EP1492775A2 - Oxo-azabicyclic compounds - Google Patents

Oxo-azabicyclic compounds

Info

Publication number
EP1492775A2
EP1492775A2 EP03708181A EP03708181A EP1492775A2 EP 1492775 A2 EP1492775 A2 EP 1492775A2 EP 03708181 A EP03708181 A EP 03708181A EP 03708181 A EP03708181 A EP 03708181A EP 1492775 A2 EP1492775 A2 EP 1492775A2
Authority
EP
European Patent Office
Prior art keywords
compound
formula
alkyl
group
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03708181A
Other languages
German (de)
French (fr)
Inventor
Bernard Gaudilliere
Henry Jacobelli
Catherine Kostlan
Jack Li
Wen-Song Yue
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1492775A2 publication Critical patent/EP1492775A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel oxo azabicyclic compounds which are useful for preparing medicinal products for treating complaints involving a therapy with a matrix metalloprotease-13 (MMP-13) inhibitor.
  • MMP-13 matrix metalloprotease-13
  • These medicinal products are useful in particular for treating certain inflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancers.
  • MMPs Matrix metalloproteases
  • TMPs tissue inhibitors of metallopro tease
  • MMP- 13 matrix metalloprotease-13 is a collagenase-type MMP which constitutes the predominant collagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
  • MMP inhibitors are known. Most of these MMP-inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or by Clark et al. (2000).
  • the compounds of the present application are novel and represent powerful inhibitors of MMP- 13. They are consequently of use in the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPDs), age-related degeneration (ARMD) and cancer.
  • the applicant has identified novel oxo azabicyclic compounds that are matrix metalloprotease inhibitors, and more specifically compounds that are selective MMP- 13 inhibitors.
  • X 2 , and X 3 independently of each other, represent a nitrogen atom or a group -CR 3 in which R represents a group selected from hydrogen, (C -C 6 )alkyl, amino, mono(C ⁇ - C 6 )alkylamino, di(CrC 6 )alkylamino, hydroxy, (C ⁇ -C 6 )alkoxy, and halogen, with the proviso that not more than two of the groups Xi, X 2 and X simultaneously represent a nitrogen atom,
  • Gi represents a group selected from those of formulae (i/a) and (i b):
  • R ⁇ and R 5 identical or different, independently of each other, represent a group selected from hydrogen, (C ⁇ -C 6 )alkyl, aryl, aryl(C ⁇ -C 6 )alkyl, cycloalkyl, cycloalkyl(C ⁇ -C 6 )alkyl, heteroaryl, heteroaryl(CrC 6 )alkyl, heterocycloalkyl, and heterocycloalkyl(C ⁇ -C 6 )alkyl,
  • R 7 and R 8 identical or different independently of each other, represent hydrogen or (C 1 -C 6 )alkyl, ⁇ (C,-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, aryl(C ⁇ -C 6 )alkyl, cycloalkyl(C ⁇ -C 6 )alkyl, heteroaryl, heteroaryl(C 1 -C 6 )alkyl, heterocycloalkyl, and heterocycloalkyl(C ⁇ -C 6 )alkyl, these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from halogen, amino, mono(C ⁇ -C 6 )alkylamino, di(C ⁇ -C 6 )alkylamino, each alkyl moiety being identical or different independently
  • Y] represents a group selected from oxygen, sulphur, -NH and -N(C]-C 6 )alkyl
  • Y 2 represents a group selected from oxygen, sulphur, -NH and -N(C ⁇ -C 6 )alkyl
  • n represents an integer from 0 to 6 inclusive
  • the hydrocarbon chain Zi optionally contains one to two isolated or conjugated multiple bonds
  • one of said -CR 9 R 10 may optionally be replaced with a group selected from oxygen, S(O) n ⁇ in which nl is as defined hereinbefore, -NH and -N(C ⁇ -C 6 )alkyl,
  • A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
  • Ri represents a group selected from :
  • p is an integer from 0 to 8 inclusive
  • hydrocarbon chain Z 2 optionally contains one or two isolated or conjugated multiple bonds
  • one of said -CRnRi 2 may optionally be replaced with a group selected from oxygen, S(O) nl in which nl is as defined hereinbefore, -NH, -N(C ⁇ -C 6 )alkyl, and carbonyl,
  • - B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
  • V the group(s) G 3 which may be identical or different independently of each other, is (are) selected from (d-C 6 )alkyl, halogen, CN, NO 2 , CF 3 , OCF 3 , -(CH 2 ) k NR ⁇ 3 R ⁇ ,
  • - X 4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (C ⁇ -C 6 )alkyl group,
  • - k is an integer from 0 to 3 inclusive
  • - kl is an integer from 0 to 2 inclusive
  • - k2 is an integer from 1 to 4 inclusive
  • R ⁇ 3 , R 14 and R 15 which may be identical or different independently of each other, are selected from hydrogen and (d-C 6 )alkyl,
  • R ⁇ 6 represents a group selected from (C ⁇ -C 6 )alkyl, -R ⁇ 9 -NR 13 R ⁇ 4 , in which R19 represents a linear or branched (C ⁇ -C 6 )alkylene group, and R 13 , R 1 and R 15 are as defined hereinbefore,
  • R 17 represents a (C 3 -C 6 )cycloalkyl group
  • - X 5 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-C 6 )alkyl group,
  • X 7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (d-C 6 )alkyl,
  • - k is an integer from 0 to 3 inclusive
  • R and Rs which may be identical or different independently of each other, are selected from hydrogen and (C ⁇ -C 6 )alkyl,
  • - X 8 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C ⁇ -C 6 )alkyl group,
  • R 20 represents 5- or 6-menbered monocycle aryl, heteroaryl, cycloalkyl, or heterocycloalkyl which is optionally substituted by one or more groups, which may be identical or different, selected from (C ⁇ -C 6 )alkyl, halogen, hydroxy and amino, and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur,
  • the invention relates to compounds of formula (I) wherein :
  • Y represents a group selected from oxygen, sulphur, -NH and -N(d-C 6 )alkyl
  • Y 2 represents a group selected from oxygen, sulphur, -NH and -N(d-C 6 )alkyl
  • the invention relates to compounds of formula (I) wherein :
  • n represents an integer from 1 to 6 inclusive
  • the invention relates to compounds of formula (I) wherein :
  • A represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
  • the invention relates to compounds of formula (I) wherein :
  • Rj represents a hydrogen atom or a group of formula (i/d)
  • - X 4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (d-C 6 )alkyl group,
  • - k is an integer from 0 to 3 inclusive
  • - kl is an integer from 1 to 2 inclusive
  • - k2 is an integer from 1 to 4 inclusive
  • R 13 , R 14 and R )5 which may be identical or different independently of each other, are selected from hydrogen and (C ⁇ -C 6 )alkyl
  • - Rie represents a group selected from (d-C 6 )alkyl, -R ⁇ 9 -NR 13 R M , in which R 19 represents a linear or branched (C ⁇ -C 6 )alkylene group, and R !3 , R ⁇ 4 and R ]5 are as defined hereinbefore
  • - R17 represents a (C 3 -C 6 )cycloalkyl group
  • - X 5 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-Q)alkyl group,
  • - R] 8 represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or
  • the substituent Ri that is preferred according to the invention is the group of formula (i/d): wherein Z 2 , p, B, G 3 and q are as defined in the compound of formula (I).
  • the substituent Ri that is preferred according to the invention is the group of formula (i/d): wherein Z 2 represents a group -CRnR 12 in which R ⁇ and R 12 represents each a hydrogen atom., and p, B, G 3 and q are as defined in the compound of formula (I).
  • substituent R] that is preferred according to the invention is the group of formula (i/d): wherein p is one, and Z 2 , B, G 3 and q are as defined in the compound of formula (I).
  • the invention relates also to the compounds of formula (I) wherein G ⁇ represents a group of formula (i/a) in which R 4 represents a hydrogen atom or a methyl group, or a group of formula (i/b) in which and R 5 , identical, represent each a hydrogen atom or a methyl group, and R 6 represents a hydrogen atom or a methyl group, and Xj, X 2 , X 3 , G 2 , Z u n, m and R 2 are as defined in formula (I).
  • Preferred compounds of the invention are compounds of formula (I) wherein Xi represents a group -CR 3 in which R 3 represents a hydrogen atom, X 2 represents a nitrogen atom or a group -CR 3 in which R 3 represents a hydrogen atom, and X 3 represents a group -CR 3 in which R 3 represents a hydrogen atom.
  • Other preferred compounds of the invention are compounds wherein G 2 represents a carbon-carbon triple bond or a group of formula (i/c) in which Yi represents an oxygen atom, and Y 2 represents a group -NH.
  • Still more preferred compounds of the invention are those compounds of formula (I) wherein Z ⁇ represents -CR9R10 in which R 9 and R 10 represent each a hydrogen atom, and n is one.
  • Especially preferred compounds of the invention are compounds wherein A represents a group selected from phenyl and pyridyl, m is zero or one, and R 2 represents a (C ⁇ -C 6 )alkoxy group or a hydrogen atom.
  • the invention relates to the following compounds of formula (I) :
  • optical isomers, the N-oxides, as well as the addition salts with a pharmaceutically- acceptable acid or base, of the preferred compounds form an integral part of the invention.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient an effective amount of a compound of formula (I) together with one or more pharmaceutically- acceptable excipients or carriers.
  • Another embodiment of the invention concerns the use of the compound of formula (I) for the preparation of a medicinal product intended for treating a disease involving therapy by inhibition of matrix metalloprotease, and more particularly of type- 13 matrix metalloprotease.
  • the invention also relates to a method for treating a living body afflicted with a disease involving a therapy by inhibition of matrix metalloprotease, and more particularly of type- 13 matrix metalloprotease, the said method comprising the administration of an effective amount of a compound of formula (I) to a patient in need thereof.
  • a preferred method of treatment according to this invention is treatment of a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
  • a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
  • a preferred method of treatment according to this invention is treatment of disease selected from arthritis, osteoarthritis and rheumatoid arthritis.
  • - a (C ⁇ -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,
  • - a (C 2 -C 6 )alkenyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more double bonds ; examples of such groups without implying any limitation are vinyl, allyl, 3-buten-l-yl, 2-methyl-buten-l-yl, hexenyl, - a (C 2 -C 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, rc-propyloxy, tert-butyloxy,
  • a mono(C ⁇ -C 6 )alkylamino denotes a amino group substituted by one (C ⁇ -C 6 )alkyl group as defined hereinbefore ; example of such groups, without implying any limitation are methyl amino, isobutyl amino, ethylamino,
  • di(C ⁇ -C 6 )alkylamino denotes a amino group substituted by two (C ⁇ -C 6 )alkyl groups as defined hereinbefore, each alkyl group being identical or different ; example of such groups, without implying any limitation are dimethylamino, diethylamino,
  • an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated ; examples of such groups without implying any limitation are, phenyl, naphthyl, indenyl, benzocyclobutenyl,
  • a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen ; examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl,
  • a cycloalkyl group denotes a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character ; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl,
  • heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen,
  • - a trihalogeno(C ⁇ -C 6 )alkyl group denotes an alkyl group as defined above which contains a trihalogeno group ; examples of such groups without implying any limitation are trifluorornethyl, 2,2,2-trifluoroethyl, - a (d-C 7 )acyl group denotes an alkyl group or a aryl group as defined above bound through a carbonyl group ; examples of such groups without implying any limitation are acetyl, ethylcarbonyl, benzoyl,
  • 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).
  • pharmaceutically acceptable salts mean non-toxic salts derived from mineral or organic acids.
  • hydrochloric acid hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc...
  • Pharmaceutically acceptable bases mean non-toxic salts derived from mineral or organic bases.
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (II): in which Xi, X 2 , X 3 , and Yi have the same definitions as the compound of formula (I), and T represents a group (d-C 6 )alkyl,
  • compounds of formulae (Fa), (I/b), (I/c) and (I/d) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (X): in which Xi, X 2 , and X 3 have the same definitions as the compound of formula (I), and Hal represents a halogen atom, which compound of formula (X) is treated in a first step with a derivate of phosgene to yield the compound of formula (XI): in which Xj, X 2 , X 3 and Hal are as defined hereinbefore,
  • compounds of formula (Fe) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
  • compound of formula (XI) is treated with an aqueous solution of ammonium hydroxide to yield compound of formula (XFa) which is reacted with triethyl orthoformate in the presence of a catalytic amount of acid like ⁇ ra-toluene sulfonic acid (PTSA).
  • PTSA ⁇ ra-toluene sulfonic acid
  • the 3H-quinazolin-4-one (Xl/b) obtained is condensed in basic medium to a compound of formula Ri-Hal, in which Ri is as defined in the compound of formula (I) and Hal represents a halogen, to yield the compound of formula (XIIFa).
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIIFe) : in which X t , X 2 , X 3 , Ri and Gi axe as defined in the compound of formula (I), and Hal is a halogen atom,
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIIFe) : in which Xi, X 2 , X 3 , Ri and Gi are as defined in the compound of formula (I), and Hal, is a halogen atom, compound of formula (XIIFe) which is reacted with carbon monoxide in an alkaline medium in the presence of a protic solvent like methanol and a catalytic amount of palladium , to yield the compound of formula (XVI):
  • compounds of formula (Ff) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIX) : in which Hal represents a halogen atom,
  • compounds of formula (Fg) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
  • the compounds of the invention that are present in the form of a mixture of diastereoisomers are isolated in a pure form by using conventional separation techniques such as chromatography.
  • compounds of formula (I) of the present invention are matrix metalloprotease inhibitors, and more particularly inhibitors of the enzyme MMP-13.
  • their use is recommended for the treatment of diseases or complaints involving a therapy by MMP- 13 inhibition.
  • 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.
  • compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
  • compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspension and emulsions, and also sterile powders for reconstituting injectable solutions or dispersions.
  • compositions according to the invention for oral administration in solid form especially include tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, for oral, nasal, buccal or ocular administration in liquid form, especially include emulsions, solutions, suspensions, drop, syrups and aerosols.
  • compositions for rectal or vaginal administration are preferably suppositories, and those for per- or trans-cutaneous administration especially include powders, aerosols, creams, ointment, gels and patches.
  • the pharmaceutical compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
  • inert, non-toxic excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colourants, aromatizing agents etc...
  • the useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments.
  • the dosage ranges from 2 mg to 1 g per day in one or more administrations.
  • the compositions are prepared by methods that are common to those skilled in the art and generally comprise 0.5% to 60% by weight of active principle (compound of formula (I)) and 40% to 99.5% by weight of pharmaceutically acceptable excipients or carriers.
  • the starting materials used are products that are known or that are prepared according to known operating procedures.
  • the various preparations yield synthetic intermediates that are useful in preparation of the compounds of the invention. Some of these intermediates are new compounds.
  • THF tetrahydrofurane
  • DMSO dimethylsulfoxide
  • TOTU O-(ethoxycarbonyl)cyanomethylamino]-N-N-N'-N -tetramethyI uronium fluoroborate
  • DIPEA diisopropylethylamine
  • Step 1 4-Amino-isophthalic acid
  • Step 2 4-Amino-3-[(4-methoxy)-benzylcarbamoyl]-phenyl-l-carboxylic acid 4-methoxy- benzylamide
  • Step 1 Methyl 6-Amino-N-(4-methoxy-benzyl)-isophthalate
  • Step 2 6-Amino-N-(4-methoxy-benzyl)-isophthalamic acid
  • Step 3 Methyl 4- ⁇ [2-Amino-5-(4-methoxy-benzylcarbamoyl)-benzoylamino]-methyl ⁇ - benzoate
  • the desired compound is obtained according to the procedure described in the Step 1 of Preparation 2 using as starting material the compound obtained in the preceding step 2 and as reactant the methyl 4-(aminomethyl)benzoate hydrochloride. It is purified by chromatography over silica gel using a mixture of dichloromethane/ether as eluant.
  • N.M.R (DMSO- ⁇ ) l H ⁇ (ppm) : 3.70 (s,3H) ;3.85 (s,3H) ; 4.40 (d,2H) ; 4.50 (d,2H) ; 6.70 (d,lH) ; 6.80-6.90 (m,4H) ; 7.25 (d,2H) ; 7.45 (d,2H) ; 7.70 (dd,lH) ; 7.95 (d,2H) ; 8.15 (s,lH) ; 8.45 (t,lH) ; 8.90 (t,lH).
  • Step 1 6-iodo-lH-benzo[a][l,3]oxazine-2,4-dione
  • Step 3 3-(4-fluorobenzyl)-6-iodo-3H-quinazolin-4-one
  • TsOH triethyl orthoformate
  • the solution is refluxed for 5h, cooled to room temperature. After removal of all volatiles in vacuo, the residue is purified using flash chromatography to give the desired quinazolinone as a brownish solid. Trituration then afforded the desired compound as a white solid (1.56 g, 58%).
  • N.M.R (DMSO- ) 1H ⁇ (ppm) 5.15 (s, 2H), 7.03 (m, IH); 7.34 (m, IH), 7.43 (d, J- 8.5
  • Step 1 Methyl 4-[(2-Amino-5-iodo-benzoylamino)-methyl]-benzoate
  • DMF dimethyl methyl
  • the reaction is stirred at room temperature for 1 h while bubbling is observed (CO 2 ), and TLC indicated the completion of the reaction.
  • the reaction content is poured into a separatory funnel charged with CH C1 2 and H 2 O. After separation, the organic layer is washed with H 2 O three times to remove DMF. It is then washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the desired amide as a brown solid (2.0 g, quantitative).
  • Step 2 Methyl 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoate
  • Step 1 6-Iodo-lH-py ⁇ do[3,4-d][l,3]oxazine-2,4-dione
  • 2-amino-5-iodo-isonicotinic acid (18.0 mmol) in H2O (20 ml) and concentrated HC1 (5 ml) is added dioxane (50 ml) until a clear solution is obtained.
  • Neat diphosgene (5.95 g, 30.0 mmol) is added dropwise (with cooling at times so that the solution does not boil) until a precipitate formed.
  • H2O 100 ml
  • the filter cake is dried in vacuo to give the desired compound.
  • Step 2 5-Amino-N-(4 ⁇ fluoro-benzyl)-2-iodo-isonicotinamide
  • Step 3 3-(4-Fluoro-benzyl)-6-iodo-3H-pyrido[3,4-d]pyrimidin-4 ⁇ one
  • Step 2 To a solution of the compound obtained in Step 2 (7.27 mmol) in triethyl orthoformate is added a catalytic amount ofp ⁇ ra-toluenesulfonic acid. The solution is refluxed for 5 hours, and cooled to room temperature. After removal of all volatiles in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
  • Step 1 Methyl 4- ⁇ [(5-Amino-2-iodo-pyridine-4 ⁇ carbonyl)-atnino]-methyl ⁇ -benzoate
  • Step 2 Methyl 4-(6-Iodo-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl)-benzoate
  • Step 2 To a solution of the compound obtained in Step 1 (4.84 mmol) in triethyl orthoformate is added a catalytic amount of TsOH. The solution is refluxed for 5 hours, and cooled to room temperature. After removal of all volatile solvents in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
  • Step 1 Methyl 3-(4-fluoro-benzyl)-4 ⁇ oxo-3,4-dihydro-quinazoline-6 ⁇ carboxylate
  • the compound is obtained according to the procedure described in Preparation 7 but using in Step 1 the compound obtained in Preparation 3 in which 4-methanesulfonyl- benzylamine is used in place of 4-fluorobenzylamine in the Step 2.
  • the compound is obtained according to the procedure described in Preparation 7 but using in step 1 the compound obtained in Preparation 3 in which 4-( ⁇ yrrolidine-l-sulfonyl)- benzylamine is used in place of 4-fluorobenzylamine in the Step 2.
  • the compound is obtained according to the procedure described in the second step of Example 3 using as substrate the compound obtained in the Example 5.
  • Example 7 4-[6-(4-Methoxy-benzylcarbamoyI)-l-methyI-4-oxo-l,4-dihydro-2H- quinazolin-3-ylmethyI]-benzoic acid
  • Step 1 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoic acid
  • Step 2 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
  • Example 11 3-(4-fluorobenzyl)-6-(3-phenyl-prop-l-ynyI)-3H-pyrido[3,4-d] pyrimidin-4-one
  • a compound of Preparation 5 (0.40 mmol)
  • benzylacetylenyl stannane freshly prepared by addition of «-BuLi to the -78°C solution of benzylacetylene, followed by quenching with tributyltin chloride
  • Step 1 4-(6-Iodo-4-oxo-4H-pyrido[3,4- ⁇ ]pyrimidin-3-ylmethyl)-benzoic acid To a solution of the compound of Preparation 6 (5.36 mmol), in 10%) H2O in THF is added
  • Step 2 4-[6-(3-phenyl-prop- 1 -ynyl)-4-oxo-4H-pyrido[3 ,4-cT]pyrimidin-3-ylmethyl]- benzoic acid
  • Example 14 3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 3-methoxy-benzylamide 0.2 g (0.671 mmol) of the compound obtained in the Preparation 7 is dissolved in 50 ml of chloroform. 110 mg of 3-methoxybenzyl amine, 205 mg of Mukaiyama reagent and 163 mg of triethylamine is added. The reaction solution is then stirred at room temperature overnight. The reaction solution is concentrated and purified on silica gel column with 1 : 1 Hexane:EtOAc to yield 150 mg of the desired product as an off white solid.
  • Example 17 4-[6-(3-Methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl]- benzoic acid.
  • the desired product is obtained by following the procedure of Example 14, except 4- flurobenzylamine in step 2 of the preparation 3 is replaced by tert-butyl 3-aminomethyl- benzoate, and at the end stirring the collected residue in an excess amount of trifluoroacetic acid for 30 minutes at room temperature. After removing the volatiles in vacuum, the residue is filtered to furnish the desired product as an off white solid.
  • Step 1 tert-Butyl 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]- benzoate
  • Step 2 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]-benzoic acid
  • the product is obtained by following the procedure of Example 18, the only difference is that 3 -phenyl- 1-propyne used in Step 1 is replaced by l-methoxy-4-pro ⁇ -2-ynyl-benzene.
  • the product is obtained as a white solid.
  • Example 20 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]- benzamide 0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop of DMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room temperature for an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuum and the residue is washed -with 1:1 water :methanol to yield 70 mg of an off-white powder as the desired product. MS(APCI), M/z 394.1 (M + l).
  • Example 21 3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoIine-6-carboxyIic acid (2-methoxy-pyridin-4-ylmethyl)-amide
  • Compound of the Preparation 7 (227 mg, 0.76 mmol), 2-methoxy-pyridin-4-yl- methylamine (138 mg, 1.0 mmol) and the Mukaiyama reagent (256 mg, 1.0 mmol) are dissolved in CHCI 3 (10 ml), Et 3 N (1 ml, excess) is added. The resulting solution is refluxed for 3 h, cooled to room temperature.
  • the mixture is then diluted with 150 ml of EtOAc, and washed with 3x100 ml of water, 1x100 ml of brine.
  • the organic layer is then dried over MgSO 4 and filtered.
  • the filtrate is concentrated in vacuo.
  • the crude product is purified via a flash chromatography to yield 225 mg of the pure desired product as a light yellow solid.
  • Step 1 6-Chloro-3-( " 3-fluoro-benzyl)-3H-pyrido[3,4-dlpyrimidm-4-one
  • the starting material, 6-chloro-3H-pyrido[3,4-d]pyrimidin-4one (710 mg, 3.92 mmol, prepared according to J. Chem. Soc, Perkin Trans. 1996, 1, 2221) is dissolved in DMF (20 ml).
  • Cs 2 CO 3 (1.66 g, 5.1 mmol) and 3-flurobenzylchloride (737 mg, 5.1 mmol) are added subsequently.
  • the reaction is stirred at room temperature overnight, poured into water.
  • Step 2 Methyl 3 -(3-fluorobenzyl)-4-oxo-3 ,4-dihydro-pyrido [3 ,4- ⁇ pyrimidine-6- carboxylate
  • Step 1 The compound obtained in the preceding Step 1 (3.0 g, 1.07 mmol), is dissolved in 50 ml of methanol, with an excess amount of triethylamine, and a catalytic amount of Pd(dppf)Cl 2 .
  • the reaction solution is poured into an autoclave and heated at 100°C for 4 hours under the carbon monoxide atmosphere.
  • the reaction is cooled to room temperature and filtered.
  • the filtrate is concentrated in vacuum and the residue is purified on a silica gel column using 1 : 1 Hex:EtOAc to yield the desired product as a white solid (100%).
  • Step 3 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydiO-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide To a 0°C solution of 3-methoxybenzylamine (144 mg, 1.05 mmol) in CH 2 C1 2 is added
  • Example 25 4-[4-Oxo-6-(3-phenyl-propa-l,2-dienyl)-4H-quinazolm-3-ylmethyl]- benzoic acid 0.105 g (0.257 mmol) of the compound of Example 9 is dissolved in 25 ml of 90% THF: 10%) water. 10 equivalents of LiOH are added. The reaction is refluxed for 3 hours, 200 ml of EtOAc are added, acidified by concentrated HC1 and the solution is washed with 2x100 ml of water and 1x100 ml of brine. Organic layer dried over MgSO 4 , and concentrated. The residue is purified on a silica gel column with 95% EtOAc:5% MeOH to yield 30 mg of the product as a light yellow powder.
  • Examples 26 to 71 These compounds are obtained according to the procedure described in the Preparation 5 and Example 8 using the corresponding substrates and reagents.
  • Examples 104 and 105 These compounds are obtained according to the procedure described in Examples 14 and 21 using the corresponding substrates and reagents.
  • Example 106 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 pro teo lysis 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 IC 50 value, which is the concentration of inhibitor for which an inhibition of 50% of the activity of the matrix metalloprotease under consideration is observed.
  • reaction medium of 100 ⁇ l volume is prepared, containing: 50 mM of HEPES buffer, 10 mM of CaCl 2 and 1 mM of 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), and 100 ⁇ M of substrate, the pH being adjusted to 7.0.
  • HEPES buffer 50 mM of HEPES buffer
  • CaCl 2 10 mM of CaCl 2
  • DTNB 5,5'-dithiobis-(2-nitrobenzoic acid)
  • Increasing concentrations of the inhibitory compound present in a 2.0% DMSO solution and 2.5 nM of the catalytic domain of human MMP-13 are added to the test samples.
  • the concentrations of inhibitors present in the test samples range from 100 ⁇ M to 0.5 nM.
  • the measurement of the proteolysis of the substrate peptide is monitored by measuring the absorbence at 405 urn 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 10, 14-19, 21, 23-25, 58- 60, 62, 64-71, 104, 105 are all below 1 ⁇ M.
  • the test described above for the inhibition of MMP- 13 was also adapted and used to determine the ability of the compounds of formula (I) to inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-14.
  • the results obtained show that the compounds according to the invention generally have IC 50 values for MMP- 13 which are about 100 times lower than the IC 50 values for the same compounds with respect to the other matrix metalloproteases tested.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Neurology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

A compound selected from those of formula (I) wherein: X1, X2, and X3, represent N or -CR3 in which R3 is as described in the description, G1 represents a group selected from those of formulae (i/a) and (i/b) in which R4, R5, and R6 are as defined in the description, G2 represents a group selected from carbon-carbon triple bond, -CH=C=CH-, C=O, C=S, S(O)n1 in which nl represents an integer from 0 to 2 inclusive, or a group of formula (i/c) in which Y1 represents O, S, -NH or -Nalkyl, and Y2 represents O, S, -NH or -Nalkyl, n is an integer from 0 to 6 inclusive, and m is an integer from 0 to 7 inclusive, Z1 represents -CR9R10,wherein R9 and R10 are as defined in the description, A represents a ring system, R1 represents a group selected from H, alkyl, alkenyl, alkynyl, optionally substituted and the group of formula (i/d) in which p, Z2, B, q and G3 are as defined in the description 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 mettaloprotease.

Description

TITLE OF THE INVENTION
Oxo-azabicyclic compounds
FIELD OF THE INVENTION
The present invention relates to novel oxo azabicyclic compounds which are useful for preparing medicinal products for treating complaints involving a therapy with a matrix metalloprotease-13 (MMP-13) inhibitor. 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 metallopro tease (TIMPs).
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 collagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
There is a need 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.
The patent application WO9826664 describes quinazolinone compounds which are used as new antifungic compounds.
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.
SUMMARY OF THE INVENTION
The applicant has identified novel oxo azabicyclic 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) : wherein:
• X], X2, and X3, independently of each other, represent a nitrogen atom or a group -CR3 in which R represents a group selected from hydrogen, (C -C6)alkyl, amino, mono(Cι- C6)alkylamino, di(CrC6)alkylamino, hydroxy, (Cι-C6)alkoxy, and halogen, with the proviso that not more than two of the groups Xi, X2 and X simultaneously represent a nitrogen atom,
• Gi represents a group selected from those of formulae (i/a) and (i b):
(i a) (i/b) in which:
- the carbon atom with number 2 is attached to the group N-Rt in the ring,
R} and R5, identical or different, independently of each other, represent a group selected from hydrogen, (Cι-C6)alkyl, aryl, aryl(Cι-C6)alkyl, cycloalkyl, cycloalkyl(Cι-C6)alkyl, heteroaryl, heteroaryl(CrC6)alkyl, heterocycloalkyl, and heterocycloalkyl(Cι -C6)alkyl,
- Rό represents a group selected from :
■/ hydrogen, trifluoromethyl, OR7, NR7R8, in which R7 and R8, identical or different independently of each other, represent hydrogen or (C1-C6)alkyl, ✓ (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Cι-C6)alkyl, cycloalkyl(Cι-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, heterocycloalkyl, and heterocycloalkyl(Cι-C6)alkyl, these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from halogen, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino, each alkyl moiety being identical or different independently of each other, cyano, trihalogeno(Cι-C6)alkyl, (d-C6)acyl, -C(=O)OR7, -OR7 and -SR7, in which R7 is as defined hereinbefore,
• G2 represents a group selected from carbon-carbon triple bond, -CH=C=CH-, CO, C=S, S(O)ni in which nl represents an integer from 0 to 2 inclusive, and a group of formula (i/c):
in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Y] represents a group selected from oxygen, sulphur, -NH and -N(C]-C6)alkyl, and Y2 represents a group selected from oxygen, sulphur, -NH and -N(Cι-C6)alkyl,
• n represents an integer from 0 to 6 inclusive,
• Z\ represents -CR9Rιo, wherein R9 and R10j identical or different independently of each other, represent a group selected from hydrogen, (Cι-C6)alkyl, trihalogeno(C]-C6)alkyl, halogen, -OR , -SR7, and -C(:=O)OR7, in which R7 is as defined hereinbefore, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino in which each alkyl moiety is identical or different independently of each other, and
- wherein when n is greater than or equal to 2, the hydrocarbon chain Zi optionally contains one to two isolated or conjugated multiple bonds,
-and/or wherein when n is greater than or equal to 2, one of said -CR9R10 may optionally be replaced with a group selected from oxygen, S(O)nι in which nl is as defined hereinbefore, -NH and -N(Cι-C6)alkyl,
• A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
• Ri represents a group selected from :
- hydrogen, (d-C^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, these groups may be optionally substituted with one or more groups, which may be identical or different independently of each other, selected from amino, cyano, trihalogeno(Cι-C6)alkyl, cycloalkyl, -C(=O)NR7R8, -C(=O)OR8, OR8, SR8, in which R7 and R8, which may be identical or different independently of each other, represent hydrogen or (d-
C6)alkyl, and the group of formula (i/d) :
in which p is an integer from 0 to 8 inclusive,
Z2 represents -CRπR12 wherein Rn and Rj2, identical or different independently of each other, represent a group selected from hydrogen, (Cι-C6)alkyl, phenyl, trihalogeno(Cι-C6)alkyl, halogen, amino, OR , SR7 and -C(=O)OR7 in which R7 represents hydrogen or ( -C^alkyl, and
- wherein when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or two isolated or conjugated multiple bonds,
- and/or wherein n is greater than or equal to 2, one of said -CRnRi2 may optionally be replaced with a group selected from oxygen, S(O)nl in which nl is as defined hereinbefore, -NH, -N(Cι-C6)alkyl, and carbonyl,
- B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
•/ q is an integer from 0 to 7 inclusive,
V the group(s) G3, which may be identical or different independently of each other, is (are) selected from (d-C6)alkyl, halogen, CN, NO2, CF3, OCF3, -(CH2)kNRι3Rι ,
-N(Rι3)C(=0)Ri4, -N(Rι3)C(=O)ORi4, -N(R13)SO2RI4, -N(SO2Rι3)2, -OR13, -S(0)kiRi3, -SO2-N(Rι3)-(CH2)k2-NRι4R15, -(CH2)kSO2NRι3Rι4,
-X4(CH2)kC(=O)OR13, -(CH2)kC( ))OR13, -C(=O)O-(CH2)k2-NR13Ri4, -C(=O)O-(CH2)k2-C(=O)OR16, -X4(CH2)kC(=O)NR13R14, -(CH2)kC(=O)NR13R14, -Ri7-C(=0)OR13, -X5-R18, and -C(=O)-R19-NR13Rι4 in which :
- X4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (Cι-C6)alkyl group,
- k is an integer from 0 to 3 inclusive,
- kl is an integer from 0 to 2 inclusive,
- k2 is an integer from 1 to 4 inclusive,
Rι3, R14 and R15, which may be identical or different independently of each other, are selected from hydrogen and (d-C6)alkyl,
- Rι6 represents a group selected from (Cι-C6)alkyl, -Rι9-NR13Rι4, in which R19 represents a linear or branched (Cι-C6)alkylene group, and R13, R1 and R15 are as defined hereinbefore,
- R17 represents a (C3-C6)cycloalkyl group,
- X5 represents a group selected from single bond, -CH2-, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-C6)alkyl group,
- Ris represents a group selected from : o 5- or 6-menbered monocycle aryl, heteroaryl, which is optionally substituted by one or more groups, which may be identical or different, selected from (d- C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (d-C6)alkyl, o and 5- or 6-menbered monocycle cycloalkyl, heterocycloalkyl, which is optionally substituted by one or more groups, which may be identical or different, selected from (Cι-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (Cι-C6)alkyl,
• m is an integer from 0 to 7 inclusive,
• the group(s) R2, which may be identical or different independently of each other, is (are) selected from (d-C6)alkyl, halogen, -CN, NO2, SCF3, -CF3, -OCF3, -NR7R8, -OR8, - SR8, -SOR8, -SO2R8, -(CH2)kSO2NR7R8, -X7(CH2)kC(=O)OR8, -(CH2)kC(=O)OR8, -X7(CH2)kC(=O)NR7R8, -(CH2) C(=O)NR7R8, and -X8-R20 in which:
X7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (d-C6)alkyl,
- k is an integer from 0 to 3 inclusive,
- R and Rs, which may be identical or different independently of each other, are selected from hydrogen and (Cι-C6)alkyl,
- X8 represents a group selected from single bond, -CH2-, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (Cι-C6)alkyl group,
- R20 represents 5- or 6-menbered monocycle aryl, heteroaryl, cycloalkyl, or heterocycloalkyl which is optionally substituted by one or more groups, which may be identical or different, selected from (Cι-C6)alkyl, halogen, hydroxy and amino, and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur,
optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof. According to a first embodiment, the invention relates to compounds of formula (I) wherein :
• G2 represents a group selected from C=O, C=S, S(O)nl in which nl represents an integer from 0 to 2 inclusive, or a group of formula (i/c):
^ (i/e) Y. in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Y] represents a group selected from oxygen, sulphur, -NH and -N(d-C6)alkyl, and Y2 represents a group selected from oxygen, sulphur, -NH and -N(d-C6)alkyl,
• Xi, X2, X3, Gi, n, Zi, A, Rι( m and R2 are as defined in formula (I).
According to a second embodiment, the invention relates to compounds of formula (I) wherein :
• G2 represents a carbon-carbon triple bond,
• n represents an integer from 1 to 6 inclusive,
• Xi, X2, X , Gi, Z], A, R\, m and R2 are as defined hereinbefore.
According to a third embodiment, the invention relates to compounds of formula (I) wherein :
• G2 represents a carbon-carbon triple bond,
• n is zero,
• Zi is absent, • A represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
• Xi , X2, X , Gi , Ri , m and R2 are as defined hereinbefore.
According to a fourth embodiment, the invention relates to compounds of formula (I) wherein :
• G2 represents a carbon-carbon triple bond,
• n is zero, • Zi is absent,
• A represents a phenyl group,
• Rj represents a hydrogen atom or a group of formula (i/d)
in which p is an integer from 0 to 8 inclusive, Z2 represents -CRi ιR12 wherein Ri i and R]2, identical or different independently of each other, represent a group selected from hydrogen, (Cι-C6)alkyl, phenyl, trihalogeno(Cι-C6)alkyl, halogen, amino, OR7, SR7 and -C(=O)OR7 in which R7 represents hydrogen or (Cι-C6)alkyl, and - wherein when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or two isolated or conjugated multiple bonds, and/or wherein n is greater than or equal to 2, one of said -CRπRι2 may optionally be replaced with a group selected from oxygen, S(O)nl in which nl is as defined hereinbefore, -NH, -N(d-C6)alkyl, and carbonyl, B represents a phenyl group, q is an integer from 1 to 7 inclusive, the group(s) G3, which may be identical or different independently of each other, is (are) selected from -(CH2)kNRι3R14, -N(Rι3)C(=O)ORι4, -N(R]3)SO2Rι4, -N(SO2Rι3)2, -S(O)klR13, -SO2-N(R13)-(CH2)k2-NR14R15, -(CH2)kSO2NR13R14, -X4(CH2)kC(=O)OR13, -(CH2)kC(=O)OR13, -C(=O)O-(CH2)k2-NR13Ri4,
-C(=O)O-(CH2)k2-C(=O)OR16, -X4(CH2)kC(=O)NRι3R14, -(CH2)kC(=O)NR13R14, -Rι7-C(=0)ORi3, -Xs-Ris, -C(=O)-R19-NR13R14 and -X6-R2ι in which :
- X4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (d-C6)alkyl group,
- k is an integer from 0 to 3 inclusive,
- kl is an integer from 1 to 2 inclusive,
- k2 is an integer from 1 to 4 inclusive,
- R13, R14 and R)5, which may be identical or different independently of each other, are selected from hydrogen and (Cι-C6)alkyl, - Rie represents a group selected from (d-C6)alkyl, -Rι9-NR13RM, in which R19 represents a linear or branched (Cι-C6)alkylene group, and R!3, Rϊ4 and R]5 are as defined hereinbefore, - R17 represents a (C3-C6)cycloalkyl group,
- X5 represents a group selected from single bond, -CH2-, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-Q)alkyl group,
- R]8 represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or
6- membered monocycle, which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (Cι-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (d-C6)alkyl, - X6 represents a group selected from -CH2-, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-C6)alkyl group,
- R2ι represents a phenyl group which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (C]-C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (d-C6)alkyl, • and Xi , X2, X3, Gi , m and R2 are as defined in formula (I).
The substituent Ri that is preferred according to the invention is the group of formula (i/d): wherein Z2, p, B, G3 and q are as defined in the compound of formula (I).
More particularly, the substituent Ri that is preferred according to the invention is the group of formula (i/d): wherein Z2 represents a group -CRnR12 in which Rπ and R12 represents each a hydrogen atom., and p, B, G3 and q are as defined in the compound of formula (I).
More particularly, the substituent R] that is preferred according to the invention is the group of formula (i/d): wherein p is one, and Z2, B, G3 and q are as defined in the compound of formula (I).
More particularly, the substituent R! that is preferred according to the invention is the group o f formula (i/d) : wherein B represents a phenyl group, q is equal to 0 or 1, and G3, when it is present, represents a group selected from ORι3, halogen, S(O)kιRj3 and (CH2)kC(=O)ORι3 in which Rπ represents an hydrogen atom or a (Cι-C6)alkyl group, k is zero, and ki is two, and Z2, p are as defined in the compound of formula (I).
The invention relates also to the compounds of formula (I) wherein G\ represents a group of formula (i/a) in which R4 represents a hydrogen atom or a methyl group, or a group of formula (i/b) in which and R5, identical, represent each a hydrogen atom or a methyl group, and R6 represents a hydrogen atom or a methyl group, and Xj, X2, X3, G2, Zu n, m and R2 are as defined in formula (I).
Preferred compounds of the invention are compounds of formula (I) wherein Xi represents a group -CR3 in which R3 represents a hydrogen atom, X2 represents a nitrogen atom or a group -CR3 in which R3 represents a hydrogen atom, and X3 represents a group -CR3 in which R3 represents a hydrogen atom. Other preferred compounds of the invention are compounds wherein G2 represents a carbon-carbon triple bond or a group of formula (i/c) in which Yi represents an oxygen atom, and Y2 represents a group -NH.
Still more preferred compounds of the invention are those compounds of formula (I) wherein Z\ represents -CR9R10 in which R9 and R10 represent each a hydrogen atom, and n is one.
Especially preferred compounds of the invention are compounds wherein A represents a group selected from phenyl and pyridyl, m is zero or one, and R2 represents a (Cι-C6)alkoxy group or a hydrogen atom.
More particularly, the invention relates to the following compounds of formula (I) :
3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy- benzylamide
3-(4-methoxy-benzyl)-2-methyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4- methoxy-benzylamide, hydrochloride - 3-(4-methoxy-benzyl)- 1 -methyl-4-oxo- 1 ,2,3 ,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
- 3 -(4-methoxy-benzyl)- 1 ,2,2-trimethyl-4-oxo- 1 ,2,3 ,4-tetrahydro-quinazoline-6- carboxylic acid 4-methoxy-benzylamide
. 4-[6-(4-methoxy-benzylcarbamoyl)-4-oxo- 1 ,4-dihydro-2H-quinazolin-3-ylmethyl]- benzoic acid
. 4-[6-(4-methoxy-benzylcarbamoyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-2H-quinazolin-3- ylmethyl] -benzoic acid methyl ester 4.[6-.(4.methoxy-benzylcarbamoyl)-l-methyl-4-oxo-l,4-dihydro-2H-quinazolin-3- ylmethyl] -benzoic acid, - 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 3-methoxy- benzylamide
- 3-(4-methanesulfonyl)-benzyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4- methoxy-benzylamide 4-Oxo-3-[4-(pyrrolidine-l-sulfonyl)-benzyl]-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
4-[6-(3-methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid, 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy- pyridin-4-ylmethyl)-amide,
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3- methoxy-benzylamide, and 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid
4-methoxy-benzylamide
Further preferred compounds are:
- 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy- pyridin-4-ylmethyl)-amide
- 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy- benzylamide.
More particularly, the invention relates also to the following compounds of formula (I) :
- 3-(4-fluorobenzyl)-6-(3-phenyl-prop-l-ynyl)-3 H-quinazolin-4-one,
- methyl 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoate, . 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid, - 3-(4-fluorobenzyl)-6-(3-phenyl-prop- 1 -ynyl)-3H-pyrido[3,4-< jpyrimidin-4-one,
- methyl 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-ρyrido[3,4-cT|pyrimidin-3-ylmethyl]- benzoate,
- 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-pyrido[3,4- |pyrimidin-3-ylmethyl]-benzoic acid, - 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]-benzoic acid,
- 4-{6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazoline-3-ylmethyl}-benzoic acid, . 4_[4-0χo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]-benzamide
- and 3-[(3,5-difluoro-4-hydroxy)-benzyl]-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4- one. Further preferred compounds are:
- 4-[6-(3-Imidazol-l-yl-ρroρ-l-ynyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid
- 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzenesulfonamide
- 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzonitrile
- 3-(3-Chloro-benzyl)-6-(4-phenyl-but-l-ynyl)-3H-quinazolin-4-one
- 3-(3-Chloro-benzyl)-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one
- 4-[4-Oxo-6-(3-pyrazol- 1 -yl-prop- 1 -ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
- 6-(3-Phenyl-prop-l-ynyl)-3-[4-(lH-tetrazol-5-yl)-benzyl]-3H-quinazolin-4-one
- 3-(3,4-Difluoro-benzyl)-6-[3-(pyridin-4-yloxy)-proρ-l-ynyl]-3H-quinazolin-4-one
- 3 -(3 ,4-Difluoro-benzyl)-6-[3 -(4-methoxy-phenyl)-prop- 1 -ynyl]-3H-quinazolin-4-one
- N-{4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-phenyl}-acetamide
- 3-(3,4-Difluoro-benzyl)-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one
- 3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin-4-one
- 6-(3-Phenyl-prop- 1 -ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one
- 6-[3-(4-Methoxy-phenyl)-prop-l-ynyl]-3-pyridin-4-ylmethyl-3H-quinazolin-4-one
Most preferred are the compounds listed in the table below, which refers to the examples later in the application.
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.
More particularly, a preferred method of treatment according to this invention is treatment of disease selected from arthritis, osteoarthritis and rheumatoid arthritis. 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 (Cι-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 (Cι-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, rc-propyloxy, tert-butyloxy,
- a mono(Cι-C6)alkylamino denotes a amino group substituted by one (Cι-C6)alkyl group as defined hereinbefore ; example of such groups, without implying any limitation are methyl amino, isobutyl amino, ethylamino,
- a di(Cι-C6)alkylamino denotes a amino group substituted by two (Cι-C6)alkyl groups as defined hereinbefore, each alkyl group being identical or different ; example of such groups, without implying any limitation are dimethylamino, diethylamino,
- an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated ; examples of such groups without implying any limitation are, phenyl, naphthyl, indenyl, benzocyclobutenyl,
- a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen ; examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl,
- a cycloalkyl group denotes a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character ; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl,
- 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 and,
- a trihalogeno(Cι-C6)alkyl group denotes an alkyl group as defined above which contains a trihalogeno group ; examples of such groups without implying any limitation are trifluorornethyl, 2,2,2-trifluoroethyl, - a (d-C7)acyl group denotes an alkyl group or a aryl group as defined above bound through a carbonyl group ; examples of such groups without implying any limitation are acetyl, ethylcarbonyl, benzoyl,
- a multiple bond denotes double bond or triple bond,
- a halogen atom means fluoro, chloro, bromo or iodo, - 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. Sci, 1977, 66, 1-19. Pharmaceutically acceptable acids mean non-toxic salts derived from mineral or organic acids. Among those there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc... Pharmaceutically acceptable bases mean non-toxic salts derived from mineral or organic bases. Among those, there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine, dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, quaternary ammonium hydroxides etc...
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (II): in which Xi, X2, X3, and Yi have the same definitions as the compound of formula (I), and T represents a group (d-C6)alkyl,
compound of formula (II) which is treated with a compound of formula (III): in which Z\, Y2, R2, A, n and m have the same definitions as the compound of formula (I),
by activating the acid function with an activator, in the presence of diisopropylethylamine and a solvent, to yield the compound of formula (IV) : in which Xi, X2, X3, Yi , T, Z\, Y2, R2, A, n and m are as defined hereinbefore,
compound of formula (IV) in which the ester group is hydrolyzed and the subsequently compound obtained is then treated with an activator in the presence of a base and a primary amine with the general formula R NH2 in which Ri is as defined in the compound of formula (I),
to yield the compound of formula (V) : in which Xls X2, X3, Yi, Y2, Zl s R2, Rls A, n and m are as defined hereinbefore,
which compound of formula (V) is treated :
• either with triethyl orthoformate under heating condition, to yield the compound of formula (I/a), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Yl5 Y2, Zi, R2, Rl5 A, n and m are as defined hereinbefore,
or under heating condition in the presence of acid, with a compound of formula (VI):
R. .R.
(VI) O O in which R4 has the same definition as the compound of formula (I), to yield the compound of formula (I/b), which is a particular case of the compound of formula (I): in which Xh X2, X3, Yi, Y2j Zh R2, Ri, R , A, n and m are as defined hereinbefore,
• or with a compound of formula (VII) in basic condition: in which R4 and R5 have the same definition as the compound of formula (I), to yield the compound of formula (I/c), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Yj, Y2, Z\, R2, Rj, R4, R5, A, n and m are as defined hereinbefore,
which compound of formula (I/c) is optionally treated with a hydride, in the presence of a compound of formula (VIII):
R6-Hal (VIII) in which Re has the same definition as the compound of formula (I), to yield the compound of formula (I/d), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Yj, Y2, Z\, R2, R\, R4, R5, Re, A, n and m are as defined hereinbefore,
compounds of formulae (Fa), (I/b), (I/c) and (I/d) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (X): in which Xi, X2, and X3 have the same definitions as the compound of formula (I), and Hal represents a halogen atom, which compound of formula (X) is treated in a first step with a derivate of phosgene to yield the compound of formula (XI): in which Xj, X2, X3 and Hal are as defined hereinbefore,
which compound of formula (XI) is treated in basic medium with a primary amine of general formula Rι-NH2 in which Ri has the same definition as in the compound of formula (I),
to yield the compound of formula (XII): in which Xi, X2, X3, Ri and Hal are as defined hereinbefore,
which compound of formula (XII) is treated: • either with triethyl orthoformate under heating condition, to yield the compound of formula (XHI/a) : in which Xi, X2, X3, R and Hal are as defined hereinbefore,
or under heating condition in the presence of an acid, with a compound of formula
(VI): in which R4 has the same definition as the compound of formula (I), to yield the compound of formula (XIII/b) : in which Xi, X2, X3, Hal, Ri and R4 are as defined hereinbefore,
• or with a compound of formula (VII) in basic conditions: in which R4. and R5 have the same definition as the compound of formula (I),
to yield the compound of formula (XIII/c) : in which Xi, X2, X3, Hal, Ri, R4 and R5 are as defined hereinbefore,
which compound of formula (XIII/c) is optionally treated with a hydride, in the presence of a compound of formula (VIII):
R^-Hal (VIII) in which R6 has the same definition as the compound of formula (I), and Hal is a halogen atom, to yield the compound of formula (XIIFd), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Hal, Ri, R4, R5 and R^ are as defined hereinbefore,
all compounds of formulae (Xlll/a), (XHI/b), (XIII/c) and (XIIFd) constitute the compound of formula (XHI/e): in which Xi, X2, X3, Hal, Ri and G\ are as defined in the compound of formula (I),
compound of formula (XIIFe) which is treated under conditions of palladium-catalyzed alkynylation with a compound of formula (XIV): in which Zi, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (Fe), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Ri, Gt, Zλ, R2, A, n and m have the same definitions as the compound of formula (I), compounds of formula (Fe) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
An alternative way to obtain the compound of formula (XIIFa) from compound of formula (XI) is described in the following scheme 1 :
Scheme 1
Wherein X[, X2, X , Ri and Hal, are as defined above.
In a first step, compound of formula (XI) is treated with an aqueous solution of ammonium hydroxide to yield compound of formula (XFa) which is reacted with triethyl orthoformate in the presence of a catalytic amount of acid like αra-toluene sulfonic acid (PTSA). The 3H-quinazolin-4-one (Xl/b) obtained is condensed in basic medium to a compound of formula Ri-Hal, in which Ri is as defined in the compound of formula (I) and Hal represents a halogen, to yield the compound of formula (XIIFa).
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIIFe) : in which Xt, X2, X3, Ri and Gi axe as defined in the compound of formula (I), and Hal is a halogen atom,
compound of formula (XHI/e) which is condensed, in the presence of dichlorobis(triphenylphosphine)palladium, cupper iodide and N.N'-diisopropylethylamine in dimethylformamide, on a compound of formula (XV) : in which Zi, R , A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (Fe), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Ri, Gi, Zl s R2, A, n and m have the same definitions as the compound of formula (I).
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIIFe) : in which Xi, X2, X3, Ri and Gi are as defined in the compound of formula (I), and Hal, is a halogen atom, compound of formula (XIIFe) which is reacted with carbon monoxide in an alkaline medium in the presence of a protic solvent like methanol and a catalytic amount of palladium , to yield the compound of formula (XVI):
in which Xl s X2, X3, Ri and Gi are as defined in the compound of formula (I),
compound of formula (XVI) which is hydrolysed under basic medium to yield the compound of formula (XVII):
in which Xi , X , X3, Rj and G are as defined in the compound of formula (I),
compound of formula (XVII) which is condensed under basic. medium in the presence of a Mukayama reagent, on the compound of formula (XVIII): CXVΠD in which Z\ , R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (Ff), which is a particular case of the compound of formula (I):
in which X, , X2, X3, Z] , R2, Ri , A, n and m are as defined hereinbefore, compounds of formula (Ff) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIX) : in which Hal represents a halogen atom,
compound of formula (XIX) which is heated in the presence of formamidine acetate in a polar solvent like 2-methoxyethan-l-ol, to yield the compound of formula (XX): in which Hal is as defined hereinbefore,
compound of formula (XX) which is treated in basic medium with a compound of formula Ri-Hal, in which R] is as defined in the compound of formula (I) and Hal represents a halogen atom, to yield the compound of formula (XXI): in which Hal and Ri are as defined hereinbefore,
compound of formula (XXI) which is reacted with carbon monoxide under basic medium in the presence of an alcoholic solvent like methanol and a catalytic amount of palladium like PdCl2(dppf) , to yield the compound of formula (XXII): in which R\ is as defined hereinbefore,
compound of formula (XXII) which is condensed, in the presence of trimethylaluminium, with a compound of formula (XVIII):
(XVIII) in which Zj, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (Fg), which is a particular case of the compound of formula (I): in which Z\, R , Ri, A, n and m are as defined hereinbefore, compounds of formula (Fg) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
The compounds of the invention that are present in the form of a mixture of diastereoisomers are isolated in a pure form by using conventional separation techniques such as chromatography.
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, colourants, aromatizing agents etc...
The useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments. The dosage ranges from 2 mg to 1 g per day in one or more administrations. The compositions are prepared by methods that are common to those skilled in the art and generally comprise 0.5% to 60% by weight of active principle (compound of formula (I)) and 40% to 99.5% by weight of pharmaceutically acceptable excipients or carriers.
The 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 spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, ...) In the Preparations and Examples, it is understood that :
- DMF means Dimethylformamide,
- THF means tetrahydrofurane, - DMSO means dimethylsulfoxide, - TOTU means O-(ethoxycarbonyl)cyanomethylamino]-N-N-N'-N -tetramethyI uronium fluoroborate,
- DIPEA means diisopropylethylamine.
EXAMPLES
Preparation 1 : 4-Amino-3-[(4-methoxy)-benzylcarbamoyl]-l-carboxyIic acid 4- methoxy-benzylamide
Step 1 : 4-Amino-isophthalic acid
6.3 g (150 mmol) of LiOH.H2O are added to a stirred solution of 15.7 g (75 mmol) of methyl 4-amino-isophtalate in 300 ml of dioxane and 1200 ml of water. The reaction mixture is heated for 1 hour to 100°C, cooled and acidified to pH=l by the addition of concentrated HC1. A precipitate is obtained then filtered off, washed, and dried under vacuum to yield 13 g (yield = 95.7%) of the desired compound.
N.M.R (OMSO-d6) 1H δ (ppm ) : 6.80 (d,lH); 6.80-7.80 (bs); 7.80 (dd,lH); 8.35 (s,lH); 11.9-13.1 (bs)
Step 2 : 4-Amino-3-[(4-methoxy)-benzylcarbamoyl]-phenyl-l-carboxylic acid 4-methoxy- benzylamide
2.25 g (16.5 mmol) of 4-methoxybenzylamine, 5.4 g (16.5 mmol) of TOTU and 5.4 ml (3.9 g, 30 mmol) of DIPEA are added successively to a stirred solution of 2.7 g (15 mmol) of the compound obtained in Step 1 to 100 ml of DMF. The reaction mixture is stirred overnight at room temperature, then the solvent is removed under vacuum. The crude mixture is taken up in dichloromethane, and washed successively with HC1 IN and NaOH IN. After separation by decantation the organic phase is dried over Na2SO4 and concentrated under vacuum. The crude product is purified by chromatography and concretized from a mixture of dichloromethane and ether to yield 3.1 g (yield=49.3%) of the desired compound. N.M.R (OMSO-d6) 1H δ (ppm) : 3.70 (s,6H) ; 4.35 (t,4H) ; 6.70 (d,lH) ; 6.80-6.90 (m,6H) ; 7.20-7.30 (m,4H) ; 7.65 (dd,lH) ; 8.10 (s,lH) ; 8.45 (t,lH) ; 8.75 (t,lH)
Preparation 2 : Methyl 4-{[2-Amiαo-5-(4-methoxy-benzykarbamoyl)-benzoylamino]- methyI}-benzoate
Step 1 : Methyl 6-Amino-N-(4-methoxy-benzyl)-isophthalate
6.56 g (20 mmol) of TOTU and 2.6 ml (2.74 g, 20 mmol) of 4- methoxybenzylamine are added to a stirred solution of 4.2 g (18.1 mmol) of 4-amino-3 -methyl carboxylate-1 -phenyl carboxylic acid in 150 ml of anhydrous DMF. The mixture is cooled at 0°C and 9.5 ml (7.02 g, 54.3 mmol) of DIPEA are added. The reaction mixture is stirred overnight at room temperature and concentrated under vacuum. The residue is taken up in 150 ml of dichloromethane, washed with 100ml of a saturated solution of NaHCO3. The organic layer is dried and concentrated under vacuum. After a chromatography over silica gel 3.5 g (yield=62%) of the desired compound are isolated. TLC : CH2Cl2/MeOH 90/10 Rf = 0.80
N.M.R (DMSO-ck) Η δ (ppm) : 3.80 (s,3H) ; 3.90 (s,3H) ; 4.55 (d,2H) ; 6.0-6.15 (bs,2H) ;
6.15-6.30 (bs,lH) ; 6.65 (d,lH) ; 6.90 (d,lH) ; 7.25-7.30 (m,2H) ; 7.80 (d,lH) ; 8.25
(S.1H).
PURITY : HPLC = 98.5%
Step 2 : 6-Amino-N-(4-methoxy-benzyl)-isophthalamic acid
0.3 g (7 mmol) of LiOH, H2O is added to a stirred solution of 1.1 g (3.5 mmol) of the compound obtained in the preceding Step 2 in 10 ml of dioxane and 40 ml of water. The reaction mixture is heated under reflux for 2 hours, cooled, and acidified at pH=l by addition of concentrated HC1. The precipitate obtained is filtered off and dried to give the desired compound.
N.M.R (DMSO- ) 1H δ (ppm) : 3.70 (s,3H) ; 4.35 (d,2H) ; 6.75 (d,lH) ; 6.85 (d,2H) ; 7.20 (d,2H) ; 7.75 (dd,lH) ; 8.30 (slH) ; 8.65 (t,lH).
Step 3 : Methyl 4-{[2-Amino-5-(4-methoxy-benzylcarbamoyl)-benzoylamino]-methyl}- benzoate The desired compound is obtained according to the procedure described in the Step 1 of Preparation 2 using as starting material the compound obtained in the preceding step 2 and as reactant the methyl 4-(aminomethyl)benzoate hydrochloride. It is purified by chromatography over silica gel using a mixture of dichloromethane/ether as eluant. N.M.R (DMSO-^) lH δ (ppm) : 3.70 (s,3H) ;3.85 (s,3H) ; 4.40 (d,2H) ; 4.50 (d,2H) ; 6.70 (d,lH) ; 6.80-6.90 (m,4H) ; 7.25 (d,2H) ; 7.45 (d,2H) ; 7.70 (dd,lH) ; 7.95 (d,2H) ; 8.15 (s,lH) ; 8.45 (t,lH) ; 8.90 (t,lH).
Preparation 3 : 3-(4-fluorobenzyl)-6-iodo-3H-quinazoIin-4-one
Step 1 : 6-iodo-lH-benzo[a][l,3]oxazine-2,4-dione
To a suspension of 2-amino-5-iodobenzoic acid (4.9 g, 18.0 mmol) in H2O (20 ml) and concentrated HC1 (5 ml) is added dioxane (50 ml) until a clear solution is obtained. Neat diphosgene (5.95 g, 30.0 mmol) is added dropwise (with cooling at times so that the solution would not boil) to give a white precipitate. After stirring at room temperature for 10 min., H2O (ca. 100 ml) is added and the precipitate is filtered and washed with copious amount of H2O. It is dried in vacuo to give the desired product (5.2 g, quantitative) as white crystals. N.M.R (OMSO-d6) 1H δ (ppm) : 6.93 (d, J= 8.6 Hz, IH), 8.00 (dd, J = 8.6, 2.0 Hz, IH), 8.10 (d, J= 2.0 Hz, IH), 11.8 (s, IH); MS (APCI), M/z 288.0 (M - 1).
Step 2 : 2-amino-N-(4-fluorobenzyl)-5-iodo-benzamide
To a 50°C solution of the compound obtained in the preceding Step 1(2.1 g, 7.27 mmol) in DMF (20 ml) are added neat 4-fluorobenzylamine (1.18 g, 9.45 mmol) dropwise. The reaction is stirred at room temperature for 10 min. while bubbling is observed (CO ), and TLC indicated the completion of the reaction. The reaction content is poured into a separatory funnel charged with CH2C12 and H2O. After separation, the organic layer is washed with H2O(3x50 ml) and brine (50 ml). It is dried (Na2SO4), filtered and concentrated in vacuo to give a white solid which is purified using flash chromatography to give the desired compound as a white solid (2.5 g, 93%). N.M.R (DMSO-cfe) Η δ (ppm) : 5.15 (d, J= 5.8 Hz, 2H), 6.50 (s, IH), 7.03 (m, IH); 7.34 (m, IH), 7.43 (d, J= 8.5 Hz, IH), 8.02 (m, IH), 8.10 (s, IH), 8.66 (d, / = 1.9 Hz, IH), 9.18
(t, J= 5.8 Hz, IH); MS (APCI), M/z 371.0 (M + 1).
Step 3 : 3-(4-fluorobenzyl)-6-iodo-3H-quinazolin-4-one To the solution of the compound obtained in the preceding Step 2 (2.69 g, 7.27 mmol) in triethyl orthoformate is added catalytic amount of TsOH. The solution is refluxed for 5h, cooled to room temperature. After removal of all volatiles in vacuo, the residue is purified using flash chromatography to give the desired quinazolinone as a brownish solid. Trituration then afforded the desired compound as a white solid (1.56 g, 58%). N.M.R (DMSO- ) 1H δ (ppm) : 5.15 (s, 2H), 7.03 (m, IH); 7.34 (m, IH), 7.43 (d, J- 8.5
Hz, IH), 8.02 (m, IH), 8.10 (s, IH), 8.66 (d, J- 1.9 Hz, IH); MS (APCI), M/z 381.0 (M + 1).
Preparation 4 : Methyl 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoate
Step 1: Methyl 4-[(2-Amino-5-iodo-benzoylamino)-methyl]-benzoate To a 50°C solution of the compound obtained in the Step 1 of Preparation 3 (1.4 g, 4.84 mmol) in DMF (20 ml) is added the hydrochloride salt of 4-carbomethoxy-benzylamine (1.17 g, 5.8 mmol). The reaction is stirred at room temperature for 1 h while bubbling is observed (CO2), and TLC indicated the completion of the reaction. The reaction content is poured into a separatory funnel charged with CH C12 and H2O. After separation, the organic layer is washed with H2O three times to remove DMF. It is then washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the desired amide as a brown solid (2.0 g, quantitative).
N.M.R 8.6 Hz, IH), 6.59 (s, 2H), 7.15 (m, 2H), 7.35 (m, 4H), 7.80 (d, J= 1.9 Hz, IH), 8.88 (t, J= 5.9 Hz, IH);
MS (APCI), M/z 411.0 (M + 1).
Step 2 : Methyl 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoate
To a solution of the compound obtained in the preceding Step 1 (2.0 g, 4.84 mmol) in triethyl orthoformate is added catalytic amount of TsOH. The solution is refluxed for 5h, cooled to room temperature. After removal of all volatile solvents in vacuo, the residue is purified using flash chromatography to give the desired quinazolinone as a brownish solid.
Trituration then afforded the desired compound as a white solid (1.0 g, 50%).
N.M.R (CDC13) 1H δ (ppm) 3.31 (s, 3H), 5.26 (d, 2H), 7.48 (m, 4 H), 7.90 (d, J= 6.8 Hz, 2H), 8.10 (m, IH), 8.40 (d, J= 1.7 Hz, IH), 8.60 (d, J= 1.5 Hz, IH) 2277
37 MS (APCI), M/z 421.3 (M + 1).
Preparation 5 : 3-(4-Fluoro-benzyl)-6-iodo-3H-pyrido[3,4-d]pyrimidin-4-one
Step 1 : 6-Iodo-lH-pyήdo[3,4-d][l,3]oxazine-2,4-dione To a suspension of 2-amino-5-iodo-isonicotinic acid (18.0 mmol) in H2O (20 ml) and concentrated HC1 (5 ml) is added dioxane (50 ml) until a clear solution is obtained. Neat diphosgene (5.95 g, 30.0 mmol) is added dropwise (with cooling at times so that the solution does not boil) until a precipitate formed. After stirring at room temperature for 10 minutes, H2O (100 ml) is added, and the precipitate is filtered and washed with a copious amount of H2O. The filter cake is dried in vacuo to give the desired compound.
Step 2 : 5-Amino-N-(4~fluoro-benzyl)-2-iodo-isonicotinamide
To a 50°C solution of a compound obtained in Step 1 (7.27 mmol) in DMF (20 ml) is added 4-fluorobenzylamine (9.45 mmol) dropwise. The reaction is stirred at room temperature for 10 minutes while bubbling is observed (CO2), and TLC indicates completion of the reaction. The reaction content is poured into a separatory funnel charged with CH2CI2 and H2O. After separation, the organic layer is washed with H2O (3x50 ml) and brine (50 ml). The organic layers are then dried (Na2SO4), filtered and concentrated in vacuo, and the residue optionally is purified using flash chromatography on silica gel to give the desired compound. Step 3 : 3-(4-Fluoro-benzyl)-6-iodo-3H-pyrido[3,4-d]pyrimidin-4~one
To a solution of the compound obtained in Step 2 (7.27 mmol) in triethyl orthoformate is added a catalytic amount ofpαra-toluenesulfonic acid. The solution is refluxed for 5 hours, and cooled to room temperature. After removal of all volatiles in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
Preparation 6 : Methyl 4-(6-Iodo-4-oxo-4H-pyrido[3,4-rf]pyrimidin-3-ylmethyl)- benzoate
Step 1 : Methyl 4-{[(5-Amino-2-iodo-pyridine-4~carbonyl)-atnino]-methyl}-benzoate
To a 50°C solution of the compound obtained in the Step 1 of Preparation 6 (4.84 mmol), in DMF (20 ml) is added the hydrochloride salt of 4-carbomethoxy-benzylamine (1.17 g, 5.8 mmol). The reaction is stirred at room temperature for 1 hour while bubbling is observed (CO2 evolution), and TLC indicates the completion of the reaction. The reaction content is poured into a separatory funnel charged with CH2CI2 and H2O. After separation of the layers, the organic layer is washed with H2O three times to remove DMF. The organic layer is then washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the desired compound.
Step 2 : Methyl 4-(6-Iodo-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl)-benzoate
To a solution of the compound obtained in Step 1 (4.84 mmol) in triethyl orthoformate is added a catalytic amount of TsOH. The solution is refluxed for 5 hours, and cooled to room temperature. After removal of all volatile solvents in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
Preparation 7 : 3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid
Step 1: Methyl 3-(4-fluoro-benzyl)-4~oxo-3,4-dihydro-quinazoline-6~carboxylate
2.0 g (5.27 mmol) of the compound prepared from preparation 3, is dissolved in 50 ml of 1:1 DMF.Methanol, an excess amount of triethylamine, and a catalytic amount of Pd(dppf)Cl2. The reaction solution is poured into an autoclave and heated at 100°C for 4 hours under carbon monoxide atmosphere. The reaction is cooled to room temperature and filtered. The filtrate is concentrated in vacuo and the residue purified on a silica gel column using 1:1 Hex:EtOAc to yield the desired product as a white solid (100%).
Step2: 3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid
1.7g (5.27 mmol) of the compound obtained in the preceding Step 1 is dissolved in 50 ml of 90% THF:10% Water. 10 equivalents of LiOH is added, and the reaction solution is refluxed for 5 hours. The reaction solution is diluted with 100 ml of water, and concentrated HC1 is used to acidify the solution pH to 1.0. The solution is extracted with 200 ml of EtOAc, and the organic layer is washed with 2x100 ml of water and 1x100 ml of brine. The organic layer is dried over MgSO4 and concentrated to yield 1.5 g of the desired product as an off-white solid. Preparation 8 3-(4-Methanesulfonyl-benzyI)-4-oxo-3,4-dihydro-quinazoline-6- carboxylic acid
The compound is obtained according to the procedure described in Preparation 7 but using in Step 1 the compound obtained in Preparation 3 in which 4-methanesulfonyl- benzylamine is used in place of 4-fluorobenzylamine in the Step 2.
Preparation 9 : 3 -[4-(Pyrrolidine-l-sulfonyl)-benzyl] -4-oxo -3,4- -dihydro -quinazoline-
6-carboxylic acid
The compound is obtained according to the procedure described in Preparation 7 but using in step 1 the compound obtained in Preparation 3 in which 4-(ρyrrolidine-l-sulfonyl)- benzylamine is used in place of 4-fluorobenzylamine in the Step 2.
Preparation 10 : tert-butyl 4-(6-iodo-4-oxo-4H-quinazolin-3-yImethyl)-benzoate
Step 1: 2-Amino-5-iodo-benzamide
2.0 g (6.90 mmol) of the compound obtained in Step 1 of Preparation 3 is dissolved in approximately 50 ml of DMF, and an excess amount of aqueous ammonium hydroxide is added. After 10 minutes of stirring, the reaction solution is poured into 100 ml of water, and acidified with concentrated HC1, then extracted with 2x100 ml of EtOAc. The combined organic layer is then concentrated to yield 1.8 g (100%) of the desired product as an off-white powder. N.M.R (DMSO-cfe) 1H δ (ppm) : 6.50 (d, J = 8.8Hz, IH), 6.68 (s, 2H), 7.12 (s, IH), 7.33 (dd, J! = 8.8Hz, J2 = 2.1Hz, IH), 7.77 (d, J= 1.9Hz, 2H).
Step 2 : 6-Iodo-3H-quinazolin-4-one
1.8 g (6.90 mmol) of compound obtained in the preceding Step 1 is suspended in 30 ml of triethyl orthoformate. A catalytic amount of para-toluene sulfonic acid is added, and the suspension is refluxed for 3 hours. All volatiles are removed in vacuo, and the residue is washed with 1:1 dichloromethane:Hexane to yield 1.5 g (80%) of an off white powder as the desired product.
MS(APCI), M/z 270.9 (M-l)
N.M.R (OMSO-d6) 1H δ (ppm) : 7.42 (d, J= 8.5Hz, IH), 8.09 (dd, Jx = 8.5Hz, J2 = 2.2Hz,
IH), 8.09 (s, IH), 8.34 (d, J= 2.2Hz, IH), 12.38 (broad s, IH).
Step 3: tert-Butyl 4-(6-Iodo-4~oxo-4H-quinazolin-3-ylmethyl)-benzoate
0.9 g (3.31 mmol) of compound obtained in the preceding Step 2 is dissolved in 50 ml of DMF. 1.18 g (3.64 mmol) of cesium carbonate and 0.986 g (3.64 mmol) of ter-butyl 4- bromomethyl-benzoate is added. The reaction is stirred at room temperature for 24 hours. 200 ml of EtOAc is then added, and then washed with 3 x 100 ml of water. The organic layer is dried over MgSO4 and concentrated. The residue is purified on a silica gel column using 4:1 dichloromethane:hexane increasing gradually to a 1:1 ratio, to yield 0.97 g (62%) of white powder as the desired product. MS(APCI), M/z 270.9 (MT) N.M.R (CDC13) 1H δ (ppm) 5.21 (s, 2H), 7.36 (d, J- 8.5Hz, 2H), 7.43 (d, J- 8.5 Hz, IH), 7.96 (dd, J, = 6.6Hz, J2 = 3.1Hz, 2H), 8.01 (dd, Jx = 6.5Hz, J2 = 2.1Hz, IH), 8.07 (s, IH), 8.64 (d, J= 1.8Hz, IH) Example 1 : 3-(4-Methoxy-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide 0.42 g (1.0 mmol) of the compound of Preparation 1 and 2.1 ml (1.85 g, 12.5 mmol) of triethylortho formate are stirred for 20 hours at 160°C. After cooling, the precipitate obtained are filtered off, and recrystallized from acetonitrile to yield 0.180 g (yield=42%) of the desired compound.
TLC : CH2Cl2/MeOH 90/10 Rf = 0.46 N.M.R (OMSO-d6) 1H δ (ppm) : 3.75 (2s,6H) ;4.40 (d,2H) ; 5.15 (s,2H) ; 6.85-6.95
(m,4H) ; 7.25 (d,2H) ; 7.35 (d,2H) ; 7.75 (d,lH) ; 8.25 (d,lH) ; 8.65 (s,lH) ; 8.70 (s,lH) ;
9.25 (t,lH)
IR : 3282, 1661, 1606, 1513, 1248, 1032, 841 cm"1
MP = 169°C PURITY : HPLC = 96.7%
Example 2 : 3-(4-Methoxy-benzyl)-2-methyl-4-oxo-3,4-dihydro-quinazoIine-6- carboxylic acid 4-methoxy-benzyIamide, hydrochloride
0.42 g (1.0 mmol) of the compound of Preparation 1, 1 ml of ethanol at 6% of HC1 and 103 μl (100 mg, 1 mmol) of acetylacetone are stirred and then heated overnight under reflux.
After cooling, the precipitate obtained are filtered off, and recrystallized from acetonitrile to yield the desired compound.
TLC : CH2Cl2/MeOH 90/10 Rf = 0.56
N.M.R (OMSO-d6) Η δ (ppm) : 2.70 (s,3H) ; 3.75 (s,6H) ;4.45 (d,2H) ; 5.35 (s,2H) ; 6.85 -6.95 (m,4H) ; 7.20-7.30 (m,4H) ; 7.30-7.80 (bs,lH) 7.80(d,lH) ; 8.35 (d,lH) ; 8.70
(s,lH) ; 9.35 (t,lH).
-i
IR : 3282, 1702, 1648, 1634, 1547, 1512, 1250, 1178 , 1035, 793 cm' MP = 208°C
PURITY : HPLC = 98.9%
Example 3 : 3-(4-Methoxy-benzyl)-l-methyl-4-oxo-l,2,3,4-tetrahydro-quinazoline- 6-carboxylic acid 4-methoxy-benzylamide
To a stirred solution of 0.42 g (1 mmol) of the compound of Preparation 1 in 2 ml of methanol are added 75 μl (1 mmol) of formaldehyde. The solution obtained is refluxed for 1 hour. Then 820 μl of a solution of NaOH 2M are added, and the reflux is maintained for 20 minutes. After cooling, water is added and the solution extracted with ethyl acetate. The organic layer is decanted, dried and concentrated under vacuum. The crude product (0.32 g 0.75 mmol) is dissolved into 3 ml of anhydrous DMF and stirred under inert atmosphere. 35 mg (0.09 mmol) of NaH are added to this solution and the yellow solution obtained is stirred for 30 minutes at room temperature and then 55 μl (125 mg, 0.9 mmol) of methyl iodide are added. After 30 minutes stirring, the reaction mixture is treated as usual and chromatographied over silica gel (dichloromethane/ether) to give the desired compound.
N.M.R (OMSO-d6) 1H δ (ppm) : 2.85 (s,3H) ; 3.70 (s,6H) ; 4.40 (d,2H) ; 4.50 (s,2H) ; 4.60 (s,2H) ; 6.80 -6.95 (m,5H) ; 7.20-7.30 (m,4H) ; 7.95 (d,lH) ; 8.35 (s,lH) ; 8.90 (t,lH) IR : 1637, 1511, 1467, 1247, 1175 cm-1 MP = 182°C PURITY : HPLC = 95.6%
Example 4 : 3-(4-Methoxy-benzyl)-l,2,2-trimethyl-4-oxo-l,2,3,4-tetrahydro- quinazoline-6-carboxylic acid 4-methoxy-benzylamide
5 mg of αrα-toluenesulfonic acid are added to a stirred solution of 0.42 g of the compound of preparation 1 in 3 ml of acetone. The reaction mixture is stirred overnight at room temperature. This process is repeated to obtain a complete reaction. The solution is concentrated under vacuum and the crude product is methylated by addition of methyl iodide in the presence of NaH as described in Example 3. After purification by chromatography, the product obtained is crystallized in a mixture of dichloromethane and ether to give the desired compound.
TLC : CH2Cl2/Aceton 90/10 Rf = 0.36
N.M.R (DMSO- *) 1H δ (ppm) : 1.40 (s,6H) ; 2.90 (s,3H) ; 3.75 (s,6H) ;4.40 (d,2H) ;4.80 (s,2H) ; 6.80-6.90 (m,4H) ; 6.95 (d,lH) ; 7.20-7.30 (m,4H) ; 7.90 (d,lH) ; 8.40 (s,lH) ; 8.90 (t,lH) IR : 1638, 1608, 1511, 1499, 1299, 1249, 1174 cm"1
MP = 168°C PURITY : HPLC - 96.4%
Example 5 : 4-[6-(4-Methoxy-benzylcarbamoyl)-4-oxo-l,4-dihydro-2H-quinazolin- 3-ylmethyl]-benzoic acid
The compound is obtained according to the procedure described in the first step of Example 3 using as substrate the compound obtained in the Preparation 2 TLC : CH2Cl2/MeOH 90/10 Rf = 0.10
N.M.R (DMSO-^) 1H δ (ppm) : 3.70 (s,3H) ; 4.35 (d,2H) ;4.60 (s,2H); 4.70 (s,2H) ; 6.75 (d,lH) ; 6.85 (d,2H) ; 7.20-7.30 (m,3H) ; 7.45 (d,2H) ; 7.80 (d,lH) ;7.90 (d,2H) ; 8.30 (s,lH) ; 8.85 (t,lH) ; 12.85 (bs,lH) IR : 3314, 1678, 1629, 1513, 1294, 1248 cm"1 MP = 270°C PURITY : HPLC = 97.9% Example 6 : Methyl 4-[6-(4-Methoxy-benzylcarbamoyl)-l-methyl-4-oxo-l,4- dihydro-2H-quinazolin-3-ylmethyl]-benzoate
The compound is obtained according to the procedure described in the second step of Example 3 using as substrate the compound obtained in the Example 5.
TLC : CH2Cl2/MeOH 90 /10 Rf = 0.70
N.M.R (OMSO-d6) 1H δ (ppm) : 2.85 (s,3H) ; 3.70 (s,3H) ;3.85 (s,3H) ; 4.40 (d,2H) ;4.55
(s,2H) 4.75 (s,2H) ; 6.80-6.90 (m,3H) ; 7.25 (d,2H) ; 7.45 (d,2H) ; 7.95 (m,3H) ; 8.35
(s,lH) ; 8.90 (t,lH) IR : 3370, 1720, 1651, 1631, 1608, 1514, 1475, 1275, 1246, 1111 cm"1
MP = 175°C
PURITY : HPLC = 94.5%
Example 7 : 4-[6-(4-Methoxy-benzylcarbamoyI)-l-methyI-4-oxo-l,4-dihydro-2H- quinazolin-3-ylmethyI]-benzoic acid
The compound is obtained according to the procedure described in the Step 2 of Preparation 5 using as substrate the compound of Example 6. TLC : CH2Cl2/MeOH 90/10 Rf = 0.35
N.M.R (OMSO-d6) 1H δ (ppm) : 2.85 (s,3H) ; 3.70 (s,3H) ; 4.40 (d,2H) ; 4.55 (s,2H); 4.75 (s,2H) ; 6.80-6.90 (m,3H) ; 7.25 (d,2H) ; 7.45 (d,2H) ; 7.95-8.00 (m,3H) ; 8.40 (s,lH) ; 8.90 (t,lH) ; 12.90 (bs,lH)
IR : 3540, 2740, 1709, 1637, 1513, 1476, 1313, 1245, 1173 cm"1 MP = 124°C PURITY : HPLC = 95.4% Example 8 : 3-(4-fluorobenzyl)-6-(3-phenyl-pro-l-ynyl)-3 H-quinazolin-4-one
To a THF solution of the compound of Preparation 3 (153 mg, 0.40 mmol) and benzylacetylenylstannane (freshly prepared by addition of H-BuLi to the - 78 °C solution of benzylacetylene, followed by quenching with tributyltin chloride) is added catalytic amount of PdCl2(Ph3P)2 and Cul. The resulting suspension is refluxed for 1 hour and cooled to room temperature. After filtration and removal of volatiles in vacuo, the residue is purified using flash chromatography to give the desired compound as a white solid (80 mg, 54%). N.M.R (CDC13) 1H δ (ppm) 3.87 (s,2H), 5.15 (s,2H), 7.15 (t, J - 8.3 Hz,lH), 7.26-7.43 (m,5H), 7.62 (d, J= 8.3 Hz,lH), 7.77 (dd, J= 8.3, 1.9 Hz,lH), 8.08 (s,lH), 8.39 (d, J= 1.9 Hz,lH); MS (APCI), M/z 369.5 (M + 1).
Example 9 : Methyl 4-[4-Oxo-6-(3-phenyl-prop-l-ynyI)-4H-quinazolin-3-ylmethyl] -benzoate
To a THF solution of the compound of Preparation 4 (165 mg, 0.39 mmol) and benzylacetylenylstannane (239 mg, 0.59 mmol, freshly prepared by addition of rc-BuLi to the - 78°C solution of benzylacetylene, followed by quenching with tributyltin chloride) is added catalytic amount of Pd(PPh3)2Cl2 and Cul. The resulting suspension is refluxed for 1 hour. After filtration and removal of volatiles in vacuo, the residue is purified using flash chromatography to give the desired compound as a white solid.
N.M.R (CDC13) 1H δ (ppm) : 3.85 (s,2H), 3.89 (s,3H), 5.23 (s,2H), 7.40 (m,5H), 7.80
(s,lH), 8.00 (d, J= 8.3 Hz,2H), 8.40 (s,lH) MS (APCI), M/z 409.5 (M + 1). Example 10 : 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
Step 1 : 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoic acid
To a solution of the compound of PreAparation 4 (2.25 g, 5.3,6 mmol) in 10% H2O in THF is added LiOH (2.25 g, 53.6 mmol). The reaction is stirred overnight at room temperature. After acidification using concentrated HC1, the reaction mixture is extracted with EtOAc. The organic layer is washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product is triturated using a mixture of hexane/EtOAc: 4/1 to yield 2.00g of the desired carboxylic acid as a white powder.
N.M.R (OMSO-d6) 1H δ (ppm) : 5.23 (s,2H), 7.40 (d, J = 8.3 Hz,2H), 7.47 (d, J = 8.6 Hz,lH), 7.87 (d, J= 8.1,2H), 8.1 (dd, J, = 8.6 Hz, J2=1.9Hz,lH) 8.38 (d, J= 1.7 Hz,lH), 8.59 (s,lH), 12.94 (br s,lH) MS (APCI), M/z 404.9 (M " 1).
Step 2 : 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
To a solution of the compound obtained in Step 1 (0.3 g, 0.739 mmol) in 6.5 ml of DMF, is added diisopropylethylamine (0.381 g, 2.96 mmol), Cul (catalytic amount), 3-ρhenyl-l- propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture is heated to 50°C for 4 hours. The mixture is then diluted with 150 ml of EtOAc, and washed with 3x100 ml of water, 1x100 ml of brine. The organic layer is then dried over MgSO4, and filtered. The filtrate is concentrated in vacuo. The crude product is triturated with a mixture of hexane/ethyl acetate: 8/1 to yield 225 mg of the pure desired product as a light yellow solid. T EP03/02277
48
N.M.R (DMSO- d) Η δ (ppm) : 3.91 (s,2H), 5.23 (s,2H), 7.23-7.43 (m,9H), 7.66 (d, J=8.3
Hz,lH), 7.83 (dd, J=8.6 Hz, J2=1.7 Hz,lH), 7.87 (br s,lH), 8.09 (d, J=1.6 Hz,lH), 8.58
(s,lH)
MS (APCI), M/z 395.1 (M + 1).
Example 11 : 3-(4-fluorobenzyl)-6-(3-phenyl-prop-l-ynyI)-3H-pyrido[3,4-d] pyrimidin-4-one To a THF solution of a compound of Preparation 5 (0.40 mmol) and benzylacetylenyl stannane (freshly prepared by addition of «-BuLi to the -78°C solution of benzylacetylene, followed by quenching with tributyltin chloride) is added a catalytic amount of
PdCl2(Ph3P)2 and Cul. The resulting suspension is refluxed for 1 hour, and cooled to room temperature. After filtration and removal of volatiles in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
Example 12: Methyl 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-pyrido[3,4-d]pyrimidin- 3-ylmethyl]-benzoate
To a THF solution of the compound of Preparation 6 (0.39 mmol) and benzylacetylenylstannane (239 mg, 0.59 mmol), freshly prepared by addition of ra-BuLi to the -78°C solution of benzylacetylene, followed by quenching with tributyltin chloride) is added catalytic amount of PdCl2(Ph3P)2 and Cul. The resulting suspension is refluxed for 1 hour. After filtration and removal of volatile in vacuo, the residue is purified using flash chromatography to give the desired product. Example 13 : 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-pyrido[3,4-d]pyrimidin- 3-yImethyl]-benzoic acid
Step 1 : 4-(6-Iodo-4-oxo-4H-pyrido[3,4-< ]pyrimidin-3-ylmethyl)-benzoic acid To a solution of the compound of Preparation 6 (5.36 mmol), in 10%) H2O in THF is added
LiOH (2.25 g, 53.6 mmol). The reaction is stirred overnight at room temperature. After acidification using concentrated HC1, the reaction mixture is extracted with EtOAc. The organic layer is washed with water and brine, dried (MgSO4) and filtered in vacuo. The crude product is triturated using 4/1 hexane/EtOAc to give the desired compound.
Step 2: 4-[6-(3-phenyl-prop- 1 -ynyl)-4-oxo-4H-pyrido[3 ,4-cT]pyrimidin-3-ylmethyl]- benzoic acid
To a solution of the compound obtained in Step 1 (0.739 mmol) in 6.5 ml of DMF, is added diisopropylethylamine (0.381 g, 2.96 mmol), Cul (catalytic amount), 3-phenyl- 1-propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture is warmed to 50°C for 4 hours. The mixture is then diluted with 150 ml of EtOAc, and washed with 3x100 ml of water, 1x100 ml of brine. The organic layer is then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo. The crude product is triturated with 8/1 : hexane/EtOAc to yield the desired compound.
Example 14 : 3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 3-methoxy-benzylamide 0.2 g (0.671 mmol) of the compound obtained in the Preparation 7 is dissolved in 50 ml of chloroform. 110 mg of 3-methoxybenzyl amine, 205 mg of Mukaiyama reagent and 163 mg of triethylamine is added. The reaction solution is then stirred at room temperature overnight. The reaction solution is concentrated and purified on silica gel column with 1 : 1 Hexane:EtOAc to yield 150 mg of the desired product as an off white solid.
N.M.R (CDC13) 1H δ (ppm) : 3.79 (s, 3H), 4.62 (d, J= 5.6Hz, 2H), 5.13 (s, 2H), 6.63 (s, IH), 6.81-7.34 (m, 8 H), 7.75 (d, J= 8.6Hz, IH), 8.13 (s, IH), 8.30 (dd, Jx = 8.6Hz, J2 = 2.2Hz, IH), 8.56 (d, J= 2.0Hz, IH).
Example 15 : 3-(4-MethanesulfonyI-benzyl-4-oxo-3,4-dihydro-quinazoline-6- carboxylic acid 4-methoxy-benzylamide
The compound is obtained according to the procedure described in Example 14 using as substrate the compound obtained in Preparation 8 and 4-methoxybenzylamine. MS(APCI), M/z 478.1 (M+l)
N.M.R (DMSO-rfd) Η δ (ppm) : 3.18 (s, 3H), 3.72 (s, 3H), 4.39 (d, J= 5.1Hz, 2H), 5.18 (s, 2H), 6.87 (d, J= 8.3Hz, 2H), 7.23 (d, J= 8.1Hz, 2H), 7.25 (s, IH), 7.56 (d, J= 8.3Hz, 2H), 7.85 (d, J- 8.1Hz, 2H), 8.16 (d, J= 8.7Hz, IH), 8.51 (s, 1H), 9.15 (s, IH).
Example 16 : 4-Oxo-3-[4-(pyrrolidine-l-sulfonyl)-benzyl]-3,4-dihydro-quinazoline-
6-carboxylic acid 4-methoxy-benzylamide
The compound is obtained according to the procedure described in Example 14 using as substrate the compound obtained in Preparation 9 and 4-methoxybenzylamine. MS(APCI), M/z 533.2 (M+l)
N.M.R (DMSO-cfc) 1H δ (ppm) : 1.59 (s, 4H). 3.07 (s, 4H), 3.68 (s, 3H), 4.39 (d, J=5.5Hz, 2H), 5.29 (s, 2H), 6.85 (d, J= 8.3Hz, 2H), 7.23 (d, J= 8.0Hz, 2H), 7.25 (s, IH), 7.54 (d, J = 8.1Hz, 2H), 7.74 (d, J= 8.1Hz, 2H), 8.26 (d, J= 8.3Hz, IH), 8.64 (s, IH), 8.66 (s, IH), 9.27 (s, IH).
Example 17 : 4-[6-(3-Methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl]- benzoic acid.
The desired product is obtained by following the procedure of Example 14, except 4- flurobenzylamine in step 2 of the preparation 3 is replaced by tert-butyl 3-aminomethyl- benzoate, and at the end stirring the collected residue in an excess amount of trifluoroacetic acid for 30 minutes at room temperature. After removing the volatiles in vacuum, the residue is filtered to furnish the desired product as an off white solid. N.M.R (DMSO-dtf) Η δ (ppm) : 3.71 (s, 3H), 4.43 (d, J = 4.6Hz, 2H), 5.15 (s, 2H), 6.79 (d, J = 7.6Hz, IH), 6.86 (s, 2H), 7.20-7.26 (m, 2H), 7.40 (d, J = 7.3Hz, 2H), 7.86 (d, J = 7.6Hz, 2H), 8.16 (d, J- 8.1Hz, IH), 8.53 (s, IH), 9.20 (s, IH), 11.80 (s, IH).
Example 18 : 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]- benzoic acid
Step 1 : tert-Butyl 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]- benzoate
3.0 g (6.48 mmol) of the compound of Preparation 10 is dissolved in 50 ml of DMF. 3.34 g (25.9 mmol) of diisopropylethylamine, catalytic amount of copper(I) iodide, 3.01 g (25.9 mmol) 3 -phenyl- 1-ρroρyne and catalytic amount of Pd(PPh3)2Cl2 is then added in that order. The reaction solution is stirred at 50°C for 24 hours, then diluted with 300 ml of
EtOAc and washed with 3x200 ml of water, 1x200 ml of brine. The organic layer is dried over MgSO and concentrated. The residue is purified on silica gel column with 4:1 Hexane:EtOAc gradually increasing to 1:1 Hexane:EtOAC to yield a waxy substance as the desired product.
N.M.R DMSO-d6) 1H δ (ppm) : 1.50 (s, 9H), 5.24 (s, 2H), 7.42 (d, J = 8.8Hz, 2H), 7.49 (d, J= 8.6Hz, IH), 7.84 (d, J= 8.6 Hz, 2H), 8.11 (dd, J = 8.6 Hz, J2 = 2.2 Hz, IH), 8.39 (d, J= 2.0 Hz, IH), 8.59 (s, IH).
Step 2: 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]-benzoic acid
An excess amount (20 ml) of trifluroacetic acid is added to the compound obtained in the preceding Step 1. After 30 minutes of stirring, all volatiles are removed and the residue triturated with 1:1 Hexane: EtOAc. The precipitate is collected via filtration and washed with a small amount of methanol to yield 1.82 g of the desired product as an off-white solid.
N.M.R (OMSO-d6) 1H δ (ppm) : 3.91 (s, 2H), 5.23 (s, 2H), 7.23-7.43 (m, 9H), 7.66 (d, J = 8.3Hz, IH), 7.83 (dd, J, = 8.6Hz, J2 = 1.7Hz, IH), 7.87 (broad s, IH), 8.09 (d, J= 1.6Hz,
IH), 8.58 (s, IH).
Example 19 : 4-{6-[3-(4-Methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazoline-3- ylmethyl}-benzoic acid
The product is obtained by following the procedure of Example 18, the only difference is that 3 -phenyl- 1-propyne used in Step 1 is replaced by l-methoxy-4-proρ-2-ynyl-benzene. The product is obtained as a white solid.
N.M.R (OMSO-d6) 1H δ (ppm) : 3.70 (s, 3H), 3.83 (s, 2H), 5.24 (s, 2H), 6.89 (d, J= 8.5Hz, 2H), 7.29 (d, J= 8.3Hz, 2H), 7.41(d, J= 8.0Hz, 2H), 7.65 (d, J= 8.3Hz, IH), 7.81 (dd, J = 8.3Hz, J2 = 1.5Hz, IH), 7.88 (d, J = 8.1Hz, 2H), 8.08 (d, J= 1.5Hz, IH), 8.58 (s, IH), 12.94 (broad s, IH). Example 20 : 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]- benzamide 0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop of DMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room temperature for an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuum and the residue is washed -with 1:1 water :methanol to yield 70 mg of an off-white powder as the desired product. MS(APCI), M/z 394.1 (M+l).
N.M.R (OMSO-d6) 1H δ (ppm) : 3.92 (s, 2H), 5.21 (s, 2H), 7.24-7.39 (m, 9H), 7.66 (d, J = 8.5 Hz, IH), 7.80-7.92 (m, 4H), 8.10 (s, 2H), 8.58 (s, IH).
Example 21 : 3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoIine-6-carboxyIic acid (2-methoxy-pyridin-4-ylmethyl)-amide Compound of the Preparation 7 (227 mg, 0.76 mmol), 2-methoxy-pyridin-4-yl- methylamine (138 mg, 1.0 mmol) and the Mukaiyama reagent (256 mg, 1.0 mmol) are dissolved in CHCI3 (10 ml), Et3N (1 ml, excess) is added. The resulting solution is refluxed for 3 h, cooled to room temperature. The solution is then purified via a flash chromatography to give the desired product as a white solid, 34 mg, 63% yield. MS (APCI), M/z 419.2 (M + 1). N.M.R (DMSO- 0 1H δ (ppm) : 9.40 (t, J = 5.9 Hz, IH), 8.70 (s, IH), 8.69 (s, IH), 8.28 (dd, IH), 8.07 (d, J= 5.4 Hz, IH), 7.77 (d, J= 8.3 Hz, IH), 7.44 (m, IH), 7.19 (t, J = 8.7 P T/EP03/02277
54
Hz, IH), 6.91 (d, J= 5.1 Hz, IH), 6.69 (s, IH), 5.19 (s, 2H), 4.45 (d, J= 5.9 Hz, IH), 3.80 (s, 3H)
Example 22 : 3-[(3,5-difluoro-4-hydroxy)-benzyl]-6-(3-phenyl-prop-l-ynyI)-3H- quinazolin-4-one
To a solution of 3-[(3,5-difluoro-4-hydroxy)-benzyl]-6-iodo-3H-quinazolin-4-one (obtained following the procedure of preparation 3 but using in step 2 (3,5-difluoro-4- hydroxy)-benzylamine) (0.3 g, 720 mmol) in 6.5 ml of DMF, is added diisopropylethyl amine (0.381 g, 2.96 mmol), 3 -phenyl- 1-propyne (0.34 g, 2.9 mmol), Cul (catalytic amount), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture is heated to 50°C for 4 hours. The mixture is then diluted with 150 ml of EtOAc, and washed with 3x100 ml of water, 1x100 ml of brine. The organic layer is then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo. The crude product is purified via a flash chromatography to yield 225 mg of the pure desired product as a light yellow solid.
MS (APCI), M/z 403.1 (M + l).
N.M.R (DMSO- 0 Η δ (ppm) : 8.46 (s, IH), 8.25 (d, J = 2.0 Hz, IH), 7.1-7.8 (m, 9H), 5.20 (s, 2H), 3.91 (s, 2H)
Example 23 : 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6- carboxylic acid 3-methoxy-benzylamide
Step 1 : 6-Chloro-3-("3-fluoro-benzyl)-3H-pyrido[3,4-dlpyrimidm-4-one The starting material, 6-chloro-3H-pyrido[3,4-d]pyrimidin-4one (710 mg, 3.92 mmol, prepared according to J. Chem. Soc, Perkin Trans. 1996, 1, 2221) is dissolved in DMF (20 ml). Cs2CO3 (1.66 g, 5.1 mmol) and 3-flurobenzylchloride (737 mg, 5.1 mmol) are added subsequently. The reaction is stirred at room temperature overnight, poured into water. After extraction with CH2C12, the organic layer is washed with H2O and brine, dried (Na2SO4) and filtered. After removal of the solvents, the residue is purified via a flash chromatography to give the product as a white solid. MS (APCI), M/z 290.0 (M + 1).
N.M.R (CDC13) 1H δ (ppm) 8.92 (s, IH), 8.10 (d, J= 9.6 Hz,2H), 7.0-7.4 (m, 5H), 5.17 (m, 2H).
Step 2: Methyl 3 -(3-fluorobenzyl)-4-oxo-3 ,4-dihydro-pyrido [3 ,4-^pyrimidine-6- carboxylate
The compound obtained in the preceding Step 1 (3.0 g, 1.07 mmol), is dissolved in 50 ml of methanol, with an excess amount of triethylamine, and a catalytic amount of Pd(dppf)Cl2. The reaction solution is poured into an autoclave and heated at 100°C for 4 hours under the carbon monoxide atmosphere. The reaction is cooled to room temperature and filtered. The filtrate is concentrated in vacuum and the residue is purified on a silica gel column using 1 : 1 Hex:EtOAc to yield the desired product as a white solid (100%). MS (APCI), M/z 314.0 (M + 1). N.M.R (CDCI3) 1H δ (ppm) : 9.24 (s, IH), 8.95 (s, IH), 8.28 (s, IH), 7.0-7.4 (m, 4H), 5.24 (s, 2H), 4.08 (s, 3H)
Step 3: 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydiO-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide To a 0°C solution of 3-methoxybenzylamine (144 mg, 1.05 mmol) in CH2C12 is added
AlMe3 (0.52 ml, 1.05 mmol). The reaction is stirred at room temperature for 2 h. Then a solution of the compound obtained in the preceding Step 2 (111 mg, 0.35 mmol) in CH2C12 is added and the resulting reaction is stirred at room temperature for 2 h, and poured into P T/EP03/02277
56
water. After extraction with CH2C12, the organic layer is washed with H2O and brine, dried
(Na2SO4) and filtered. After removal of the solvents, the residue is purified via a flash chromatography to give the product as a white solid.
MS (APCI), M/z 419.1 (M + 1).
N.M.R (CDC13) Η δ (ppm) : 9.40 (t, IH), 9.09 (s, IH), 8.76 (s, IH), 8.54 (s, IH), 6.7-7.4
(m, 11H), 5.22 (s, 2H), 4.45 (d, J= 6.6 Hz, IH), 3.67 (s, 3H)
Example 24 : 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6- carboxylic acid 4-methoxy-benzylamide
The compound is obtained according to the procedure of Example 23 using in the Step 3, 4-methoxybenzylamine. MS (APCI), M/z 419.1 (M + 1).
N.M.R (CDC1) ]H δ (ppm) : 9.40 (t, IH), 9.09 (s, IH), 8.76 (s, IH), 8.54 (s, IH), 7.0-7.4 (m, 9H), 6.80 (d, J= 1.6 Hz, 2H), 5.22 (s, 2H), 4.45 (d, J= 6.6 Hz, IH), 3.67 (s, 3H)
Example 25 : 4-[4-Oxo-6-(3-phenyl-propa-l,2-dienyl)-4H-quinazolm-3-ylmethyl]- benzoic acid 0.105 g (0.257 mmol) of the compound of Example 9 is dissolved in 25 ml of 90% THF: 10%) water. 10 equivalents of LiOH are added. The reaction is refluxed for 3 hours, 200 ml of EtOAc are added, acidified by concentrated HC1 and the solution is washed with 2x100 ml of water and 1x100 ml of brine. Organic layer dried over MgSO4, and concentrated. The residue is purified on a silica gel column with 95% EtOAc:5% MeOH to yield 30 mg of the product as a light yellow powder.
MS(APCI), M/z 481.2 (M+l) N.M.R (DMSO-cfc) 1H δ (ppm) : 5.23 (s, 2H). 6.90 (d, J= 6.6Hz, IH), 7.02(d, J= 6.6Hz, IH), 7.24 (m, IH), 7.33 (d, J = 4.1, 4H), 7.40 (d, J = 8.3Hz, 2H), 7.65(d, J= 8.3Hz, IH), 7.75 (dd, J, = 8.5Hz, J2 = 1.7Hz, IH), 7.87 (d, J= 8.1Hz, 2H), 8.07 (s, IH), 8.53(s, IH).
Examples 26 to 71 : These compounds are obtained according to the procedure described in the Preparation 5 and Example 8 using the corresponding substrates and reagents.
26. 4-{6-[3-(4-Methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}- benzoic acid, 27. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l -ynyl]-3H- quinazolin-4-one,
28. 4-{6-[3-(3-Methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}- benzoic acid,
29. 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methoxy-phenyl)-prop-l-ynyl]-3H- quinazolin-4-one,
30. 4-[4-oxo-6-(3-pyridin-4-yl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid,
31. 3 -(4-Methanesulfonyl-benzyl)-6-(3 -pyridin-4-yl-prop- 1 -ynyι)-3H-quinazolin-4- one 32. 4-[4-oxo-6-(3-pyridin-3 -yl-prop- 1 -ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid,
33. 3-(4-Methanesulfonyl-benzyl)-6-(3 -ρyridin-3-yl-ρroρ- 1 -ynyl)-3H-quinazolin-4- one,
34. 4- {6-[3-(4-fluro-ρhenyl)-ρroρ- 1 -ynyl]-4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
35. 6-[3-(4-Fluro-phenyl)-ρroρ-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- quinazolin-4-one,
36. 4-{6-[3-(3-fluro-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}-benzoic acid, 37. 6-[3-(3-Fluro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- quinazolin-4-one, 38. 4-{6-[3-(4-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}- benzoic acid,
39. 6-[3-(4-Chloro-phenyl)-ρrop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- quinazolin-4-one, 40. 4- {6-[3-(3-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}- benzoic acid,
41. 6-[3-(3-Chloro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- quinazolin-4-one,
42. 4-{6-[3-(4-bromo-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}- benzoic acid,
43. 6-[3-(4-bromo-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- quinazolin-4-one,
44. 4-{6-[3-(3-bromo-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}- benzoic acid, 45. 6-[3-(3-bromo-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- quinazolin-4-one,
46. 4- {6-[3-(4-nitro-phenyl)-prop-l -ynyl] -4-oxo-4H-quinazolin-3 -ylmethyl} -benzoic acid,
47. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-nitro-phenyl)-prop-l-ynyl]-3H-quinazolin- 4-one,
48. 4-{6-[3-(2-methoxy-pyridin-4-yl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3- ylmethyl} -benzoic acid,
49. 3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-l-ynyl]-3H- quinazolin-4-one, 50. 4-{6-[3-(4-methylsulfanyl-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3- ylmethyl} -benzoic acid.
51. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methylsulfanyl-phenyl)-prop- 1 -ynyl]-3H- quinazolin-4-one
52. 4-{6-[3-(3-methylsulfanyl-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3- ylmethyl} -benzoic acid
53. 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methylsulfanyl-phenyl)-prop-l-ynyl]-3H- quinazolin-4-one 54. 4-[4-oxo-6-(3-p-tolyl-prop- 1 -ynyl)-4H-quinazolin-3 -ylmethyl] -benzoic acid
55. 3-(4-Methanesulfonyl-benzyl)-6-(3- 7-tolyl-prop-l-ynyl)-3H-quinazolin-4-one
56. 4-[4-oxo-6-(3- -tolyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
57. 3-(4-Methanesulfonyl-benzyl)-6-(3-m-tolyl-prop-l-ynyl)-3H-quinazolin-4-one 58. 4-[6-(3-Imidazol-l-yl-prop-l-ynyl)-4-oxo-4Η-quinazolin-3-ylmethyl]-benzoic acid
59. 4- [4-Oxo-6-(3 -phenyl-prop- 1 -ynyl)-4H-quinazolin-3 -ylmethyl] - benzenesulfonamide
60. 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzonitrile 61. 3-(3-Chloro-benzyl)-6-(4-phenyl-but-l-ynyl)-3H-quinazolin-4-one
62. 3-(3-Chloro-benzyl)-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one
63. 4-[4-Oxo-6-(3-pyrazol-l-yl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
64. 6-(3-Phenyl-prop-l-ynyl)-3-[4-(lH-tetrazol-5-yl)-benzyl]-3H-quinazolin-4-one 65. 3-(3,4-Difluoro-benzyl)-6-[3-(pyridin-4-yloxy)-prop-l-ynyl]-3H-quinazolin-4- one
66. 3-(3,4-Difluoro-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin-4- one
67. N-{4-[4-Oxo-6-(3-ρhenyl-ρrop-l-ynyl)-4H-quinazolin-3-ylmethyl]-phenyl}- acetamide
68. 3-(3,4-Difluoro-benzyl)-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one
69. 3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin-4-one
70. 6-(3-Phenyl-prop-l-ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one
71. 6-[3-(4-Methoxy-phenyl)-ρrop-l-ynyl]-3-pyridin-4-ylmethyl-3H-quinazolin-4- one
Examples 72 to 103 :
These compounds are obtained according to the procedure described in the Preparation 6 and Example 11 using the corresponding substrates and reagents.
72. 4-{6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-ρyrido[3,4-J]pyrimidin-3- ylmethyl} -benzoic acid, 73. 3-(4-methanesulfonyl-benzyl)-6-[3-(4-methoxyl-phenyl)-prop-l-ynyl]-3H-pyrido [3 ,4-< ]pyrimidin-4-one,
74. 4-{6-[3-(3-methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4-( |pyrimidin-3- ylmethyl} -benzoic acid, 75. 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methoxyl-phenyl)-prop- 1 -ynyl]-3H-pyrido
[3 ,4-d]pyrimidin-4-one,
76. 4-[4-oxo-6-(3-pyridin-4-yl-prop-l-ynyl)-4H-ρyrido[3,4- ]pyrimidin-3-ylmethyl]- benzoic acid,
77. 3 -(4-Methanesulfonyl-benzyl)-6-(3 -pyridin-4-yl-prop- 1 -ynyl)-3H-pyrido [3 ,4-d] pyrimidin-4-one,
78. 4-[4-oxo-6-(3-pyridin-3-yl-prop-l-ynyl)-4H-pyrido[3,4- ]pyrimidin-3-ylmethyl]- benzoic acid,
79. 3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-3-yl-prop-l-ynyl)-3H-pyrido[3,4- d] pyrimidin-4-one, 80. 4-{6-[3-(4-fluro-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4-<flpyrimidin-3- ylmethyl} -benzoic acid,
81. 6-[3-(4-Fluro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- pyrido[3 ,4- ]pyrimidin-4-one,
82. 4-{6-[3-(3-fluro-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4-(i]pyrimidin-3- ylmethyl} -benzoic acid,
83. 6-[3-(3-Fluro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- pyrido[3 ,4-cTjpyrimidin-4-one,
84. 4-{6-[3-(4-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4-fi?]pyrimidin-3- ylmethyl} -benzoic acid, 85. 6-[3-(4-Chloro-phenyl)-prop- 1 -ynyl]-3-(4-methanesulfonyl-benzyl)-3H- pyrido[3 ,4-<fJpyrimidin-4-one,
86. 4-{6-[3-(3-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4- ]pyrimidin-3- ylmethyl} -benzoic acid,
87. 6-[3-(3-Chloro-phenyl)-ρroρ-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- pyrido[3,4-< Jpyrimidin-4-one,
88. 4- {6-[3-(4-bromo-phenyl)-ρrop-l -ynyl]-4-oxo-4H-ρyrido[3,4- lpyrimidin-3- ylmethyl} -benzoic acid, 89. 6-[3-(4-Bromo-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- pyrido[3,4-<fJpyrimidin-4~one,
90. 4-{6-[3-(3-bromo-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4-cT]pyrimidin-3- ylmethyl} -benzoic acid, 91. 6-[3-(3-Bromo-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H- pyrido[3,4-rf]pyrimidin-4-one,
92. 4-{6-[3-(4-nitro-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4-cr|pyrimidin-3- ylmethyl} -benzoic acid,
93. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-nitro-phenyl)-prop-l-ynyl)-3H-pyrido[3,4- d]pyrimidin-4-one,
94. 4- {6-[3-(2-methoxy-pyridin-4yl)-prop- 1 -ynyl]-4-oxo-4H-pyrido[3 ,4-cT|pyrimidin- 3 -ylmethyl} -benzoic acid,
95. 3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-l-ynyl)-3H- pyrido [3 ,4- ]pyrimidin-4-one, 96. 4-{6-[3-(4-methylsulfanyl-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4-
J]pyrimidin-3 -ylmethyl} -benzoic acid,
97. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methylsulfanyl-phenyl)-prop-l-ynyl)-3H- pyrido[3,4-<f]pyrimidin-4-one,
98. 4- {6-[3 -(3-methylsulfanyl-ρhenyl)-prop- 1 -ynyl] -4-oxo-4H-pyrido [3 ,4- βTjpyrimidin-3-ylmethyl} -benzoic acid,
99. 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methylsulfanyl-phenyl)-prop-l-ynyl)-3H- pyrido[3,4-rf]pyrimidin-4-one,
100. 4-[4-oxo-6-(3- -tolyl-prop-l-ynyl)-4H-ρyrido[3,4-( ]pyrimidin-3-ylmethyl]- benzoic acid, 101. 3-(4-Methanesulfonyl-benzyl)-6-(3- -tolyl-proρ- 1 -ynyl)-3H-pyrido[3 ,4-
J]pyrimidin-4-one,
102. 4-[4-oxo-6-(3- -tolyl-prop-l-ynyl)-4H-pyrido[3,4- lpyrimidin-3-ylmethyl]- benzoic acid,
103. and 3-(4-Methanesulfonyl-benzyl)-6-(3-w-tolyl-ρrop- 1 -ynyl)-3H-ρyrido [3 ,4- d]pyrimidin-4-one.
Examples 104 and 105 These compounds are obtained according to the procedure described in Examples 14 and 21 using the corresponding substrates and reagents.
104. 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2- methoxy-pyridin-4-ylmethyl)-amide 105. 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4- methoxy-b enzylamide
PHARMACOLOGICAL STUDIES OF COMPOUNDS OF THE INVENTION
Example 106 : 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 pro teo lysis 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 urn 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 10, 14-19, 21, 23-25, 58- 60, 62, 64-71, 104, 105 are all below 1 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 IC50 values for the same compounds with respect to the other matrix metalloproteases tested.

Claims

1- A compound selected from those of formula (I) wherein: • X] , X2, and X3, independently of each other, represent a nitrogen atom or a group -CR3 in which R represents a group selected from hydrogen, (Cι-C6)alkyl, amino, mono(Cι- C6)alkylamino, di(Cι-C6)alkylamino, hydroxy, ( -C^alkoxy, and halogen, with the proviso that not more than two of the groups X1} X2 and X3 simultaneously represent a nitrogen atom,
• Gi represents a group selected from those of formulae (i/a) and (i/b):
(i a) (i/b) in which:
- the carbon atom with number 2 is attached to the group N-Rj in the ring,
R4 and R5, identical or different, independently of each other, represent a group selected from hydrogen, (Cι-C6)alkyl, aryl, aryl(C1-C6)alkyl, cycloalkyl, cycloalkyl(Cι-C6)alkyl, heteroaryl, heteroaryl(Cι-C6)alkyl, heterocycloalkyl, and heterocycloalkyl(Cι-C6)alkyl,
- R6 represents a group selected from : hydrogen, trifluoromethyl, OR7, NR7R8, in which R7 and Rs, identical or different independently of each other, represent hydrogen or (CrC6)alkyl, (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(C C6)alkyl, cycloalkyl(C C6)alkyl, heteroaryl, heteroaryl(C C6)alkyl, heterocycloalkyl, and heterocycloalkyl(Cι-C6)alkyl, these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from halogen, amino, mono(Cι-C6)alkylamino, di(C1-C6)alkylamino, each alkyl moiety being identical or different independently of each other, cyano, trihalogeno(Cι-C6)alkyl, (Cι-C6)acyl, -C(=O)OR7, -OR7 and -SR7, in which R7 is as defined hereinbefore,
• G2 represents a group selected from carbon-carbon triple bond, -CH=C=CH-, C=O, C=S, S(O)nι in which nl represents an integer from 0 to 2 inclusive, and a group of formula (i/c):
I (i c)
Y ι in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Yi represents a group selected from oxygen, sulphur, -NH and -N(Cι-C6)alkyl, and Y2 represents a group selected from oxygen, sulphur, -NH and -N(Cι-C6)alkyl,
• n represents an integer from 0 to 6 inclusive,
• Zi represents -CR9Rιo, wherein R9 and RIQ, identical or different independently of each other, represent a group selected from hydrogen, (Cι-C6)alkyl, trihalogeno(Cι-C6)alkyl, halogen, -OR7, -SR7, and -C(=O)OR7, in which R7 is as defined hereinbefore, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino in which each alkyl moiety is identical or different independently of each other, and
- wherein when n is greater than or equal to 2, the hydrocarbon chain Z\ optionally contains one to two isolated or conjugated multiple bonds,
-and/or wherein when n is greater than or equal to 2, one of said -CR R10 may optionally be replaced with a group selected from oxygen, S(O)nι in which nl is as defined hereinbefore, -NH and -N(Cι-C6)alkyl,
• A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle, R] represents a group selected from :
- hydrogen,
- (Cι-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, these groups may be optionally substituted with one or more groups, which may be identical or different independently of each other, selected from amino, cyano, trihalogeno(Cι-C6)alkyl, cycloalkyl, -C(=O)NR7R8, -C(=O)OR8, OR8, SR8, in which R7 and R8, which may be . identical or different independently of each other, represent hydrogen or (C\~ C6)alkyl, - and the group of formula (i/d) :
in which p is an integer from 0 to 8 inclusive,
Z2 represents -CRnRι2 wherein Rπ and Rj2, identical or different independently of each other, represent a group selected from hydrogen, ( -C^alkyl, phenyl, trihalogeno(Cι-C6)alkyl, halogen, amino, OR7, SR7 and -C(=O)OR7 in which R7 represents hydrogen or (Cι-C6)alkyl, and
- wherein when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or two isolated or conjugated multiple bonds,
- and/or wherein n is greater than or equal to 2, one of said -CRπR12 may optionally be replaced with a group selected from oxygen, S(O)nι in which nl is as defined hereinbefore, -NH, -N(CrC6)alkyl, and carbonyl,
B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
q is an integer from 0 to 7 inclusive, the group(s) G3, which may be identical or different independently of each other, is (are) selected from (C1-C6)alkyl, halogen, CN, NO2, CF3, OCF3, -(CH2)kNRι3R14, -N(R,3)C(=O)R,4, -N(Rι3)C(=O)ORi4, -N(R13)SO2RI4, -N(SO2R13)2, -OR13, -S(O)klR,3, -SO2-N(R13)-(CH2)k2-NRι4Rι5, -(CH2)kSO2NR13R14, -X4(CH2)kC(=O)OR,3, -(CH2)kC(=O)OR13, -C(=O)O-(CH2)k2-NR13R14, in which :
- X4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (Cι-C6)alkyl group,
- k is an integer from 0 to 3 inclusive,
- kl is an integer from 0 to 2 inclusive,
- k2 is an integer from 1 to 4 inclusive,
- Rϊ3, Ri4 and R15, which may be identical or different independently of each other, are selected from hydrogen and (Cι-C6)alkyl,
- Rι6 represents a group selected from (C]-C6)alkyl, -R]9-NRι3Ri4, in which R[9 represents a linear or branched (Cι-C6)alkylene group, and R13, R14 and R15 are as defined hereinbefore,
- Rπ represents a (C3-C6)cycloalkyl group,
- X5 represents a group selected from single bond, -CH2-, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (Ci-Cβjalkyl group,
- Ri8 represents a group selected from : o 5- or 6-menbered monocycle aryl, heteroaryl, which is optionally substituted by one or more groups, which may be identical or different, selected from (Ci- C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (Cι-C6)alkyl, o and 5- or 6-menbered monocycle cycloalkyl, heterocycloalkyl, which is optionally substituted by one or more groups, which may be identical or different, selected from (d-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (CrC6)alkyl,
• m is an integer from 0 to 7 inclusive,
• the group(s) R2, which may be identical or different independently of each other, is (are) selected from (Cι-C6)alkyl, halogen, -CN, NO2, SCF3, -CF3, -OCF3, -NR7R8, -OR8, - SR8, -SOR8, -SO2R8, -(CH2)kSO2NR7R8, -X7(CH2)kC(O)0R8, -(CH2)kC(=O)OR8,
-X7(CH2)kC(=O)NR7R8, -(CH2)kC(=O)NR7R83 and -X8-R20 in which: - X7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (Cι-C6)alkyl,
- k is an integer from 0 to 3 inclusive,
- R7 and Rs, which may be identical or different independently of each other, are selected from hydrogen and (C]-C6)alkyl,
- X8 represents a group selected from single bond, -CH2-, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (Cι-C6)alkyl group,
- R20 represents 5- or 6-menbered monocycle aryl, heteroaryl, cycloalkyl, or heterocycloalkyl which is optionally substituted by one or more groups, which may be identical or different, selected from (Cι-C6)alkyl, halogen, hydroxy and amino, and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof, it being understood that when no specification are described:
- 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,
- and 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 characterized in that :
• G2 represents a group selected from C=O, C=S, S(O)nι in which nl represents an integer from 0 to 2 inclusive, or a group of formula (i/c): in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Yi represents a group selected from oxygen, sulphur, -NH and ^(C^C^alkyl, and Y2 represents a group selected from oxygen, sulphur, -NH and -N(C]-C6)alkyl,
• Xi , X2, X3, G\ , n, Zj , A, R\ , m and R2 are as defined in formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
3- A compound according to Claim 1 characterized in that:
• G2 represents a carbon-carbon triple bond, • n represents an integer from 1 to 6 inclusive,
• Xi, X2, X3, Gi, Zi, A, Ri, m and R2 are as defined in formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
4- A compound according to claim 1 characterized in that:
• G2 represents a carbon-carbon triple bond,
• n is zero,
• Zi is absent,
• A represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
• X), X2, X3, G], R1( m and R2 are as defined in formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
5-A compound according to claim 1 characterized in that:
• G2 represents a carbon-carbon triple bond,
• n is zero,
• Zi is absent,
• A represents a phenyl group, • R] represents a hydrogen atom or a group of formula (i/d) :
in which p is an integer from 0 to 8 inclusive,
■ Z2 represents -CRi ιR12 wherein Ri i and Rι2, identical or different independently of each other, represent a group selected from hydrogen, (d-C^alkyl, phenyl, trihalogeno(C1-C6)alkyl, halogen, amino, OR7, SR7 and -C(=O)OR7 in which R7 represents hydrogen or (Cι-C6)alkyl, and - wherein when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or two isolated or conjugated multiple bonds, and/or wherein n is greater than or equal to 2, one of said -CR] ιR12 may optionally be replaced with a group selected from oxygen, S(O)nl in which nl is as defined hereinbefore, -NH, -N(Cι-C6)alkyl, and carbonyl, B represents a phenyl group, V q 1S an integer from 1 to 7 inclusive, the group(s) G , which may be identical or different independently of each other, is (are) selected from -(CH2)kNR13Rι4, -N(R13)C(=O)OR14, -N(Rι3)SO2Rι4, -N(SO2R13)2, -S(O)klR13, -SO2-N(R13)-(CH2)k2-NR14R15, -(CH2)kSO2NR13R14, -X4(CH2)kC(=O)OR13, -(CH2)kC(=O)OR13, -C(O)0-(CH2)k2~NR13R14, -C(=O)O-(CH2)k2-C(=O)ORι6, -X4(CH2)kC(=O)NR13R14, -(CH2)kC(=O)NR13R14,
-Ri7-C(=O)ORi3, -X5-R18, -C(=O)-R19-NR13R14 and -X6-R21 in which :
- X4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (C]-C6)alkyl group, - k is an integer from 0 to 3 inclusive, kl is an integer from 1 to 2 inclusive,
- k2 is an integer from 1 to 4 inclusive,
- Rι3, Rι4 and Rι5, which may be identical or different independently of each other, are selected from hydrogen and (Cι-C6)alkyl, - R16 represents a group selected from (Cι-C6)alkyl, -Rι9-NR13R] ,
-Rι9-NRi3-C(=O)-R19-NRι4R15, and -C(=O)O-R19-NR13R14 in which Rϊ9 represents a linear or branched (Cι-C6)alkylene group, and R!3, R1 and R15 are as defined hereinbefore,
- R]7 represents a (C3-C6)cycloalkyl group, - X5 represents a group selected from single bond, -CH -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (CrC6)alkyl group,
- Ri8 represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or 6- membered monocycle, which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (Cι-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (CrC6)alkyl,
- X6 represents a group selected from -CH2-, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (Cι-C6)alkyl group,
- R ι represents a phenyl group which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (Cι-C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (C1-C6)alkyl, - Xi, X2, X3, Gi, m and R2 are as defined in formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
6- A compound according to Claim 1 characterized in that: Ri represent a group of formula (i/d):
wherein Z2, p, B, G3 and q are as defined in the compound of formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
7- A compound according to Claim 6 characterized in that Z2 represents a group -C πRι2 in which Rt i and R]2 represents an hydrogen atom, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
8- A compound according to claim 6 characterized in that p is one, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof. 9- A compound according to claim 6 characterized in that B represents a phenyl group, q is equal to 0 or 1, and G3, when it is present, represents a group selected from OR13, halogen, S(O)kιRι3 and (CH2)kC(=O)ORι3 in which R13 represents an hydrogen atom or a ( - C6)alkyl group, k is zero, and k] is two, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
10- A compound according to claim 1 characterized in that Gi represent a group of formula (i/a) in which R4 represents a hydrogen atom or a methyl group, or a group of formula (i/b) in which R4 and R5, identical, represent each a hydrogen atom or a methyl group, and R6 represents a hydrogen atom or a methyl group, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
11- A compound according to claim 1 characterized in that X\ represents a group -CR3 in which R3 represents a hydrogen atom, X2 represents a nitrogen atom or a group -CR3 in which R3 represents a hydrogen atom, and X3 represents a group -CR3 in which R3 represents a hydrogen atom, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
12- A compound according to claim 1 characterized in that G2 represent a carbon-carbon triple bond or a group of formula (i/c) in which Y\ represents an oxygen atom, and Y2 represents a group -NH, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
13- A compound according to claim 1 characterized in that Z\ represents -CR9R10 in which R9 and Rio represent each a hydrogen atom, and n is one, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof. 14- A compound according to claim 1 characterized in that A represents a group selected from phenyl and pyridyl, m is equal to zero or one, and R2 represents a (C]-C6)alkoxy group or a hydrogen atom, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
15- A compound according to claim 1, which is selected from:
- 3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy- benzylamide
- 3-(4-methoxy-benzyl)-2-methyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4- methoxy-benzylamide, hydrochloride
- 3-(4-methoxy-benzyl)-l-methyl-4-oxo-l,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
- 3-(4-methoxy-benzyl)- 1 ,2,2-trimethyl-4-oxo- 1 ,2,3,4-tetrahydro-quinazoline-6- carboxylic acid 4-methoxy-benzylamide - 4-[6-(4-methoxy-benzylcarbamoyl)-4-oxo-l,4-dihydro-2H-quinazolin-3-ylmethyl]- benzoic acid
- 4-[6-(4-methoxy-benzylcarbamoyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-2H-quinazolin-3- ylmethyl]-benzoic acid methyl ester
4- [6-(4-methoxy-benzylcarbamoyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-2H-quinazolin-3- ylmethyl] -benzoic acid,
- 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 3-methoxy- benzylamide
- 3-(4-methanesulfonyl-benzyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4- methoxy-b enzylamide - 4-Oxo-3-[4-(ρyrrolidine-l-sulfonyl)-benzyl]-3,4-dihydro-quinazoline-6-carboxylic acid
4-methoxy-benzylamide . 4-[6-(3-methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid,
- 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy- pyridin-4-ylmethyl)-amide, - 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3- methoxy-benzylamide, - 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 4- methoxy-b enzylamide
- 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy- pyridin-4-ylmethyl)-amide and - 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy- benzylamide.
16- A compound according to claim 1, which is selected from:
- 3-(4-fluorobenzyl)-6-(3-phenyl-pro-l-ynyl)-3 H-quinazolin-4-one,
- methyl 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoate, - 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid,
- 3-(4-fluorobenzyl)-6-(3-phenyl-prop-l-ynyl)-3H-pyrido[3,4-c ]pyrimidin-4-one,
- methyl 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-pyrido[3,4- ]pyrimidin-3-ylmethyl]- benzoate,
- 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-pyrido[3,4-c ipyrimidin-3-ylmethyl]-benzoic acid,
- 4-[4-oxo-6-(3-phenyl-proρ-l-ynyl)-4Η-quinazoline-3-ylmethyl]-benzoic acid,
- 4- {6-[3-(4-methoxy-phenyl)-ρrop-l -ynyl]-4-oxo-4H-quinazoline-3-ylmethyl} -benzoic acid,
- 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]-benzamide - 3-[(3,5-difluoro-4-hydroxy)-benzyl]-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one
- 4-[6-(3-Imidazol-l-yl-prop-l-ynyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid _ 4-[4-θxo-6-(3-phenyl-ρroρ-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzenesulfonamide _ 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzonitrile
- 3-(3-Chloro-benzyl)-6-(4-phenyl-but-l-ynyl)-3H-quinazolin-4-one - 3 -(3-Chloro-benzyl)-6-(3 -phenyl-prop- 1 -ynyl)-3H-quinazolin-4-one
_ 4-[4-Oxo-6-(3-pyrazol-l -yl-ρrop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
- 6-(3-Phenyl-prop-l-ynyl)-3-[4-(lH-tetrazol-5-yl)-benzyl]-3H-quinazolin-4-one
- 3-(3,4-Difluoro-benzyl)-6-[3-(pyridin-4-yloxy)-prop-l-ynyl]-3H-quinazolin-4-one
- 3-(3,4-Difluoro-benzyl)-6-[3-(4-methoxy-phenyl)-ρrop-l-ynyl]-3H-quinazolin-4-one - N-{4-[4-Oxo-6-(3-phenyl-ρrop-l-ynyl)-4H-quinazolin-3-ylmethyl]-phenyl}-acetamide
- 3-(3,4-Difluoro-benzyl)-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one 3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin-4-one
6-(3-Phenyl-prop-l-ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one and
6-[3-(4-Methoxy-phenyl)-prop-l-ynyl]-3-pyridm-4-ylmethyl-3H-quinazolin-4-one.
17- A compound according to claim 1, which is selected from:
- Methyl 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl] benzoate
- 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
- 4-[6-(3-Methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl] benzoic acid
- 4-{6-[3-(4-Methoxy-ρhenyl)-ρroρ-l-ynyl]-4-oxo-4H-quinazoline-3-ylmethyl}-benzoic acid
- 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6 carboxylic acid 3- methoxy-b enzylamide
- 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6 carboxylic acid 4- methoxy-b enzylamide - 4-[6-(3-Imidazol-l-yl-prop-l-ynyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid
- 4-[4-Oxo-6-(3-phenyl-ρrop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzenesulfonamide
- 4- [4-Oxo-6-(3 -phenyl-prop- 1 -ynyl)-4H-quinazolin-3-ylmethyl] -benzonitrile
- 6-(3-Phenyl-prop-l-ynyl)-3-[4-(lH-tetrazol-5-yl)-benzyl]-3H-quinazolin-4-one
- 3-(3,4-Difluoro-benzyl)-6-[3-(pyridin-4-yloxy)-prop-l-ynyl]-3H-quinazolin-4-one - 3 -(3 ,4-Difluoro-benzyl)-6-[3-(4-methoxy-phenyl)-prop- 1 -ynyl] -3H-quinazolin-4-one
- N-{4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-phenyl}-acetamide
- 3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin-4-one
- 6-(3-Phenyl-prop-l-ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one and
. 6-[3-(4-Methoxy-phenyl)-prop-l-ynyl]-3-pyridin-4-ylmethyl-3H-quinazolin-4-one.
18- A process for the preparation of compounds according to claim 1 which uses as starting material a compound of formula (II):
(ID in which X], X2, X3, and Yi have the same definitions as the compound of formula (I) in claim 1, and T represents a group (Cι-C6)alkyl,
compound of formula (II) which is treated with a compound of formula (III): in which Zi, Y2, R2, A, n and m have the same definitions as the compound of formula (I), by activating the acid function with an activator, in the presence of diisopropylethylamine and a solvent, to yield the compound of formula (IV) : in which Xi , X2, X3, Yi , T, Zj , Y2, R2, A, n and m are as defined hereinbefore,
compound of formula (IV) in which the ester group is hydrolyzed and the subsequently compound obtained is then treated with an activator in the presence of a base and a primary amine with the general formula R]-NH2 in which Ri is as defined in the compound of formula (I), to yield the compound of formula (V) : in which Xi, X2, X3, Yi, Y2, Zt, R2, Ri, A, n and m are as defined hereinbefore,
which compound of formula (V) is treated :
• either with triethyl orthoformate under heating condition, to yield the compound of formula (I/a), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Yls Y2, Zi, R2, Ri, A, n and m are as defined hereinbefore,
or under heating condition in the presence of acid, with a compound of formula (VI): in which R4 has the same definition as the compound of formula (I), to yield the compound of formula (Fb), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Yi, Y2, Zj, R2, Ri, Rt, A, n and m are as defined hereinbefore,
• or with a compound of formula (VII) in basic condition: in which * and R5 have the same definition as the compound of formula (I),
to yield the compound of formula (Fc), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Yi, Y2, Zi, R2, Ri, RA, R5, A, n and m are as defined hereinbefore, which compound of formula (Fc) is optionally treated with a hydride, in the presence of a compound of formula (VIII):
R6-Hal (VIII) in which R6 has the same definition as the compound of formula (I), to yield the compound of formula (Fd), which is a particular case of the compound of formula (I): in which Xj, X2, X3, Yi, Y2, Zj, R2, Rj, R4, R5, Re, A, n and m are as defined hereinbefore,
compounds of formulae (Fa), (Fb), (Fc) and (I/d) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
19- A process for the preparation of compounds according to claim 1 which uses as starting material a compound of formula (X): in which Xi, X2, and X3 have the same definitions as the compound of formula (I), and Hal represents a halogen atom, which compound of formula (X) is treated in a first step with a derivate of phosgene to yield the compound of formula (XI): 03 02277
80 in which Xj, X2, X3 and Hal are as defined hereinbefore,
which compound of formula (XI) is treated in basic medium with a primary amine of general formula Rι-NH2 in which Ri has the same definition as in the compound of formula (I), to yield the compound of formula (XII): in which Xu X2, X3, Ri and Hal are as defined hereinbefore,
which compound of formula (XII) is treated:
• either with triethyl orthoforaiate under heating condition, to yield the compound of formula (XIIFa) : in which Xi, X2, X3, Ri and Hal are as defined hereinbefore,
• or under heating conditions in the presence of an acid, with a compound of formula
(VI):
R,YΥR< CV*
O O in which R4 has the same definition as the compound of formula (I), to yield the compound of formula (XIIFb) : in which Xj, X2, X3, Hal, Ri, and R4 are as defined hereinbefore,
• or with a compound of formula (VII) in basic conditions:
R< RS (VD) o in which R4 and R5 have the same definition as the compound of formula (I),
to yield the compound of formula (XIIFc) : in which Xi, X2, X3, Hal, Rj, R4, and R5 are as defined hereinbefore,
which compound of formula (XIIFc) is optionally treated with a hydride, in the presence of a compound of formula (VIII):
R6-Hal (VIII) in which R6 has the same definition as the compound of formula (I), and Hal is a halogen atom, to yield the compound of formula (XIlFd), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Hal, Ri, R4, R5 and R6 are as defined hereinbefore, all compounds of formulae (XIIFa), (XHI/b), (XIIFc) and (XIIFd) constitute the compound of formula (XIIFe): in which Xi, X2, X3, Hal, R1 and Gi are as defined in the compound of formula (I),
compound of formula (XIIFe) which is treated xmder conditions of palladium-catalyzed alkynylation with a compound of formula (XIV): in which Zi, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (Fe), which is a particular case of the compound of formula (I): in which Xi, X2, X3, Ri, Gi, Z\, R2, A, n and m have the same definitions as the compound of formula (I), compounds of formula (Fe) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
20- A process for the preparation of compounds according to claim 1 wherein it is used as starting material a compound of formula (XIIFe) in which Xi, X2, X3, Ri and Gi are as defined in the compound of formula (I), and Hal is a halogen atom, compound of formula (XIIFe) which is condensed, in the presence of dichlorobis(triphenylphosphine)palladium, cupper iodide and N,N '-diisopropylethylamine in dimethylformamide, on a compound of formula (XV) : in which Zi, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (Fe), which is a particular case of the compound of formula (I): in which X1 } X2, X3, Ri, Gi, Zi, R2, A, n and m have the same definitions as the compound of formula (I).
21 - A process for the preparation of compounds according to claim 1, which uses as starting material a compound of formula (XIIFe) : in which Xi, X2, X3, Ri and Gi are as defined in the compound of formula (I), and Hal is a halogen atom, compound of formula (XIIFe) which is reacted with carbon monoxide in an alkaline medium in the presence of a protic solvent and a catalytic amount of palladium, to yield the compound of formula (XVI): in which Xj, X2, X3, Ri and Gi are as defined in the compound of formula (I),
compound of formula (XVI) which is hydrolyzed under basic medium to yield the compound of formula (XVII):
in which Xi, X2, X , Ri and Gi are as defined in the compound of formula (I),
compound of formula (XVII) which is condensed under basic medium in the presence of a Mukayama reagent, on the compound of formula (XVIII): in which Zi , R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (Ff), which is a particular case of the compound of formula (I): in which Xi , X2, X3, Z\ , R2, Ri , A, n and m are as defined hereinbefore, compounds of formula (Ff) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
22 - A process for the preparation of compounds according to claim 1, which uses as starting material a compound of formula (XIX) : in which Hal represents a halogen atom,
compound of formula (XIX) which is heated in the presence of formamidine acetate in a polar solvent, to yield compound of formula (XX): in which Hal is as defined hereinbefore,
compound of formula (XX) which is treated in basic medium with a compound of formula R]-Hal, in which Ri is as defined in the compound of formula (I) and Hal represents a halogen atom, to yield the compound of formula (XXI): in which Hal and Ri are as defined hereinbefore,
compound of formula (XXI) which is reacted with carbon monoxide under basic medium in the presence of an alcoholic solvent and a catalytic amount of palladium, to yield the compound of formula (XXII): in which R] is as defined hereinbefore,
compound of formula (XXII) which is condensed, in the presence of trimethylaluminium, with a compound of formula (XVIII): in which Z\, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (Fg), which is a particular case of the compound of formula (I): in which Z\, R2, Ri, A, n and m are as defined hereinbefore, compounds of formula (Fg) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
23- 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.
24- 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 cancers, 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.
25- 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.
26- A pharmaceutical composition useful in the method of Claim 23 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.
27- A pharmaceutical composition useful in the method of Claim 23 comprising as active ingredient an effective amount of a compound as claimed in claim 16, together with one or more pharmaceutically-acceptable excipients or carriers.
28- A pharmaceutical composition useful in the method of Claim 23 comprising as active ingredient an effective amount of a compound as claimed in claim 17, together with one or more pharmaceutically-acceptable excipients or carriers.
29- 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.
30- Use according to Claim 29, 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 cancers.
31- Use according to Claim 30, characterized in that the disease is arthritis. - Use according to Claim 30, characterized in that the disease is osteoarthritis.- Use according to Claim 30, characterized in that the disease is rheumatoid arthritis.
EP03708181A 2002-03-08 2003-03-06 Oxo-azabicyclic compounds Withdrawn EP1492775A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/EP2002/003240 WO2003076416A1 (en) 2002-03-08 2002-03-08 Oxo azabicyclic compounds
WOPCT/EP02/03240 2002-03-08
PCT/EP2003/002277 WO2003076417A2 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds

Publications (1)

Publication Number Publication Date
EP1492775A2 true EP1492775A2 (en) 2005-01-05

Family

ID=27798761

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03708181A Withdrawn EP1492775A2 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds

Country Status (25)

Country Link
EP (1) EP1492775A2 (en)
JP (1) JP2005526070A (en)
KR (1) KR20040095270A (en)
CN (1) CN1738806A (en)
AP (1) AP2004003125A0 (en)
AR (1) AR039562A1 (en)
AU (2) AU2002249275A1 (en)
BR (1) BR0308280A (en)
CA (1) CA2478706A1 (en)
CO (1) CO5601020A2 (en)
EA (1) EA200401053A1 (en)
EC (1) ECSP045278A (en)
IL (1) IL163818A0 (en)
IS (1) IS7414A (en)
MA (1) MA27183A1 (en)
MX (1) MXPA04008681A (en)
NO (1) NO20044041L (en)
OA (1) OA12782A (en)
PA (1) PA8568501A1 (en)
PE (1) PE20031018A1 (en)
PL (1) PL372622A1 (en)
SV (1) SV2003001495A (en)
TN (1) TNSN04169A1 (en)
UY (1) UY27700A1 (en)
WO (2) WO2003076416A1 (en)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PA8539501A1 (en) 2001-02-14 2002-09-30 Warner Lambert Co TRIAZOLO COMPOUNDS AS MMP INHIBITORS
US6962922B2 (en) 2001-10-12 2005-11-08 Warner-Lambert Company Llc Alkynylated quinazoline compounds
US6894057B2 (en) 2002-03-08 2005-05-17 Warner-Lambert Company Oxo-azabicyclic compounds
AU2003249539A1 (en) * 2002-08-13 2004-02-25 Warner-Lambert Company Llc Cyclic compounds containing zinc binding groups as matrix metalloproteinase inhibitors
MXPA05001603A (en) 2002-08-13 2005-04-25 Warner Lambert Co Monocyclic derivatives as matrix metalloproteinase inhibitors.
AU2003253186A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Fused tetrahydropyridine derivatives as matrix metalloproteinase inhibitors
PA8578101A1 (en) 2002-08-13 2004-05-07 Warner Lambert Co HETEROBIARILO DERIVATIVES AS METALOPROTEINASE IN MATRIX INHIBITORS
ES2283851T3 (en) 2002-08-13 2007-11-01 Warner-Lambert Company Llc DERIVATIVES OF PIRIMIDIN-2,4-DIONA AS INHIBITORS OF METALOPROTEINASES OF MATRIX.
WO2004014378A1 (en) 2002-08-13 2004-02-19 Warner-Lambert Company Llc 3-isoquinolinone derivatives as matrix metalloproteinase inhiitors
BR0313724A (en) 2002-08-13 2005-06-28 Warner Lambert Co Azaisoquinoline derivatives as matrix metalloproteinase inhibitors
WO2004014375A2 (en) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Fused bicyclic metalloproteinase inhibitors
CA2497658A1 (en) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Chromone derivatives as matrix metalloproteinase inhibitors
WO2004014923A1 (en) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Pyrimidinone fused bicyclic metalloproteinase inhibitors
WO2005016926A1 (en) * 2003-08-19 2005-02-24 Warner-Lambert Company Llc Pyrido [3,4-d] pyrimidine derivatives as matrix metalloproteinase-13 inhibitors
DE10360835A1 (en) * 2003-12-23 2005-07-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg New bicyclic imidazole derivatives are dipeptidylpeptidase-IV inhibitors useful to treat e.g. arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis
ZA200609259B (en) * 2004-04-30 2008-07-30 Takeda Pharmaceutical Heterocyclic amide compound and use thereof as an mmp-13 inhibitor
MXPA06014696A (en) * 2004-06-15 2007-02-12 Astrazeneca Ab Substituted quinazolones as anti-cancer agents.
CA2665476A1 (en) 2006-10-05 2008-04-10 Cv Therapeutics, Inc. Bicyclic nitrogen-containing heterocyclic compounds for use as stearoyl coa desaturase inhibitors
AR083475A1 (en) 2010-10-18 2013-02-27 Merz Pharma Gmbh & Co Kgaa METABOTROPIC GLUTAMATE RECEIVERS MODULATORS
CN103524431B (en) * 2013-09-24 2016-01-13 西安交通大学 3-benzyl-4-quianzolinones and synthetic method thereof and application
JO3512B1 (en) 2014-03-26 2020-07-05 Astex Therapeutics Ltd Quinoxaline derivatives useful as fgfr kinase modulators
EP3353164B1 (en) 2015-09-23 2021-11-03 Janssen Pharmaceutica, N.V. Bi-heteroaryl substituted 1,4-benzodiazepines and uses thereof for the treatment of cancer
US11155555B2 (en) 2015-09-23 2021-10-26 Janssen Pharmaceutica Nv Compounds
FR3046793B1 (en) * 2016-01-14 2018-01-05 Les Laboratoires Servier NOVEL PHOSPHINAN DERIVATIVES AND AZAPHOSPHINANES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR9714222A (en) * 1996-12-17 2000-04-18 Du Pont Method for controlling plant diseases
PA8539301A1 (en) * 2001-02-14 2002-09-30 Warner Lambert Co INHIBITORS OF THE METALOPROTEINASE OF THE MATRIX
PA8539401A1 (en) * 2001-02-14 2002-10-28 Warner Lambert Co QUINAZOLINAS AS INHIBITORS OF MMP-13

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03076417A2 *

Also Published As

Publication number Publication date
TNSN04169A1 (en) 2007-03-12
WO2003076417A3 (en) 2003-11-13
KR20040095270A (en) 2004-11-12
IS7414A (en) 2004-08-19
AP2004003125A0 (en) 2004-09-30
AU2003212307A1 (en) 2003-09-22
AU2002249275A1 (en) 2003-09-22
PL372622A1 (en) 2005-07-25
WO2003076417A2 (en) 2003-09-18
IL163818A0 (en) 2005-12-18
AR039562A1 (en) 2005-02-23
NO20044041L (en) 2004-10-07
JP2005526070A (en) 2005-09-02
SV2003001495A (en) 2003-11-04
PE20031018A1 (en) 2004-01-09
BR0308280A (en) 2004-12-28
ECSP045278A (en) 2004-10-26
MXPA04008681A (en) 2004-12-06
OA12782A (en) 2006-07-10
WO2003076416A1 (en) 2003-09-18
MA27183A1 (en) 2005-01-03
UY27700A1 (en) 2003-10-31
CO5601020A2 (en) 2006-01-31
CA2478706A1 (en) 2003-09-18
CN1738806A (en) 2006-02-22
PA8568501A1 (en) 2003-12-19
EA200401053A1 (en) 2005-04-28

Similar Documents

Publication Publication Date Title
US6894057B2 (en) Oxo-azabicyclic compounds
WO2003076417A2 (en) Oxo-azabicyclic compounds
US6747147B2 (en) Oxo-azabicyclic compounds
AU708979B2 (en) Quinoline and quinazoline compounds useful in therapy
AU681075B2 (en) Antiproliferative quinazolines
US6962922B2 (en) Alkynylated quinazoline compounds
CA2651573C (en) Pyridopyrimidinone derivatives
EP1368324A1 (en) Quinazolines as mmp-13 inhibitors
JPH0794447B2 (en) Quinazoline derivative
JP2009221233A (en) Novel compound
ES2389907T9 (en) Heterocyclic amide compound and use thereof as an MMP-13 inhibitor
US20050245548A1 (en) Alkynylated fused ring pyrimidine compounds
MXPA05011103A (en) Quinazoline compounds useful as p38 kinase inhibitors.
AU2004212435A1 (en) Process for preparing pyrrolotriazine kinase inhibitors
US6649620B2 (en) Quinoline and quinazoline compounds useful in therapy
WO2004000321A1 (en) Thiazine and oxazine derivatives as mmp-13 inhibitors for treating arthritis
WO2004007469A1 (en) New alkynylated quinazolin compounds as mmp-13 inhibitors
WO1994003439A1 (en) Antiproliferative tricyclic compounds
TW200305401A (en) Oxo-azabicyclic compounds
EP1465878A1 (en) Alkynylated fused ring pyrimidine compounds as matrix metalloprotease-13 inhibitors
AU2002253070A1 (en) Quinazolines as MMP-13 inhibitors
MXPA98003607A (en) Compounds of quinoline and quinazoline useful in tera
MX2008007362A (en) Trisubstituted quinazolinone derivatives as vanilloid antagonists
MXPA98005122A (en) Compounds of quinoline and quinazoline useful in tera
MXPA06007287A (en) Bicycloheteroarylamine compounds as ion channel ligands and uses thereof

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20041008

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

17Q First examination report despatched

Effective date: 20041228

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050708