di(Ci-C6)alkylamino, cyano, trihalogeno(C1-C6)alkyl, (d-C )acyl, -C(=O)OR4,
-OR4 and -SR4, wherein R4 represents a hydrogen atom or a (Cι-C6)alkyl group,
Ti represents a halogen atom, and Ri, Xl5 X2, and X3 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.
Scheme 1
Figure imgf000025_0001
In these compounds of formulae (LI/A1) and (LI/A2), the substituents Xls X2, X3, Wi, W2, Ri and Ti are as defined in the compounds of formula (II/A). In the compound X-W2, W2 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.
In another preferred embodiment, 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.
Scheme 2
Figure imgf000025_0002
w2-x K2C03 DMF
Figure imgf000025_0003
(π/A)
In a first step 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).
Compounds of the formula (LI/B) are obtained through the synthetic way described in scheme 3 and in scheme 4.
Scheme 3
Figure imgf000026_0001
Scheme 4
Figure imgf000027_0001
In Scheme 3 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 ΝH 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).
In Scheme 4 the compound (II/B10) is obtained starting from compound (II/B1) which is treated in a first step with benzyl isothiocyanate to give the thiocarbonyl derivative (II/B3). This compound is heated, in a refluxing alcohol, in the presence of hydrazine hydrate to give the correspondmgliydrazine (II/B6) which is in turn cyclized by reaction with an acid chloride or an orthoester to yield compound of formula (TUBS). 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 (H/BIO). The compound of formula (II/B10) is a particular subgroup of the compounds of formula (It) used as starting material in the general process for manufacturing compounds of formula (I).
In Scheme 4, the compound (II/Bll) 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 (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).
Generally, 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.
As mentioned above, compounds of formula (I) of the present invention are matrix metalloprotease inhibitors, and more particularly inhibitors of the enzyme MMP-13.
In this respect, their use is recommended for the treatment of diseases or complaints involving a therapy by MMP-13 inhibition. By way of example, 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.
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.
Among the pharmaceutical 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.
Pharmaceutical 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.
Pharmaceutical 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.
The pharmaceutical compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
Among the pharmaceutically acceptable, 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 examples that follow illustrate the invention but do not limit it in any way.
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,
- THF means Tetrahydrofurane,
- DMSO means Dimethylsulfoxyde,
- TOTU means O-(ethoxycarbonyl)cyanomethylamino]-N-N-N -N'-tetramethyl uronium fluoroborate, - ED AC means 1 -(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
- and HOBT means 1-hydroxybenzotriazole hydrate.
EXAMPLES
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
20.0 g (72.2 mmol) of 5-iodo-2-methylamino-benzoic acid and 70 ml of acetic acid are introduced into a round-bottomed flask. 11.7 g (144.0 mmol) of potassium isocyanate is added. The mixture is maintained at 80-85°C for 18 hours before cooling to room temperature. The product is precipitated with the addition of water and filtered. The product is reslurried in hot ethyl acetate and filtered. The product is obtained as follows: Weight: 12.3 g Yield: 77%
MS: m/z (APCI, AP+) 302.9 [M]+
1H ΝMR (400 MHz, DMSO-d6) δ (ppm) 3.38 (s, 3H); 7.23 (m, 1H); 8.02 (m, 1H), 8.17 (lH, m)
Step 2: 3-(3,4-Difluoro-benzyl)-6-iodo-l-methyl-lH-quinazoline-2,4-dione
0.5 g (1.6 mmol) of 6-Iodo-lH-quinazoline-2,4-dione from the preceding stage is dissolved in 10 ml of dimethylformamide and 1.0 g (3.2 mmol) of cesium carbonate is added. The mixture is stirred 10 minutes before adding 3,4-di-fluorobenzyl bromide 0.38 g (1.8 mmol).__StirringJs_continued overnight at room temperature. Water (30 ml) is added and the product is filtered. Slurried solid product in hot ethyl acetate and filtered to obtain: Weight: 0.49 g Yield: 68%
MS: m/z (APCI, AP+) 429.0 M CHN Analysis: Ci6H11F2IN2O2- 0.13 H2O
Calcd: C.44.64; H, 2.65; N, 6.51.
Found: C, 44.25; H, 2.35; N, 6.32.
Step 3 : 3-(3,4-Difluoro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline- 2,4-dione To 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). 0.18 g (1.3 mmol) 3-phenyl-propyne is added and the mixture is heated to 70°C for 6 hours. The mixture is allowed to cool to room temperature and stirred overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturated solid in hot EtOAc and filtered. Purified by flash chromatography (EtOAc/ hexane eluent). Weight: 0.13 g Yield: 8%
MS: m z (APCI, AP+) 417.2 [M]+ CHN Analysis: C25H18F2N2O2 ■ 0.54 H2O Calcd: C,70.46 ; H, 4.51 ; N, 6.57.
Found: C, 70.07 ; H, 4.36 ; N, 6.58.
Example 2: 3-(3,4-Difluoro-benzyl)-6-[3-(4-fluoro-phenyl)-prop-l-ynyl]-l-methyl- ljfi -quinazoliiie-2,4-dione
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/ Et2O (2x). The organic extracts were combined and washed with saturated aqueous NaCI solution, then dried (MgSO4). Purified by flash chromatography with 5% EtOAc/ hexane eluent to obtain a yellow oil. Weight: 4.8 g Yield: 80%
MS: m/z (APCI, AP+) 151.1 [M' 1H NMR (CDC13) δ (ppm) 2.41 (1H, d, J = 6.1); 2.68 (1H, d, J = 2.2); 5.45 (1H, m), 7.03-
7.09 (2H, m); 7.50-7.56 (1H, m)
Step 2 : l-Fluoro-4-prop-2-ynyl-benzene
To a solution of 4.7 g (31.3 mmol) 4-(Fluoro-ρhenyl)-ρrop-2-yn-l-ol in CH2C12 (20 ml) cooled to -78°C is added 4.4 g (37.6 mmol) Et3SiH in one portion followed by 5.3 g (37.6 mmol) BF3 Et2O dropwise over 2 minutes. The solution was warmed briefly to -20°C and then re-cooled to -78C and stirred 1 hour. The mixture is then allowed to warm to room temperature and stirred 1 hour. Saturated aqueous NH4CI is added and the solution extracted with EtOAc (2x). The organic extracts are combined and washed with saturated aqueous NaCI solution and dried (MgSO ). Purify by flash chromatography (EtOAc/ hexane eluent).
Weight: 3.1 g Yield: 74%
MS: m/z (APCI, AP+) 135.1 [M]+
1H NMR (CDCI3) δ (ppm) 2.19 (1H, m); 2.68 (1H, d, J = 2.2); 3.57 (2H, m), 7.01-7.09
(2H, m); 7.29-7.33 (2H, m)
Step 3 : 3-(3,4-Difluoro-benzyl)-6-[3-(4-fluoro~phenyl)-prop~l-ynyl]-l-methyl-lH- quinazoline-2,4-dione
To 0.5 g (1.06 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-l-methyl-lH-quinazoline-2,4-dione and 0.52 g (4.2 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis- triphenylphosphine palladium di-chloride (catalytic) followed by Cul (catalytic). 0.15 g (1.3 mmol) l-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70 °C for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturated solid in hot EtOAc and filtered. Purified by flash chromatography (EtOAc/ hexane eluent). Weight: 0.075 g Yield: 36% MS: m/z (APCI, AP+) 435.2 [M' CHN Analysis: Calcd: C, 69.12 ; E -3.94 ; N, 6.45 . Found: C, 68.82 ; H, 3.59 ; N, 6.12.
Example 3: 3-(4-Bromo-bensyl)-l-metlιyl-6-(3-plιenyl-prop-l-ynyϊ)-l^-qtιinasolin - 2,4-dione
Ste l: 3-(4-Bromo-benzyl)-6-iodø-l-methyl-lH-quinazoline-2,4-dione 0.5 g (1.6 mmol) of 6-Iodo-l -methyl- lH-quinazoline-2,4-dione from Example 1 Step 1 is dissolved in 10 ml of dimethylformamide and 1.0 g (3.2 mmol) of cesium carbonate is added. The mixture is stirred 10 minutes before adding 4-bromobenzyl bromide 0.45 g (1.8 mmol). Stirring is continued overnight at room temperature. Water (30 ml) is added and the product is filtered. Slurried solid product in hot ethyl acetate and filtered to obtain: Weight: 0.52 g Yield: 69%
MS: m z (APCI, AP+) 470.9 [M]+ CΗN Analysis: Calcd: C,40.79; Η, 2.57; N, 5.95. Found: C, 40.43; Η, 2.41; N, 5.89.
Step 2 : 3-(4-Bromo-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione To 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). 0.15 g (1.3 mmol) 3-phenyl-propyne is added and the mixture is heated to 70 °C for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturate solid in hot EtOAc and filter. Dissolve in TΗF and filter through a plug of silica gel with TΗF eluent. Triturate solid in hot EtOAc and filter.
Weight: 0.11 g Yield: 23%
MS: m/z (APCI, AP+) 461.2 [M"]+ CΗN Analysis: Calcd: C, 65.37 ; Η, 4.17 ; N, 6.10. Found: C, 65.66 ; Η, 4.09 ; N, 6.08.
Example 4: ter«t-ButyI 4-[6-(3-biphenyl-4-yl-prop-l-ynyl)-l-methyl-2,4-dioxo-l,4- dihydro-2JBT-quinazolin-3-ylmethyl]-benzoate Step 1: iei'i-butyl 4-(6-iodø-l- ethyl-2,4-dwxø-l,4-dihyds' ,o-2M-qumazølin-3 -ylmethyl)-benzoate
7.8 g (25.8 mmol) of 6-Iodo-l -methyl- lH-quinazoline-2,4-dione from Example 1 Step 1 is dissolved in 60 ml of dimethylformamide and 9.8 g (30.1 mmol) of cesium carbonate is added. The mixture is stirred 10 minutes before adding 4-bromomethyl-benzoic acid tert- butyl ester 8.4 g (30.1 mmol). Stirring is continued overnight at room temperature. Water (100 ml) is added and the product is filtered. Slurried solid product in hot ethyl acetate and filtered to obtain:
Weight: 7.1 g Yield: 56% MS: m/z (APCI, AP+) 437.0 (492 - tert-butyl) [M]+
CΗN Analysis: Calcd: C.51.23; Η, 4.40; N, 5.69. Found: C, 51.13; Η, 4.32; N, 6.04.
Step 2 : l-Biphenyl-4-yl-prop-2-yn-l-ol
A -78°C solution of 4-ρhenylbenzaldehyde 5.0 g (27.4 mmol) in 20 ml TΗF is treated dropwise with a solution of alkynyl magnesium chloride (60.0 mmol, 120 ml of a 0.5 M solution in TΗF). After the addition is complete the mixture is allowed to warm to room temperature and stir overnight. Saturated aqueous NΗ4C1 is added and the product extracted with 1:1 EtOAc/ Et2O (2x). The organic extracts were combined and washed with saturated aqueous NaCI solution, then dried (MgSO4). Purified by flash chromatography with EtOAc/ hexane eluent followed by crystallization from EtOAc/ hexane to obtain a white solid.
Weight: 4.6 g Yield: 81%
MS: m/z (APCI, AP+) 149.0 [M]+ CHN Analysis: Calcd: C,86.51; H, 5.81. Found: C, 86.11; H, 5.77.
Step 3: 4-Prop-2-ynyl-biphenyl To a solution of 3.0 g (14.4 mmol) l-biρhenyl-4-yl-prop-2-yn-l-ol in CH2C12 (20 ml) cooled to -78 °C is added 2.2 g (18.7 mmol) Et3SiH in one portion followed by 2.7 g (18.7 mmol) BF3 Et2O 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 NH4C1 is added and the solution extracted with EtOAc (2x). The organic extracts are combined and washed with saturated aqueous NaCI solution and dried (MgSO4). Purify by flash chromatography (EtOAc/ hexane eluent). Obtain low melting solid.
Weight: 0.5 g Yield: 18%
MS: m/z (APCI, AP+) 191.1 [Mf
Step 4: tert-butyl 4-[6-(3-biphenyl-4-yl-prop-l-ynyl)-l-methyl-2,4-diøxo-l,4-dihydro-
2H-quinazolin-3-ylmeiIιyl]-benzoate
To 0.50 g (1.0 mmol) 4-(6-Iodo-l-methyl-2,4-dioxo-l,4-dihydro-2H-quinazolin-3- ylmethyl)-benzoic acid tert-butyl ester and 0.52 g (4.0 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by Cul (catalytic). 0.25 g (1.3 mmol) 4-prop-2-ynyl-biphenyl is added and the mixture is heated to 70 °C for 6 hrs. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturate solid in hot EtOAc and filter. Dissolve in TΗF and filter through a plug of silica gel with TΗF eluent. Triturate solid in hot EtOAc and filter Weight: 0.21 g Yield: 38%
MS: m/z (APCI, AP+) 555.2 [M]" CΗN Analysis: Calcd: C, 77.68 ; Η, 5.79 ; N, 5.03. Found: C, 77.68 ; Η, 5.62 ; N, 4.78.
Example 5 : fert,-Butyl 4-{6-[3-(4-fluoro-phenyl)-prop-l-ynyl]-l-metlιyl-2,4-dioxo- l,4-dihydro-2H-quinazolin-3-yImethyl}-benzoate
To 1.0 g (2.0 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-l-methyl-lΗ-quinazoline-2,4-dione from Example 4 Step 1 and 1.0 g (8.4 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by Cul (catalytic). 0.44 g (3.3 mmol) l-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70 °C for 6 hrs. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and dry under reduced pressure.
Weight: 0.11 g Yield: 11%
MS: m/z (APCI, AP+) 497.2 [M]" CHN Analysis: Calcd: C, 72.28 ; H, 5.46 ; N, 5.62 . Found: C, 72.38 ; H, 5.83 ; N, 5.29. fe?rom>le 6: 4-(6-{3-[4-(fer -Biityl-dimeiaiyl-saanylosy)-pIieEyll-prop-l-5rnyl}-l- niet yI-2s4-diosQ-lj4-dihydro-2H-qttittasolm-3-ylmethyl)-beasoic aeid
Step 1 : 4~(teti-Butyl-dimethyl-sUanyloxy)-bemzaldehyde
3.0 g (24.5 mmol) of 4-hydroxy-benzaldehyde in 20 ml THF is treated with 4.8 g (31.9 mmol) tert-Butyl-chloro-dimethyl-silane followed by 6.2 g (47.8 mmol) di-isopropyl ethylamine and imidazole (catalytic). The resulting mixture is stirred overnight at room temperature. Dilute with 1:1 EtOAc/ Et2O and wash with saturated aqueous NaHCO3 solution, saturated aqueous NaCI (3x), and dried (MgSO4). Purify by flash chromatography (EtOAc/ hexane eluent). Weight: 4.8 g Yield: 83%
MS: m/z (APCI, AP+) 263.0 [M]+
1H NMR (CDC13) δ (ppm) 0.0 (6H, s); 0.75 (9H, s); 6.67-6.71 (2H, m); 7.52-7.56 (2H, m); 9.64 (lH,s)
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 NH4C1 is added and the product extracted with 1:1 EtOAc/ Et2O (2x). The organic extracts were combined and washed with saturated aqueous NaCI solution, then dried (MgSO4). Purified by flash chromatography with EtOAc/hexane eluent followed by crystallization from EtOAc/ hexane to obtain a white solid. Weight: 3.1 g Yield: 85%
1H NMR (CDC13) δ (ppm) 0.0 (6H, s); 0.78 (9H, s); 1.89 (1H, d, J = 6.1); 2.46 (1H, d, J = 2.2); 5.21-5.22 (1H, m); 6.62-6.66 (2H, m); 7.20-7.24 (2H, m)
Step 3: tert-Butyl-dimethyl-(4-prop-2-ynyl-phenoxy)-silane
To a solution of 3.0 g (11.4 mmol) l-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-prop-2- yn-l-ol in CH2C12 (20 ml) cooled to -78 °C is added 1.6 g (13.7 mmol) Et3SiH in one portion followed by 1.9 g (13.7 mmol) BF3Et2O dropwise over 2 minutes. The solution was warmed briefly to -20°C and then re-cooled to — 78°C and stirred 2.5 hours. The mixture is then allowed to warm to room temperature and stir 1 hour. Saturated aqueous NH4.CI is added and the solution extracted with EtOAc (2x). The organic extracts are combined and washed with saturated aqueous NaCI solution and dried (MgSO ). Purify by flash chromatography (EtOAc/ hexane eluent). Yellow oil. Weight: 0.57 g Yield: 20%
MS: m z (APCI, AP+) 247.0 [M']+
*H NMR (CDC13) δ (ppm) 0.0 (6H, s); 0.79 (9H, s); 1.98 (1H, m); 3.35 (2H, m); 6.58-6.62 (2H, m); 7.00-7.02 (2H, m)
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
To 0.65 g (1.5 mmol) 4-(6-Iodo-l-methyl-2,4-dioxo-l,4-dihydro-2H-quinazolin-3- ylmethyl)-benzoic acid and 0.77 g (6.0 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by Cul (catalytic). 0.5 g (2.0 mmol) tert-Butyl-dimethyl-(4-prop-2-ynyl-phenoxy)-silane is added and the mixture is heated to 70 °C for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filter and dry under reduced pressure. Purify by flash chromatography (EtOAc/ hexane eluent) Weight: 0.097 g Yield: 12% MS: m/z (APCI, AP+) 555.3 [M]+
CHN Analysis: C32H34N2O5Si • 0.21 H2O Calcd: C, 68.82 ; H, 6.21 ; N, 5.02 . Found: C, 68.42 ; H, 6.14 ; N, 4.97.
Example 7: Methyl 4- [l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4-dihydro-2fl- quinazolin-3-ylmethylJ-benzoate
Step 1: Methyl 4-[(5-iodo-2-methylamino-benzoylamino)-methyl]-benzoate
To 13.4 g (48.3 mmol) 5-Iodo-2-methylamino-benzoic acid 11.1 g (57.9 mmol) EDAC- HC1, 7.8 g (57.9 mmol) HOBT, and di-isopropyl ethylamine 7.5 g (57.9 mmol) in 200 ml DMF is treated with 11.7 g (57.9 mmol) 4-aminomethyl-benzoic acid methyl ester hydrochloride. The resulting mixture is stirred overnight at room temperature before diluting with water and stirring 20 minutes. The solid is filtered and then triturated in hot EtOAc, cooled and filtered. Weight: 14.5 g Yield: 71%
MS: m/z (APCI, AP+) 424.2 [Mf *H NMR (400 MHz, DMSO-d6) δ (ppm) 2.7 (3H, d, J = 4.8); 3.80 (3H, s); 4.43 (2H, d, J = 5.8); 6.46 (1H, m); 7.39-7.41 (2H, m); 7.51-7.54 (1H, m); 7.73-7.74 (1H, ); 7.86-7.90 (3H, m); 9.03 (lH, m).
Step 2: Methyl 4-(6 odo-l-methyl-2,4-dioxo-l,4-dihydro-2H-quinaz lin-3-ylmethyl)- benzoate To 3.4 g (8.0 mmol) 4-[(5-Iodo-2-methylamino-benzoylamino)-methyl]-benzoic acid methyl ester in 20 ml THF and 10ml pyridine is added 2.4 g (8.0 mmol) triphosgene portionwise. After the addition is complete 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 NaHCO3. The resulting solid is filtered and triturated in hot EtOAc. Weight: 2.4 g Yield: 66%
MS: m/z (APCI, AP+) 451.0 [M]+
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.30 (3H, s); 3.82 (3H, s); 4.72 (2H, s); 7.09 (1H, d, J = 8.79); 7.54-7.57 (2H, m); 7.51-7.54 (1H, m); 7.89-7.93 (2H, m); 8.23 (1H, m).
Step 3: Methyl 4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4-dihydro-2H- quinazolin-3-ylmethyl]-benzoate
To 19.6 g (44.9 mmol) 4-(6-Iodo-l-methyl-2,4-dioxo-l,4-dihydro-2H-quinazolin-3- ylmethyl)-benzoic acid methyl ester and 23.2 g (179.6 mmol) di-isopropyl ethylamine in 200 ml DMF is added bis-triphenylphosphine palladium di-chloride (1.0 g, catalytic) followed by Cul (0.4 g, catalytic). 7.3 g (62.9 mmol) 3-phenyl-propyne is added and the mixture is heated to 70 °C for 6 hrs. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filter and dry under reduced pressure. Solid from EtOAc. Weight: 5.0 g Yield: 27%
MS: m z (APCI, AP+) 425.1 [M]+ CHN Analysis: Calcd: C, 73.96 ; H, 5.06 ; N, 6.39 . Found: C, 73.60 ; H, 5.11 ; N, 6.37. Exam le 8: 2-Dimetaylaπmno-eftyl 4-[l-m tiyl-2s4-dioκo-6-(3-plιenyϊ-prop-l-yEyl)- ls4-dihydro-2i¥-qumaεQlin-3-ylmetlιyll-l)eιιsoate
A mixture of 0.72 g (1.7 mmol) 4-[l-Methyl-2,4-dioxo-6-(3-phenyl-proρ-l -ynyl)- 1,4- dihydro-2H-quinazolin-3 -ylmethyl] -benzoic acid, 0.43 g (2.2 mmol) EDAC-HCl, 0.29 g (2.2 mmol) HOBT in 10 ml DMF is treated with 0.19g (2.2 mmol) ethanolamine. The resulting mixture is stirred overnight at room temperature before diluting with water and extracting with 1:1 EtOAc/ Et O (2x). The combined organic extracts are washed with saturated aqueous NaCI (3x), dried (MgSO4). The resulting oil is dissolved in EtOAc and treated with saturated methanolic HCl. Concentration provided a solid which is triturated in EtOAc and filtered.
Weight: 0.21 g Yield: 23%
MS: m/z (APCI, AP+) 496.2 [M]+
CHN Analysis: C30H29N3O4 ' 0.25 H2O Calcd: C.67.16 ; H, 5.73 ; N, 7.83 . Found: C,
66.77 ; H, 5.56 ; N, 7.64.
Example 9: iV^V-Dimethyl-4-[l-methyl-2,4-dioxo-6-(3-phenyl-prαp-l-ynyl)-l,4- dihydro-2H-quinazolin-3-ylmethyl]-benzamide
Step 1 : 4-[l~Methyl~2,4-dioxo-6-(3~phenyl-prop-l-ynyl)-l,4-dihydro-2H-quinazolin-3- ylmethylj-benzoyl chloride
To a stirred suspension of 4.0 g (9.4 mmol) of compound obtained in Example 2 in 150 ml of dichloromethane were added, under nitrogen atmosphere, 4 drops of N,N- dimethylformamide and 0.9 mL (10.4 mmol) of oxalyl chloride. The mixture was stirred for 4 hours at room temperature. The suspension had partially cleared. An additional 1.8 L (20.8 mmol) of oxalyl chloride was added and the reaction went immediately clear. The reaction was stirred for an additional hour and then concentrated under vacuum. The resulting solid was redissolved in diethyl ether and again concentrated in vacuo. The resulting yellowish solid was stored under nitrogen and used without further purification. Step 2 : N,N- imethyl-4-[l--methyl-2,4-dioxø-6-(3-phenyl-prøp-l-ynyl)-l,4'dihydrø- 2H-quin zølin-3-ylmethyl]-benzamide
To a solution of 0.5 g (1.1 mmol) of compound obtained in Step 1 in 50 ml of dichloromethane, 10 ml of dimethylamine in ether were added and stirring was continued at room temperature for 16 hours. The reaction mixture was partitioned between 1 M HCl and dichloromethane. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to give 0.4g of the desired product.
1H NMR (CDC13) δ (ppm); 8.30 (s, 1H), 7.71 (dd, 1H), 7.53 (d, 2H), 7.41-7.25 (m, 7H), 7.12 (d, 1H), 5.27 (s, 2H), 3.84 (s, 2H), 3.58 (s, 3H), 3.07 (bs, 3H), and 2.94 (bs, 3H) MS : M+ +1 = 452.2 Da Mp = 171-173 °C Purity (HPLC) : 100%
Example 10: l-Methyl-6-(3-phenyl-prop-l-ynyl)-3-[4-(piperidine-l-carbonyl)- benzyl]-ljH-quinazoline-2,4-dione
The compound is obtained, as a white solid, according to the procedure of Example 9, Step 2, but using piperidine.
1H NMR (CDCI3) δ (ppm); 8.30 (s, 1H), 7.70 (dd, 1H), 7.53 (d, 2H), 7.41-7.25 (m, 7H), 7.12 (d, 1H), 5.27 (s, 2H), 3.83 (s, 2H), 3.65 (bs, 2H), 3.58 (s, 3H), 3.32 (bs, 2H), and 1.64 (bs, 6H)
MS : M+ +1 = 492.3 Da Purity (HPLC) : 100%
Example 11: N-Ethyl-4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4-dihydro- 2H-quinazolin-3-ylmethyl]-benzamide
The compound is obtained, as a white solid, according to the procedure of Example 9, Step 2, but using ethylamine. *H NMR (400 MHz, DMSO-d6) δ (ppm); 8.37 (bt, 1H), 8.02 (s, 1H), 7.82 (dd, 1H), 7.73 (dd, 2H), 7.46 (d, 1H), 7.41-7.32 (m, 6H), 7.26-7.22 (m, 1H), 5.14 (s, 2H), 3.90 (s, 2H), 3.50 (s, 3H), 3.24 (q, 2H), and 1.08 (t, 3H) MS : M" +1 = 452.3 Da Purity (HPLC) : 100%
Example 12: 1 -Methyl-3- [4-(4-methyl-piperazine-l -carbonyl)-benzyl] -6-(3-pfaenyl- prop-l-yuyl)-lJEf-quinazoline-2,4-dione
When in the procedure of Example 9, Step 2, dimethylamine is replaced with N-methyl piperazine, and the reaction is concentrated and triturated with saturated sodium bicarbonate solution, the title compound is obtained as an off-white solid.
1H NMR (CDCI3) δ (ppm); 8.30 (s, 1H), 7.70 (dd, 1H), 7.53 (d, 2H), 7.41-7.25 (m, 7H), 7.13 (d, 1H), 5.27 (s, 2H), 3.83 (bs, 4H), 3.58 (s, 3H), 3.48 (bs, 2H), 2.52 (bs, 4H), and 2.36 (s, 3H) MS : M+ +1 = 507.3 Da
Example 13: iV,iV-Bis-(2-hydroxy-ethyl)-4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l- ynyl)-l,4-dihydro-2jfiT-quinazoliιι-3-ylmethyl]-benzamide
The compound is obtained according to the procedure of Example 9, Step 2, but using diethanolamine; the title compound is isolated as an off-white solid. 1H NMR (CDCI3) δ (ppm); 8.29 (s, 1H), 7.70 (dd, 1H), 7.52 (d, 2H), 7.41-7.25 (m, 7H), 7.12 (d, 1H), 5.26 (s, 2H), 3.94 (bs, 2H), 3.83 (s, 2H), 3.67 (bs, 4H), 3.58 (s, 3H), 3.42 (bs, 2H), and 2.93 (bs, 2H) MS : M+ +1 = 512.3 Da
Example 14: 3-(4-Hydroxymethyl-benzyl)-l-methyl-6-(3-phenyI-prop-l-ynyl)-lHr- quinazoline-2,4-dione
A solution of 0.5 g (1.1 mmol) of compound obtained in Example 9, Step 1 in 50 ml of tetrahydrofuran, was added dropwise to a suspension of 0.047 g (1.2 mmol) lithium alumhium hydride in 50 ml tetrahydrofuran at 0°C. After complete addition, the off-white suspension was warmed to room temperature and stirring was continued for 4 hours. The reaction mixture was concentrated in vacuum and carefully partitioned between 1 M HCl and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily yellow solid. Chromatography (silica, 1:1 ethyl acetate/hexanes) gave 0.25 g of the title compound as a white solid. 1H NMR (CDC13) δ (ppm); 8.30 (s, 1H), 7.69 (dd, 1H), 7.50 (d, 2H), 7.41-7.25 (m, 7H), 7.11 (d, 1H), 5.26 (s, 2H), 4.64 (bs, 2H), 3.84 (s, 2H), 3.57 (s, 3H), and 1.56 (bs, 1H) MS : W? +1 = 411.2 Da Mp = 161-164 °C
Purity (HPLC) : 100%
Example 15: 3-(3-Chloro-benzyl)-l-methyI-6-(3-phenyl-prop-ynyl)-lJHr-quinazoMne- 2,4-dione
Step 1 : 3-(3-Chloro-benzyl)-6-iodo-l-methyl-lH-quinazoline~2,4-dione To 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). After stirring at room temperature for 30 min, a solution of 3-chlorobenzyl bromide (0.128 ml, 0.993 mmol) in 2 ml of DMF was added dropwise to the reaction mixture and stirred overnight. After 24 h stirring at room temperature, white solids (cesium salt) were filtered and the solution was concentrated. The resulting suspension was diluted with 10 ml of ethyl acetate and filtered again. The filtrate was concentrated and trituration with 10 ml diethyl ether gave 0.25 g (59%) of a white solid. MP: 164-166 °C MS(APCI+): m/z 427.0 (MΗ+) 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.51 (s, 3H, NCHj), 5.09 (s, 2Η, NCH2Ar), 7.26- 7.37 (m, 4Η, ArH), 7.37 (s, 1Η, ArH), 8.05 (dd, J=8.78, 2.20 Ηz, 1Η, ArH), 8.27 (d, J= 2.20 Ηz, 1Η, ArH).
Step 2 ; 3'(3-Chloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione To a mixture of 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) and Pd(PPh3)4 (0.030 g, 0.026 mmol), (after purging with nitrogen for 5 min) in 10 ml of anhydrous dioxane was added 3-phenyl-l- propyne (0.098 ml, 0.79 mmol), and followed by diisopropylamine (0.147 ml, 1.05 mmol). Under a nitrogen atmosphere, the reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, ethyl acetate (20 ml) was added and white solids, (H2N(I-Pr) Br) were filtered through celite. The filtrate was concentrated. The product was purified by flash column chromatography on silica gel (20% ethyl acetate:hexane) and concentrated. After stirring at room temperature for 24 h, the reaction mixture was concentrated affording a yellow oil. Trituration with 10 ml of diethyl ether gave 0.200 g (91.7%) of a white solid MP : 164-166°C; Anal. Calcd for C25H19N2O2Cli: C, 71.23; H, 4.72; N, 6.65. Found: C, 70.85; H, 4.39; N, 6.45.
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.50 (s, 3H, NCH5), 3.90 (s, 2Η, CCH2Ar), 5.10 (s, 2Η, NCH2Ar), 7.22-7.47 (m, 10Η, ArH), 7.82 (dd, J=8.78, 2.20, 1Η, ArH), 8.02 (d, J=2.20 Ηz, 1Η, ArH); MS(APCI+): m/z 413.1 (MΗ").
Example 16 : 3-(3-Fluoro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lΗ-quinazoIine- 2,4-dione
Step 1 : 3-(3-Fluoro-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 3- fluorobenzyl bromide and the compound obtained in the preceding Step 1.
Weight: 0.30 g; Yield = 75% MP = 153-155 °C
MS(APCI+): m/z 408.9 (MH1")
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.51 (s, 3H, NCH5), 5.10 (s, 1Η, NCH2Ar), 7.05-
7.30 (m, 3Η, ArH), 7.31-7.35 (m, 2Η, ArH), 8.06 (dd, J=8.78, 2.20 Ηz, 1Η, ArH), 8.26 (d,
J=1.95 Ηz, lΗ, ArH) Step 2 : 3-(3-CMørø-benzyl)-l-nιeihyl-6-(3 hemyl mp-l-ynyl)-lH-qminazύlin -2,4- dione The compound is obtained according to the procedure of Example 15, Step 2, but using 3- phenyl- 1 -propyne. Weight: 0.24 g Yield = 83%
MP: 143-144°C
Anal. Calcd for C25Hi9N2O2F1: C, 74.09; H, 4.91; N, 6.91. Found: C, 73.69; H, 4.61; N, 6.78.
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.50 (s, 3H, NCZ&), 3.90 (s, 2Η, CCH2Ar), 5.12 (s, 2Η, NCH2Ar), 7.14-7.41 (m, 9Η, ArH), 7.46 (d, J=8.54 Ηz, 1Η, ArH), 7.81 (dd, J=8.78, 1.95 Ηz, 1Η, ArH), 8.02 (d, J=2.20 Ηz, 1Η, ArH); MS(APCI+): m/z 397.1 (MΗ").
Example 17 : 3-(4-Chloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyI)-lH- quinazoluιe-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.
Weight: 0.40 g Yield = 94%
MS(APCI+): m/z 424.9 (MΗ")
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.51 (s, 3H, NCH5), 5.08 (s, 1Η, NCH2Ar), 7.27- 7.34 (m, 4Η, ArH), 7.31-7.35 (m, 2Η, ArH), 8.06 (dd, J=8.78, 2.20 Ηz, 1Η, ArH), 8.26 (d,
J=2.20 Ηz, lH, ArH)
Step 2 : 3-(4-Chloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione
The compound is obtained according to the procedure of Example 15, Step 2, but using 3- phenyl- 1 -propyne and the compound obtained in the preceding Step 1. Weight: 0.10 g Yield = 74%
MP: 175-176°C
Anal. Calcd for C25Ηi9N2O2Cli: C, 70.57; Η, 4.33; N, 6.18. Found: C, 70.86; Η, 4.56; N, 6.58 *H NMR (400 MHz, DMSO-d6) δ (ppm) 3.51 (s, 3H, NCH5), 3.90 (s, 2Η, CCH2Ar), 5.09 (s, 2Η, NCH2Ar), 7.24-7.47 (m, 10Η, ArH), 7.80 (dd, J=6.59, 2.20 Ηz, 1Η, ArH), 8.02 (d, J=2.20 Ηz, 1Η, ArH); MS(APCI+): m/z 413.1 (MΗ").
Example 18 : 4-[6-(3-Imidazol-l-yl-prop-l-ynyl)-l-methyl-2s4-dioxo-l,4-dihydro-ie- quinazoIin-3-ylmethylJ-benzoic acid; compound with trifiuoro-acetie acid
The compound is obtained according to the procedure of Example 15, Step 2, but using 1- prop-2-ynyl- lH-imidazole. Weight: 0.24g Yield = 96% Purity (ΗPLC) = 98.2%
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.52 (s, 3H, NCH5), 5.17 (s, 2Η, CCH2Ar), 5.42 (s, 2Η, NCH2Ar), 7.40 (d, J=8.30 Ηz, 2Η, ArH), 7.51 (d, J=8.78 Ηz, 2Η, ArH), 7.84-7.89 (m, 4Η, ArH), 8.14 (d, J=1.95 Ηz, 1Η, ArH) MS(APCI+): m/z 415.3 (MΗ+).
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
The compound is obtained according to the procedure of Example 15, Step 1, but using
3,4-difluorobenzyl bromide.
Step 2 : 3-(3,4-Difluoro-benzyl)-6-(3-imidazol-l-yl-prop-l-ynyl)-l-methyl-lH- quinazoline-2,4-dione
The compound is obtained according to the procedure of Example 15, Step 2, but using 1- prop-2-ynyl-lH-imidazole and the compound obtained in the preceding Step 1. Weight: 0.26 g Yield = 93% MP: 163-165°C
Purity (ΗPLC) = 98.4% lM NMK. (400 MHz, DMSO-dβ) δ (ppm) 3.50 (s, 3H, NCH , 5.08 (s, 2H, CCH2Ar), 5.19 (s, 2Η, NCH2Ar), 6.96 (s, 1Η, ArH), 7.17 (s, 1Η, ArH), 7.30-7.41 (m, 3Η, ArH), 7.48 (d, =8.78 Ηz, 1Η, ArH), 7.81-7.85 (m, 2Η, ArH), 8.05 (d, =2.20 Ηz, 1Η, ArH)
MS(APCI+): m/z 407.3 (MΗ+).
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.
Weight: 0.20 g Yield = 63% MP: 163-165°C
Purity (HPLC) = 99.04%
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.50 (s, 3H, NCH5), 3.91 (s, 2Η, CCH2Ar), 5.08
(s, 2Η, NCH2Ar), 7.17 (s, 1Η, ArH), 7.30-7.47 (m, 7Η, ArH), 7.82 (dd, J=6.59, 1.95 Ηz,
1Η, ArH), 8.02 (d, J=1.95 Ηz, 2Η, ArH) MS(APCI+): m/z 449.1 (MΗ+).
Example 21 : 3-(3-Chloro-benzyl)-6-[3-(4-chloro-phenyl)-prop-l-ynyl]-l-methyl-lH- qumazoline-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. Weight: 0.03 g Yield = 31%
MP: 169-171°C
Anal. Calcd for C25Hi8N2O2Cl2: C, 65.44; H, 4.19; N, 6.10. Found: C, 65.06; H, 3.96; N,
5.89
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.50 (s, 3H, NCH3), 3.91 (s, 2Η, CCH2Ar), 5.10 (s, 2Η, NCH2Ar), 7.30-7.47 (m, 9Η, ArH), 7.82 (dd, J=6.34, 2.20 Ηz, 1Η, ArH), 8.03 (d,
J=1.95 Ηz, 2Η, ArH)
MS(APCI+): m/z 448.4 (MΗ+). feϋBBfe l t 3-(3,4-Biflιιoro-pensyl)-l-metϊιyl-6-f3-ri,2 1triasol-l-yϊ-prop-l-γnyl)- lJH"-qninasoline-2s4-dioBe
The compound is obtained according to the procedure of Example 15, Step 2, but using 1- prop-2-ynyl-lH-[l,2,3]triazole. Weight: 0.20 g Yield = 70%
MP: 167-169°C Purity (HPLC) = 95.2%.
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.54 (s, 3H, NCH,), 5.07 (s, 2Η, CCH2Ar), 5.62 (s, 2Η, NCH2Ar), 7.30-7.37 (m, 3Η, ArH), 7.48 (d, =8.78 Ηz, 1Η, ArH), 7.78 (s, 1Η, ArH); 7.84 (dd, J=6.59, 2.20 Ηz, 1Η, ArH), 8.06 (s, 1Η, ArH), 8.29 (s, 1Η, ArH). MS(APCI+): m/z 408.2 (Wttt).
Example 23 3-(3,4-Difluoro-benzyl)-l-methyl-6-(3-[l,2,4]triazol-l-yl-prop-l-ynyl)- lH-quinazoline-2,4-dione
The compound is obtained according to the procedure of Example 15, Step 2, but using 1- proρ-2-ynyl-lΗ-[l,2,4]triazole.
Weight: 0.25 g Yield = 88%
MP: 185-187°C
Anal. Calcd for C21H15N5θ2F2: C, 59.4; H, 4.10; N, 16.3. Found: C, 59.7; H, 3.75; N,
16.1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.54 (s, 3H, NCH?), 5.07 (s, 2Η, CCH2Ar), 5.41
(s, 2Η, NCH2Ar), 7.32-7.35 (m, 3Η, ArH), 7.47 (d, J=8.54 Ηz, 1Η, ArH), 7.85 (dd, J=8.78,
2.20 Ηz, 1Η, ArH); 8.02-8.05 (m, 2Η, ArH), 8.67 (s, 1Η, ArH)
MS(APCI+): m/z 408.1 (MΗ+).
Example 24 : 3-(3,4-Dichloro-benzyl)-l-methyl-6-(3-[l,2,4]triazol-l-yl-prop-l-ynyl)- l,ff-qumazoline-2,4-dione
The compound is obtained according to the procedure of Example 15, Step 2, but using 1- prop-2-ynyl- lH-[ 1 ,2,4]triazole. Weight: 0.20 g Yield = 71%
MP: 171-172°C
Anal. Caled for C21H15N5O2Cl2: C, 55.6; H, 3.75; N, 15.3. Found: C, 55.7; H, 3.56; N, 14.9 1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.51 (s, 3H, NCH5), 5.08 (s, 2Η, CCH2Ar), 5.41
(s, 2Η, NCH2A1-), 7.29-7.32 (dd, J=8.54, 1.95 Ηz, 1Η, ArH), 7.48 (d, J=8.54 Ηz, 1Η, ArH), 7.54 (d, J=8.30 Ηz, 1Η, ArH), 7.59 (s, 1Η, ArH), 7.84 (dd, J=8.54, 1.95 Ηz, IH), 8.03-8.06 (m, 2Η, ArH), 8.67 (s, 1Η, ArH), MS(APCI+): m/z 441.1 (MΗ").
Example 25 : 3-(3,4-Dichloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH- quinazoline-2,4-dione
The compound is obtained according to the procedure of Example 15, Step 2, but using 3- phenyl- 1 -propyne.
Weight: 0.10 g Yield = 34% MP: 185-187°C
ΗPLC = 95.2% purity
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.50 (s, 3H, NCH3), 3.90 (s, 2Η, CCH2Ar), 5.09
(s, 2Η, NCføAr), 7.30-7.60 (m, 7Η, ArH), 7.82 (dd, J=6.83, 1.95 Ηz, 1Η, ArH), 8.02 (d,
J=2.20 Ηz, 1Η, ArH) MS(APCI+): m/z 440.2 (MΗ1 .
Example 26: 3-(4-Fluorobenzyl)-6-(3-phenyl-prop-l-ynyI)-l-methyl-lHr-quinazolin- 2,4-dione
Step 1 : 2-amino-N-(4-fluorobenzyl)-5-iodo-benzamide
To a stirred solution of 6.15 g (38 mmol) 4-fluoro-benzylamine hydrochloride and 3.84 g (38 mmol) triethylamine in 150 ml DMF are added successively 5.14 g (38 mmol) ΗOBT,
10 g (38 mmol) 2-amino-5-iodobenzoic acid and 7.29 g (38 mmol) EDAC at room temperature. After stirring overnight at this temperature, the solvent is removed under reduced pressure and the residue dissolved in dichloromethane. The organic phase obtained is washed successively with water, IN hydrochloric solution and water, dried- over sodium sulfate and concentrated to give the desired product as a solid : Weight : 13.2 g Yield : 94 %
Step 2 : 3-(4-fluoro-benzyl)-6-iodo-lH-quin zolin-2,4-dione To 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.
Weight : 11.7 g Yield : 83 %
Step 3 : 3-(4-fluoro-benzyl)~6-iodo-l-methyl-lH-quinazolitι-2,4-dione
To a stirred suspension of 11.7 g (29.5 mmol) of the compound obtained in Step 2 in 110 ml DMF were added 6.12 g (44.3 mmol) potassium carbonate and, 15 minutes later, 20.9 g (147 mmol) of iodomethane. The mixture is stirred at room temperature for 1.5 hour, the filtrate evaporated and the residue 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. Weight : 12 g Yield : 99 %
Step 4 : 3-(4-Fluorobenzyl)-6-[3-phenyl-prop-l-ynyl]-l-methyl-lH-quinazolin- 2,4-dione
To 0.5 g (1.21 mmol) of compound obtained in Step 3 and 0.625 g (4.84 mmol) of N-ethyl, N,N-di-isopropylamine in 5 ml of dimethylformamide are added bis-triphenylphosphine palladium dichloride (42 mg) followed by Cul (catalytic) under nitrogen atmosphere. 0.198 g (1.7 mmol) 3-phenyl-prop-l-yne is added and the mixture is heated to 50°C for 1.5 hour.
The mixture is allowed to cool, water added and the mixture obtained stirred for 30 minutes. Filter and dry to give 0.58 g of crude solid. Purify by chromatography (dichloromethane 70 / cyclohexane 30 eluent). Weight : 0.37 g Yield : 77 % Sample recrystallized in methanol
N.M.R: CDC13 1H δ (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
Purity (HPLC) : 99 %
Example 27: 3"(4-Fluorobenzyl)-6-[3-(4-methoxyphenyl)-prop-l-ynyl]-l-methyl-lH- qu azolin-2,4-dione
The compound is obtained according to the procedure of Example 26 from Step 1 to Step 4, but using 3-(4-methoxyphenyl)-prop-l-yne (described in the literature : J. Prakt. Chem.,
1966, 33, 84-95) in Step 4 instead 3-phenyl-prop-l-yne
Sample recrystallized in methanol
Yield : 25%
N.M.R: CDC13 1H δ (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) ;
8.29 (s, IH).
MP = 136°C
Purity (HPLC) : 98%
Example 28: 3-(4-Fluorobenzyl)-6-[3-(4-methoxyphenyl)-3-oxo— prop-l-ynyl)-l- methyHHr-qumazolin-2,4-dione
Step 1 : 3-(4-Fluorobenzyl)-6-[2-trimethylsilyl-ethyn-l-yl]-l-methyl-lH-quinazolin- 2,4-dione
To a stirred solution of 2.0 g (4.87 mmol) of the compound prepared according to the procedure of Example 26 Step 3 and 2.52 g (4.84 mmol) of N-ethyl, NN-di- isopropylamine in 20 ml of dimethylformamide is added bis-triphenylphosphine palladium dichloride (170 mg, catalytic) followed by Cul (catalytic) under nitrogen atmosphere. 0.67 g (6.8 mmol) of 2-trimethylsilylacetylene is added and the mixture is stirred at room temperature for 1.5 hour. The mixture is allowed to cool, water added and the mixture obtained stirred for 30 minutes. Filter and dry to give the crude product. Weight: 1.8 g Yield : 97 %
Step 2 : 3-(4-Fluørobenzyl)-6-(ethyn-l-yl)-l-methyl-l -qum zølin-2,4-diøne To 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.
Weight: 0.4 g Yield : 100%
Step 3 : 3-(4-Fluorobenzyl)-6-[3-(4-methoxyphenyl)-3-oxo-propyn-l-yl]-l-methyl-lH- quinazolin-2,4-dione
To a solution of 0.3 g (0.97 mmol) of the compound obtained in Step 2 and 0.39 g (3.88 mmol) of triethylamine in 5 ml of benzene are added successively 34 mg (catalytic) of bis- triphenylphosphine palladium dichloride and 0.23 g (1.36 mmol) of 4-methoxybenzoyl chloride. The mixture is heated at 70°C under stirring for 1.5 hour, allowed to cool and partitioned between water and dichloromethane. The organic phase is separated, washed with brine, dried over sodium sulfate and concentrated to give the crude product as 0.45 g of white solid. Purify by chromatography (dichloromethane eluent) : Weight : 0.2 g Yield : 46 %
N.M.R: CDC13 1H δ (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). MP = 240°C Purity (HPLC) = 96%
PHARMACOLOGICAL STUDIES OF COMPOUNDS OF THE INVENTION
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. To carry out this test, a reaction medium of 100 μl volume is prepared, containing: 50 mM of HEPES buffer, 10 mM of CaCl2 and 1 mM of 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), and 100 μM 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 μM 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 IC50 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 IC50 values on MMP-13 of the compounds of Examples 1 to 28 are all below 10 μM.
The test described above for the inhibition of MMP-13 was also adapted and used to determine the ability of the compounds of formula (I) to inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-14. The results obtained show that the compounds according to the invention generally have IC50 values for MMP-13 which are about 100 times lower than the IC5Q values for the same compounds with respect to the other matrix metalloproteases tested.

Claims

1- A compound selected from those of formula (I) :
Figure imgf000054_0001
wherein
Wi represents an oxygen atom, a sulfur atom, or a -NR3 group in which R3 represents hydrogen atom, (d-C6)alkyl, hydroxyl or cyano,
W2 represents a group selected from :
• hydrogen atom, trifluoromethyl, amino, mono(Ci-C6)alkylamino, di(Ci-C6)alkylamino,
• (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Cι-C6)alkyl, cycloalkyl(Ci-C6)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(d-C6)alkylamino, di(Ci-C6)alkylamino, cyano, trihalogeno(d-C6)alkyl, (d-C )acyl, -C(=O)OR4, -OR4 and -SR4, wherein R4 represents a hydrogen atom or a (d-C6)alkyl group,
or Wi and W2 form together a group of formula N-X4=W3 (in which the nitrogen atom is bound in place of the group Wi and the group W3 is bound in place of the group W2) wherein:
• W3 represents a nitrogen atom or a group -CR5 in which R5 is selected from :
- a hydrogen atom,
- -OR6, -SR6 in which R6 is selected from hydrogen, (d-C6)alkyl and aryl(Cι-C6)alkyl; - (d-C6)alkyl, cycloalkyl, aryl, aryl(C1-C6)allcyl, heteroaryl, -and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)P-NH2, wherein p is an integer from 0 to 4 inclusive, « X4 represents a nitrogen atom or a group -CR7 in which R7 is selected from hydrogen, -NR8R9, -OR8, -SRs, (Cι-C6)alkyl, cycloalkyl, aryl, aryl(Cj-Cιo)alkyl, heteroaryl, and heterocycloalkyl,
S each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)P-NH2, wherein p is as defined hereinbefore,
S and in which R8 and R9, identical or different independently of each other, are selected from hydrogen, (d-C6)alkyl and aryl(d-C6)alkyl,
Xi, X2 and X3, 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 :
• (C]-C6)alkyl, hydroxyl, (d-C6)alkoxy, halogen, trifluoromethyl, cyano, nitro,
• -S(O)nlR4 wherein m represents an integer from 0 to 2 inclusive and R4 represents an hydrogen atom or a (Cj-C6)alkyl group,
• and -NR10R11 wherein: Rio and Rπ, which may be identical or different independently of each other, represent a group selected from hydrogen, (d-C6)alkyl, hydroxy(Cι-C6)alkyl, and aryl(C C6)alkyl, or Rio and Rπ 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 (Cι-C6)alkyl group, with the proviso that not more than two of the groups Xi, X2 and X3 simultaneously represent a nitrogen atom,
n is an integer from 0 to 8 inclusive, Z represents -CR12Ri3, wherein R12 and Rι3, identical or different independently of each other, represent a group selected from hydrogen, (d-C6)alkyl, trihalogeno(Ci-C6)alkyl, halogen, amino, mono(d-C6)alkylamino, di(C1-C6)alkylamino, -OR4, -SR^ -C(=O)OR4, R4 being as defined hereinbefore, or -CR12Rι3 form together a carbonyl group, and
- wherein when n is greater than or equal to 2, the hydrocarbon chain Z optionally contains one or two isolated or conjugated multiple bonds,
- and/or wherein when n is greater than or equal to 2 one of said -CR1 R13 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(d-C6)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 R2, which may be identical or different independently of each other, are selected from hydrogen, (d-C6)alkyl, halogen, cyano, nitro, trihalogeno(d-C6)alkyl, -NRioRπ,
-OR14, -SR14, -SOR14) -SO2R14, (d-C7)acyl, -(CH2)kNR10Rπ, ^(CH^NR^Rπ,
-(CH2)kSO2NR14R15, -X5(CH2)kC(=O)OR14, -(CH2)kC(=O)OR14, -X5(CH2)kC(=O)NR14R15,
Figure imgf000056_0001
-Xδ- iβ and tri(d-C6)alkyl-Si-O- in which each alkyl is identical or different independently of each other, and in which : • X5 represents an oxygen atom, a sulfur atom, a -NH group, or a -N(d-C6)alkyl group,
• k is an integer from 0 to 3 inclusive,
• R10 and Rπ are as defined hereinbefore,
• R14 and R15, identical or different independently of each other, represent hydrogen or (d-C6)alkyl,
• X6 represents a single bond, -CH2-, an oxygen atom or a sulfur atom which is optionally substituted by one or two oxygen atoms,
• R16 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 (C1-Cg)alkyl, halogen, trihalogeno(Cι-C6)alkyl, hydroxyl, (d-C6)alkoxy, mercapto, (Ci-C6)alkylthio, amino, mono(C1-C6)alkylamino, and di(C1-C6)alkylamino,
q is an integer from 0 to 7 inclusive,
Ri represents a group selected from: - hydrogen, (d-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl, the groups alkyl, alkenyl and alkynyl being optionally substituted by one to three groups, which may be identical or different independently of each other, selected from amino, mono(C1-C6)alkylamino, di(d-C6)alkylamino, cyano, trihalogeno(Ci-C6)alkyl, -C(=O)OR4, -OR4, -SR4, in which R4 is as defined hereinbefore, - and the group of formula :
Figure imgf000057_0001
in which:
• m is an integer from 0 to 8 inclusive,
• Y represents -CR18R19, wherein R18 and R19, identical or different independently of each other, represent a group selected from hydrogen, (d-C6)alkyl, phenyl, trihalogeno(C1-C6)alkyl, halogen, amino, mono(d-C6)alkylamino, di(d-C6)alkylamino, -OR4, -SR4 and -C(=O)OR4 wherein R is as defined hereinbefore, and
- wherein when m is greater than or equal to 2, the hydrocarbon chain Y optionally contains one or two isolated or conjugated multiple bonds,
- and/or wherein when m is greater than or equal to 2, one of said -CR18R19 may be replaced with a group selected from oxygen, -S(O)n3 wherein n3 is an integer from 0 to 2 inclusive, -NH- and -N(Ci-C6)alkyl,
• 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,
• r is an integer from 0 to 7 inclusive, o the group(s) R17, which may be identical or different independently of each other, are selected from hydrogen, (C1-C6)alkyl, halogen, cyano, nitro, trihalogeno(d-C6)alkyl, -NR10Rll5 -OR14, -SR14, -SOR14> -SO2Ri4, (C1-C7)acyl, -(CH2)kNR10Rπ, -(CH2)k-OR14, -(CH2)k-SR14, -(CH2)k-SOR14, -(CH2)k-SO2R14, -X5(CH2)kNR10Rπ, -(CH2)kSO2NR14R15, -X5(CH2)kC(=O)OR14, -(CH2)kC(=O)OR14,
-X5(CH2)kC(=O)NR10Rπ, -(CH2)kC(=O)NRi0Rπ, -X6-Rιe, and -(CH2)k-C(O)-OR20, in which:
• X5, k, R10, Rπ, Ri4, Ris. β and R16 are as defined hereinbefore, and R20 represents a group selected from -T-ORi4, -T-NRioRπ, -T-C(O)OR14, -T-C(O)NR10Rπ in which T represents a linear or branched (C1-C6)alkylene chain and R14, R10, and Rπ are as defined hereinbefore,
and optionally, its optical isomers, N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base,
it being understood that:
- 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 ;
- 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 ;
- 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 ;
- a 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.
2- A compound according to claim 1, wherein : Wi represents an oxygen atom, a sulfur atom, or a -NR3 group in which R3 represents hydrogen atom, (d-C6)alkyl, hydroxyl or cyano, W2 represents a group selected from :
® hydrogen atom, trifluoromethyl, amino, mono(d-C6)alkylamino, di(d-C6)alkylamino,
• (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Ci-C6)alkyl, cycloalkyl(Cι-C6)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(d-C6)aIkylamino, di(C1-C6)alkylamino, cyano, trihalogeno(d-C6)alkyl, (d-C7)acyl, -C(=O)OR4, -OR4 and -SRj., wherein Rj represents a hydrogen atom or a (d-C6)alkyl group, and Xi, X2, X3, Ri, R2, A, Z, n and q are as defined in formula (I), optionally, its optical isomers , N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
3- A compound according to claim 1 in which it represents a compounds of formula (LA) :
Figure imgf000059_0001
W3 represents a nitrogen atom or a group -CR5 in which R5 is selected from :
- a hydrogen atom, - -OR5, -SR6 in which Rg is selected from hydrogen, (d-C6)alkyl and aryl(d-C6)alkyl;
- (d-C6)alkyl, cycloalkyl, aryl, aryl(Cj-C6)alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)P-NH2, wherein p is an integer from 0 to 4 inclusive, X4 represents a nitrogen atom or a group -CR7 in which R is selected from hydrogen, -NR8R9, -OR8, -SRs, (Ci-C6)alkyl, cycloalkyl, aryl, aryl(Cι-C10)alkyl, heteroaryl, and heterocycloalkyl, each of these groups being optionally substituted by a group selected from -(CH2)p-OH and -(CH2)P-NH2, wherein p is as defined hereinbefore, ■S and in which R8 and R9, identical or different independently of each other, are selected from hydrogen, (Cι-C6)alkyl and aryl(Cι-C6)alkyl, and Xi, X2, X3, Rl5 R2, A, Z, n and q are as defined hereinbefore. optionally, its optical isomers , N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
4- A compound according to claim 1 wherein : W2 represents a group (d-C6)alkyl,
Wi represents an oxygen atom, Xi represents a -CH group,
X2 represents a -CH group,
X3 represents a -CH group, and Ri, R2, A, Z, n and q are as defined in formula (I), optionally, its optical isomers , N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
5- A compound according to claim 1 wherein :
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,
the group(s) R2, which may be identical or different, are selected from hydrogen, -OR1 , -X6-Ri6, and tri(Cι-C6)alkyl-Si-O- in which each alkyl is identical or different independently of each other, in which :
• R1 represents hydrogen or (d-C6)alkyl, o X6 represents a single bond, o R16 represents a phenyl group and Wl5 W2, Xls X2, X3, Rls Z and n are as defined in formula (I), optionally, its optical isomers , N-oxides, and addition .salts thereof with a pharmaceutically-acceptable acid or base.
6- A compound according to claim 1 wherein n is equal to one, optionally, its optical isomers, N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
7- A compound according to claim 1 wherein Z represents a group -CR12R13 in which R12 and R13 represent each a hydrogen atom, optionally, its optical isomers, N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
8- A compound according to claim 1 wherein A represents a phenyl group or a 1- imidazolyl group optionally substituted by one group R2 as defined in the compound of the formula (I), optionally, its optical isomers, N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
9- A compound according to claim 8 wherein A, R2 and q, took together, represent a. para- methoxyphenyl group, optionally, its optical isomers, N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
10- A compound according to claim 1 wherein Rt represent a group of formula :
Figure imgf000061_0001
in which m is equal to one, Y represents a methylene group, B represents a phenyl group, r is equal to one, and R17 represents a group selected from (CH2) -C(=O)OR14, -(CH2)k- OR14, -(CH2)kC(=O)NRi0Rπ, -(CH2)k-C(O)-OR20, in which k, R10, Rπ, and R14 are as defined in the compound of formula (I), and R20 represents a group -T-NR10Rπ, in which T represents a linear or branched (C2-C4)alkylene chain and Rio, and Rπ are as defined in the compound of formula (I), optionally, its optical isomers, N-oxides, and addition salts thereof with a pharmaceutically-acceptable acid or base.
11- A compound according to claim 1, which is selected from :
• 3-(4-fluorobenzyl)-6-(3 -phenyl-prop- 1 -ynyl)- 1 -methyl- lH-quinazolin-2,4-dione,
• 3-(4-fluorobenzyl)-6-[3-(4-methoxyphenyl)-3-oxo~prop-l-ynyl)-l-methyl-lH- quinazolin-2,4-dione, • methyl 4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4-dihydro-2H- quinazolin-3 -ylmethyl] -benzoate,
• 3-(4-fluorobenzyl)-6-[3-(4-methoxyphenyl)-prop- 1 -ynyl] - 1 -methyl- 1H- quinazolin-2,4-dione,
• 3-(3-chloro-benzyl)-l-methyl-6-(3-phenyl-prop-ynyl)-lH-quinazoline-2,4-dione, • 3-(3-fluoro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione,
• 3-(4-Chloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-2,4- dione,
• 3-(4-bromo-benzyl)- 1 -methyl-6-(3-phenyl-prop- 1 -ynyl)- lH-quinazoline-2,4- dione,
• 3-(3 ,4-difluoro-benzyl)- 1 -methyl-6-(3-phenyl-prop- 1 -ynyl)- lH-quinazoline-2,4- dione,
• tert-butyl 4-[6-(3-biphenyl-4-yl-prop- 1 -ynyl)- 1 -methyl-2,4-dioxo- 1 ,4-dihydro- 2H-quinazolin-3-ylmethyl]-benzoate, • tert-butyl 4-{6-[3-(4-fluoro-phenyl)-prop-l-ynyl]-l-methyl-2,4-dioxo-l,4- dihydro-2H-quinazolin-3-ylmethyl}-benzoate,
• 4-[6-(3-imidazol- 1 -yl-prop- 1 -ynyl)- 1 -methyl-2,4-dioxo- 1 ,4-dihydro-2H- quinazolin-3-ylmethyl]-benzoic acid - trifluoro-acetic acid,
• 3 -(3 ,4-difluoro-benzyl)-6-(3 -imidazol- 1 -yl-prop- 1 -ynyl)- 1 -methyl- 1H- quinazoline-2,4-dione,
• 2-dimethylamino-ethyl 4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4- dihydro-2H-quinazolin-3-ylmethyl]-benzoate,
• 4-(6-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-prop-l-ynyl}-l-methyl-2,4- dioxo-l,4-dihydro-2H-quinazolin-3-yhnethyl)-benzoic acid, o NN-dimethyl-4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-1^4-dihydro-2H- quinazolin-3 -ylmethyl] -benzamide, o l-methyl-6-(3-phenyl-prop-l-ynyl)-3-[4-(piperidine-l-carbonyl)-benzyl]-lH- quinazoline-2,4-dione, • N-ethyl-4-[l-methyl-2,4-dioxo-6-(3-phenyl-prop-l-ynyl)-l,4-dihydro-2H- quinazolin-3 -ylmethyl] -b enzamide,
• 6-[3-(4-chloro-phenyl)-prop- 1 -ynyl] -3-(3 ,4-difluoro-benzyl)- 1 -methyl- 1H- quinazoline-2,4-dione,
• 3-(3-chloro-benzyl)-6-[3-(4-chloro-phenyl)-prop-l-ynyl]-l-methyl-lH- quinazoline-2,4-dione,
• 3-(4-hydroxymethyl-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH- quinazoline-2,4-dione,
• l-methyl-3-[4-(4-methyl-piperazine-l-carbonyl)-benzyl]-6-(3-phenyl-prop-l- ynyl)- lH-quinazoline-2,4-dione, • NN-bis-(2-hydroxy-ethyl)-4-[l -methyl-2,4-dioxo-6-(3 -phenyl-prop- 1 -ynyl)- 1 ,4- dihydro-2H-quinazolin-3-ylmethyl]-benzamide,
• 3-(3 ,4-difluoro-benzyl)-6-[3-(4-fluoro-phenyl)-prop- 1 -ynyl] - 1 -methyl- 1H- quinazoline-2,4-dione,
• 3-(3,4-difluoro-benzyl)- 1 -methyl-6-(3-[ 1 ,2,3]triazol- 1 -yl-prop- 1 -ynyl)- 1H- quinazoline-2,4-dione,
• 3-(3,4-difluoro-benzyl)- 1 -methyl-6-(3-[ 1 ,2,4]triazol- 1 -yl-prop- 1 -ynyl)- 1H- quinazoline-2,4-dione,
• 3 -(3 ,4-dichloro-benzyl)- 1 -methyl-6-(3- [ 1 ,2,4] triazol- 1 -yl-prop- 1 -ynyl)- 1H- quinazoline-2,4-dione, • and 3-(3,4-dichloro-benzyl)-l-methyl-6-(3-phenyl-prop-l-ynyl)-lH-quinazoline-
2,4-dione. • 12- A process for the preparation of compounds according to claim 1 in which uses as starting material a compound of formula (II):
Figure imgf000064_0001
in which R1} Wi, W2, Xi, X2 and X3 have the same definitions as the compounds of formula (I), and Ti represents a group selected from hydrogen, halogen, mesylate, triflate, formyl, acetyl, and ester,
compound of formula (LI) which is treated :
❖ either when Ti 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 (IH):
Figure imgf000064_0002
in which A, Z, R , q and n are as defined for the compounds of formula (I), to yield the compounds of formula (I),
Figure imgf000064_0003
❖ or when Ti represents an hydrogen atom, with iodine to yield in situ the corresponding iodide intermediate, which is treated directly without isolation or purification, with a compound of formula (III) as described hereinbefore, under conditions of palladium-catalyzed alkynylation in the presence of a base, to yield the compounds of formula (I),
❖ or when T\ represents an iodine atom, with 2-trimethylsilylacetylene under conditions of palladium-catalyzed alkynylation in the presence of a base, to yield the compounds of formula (IVa):
Figure imgf000065_0001
in which Rls Wls W2, Xi, X2 and X3 are as defined hereinbefore, and subsequently treated the compound of formula (INa) with a strong base in polar solvant, to yield the free alcyne compound of formula (IN):
Figure imgf000065_0002
in which Ri, Wl5 W2, Xi, X2 and X3 are as defined hereinbefore,
❖ or when Ti represents an acetyl group, first with lithium diisopropylamine at -78°C in an inert solvent to provide an enolate, second with diethyl chlorophosphate and subsequently with lithium diisopropylamine, to yield a compound of formula (IV):
Figure imgf000065_0003
in which Ri, Wi, W2, X\, X2 and X3 are as defined hereinbefore, and condensing the compound of formula (IN), in the presence of triphenylphosphin and
PdCl2(PPh3)2, under basic conditions to a compound of formula (V):
Figure imgf000065_0004
in which A, Z, R2, q and n are as defined hereinbefore and G represents a leaving group, to yield the compound of formula (I),
Figure imgf000066_0001
❖ or when Ti represents an ester group, with a reductive agent, to yield the corresponding aldehyde compound of formula (VI):
Figure imgf000066_0002
in which Ri, Wi, W2, Xi, X2 and X are as defined hereinbefore,
and subsequently :
• either condensing said compound of formula (VI), in basic conditions, with diazomethyl trimethyl silane or with diazomethyl diethoxy phosphonate, to yield, after basic treatment, a compound of formula (TV) as defined hereinbefore :
Figure imgf000066_0003
and adding said compound of formula (IV) to a compound of formula (V) as described hereinbefore :
Figure imgf000066_0004
in which R2, A, Z, q, n and G are as defined hereinbefore, to yield the compound of formula (I), or reacting, said compound of formula (VL), with tetrabromomethane in the presence of triphenylphosphine in an aprotic solvent to yield a compound of formula (VII) :
Figure imgf000067_0001
in which Ri, Wi, W2, Xi, X2 and X3 are as defined hereinbefore, and dehalogenating said compound of formula (VII) throug treatment with a strong base in an inert solvent, or with butyllithium in presence of triphenylphosphine and zinc, to yield the compound of formula (TV) as defined hereinbefore, and reacting said compound of formula (TV) with a compound of formula (V) as defined in the previous step to yield a compound of a general formula (I):
Figure imgf000067_0002
which constitute the compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically- acceptable acid or base.
13- A process for the preparation of compounds according to claim 1 wherein it is used as starting material a compound of formula (II/A) :
Figure imgf000067_0003
in v/hich Ri, Wl5 W2, Xi, X2 and X3 have the same definitions than in the -compounds of formula (I), and T'ι represents a group selected from halogen, mesylate, and triflate,
compound of formula (H/a) which is condensed, in the presence of dichlorobis(triphenylphosphine)palladium, cupper iodide and N,N'-diisopropylethylamine in dimethylformamide, on a compound of formula (10):
Figure imgf000068_0001
in which A, Z, R2, q and n are as defined in the compounds of formula (I), to yield the compounds of formula (I),
Figure imgf000068_0002
wherein Wi, W2, Xi, X2, X3, Ri, R2, A, Z, n and q are as described in claim 1.
14- A process for the preparation of compounds according to claim 2 comprising the following step :
• reacting as starting material, a compound of formula (II/A) :
Figure imgf000068_0003
in which Wi represents an oxygen atom, W2 represents a (Ci-Csalkyl group, Xi represents a -CH group, X2 represents a nitrogen atom or a -CH group, X3 represents a - CH group, and Ti represent a iodine atom or a triflate group, and Ri represents a group of formula :
Figure imgf000068_0004
in which Y represents a methylene group, m is equal to one, B represents a phenyl group, R17 is as defined in the compound of formula (I) and r is equal to one,
c with, as reagent, a compound of formula (III) :
Figure imgf000069_0001
in which Z represents a methylene group, n is equal to one, A is a phenyl group, q is equal to zero or one, and R2 is as defined in the compound of formula (I),
to yield a compound of formula (Fa), which constitutes a particular subgroup of the compounds of formula (I):
Figure imgf000069_0002
in which W2, X2, 2, q and R1 are as defined hereinbefore.
15- Intermediate compound of formula (IV) :
Figure imgf000069_0003
wherein Wi, W2, X\, X2, X3, Ri and R2 are as described in claim 1.
16- Intermediate compound of formula (VI)
Figure imgf000070_0001
wherein Wls W2, Xi, X2, X3 and Ri are as defined in claim (I).
17- Intermediate compound of formula (H/A)
Figure imgf000070_0002
wherein :
Wi represents an oxygen atom, a sulfur atom, or a -NR3 group in which R3 represents hydrogen atom, (Cι-C6)alkyl, hydroxyl or cyano,
W2 represents a group selected from :
• hydrogen atom, trifluoromethyl, amino, mono(d-C6)alkylamino, di(C1-C6)alkylamino,
• (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(d-C6)alkyl, cycloalkyl(d-C6)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(d-C6)alkylamino, di(Ci-C6)alkylamino, cyano, trihalogeno(Cι-C6)alkyl, (d-C7)acyl, -C(=O)OR4, -O t and -SR4, wherein R4 represents a hydrogen atom or a (C1-C6)alkyl group,
Ti represents a halogen atom, and Ri, Xi, X2, and X3 are as defined in the compounds of formula (I). 18- A method for treating a living body afflicted with a disease where the inhibition of type -13 matrix metalloprotease is involved, comprising the step of administering to the living body an amount of a compound of claim 1 which is effective for alleviation of said conditions.
19- A method for treating a living body afflicted with a disease selected from 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 a cancer, comprising the step of administering to the living body an amount of a compound of claim 1 which is effective for alleviation of said conditions.
20- A pharmaceutical composition comprising as active ingredient an effective amount of a compound as claimed in claim 1, alone or in combination with one or more pharmaceutically-acceptable excipients or carriers.
21- A pharmaceutical composition useful in the method of Claim 19 comprising as active ingredient an effective amount of a compound as claimed in claim 1, together with one or more pharmaceutically-acceptable excipients or carriers.
22- Use of a compound according to Claim 1, for the preparation of a medicinal product intended for treating a disease involving therapy by inhibition of type- 13 matrix metalloproteases.
23- Use according to Claim 22, characterized in that the disease is 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 a cancer.
24- Use according to Claim 22, characterized in that the disease is arthritis.
25- Use according to Claim 22, characterized in that the disease is osteoarthritis. - Use according to Claim 22, characterized in that the disease is rheumatoid arthritis.
PCT/EP2002/008475 2001-10-12 2002-07-12 New alkynylated quinazolin compounds as mmp-13 inhibitors Ceased WO2004007469A1 (en)

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SV2002001289A SV2003001289A (en) 2001-10-12 2002-10-11 PIRIMIDINE COMPOUNDS OF RENTED FUSED RING
PCT/EP2002/012194 WO2003033478A1 (en) 2001-10-12 2002-10-11 Alkynylated fused ring pyrimidine compounds as matrix metalloprotease-13 inhibitors
MXPA04003008A MXPA04003008A (en) 2001-10-12 2002-10-11 Alkynylated fused ring pyrimidine compounds as matrix metalloprotease-13 inhibitors.
ARP020103820A AR037100A1 (en) 2001-10-12 2002-10-11 PIRIMIDINE COMPOSITE OF RENTED FUSED RING, PREPARATION PROCESS, INTERMEDIATE COMPOUNDS, PHARMACEUTICAL COMPOSITION AND USI FOR PREPARATION OF A MEDICINAL PRODUCT
EP02801341A EP1465878A1 (en) 2001-10-12 2002-10-11 Alkynylated fused ring pyrimidine compounds as matrix metalloprotease-13 inhibitors
JP2003536218A JP2005509626A (en) 2001-10-12 2002-10-11 Alkynylated fused ring pyrimidine compounds as matrix metalloprotease-13 inhibitors
US10/269,197 US6962922B2 (en) 2001-10-12 2002-10-11 Alkynylated quinazoline compounds
PA20028556301A PA8556301A1 (en) 2001-10-12 2002-10-11 PIRIMIDINE COMPOUNDS OF RENTED FUSED RING
PE2002001007A PE20030541A1 (en) 2001-10-12 2002-10-11 ALKYNATED FUSED RING PYRIMIDINE COMPOUNDS AS TYPE 13 MATRIX METALOPROTEASE INHIBITORS
BR0213239-7A BR0213239A (en) 2001-10-12 2002-10-11 Alkynylated condensed ring pyrimidine compounds as type 13 matrix metalloproteinase inhibitors
CA002463159A CA2463159A1 (en) 2001-10-12 2002-10-11 Alkynylated fused ring pyrimidine compounds as matrix metalloprotease-13 inhibitors
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